Abstract

Traumatic spinal cord injury (SCI) is a life changing neurological condition with substantial socioeconomic implications for patients and their care-givers. Recent advances in medical management of SCI has significantly improved diagnosis, stabilization, survival rate and well-being of SCI patients. However, there has been small progress on treatment options for improving the neurological outcomes of SCI patients. This incremental success mainly reflects the complexity of SCI pathophysiology and the diverse biochemical and physiological changes that occur in the injured spinal cord. Therefore, in the past few decades, considerable efforts have been made by SCI researchers to elucidate the pathophysiology of SCI and unravel the underlying cellular and molecular mechanisms of tissue degeneration and repair in the injured spinal cord. To this end, a number of preclinical animal and injury models have been developed to more closely recapitulate the primary and secondary injury processes of SCI. In this review, we will provide a comprehensive overview of the recent advances in our understanding of the pathophysiology of SCI. We will also discuss the neurological outcomes of human SCI and the available experimental model systems that have been employed to identify SCI mechanisms and develop therapeutic strategies for this condition.

Keywords: spinal cord injury, secondary injury mechanisms, clinical classifications and demography, animal models, glial and immune response, glial scar, chondroitin sulfate proteoglycans (CSPGs), cell death

Spinal cord injury (SCI) is a debilitating neurological condition with tremendous socioeconomic impact on affected individuals and the health care system. According to the National Spinal Cord Injury Statistical Center, there are 12,500 new cases of SCI each year in North America (1). Etiologically, more than 90% of SCI cases are traumatic and caused by incidences such as traffic accidents, violence, sports or falls (2). There is a reported male-to-female ratio of 2:1 for SCI, which happens more frequently in adults compared to children (2). Demographically, men are mostly affected during their early and late adulthood (3rd and 8th decades of life) (2), while women are at higher risk during their adolescence (1519 years) and 7th decade of their lives (2). The age distribution is bimodal, with a first peak involving young adults and a second peak involving adults over the age of 60 (3). Adults older than 60 years of age whom suffer SCI have considerably worse outcomes than younger patients, and their injuries usually result from falls and age-related bony changes (1).

The clinical outcomes of SCI depend on the severity and location of the lesion and may include partial or complete loss of sensory and/or motor function below the level of injury. Lower thoracic lesions can cause paraplegia while lesions at cervical level are associated with quadriplegia (4). SCI typically affects the cervical level of the spinal cord (50%) with the single most common level affected being C5 (1). Other injuries include the thoracic level (35%) and lumbar region (11%). With recent advancements in medical procedures and patient care, SCI patients often survive these traumatic injuries and live for decades after the initial injury (5). Reports on the clinical outcomes of patients who suffered SCI between 1955 and 2006 in Australia demonstrated that survival rates for those suffering from tetraplegia and paraplegia is 91.2 and 95.9%, respectively (5). The 40-year survival rate of these individuals was 47 and 62% for persons with tetraplegia and paraplegia, respectively (5). The life expectancy of SCI patients highly depends on the level of injury and preserved functions. For instance, patients with ASIA Impairment Scale (AIS) grade D who require a wheelchair for daily activities have an estimated 75% of a normal life expectancy, while patients who do not require wheelchair and catheterization can have a higher life expectancy up to 90% of a normal individual (6). Today, the estimated life-time cost of a SCI patient is $2.35 million per patient (1). Therefore, it is critical to unravel the cellular and molecular mechanisms of SCI and develop new effective treatments for this devastating condition. Over the past decades, a wealth of research has been conducted in preclinical and clinical SCI with the hope to find new therapeutic targets for traumatic SCI.

SCI commonly results from a sudden, traumatic impact on the spine that fractures or dislocates vertebrae. The initial mechanical forces delivered to the spinal cord at the time of injury is known as primary injury where displaced bone fragments, disc materials, and/or ligaments bruise or tear into the spinal cord tissue (79). Notably, most injuries do not completely sever the spinal cord (10). Four main characteristic mechanisms of primary injury have been identified that include: (1) Impact plus persistent compression; (2) Impact alone with transient compression; (3) Distraction; (4) Laceration/transection (8, 11). The most common form of primary injury is impact plus persistent compression, which typically occurs through burst fractures with bone fragments compressing the spinal cord or through fracture-dislocation injuries (8, 12, 13). Impact alone with transient compression is observed less frequently but most commonly in hyperextension injuries (8). Distraction injuries occur when two adjacent vertebrae are pulled apart causing the spinal column to stretch and tear in the axial plane (8, 12). Lastly, laceration and transection injuries can occur through missile injuries, severe dislocations, or sharp bone fragment dislocations and can vary greatly from minor injuries to complete transection (8). There are also distinct differences between the outcomes of SCI in military and civilian cases. Compared to civilian SCI, blast injury is the common cause of SCI in battlefield that usually involves multiple segments of the spinal cord (14). Blast SCI also results in higher severity scores and is associated with longer hospital stays (15). A study on American military personnel, who sustained SCI in a combat zone from 2001 to 2009, showed increased severity and poorer neurological recovery compared to civilian SCI (15). Moreover, lower lumbar burst fractures and lumbosacral dissociation happen more frequently in combat injuries (1). Regardless of the form of primary injury, these forces directly damage ascending and descending pathways in the spinal cord and disrupt blood vessels and cell membranes (11, 16) causing spinal shock, systemic hypotension, vasospasm, ischemia, ionic imbalance, and neurotransmitter accumulation (17). To date, the most effective clinical treatment to limit tissue damage following primary injury is the early surgical decompression (< 24 h post-injury) of the injured spinal cord (18, 19). Overall, the extent of the primary injury determines the severity and outcome of SCI (20, 21).

Functional classification of SCI has been developed to establish reproducible scoring systems by which the severity of SCI could be measured, compared, and correlated with the clinical outcomes (20). Generally, SCI can be classified as either complete or incomplete. In complete SCI, neurological assessments show no spared motor or sensory function below the level of injury (4). In the past decades, several scoring systems have been employed for clinical classification of neurological deficits following SCI. The first classification system, Frankel Grade, was developed by Frankel and colleagues in 1969 (22). They assessed the severity and prognosis of SCI using numerical sensory and motor scales (22). This was a 5-grade system in which Grade A was the most severe SCI with complete loss of sensory and motor function below the level of injury. Grade B represented complete motor loss with preserved sensory function and sacral sparing. Patients in Grade C and D had different degrees of motor function preservation and Grade E represented normal sensory and motor function. The Frankel Grade was widely utilized after its publication due to its ease of use. However, lack of clear distinction between Grades C and D and inaccurate categorization of motor improvements in patients over time, led to its replacement by other scoring systems (20).

Other classification methods followed Frankel's system. In 1987, Bracken et al. at Yale University School of Medicine classified motor and sensory functions separately in a 5 and 7-scale systems, respectively (23). However, this scoring system failed to account for sacral function (20). Moreover, integration of motor and sensory classifications was impossible in this system and it was abandoned due to complexity and impracticality in clinical settings (20). Several other scoring systems were developed in 1970' and 1980's by different groups such as Lucas and Ducker at the Maryland Institute for Emergency Medical Services in late 1970's (24), Klose and colleagues at the University of Miami Neuro-spinal Index (UMNI) in early 1980s (25) and Chehrazi and colleagues (Yale Scale) in 1981 (26). These scoring systems also became obsolete due to their disadvantage in evaluation of sacral functions, difficulty of use or discrepancies between their motor and sensory scoring sub-systems (20).

The ASIA scoring system is currently the most widely accepted and employed clinical scoring system for SCI. ASIA was developed in 1984 by the American Spinal Cord Injury Association and has been updated over time to improve its reliability (). In this system, sensory function is scored from 02 and motor function from 0 to 5 (20). The ASIA impairment score (AIS) ranges from complete loss of sensation and movement (AIS = A) to normal neurological function (AIS = E). The first step in ASIA system is to identify the neurological level of injury (NLI). In this assessment, except upper cervical vertebrae that closely overlay the underlying spinal cord segments, the anatomical relationship between the spinal cord segments and their corresponding vertebra is not reciprocally aligned along the adult spinal cord (20). At thoracic and lumbar levels, each vertebra overlays a spinal cord segment one or two levels below and as the result, a T11 vertebral burst fracture results in neurological deficit at and below L1 spinal cord segment. Hence, the neurological level of injury (NLI) is defined as the most caudal neurological level at which all sensory and motor functions are normal (20). Upon identifying the NLI, if the injury is complete (AIS = A), zone of partial preservation (ZPP) is determined (20). ZPP is defined as all the segments below the NLI that have some preserved sensory or motor function. A precise record of ZPP enables the examiners to distinguish spontaneous from treatment-induced functional recovery, thus, essential for evaluating the therapeutic efficacy of treatments (20). Complete loss of motor and preservation of some sensory functions below the neurological level of the injury is categorized as AIS B (20). If motor function is also partially spared below the level of the injury, AIS score can be C or D (20). The AIS is scored D when the majority of the muscle groups below the level of the injury exhibit strength level of 3 or higher (for more details see ). ASIA classification combines the assessments of motor, sensory and sacral functions, thus addressing the shortcomings of previous scoring systems (20). The validity and reproducibility of ASIA system combined with its accuracy in prediction of patients' outcome have made it the most accepted and reliable clinical scoring system utilized for neurological classification of SCI (20).

ASIA scoring for the neurological classification of the SCI. A sample scoring sheet used for ASIA scoring in clinical setting is provided (adopted from: http://asia-spinalinjury.org).

In clinical management of SCI, neurological outcomes are generally determined at 72 h after injury using ASIA scoring system (20, 27). This time-point has shown to provide a more precise assessment of neurological impairments after SCI (28). One important predictor of functional recovery is to determine whether the injury was incomplete or complete. As time passes, SCI patients experience some spontaneous recovery of motor and sensory functions. Most of the functional recovery occurs during the first 3 months and in most cases reaches a plateau by 9 months after injury (20). However, additional recovery may occur up to 1218 months post-injury (20). Long term outcomes of SCI are closely related to the level of the injury, the severity of the primary injury and progression of secondary injury, which will be discussed in this review.

Depending on the level of SCI, patients experience paraplegia or tetraplegia. Paraplegia is defined as the impairment of sensory or motor function in lower extremities (27, 28). Patients with incomplete paraplegia generally have a good prognosis in regaining locomotor ability (~76% of patients) within a year (27). Complete paraplegic patients, however, experience limited recovery of lower limb function if their NLI is above T9 (29). An NLI below T9 is associated with 38% chance of regaining some lower extremity function (29). In patients with complete paraplegia, the chance of recovery to an incomplete status is only 4% with only half of these patients regaining bladder and bowel control (29). Tetraplegia is defined as partial or total loss of sensory or motor function in all four limbs. Patients with incomplete tetraplegia will gain better recovery than complete tetra- and paraplegia (30). Unlike complete SCI, recovery from incomplete tetraplegia usually happens at multiple levels below the NLI (20). Patients generally reach a plateau of recovery within 912 months after injury (20). Regaining some motor function within the first month after the injury is associated with a better neurological outcome (20). Moreover, appearance of muscle flicker (a series of local involuntary muscle contractions) in the lower extremities is highly associated with recovery of function (31). Patients with complete tetraplegia, often (6690%) regain function at one level below the injury (28, 30). Importantly, initial muscle strength is an important predictor of functional recovery in these patients (20). Complete tetraplegic patients with cervical SCI can regain antigravity muscle function in 27% of the cases when their initial muscle strength is 0 on a 5-point scale (32). However, the rate of regaining antigravity muscle strength at one caudal level below the injury increases to 97% when the patients have initial muscle strength of 12 on a 5-point scale (33).

An association between sensory and motor recovery has been demonstrated in SCI where spontaneous sensory recovery usually follows the pattern of motor recovery (20, 34). Maintenance of pinprick sensation at the zone of partial preservation or in sacral segments has been shown as a reliable predictor of motor recovery (35). One proposed reason for this association is that pinprick fibers in lateral spinothalamic tract travel in proximity of motor fibers in the lateral corticospinal tract, and thus, preservation of sensory fibers can be an indicator of the integrity of motor fiber (20). Diagnosis of an incomplete injury is of great importance and failure to detect sensory preservation at sacral segments results in an inaccurate assessment of prognosis (20).

In the past few decades, various animal models have been developed to allow understanding the complex biomedical mechanisms of SCI and to develop therapeutic strategies for this condition. An ideal animal model should have several characteristics including its relevance to the pathophysiology of human SCI, reproducibility, availability, and its potential to generate various severities of injury (36).

Small rodents are the most frequently employed animals in SCI studies due to their availability, ease of use and cost-effectiveness compared to primates and larger non-primate models of SCI (36, 37). Among rodents, rats more closely mimic pathophysiological, electrophysiological, functional, and morphological features of non-primate and human SCI (38). In rat (39), cat (40), monkey (41), and human SCI (17), a cystic cavity forms in the center of the spinal cord, which is a surrounded by a rim of anatomically preserved white matter. A study by Metz and colleagues compared the functional and anatomical outcomes of rat contusive injuries and human chronic SCI (42). High resolution MRI assessments identified that SCI-induced neuroanatomical changes such as spinal cord atrophy and size of the lesion were significantly correlated with the electrophysiological and functional outcomes in both rat and human contusive injuries (42). Histological assessments in rats also showed a close correlation between the spared white matter and functional preservation following injury (42). These studies provide evidence that rat models of contusive SCI could serve as an adequate model to develop and evaluate the structural and functional benefits of therapeutic strategies for SCI (42).

Mice show different histopathology than human SCI in which the lesion site is filled with dense fibrous connective-like tissue (4346). Mouse SCI studies show the presence of fibroblast-like cells expressing fibronectin, collagen, CD11b, CD34, CD13, and CD45 within the lesion core of chronic SCI, while it is absent in the injured spinal cord of rats (47). Another key difference between rat and mice SCI is the time-point of inflammatory cell infiltration. While microglia/macrophage infiltration is relatively consistent between rat and mouse models of SCI (47), there is a temporal difference in infiltration of neutrophils and T cells between the two species (47, 48). In SCI rats, infiltration of neutrophils, the first responders, peaks at 6 h post injury, followed by a significant decline at 2448 h after SCI (48). Similarly, in mouse SCI, neutrophil infiltration occurs within 6 h following injury; however, their numbers continue to rise and do not peak until 314 days post injury (49). T cell infiltration also varies between rat and mouse SCI models (50). In rats, T cell infiltration occurs between 3 and 7 days post injury and declines by 50% in the following 2 weeks (47), whereas in mice, T cell infiltration is not detected until 14 days post injury and their number doubles between 2 and 6 weeks post injury (47). Regardless of their pathophysiological relevance, mice have been used extensively in SCI studies primarily due to the availability of transgenic and mutant mouse models that have allowed uncovering molecular and cellular mechanisms of SCI (38).

In recent years, there has been emerging interest in employment of non-human primates and other larger animals such as pig, dog and cat as intermediate pre-clinical models (5153) to allow more effective translation of promising treatments from rodent models to human clinical trials (50). Although rodents have served as invaluable models for studying SCI mechanisms and therapeutic development, larger mammals, in particular non-human primates, share a closer size, neuroanatomy, and physiology to humans. Importantly, their larger size provides a more relevant platform for drug development, bioengineering inventions, and electrophysiological and rehabilitation studies. Nonetheless, both small and large animal models of SCI have limitations in their ability to predict the outcome in human SCI. One important factor is high degree of variability in the nature of SCI incidence, severity and location of the injury in human SCI, while in laboratory animal models, these variabilities are less (36). Values acquired by clinical scoring systems such as ASIA or Frankel scoring systems lack the consistency of the data acquired from laboratory settings, which makes the translation of therapeutic interventions from experimental to clinical settings challenging (36). A significant effect from an experimental treatment in consistent laboratory settings may not be reproducible in clinical settings due to high variability and heterogeneity in human populations and their injuries (36). To date, several pharmacological and cellular preclinical discoveries have led to human clinical trials based on their efficacy in improving the outcomes of SCI in small animal models. However, the majority of these trials failed to reproduce the same efficacy in human SCI. Thus, in pre-clinical studies, animal models, and study designs should be carefully chosen to reflect the reality of clinical setting as closely as possible (36). Larger animals provide the opportunity to refine promising therapeutic strategies prior to testing in human SCI; however, their higher cost, need for specialized facilities and small subject (sample) size have limited their use in SCI research (50). Thus, rodents are currently the most commonly employed models for preclinical discoveries and therapeutic development, while the use of larger animals is normally pursued for late stage therapies that have shown efficacy and promise in small animal models. provides a summary of available SCI models.

Animal models are also classified based on the type of SCI. The following sections will provide an overview on the available SCI models that are developed based on injury mechanisms, their specifications and relevance to human SCI ().

A complete transection model of SCI is relatively easy to reproduce (51). However, this model is less relevant to human SCI as a complete transection of the spinal cord rarely happens (51). While they do not represent clinical reality of SCI, transection models are specifically suitable for studying axonal regeneration or developing biomaterial scaffolds to bridge the gap between proximal and distal stamps of the severed spinal cord (51). Due to complete disconnection from higher motor centers, this model is also suitable for studying the role of propriospinal motor and sensory circuits in recovery of locomotion following SCI (51, 80). Partial transection models including hemi-section, unilateral transection and dorsal column lesions are other variants of transection models (51). Partial transection models are valuable for investigation of nerve grafting, plasticity and where a comparison between injured and non-injured pathways is needed in the same animal (51). However, these models lead to a less severe injury and higher magnitude of spontaneous recovery rendering them less suitable for development and evaluation of new therapies (51).

Contusion is caused by a transient physical impact to the spinal cord and is clinically-relevant. There are currently three types of devices that can produce contusion injury in animal models: weight-drop apparatus, electromagnetic impactor, and a recently introduced air gun device (51). The impactor model was first introduced by Gruner at New York University (NYU) in 1992 (81). The original NYU impactor included a metal rod of specific weight (10 g) that could be dropped on the exposed spinal cord from a specific height to induce SCI (51). This model allowed induction of a defined severity of SCI by adjusting the height, which the rod fell on the spinal cord (81). Parameters such as time, velocity at impact and biomechanical response of the tissue can be recorded for analysis and verification (51). The NYU impactor was later renamed to Multicenter Animal Spinal Cord Injury Study (MASCIS) impactor, and conditions surrounding the study and use of the MASCIS impactor were standardized (51). Since its introduction, the MASCIS impactor has been updated twice. The most recent version, MACIS III, was introduced in 2012 and included both electromagnetic control and digital recording of the impact parameters (51). However, inability to control duration of impact and weight bounce, that could cause multiple impacts, have been known limitations of MASCIS impactors (51).

The Infinite Horizon (IH) impactor is another type of impactor that utilizes a stepping motor to generate force-controlled impact in contrast to free fall in the MASICS impactor (51). This feature allows for better control over the force of impact and prevents weight bounce as the computer-controlled metal impounder can be immediately retracted upon transmitting a desired force to the spinal cord (51). IH impactor can be set to different force levels to provide mild, moderate and severe SCI in rats (ex. 100, 150, and 200 kdyn) (51). A limitation with IH impactors is unreliability of their clamps in holding the spinal column firmly during the impact that can cause inconsistent parenchymal injury and neurological deficits (51).

Ohio State University (OSU) impactor is a computer controlled electromagnetic impactor that was originally invented in 1987 and refined in 1992 to improve reliability (58). As the OSU impactor is electromagnetically controlled, multiple strikes are avoided (51). Subsequently, a modified version of the OSU impactor was developed in 2000 for use in mice (43). However, the OSU impactor is limited by its inability to determine the precise initial contact point with the spinal cord due to displacement of CSF upon loading the device (51). To date, MASCIS, IH and OSU impactor devices have been employed extensively and successfully to induce SCI. These impactor devices are available for small and large animals such as mice, rats, marmosets, cats, and pigs (51, 82).

Compressive models of SCI have been also employed for several decades (61). While contusion injury is achieved by applying a force for a very brief period (milliseconds), the compression injury consists of an initial contusion for milliseconds followed by a prolonged compression through force application for a longer duration (seconds to minutes) (51). Thus, compression injury can be categorized as contusive-compressive models (51). Various models of compressive SCI are available.

Clip compression is the most commonly used compression model of SCI in rat and mice (51, 61, 62, 83). It was first introduced by Rivlin and Tator in 1978 (61). In this model, following laminectomy, a modified aneurism clip with a calibrated closing force is applied to the spinal cord for a specific duration of time (usually 1 min) to induce a contusive-compressive injury (51). The severity of injury can be calibrated and modified by adjusting the force of the clip and the duration of compression (51). For example, applying a 50 g clip for 1 min typically produces a severe SCI, while a 35 g clip creates a moderate to severe injury with the same duration (83). Aneurysm clips were originally designed for use in rat SCI, however, in recent years smaller and larger clips have been developed to accommodate its use in mice (62) and pig models (52). The clip compression model has several advantages compared to contusion models. This method is less expensive and easier to perform (51). Importantly, in contrast to the impactor injury that contusion is only applied dorsally to the spinal cord, the clip compression model provides contusion and compression simultaneously both dorsally and ventrally. Hence, clip compression model more closely mimics the most common form of human SCI, which is primarily caused by dislocation and burst compression fractures (83). Despite its advantages, clip compression model can create variabilities such as the velocity of closing and actual delivered force that cannot be measured precisely at the time of application (51).

Calibrated forceps compression has been also employed to induce SCI in rodents. This simple and inexpensive compressive model was first utilized in 1991 for induction of SCI in guinea pigs (64). In this method, a calibrated forceps with a spacer is used to compress the spinal cord bilaterally (51). This model lacks the initial impact and contusive injury, which is associated with most cases of human traumatic SCI. Accordingly, this model is not a clinically relevant model for reproducing human SCI pathology and therapeutic development (51).

Balloon Compression model has been also utilized extensively in primates and larger animals such as dogs and cats (8486). In this model, a catheter with an inflatable balloon is inserted in the epidural or subdural space. The inflation of the balloon with air or saline for a specific duration of time provides the force for induction of SCI (51). Generally, all compression models (clip, forceps, and balloon) have the same limitation as the velocity and amount of force are unmeasurable (51).

In conclusion, while existing animal models do not recapitulate all clinical aspects of human SCI, the compression and contusion models are considered to be the most relevant and commonly employed methods for understanding the secondary injury mechanisms and therapeutic development for SCI.

Secondary injury begins within minutes following the initial primary injury and continues for weeks or months causing progressive damage of spinal cord tissue surrounding the lesion site (7). The concept of secondary SCI was first introduced by Allen in 1911 (87). While studying SCI in dogs, he observed that removal of the post traumatic hematomyelia improved neurological outcome. He hypothesized that presence of some biochemical factors in the necrotic hemorrhagic lesion causes further damage to the spinal cord (87). The term of secondary injury is still being used in the field and is referred to a series of cellular, molecular and biochemical phenomena that continue to self-destruct spinal cord tissue and impede neurological recovery following SCI () (20).

Summary of secondary injury processes following traumatic spinal cord injury. Diagram shows the key pathophysiological events that occur after primary injury and lead to progressive tissue degeneration. Vascular disruption and ischemia occur immediately after primary injury that initiate glial activation, neuroinflammation, and oxidative stress. These acute changes results in cell death, axonal injury, matrix remodeling, and formation of a glial scar.

Secondary injury can be temporally divided into acute, sub-acute, and chronic phases. The acute phase begins immediately following SCI and includes vascular damage, ionic imbalance, neurotransmitter accumulation (excitotoxicity), free radical formation, calcium influx, lipid peroxidation, inflammation, edema, and necrotic cell death (7, 20, 88). As the injury progresses, the sub-acute phase of injury begins which involves apoptosis, demyelination of surviving axons, Wallerian degeneration, axonal dieback, matrix remodeling, and evolution of a glial scar around the injury site (). Further changes occur in the chronic phase of injury including the formation of a cystic cavity, progressive axonal die-back, and maturation of the glial scar (7, 8992). Here, we will review the key components of acute secondary injury that contribute to the pathophysiology of SCI (, ).

Pathophysiology of traumatic spinal cord injury. This schematic diagram illustrates the composition of normal and injured spinal cord. Of note, while these events are shown in one figure, some of the pathophysiological events may not temporally overlap and can occur at various phases of SCI, which are described here. Immediately after primary injury, activation of resident astrocytes and microglia and subsequent infiltration of blood-borne immune cells results in a robust neuroinflammatory response. This acute neuroinflammatory response plays a key role in orchestrating the secondary injury mechanisms in the sub-acute and chronic phases that lead to cell death and tissue degeneration, as well as formation of the glial scar, axonal degeneration and demyelination. During the acute phase, monocyte-derived macrophages occupy the epicenter of the injury to scavenge tissue debris. T and B lymphocytes also infiltrate the spinal cord during sub-acute phase and produce pro-inflammatory cytokines, chemokines, autoantibodies reactive oxygen and nitrogen species that contribute to tissue degeneration. On the other hand, M2-like macrophages and regulatory T and B cells produce growth factors and pro-regenerative cytokines such as IL-10 that foster tissue repair and wound healing. Loss of oligodendrocytes in acute and sub-acute stages of SCI leads to axonal demyelination followed by spontaneous remyelination in sub-acute and chronic phases. During the acute and sub-acute phases of SCI; astrocytes, OPCs and pericytes, which normally reside in the spinal cord parenchyma, proliferate and migrate to the site of injury and contribute to the formation of the glial scar. The glial scar and its associated matrix surround the injury epicenter and create a cellular and biochemical zone with both beneficial and detrimental roles in the repair process. Acutely, the astrocytic glial scar limits the spread of neuroinflammation from the lesion site to the healthy tissue. However, establishment of a mature longstanding glial scar and upregulation of matrix chondroitin sulfate proteoglycans (CSPGs) are shown to inhibit axonal regeneration/sprouting and cell differentiation in subacute and chronic phases.

Disruption of spinal cord vascular supply and hypo-perfusion is one of the early consequences of primary injury (93). Hypovolemia and hemodynamic shock in SCI patients due to excessive bleeding and neurogenic shock result in compromised spinal cord perfusion and ischemia (93). Larger vessels such as anterior spinal artery usually remain intact (94, 95), while rupture of smaller intramedullary vessels and capillaries that are susceptible to traumatic damage leads to extravasation of leukocytes and red blood cells (93). Increased tissue pressure in edematous injured spinal cord and hemorrhage-induced vasospasm in intact vessels further disrupts blood flow to the spinal cord (93, 95). In rat and monkey models of SCI, there is a progressive reduction in blood flow at the lesion epicenter within the first few hours after injury which remains low for up to 24 h (96). The gray matter is more prone to ischemic damage compared to the white matter as it has a 5-fold higher density of capillary beds and contains neurons with high metabolic demand (95, 97, 98). After injury, white matter blood flow typically returns to normal levels within 15 min post injury, whereas there are multiple hemorrhages in the gray matter and as a result, re-perfusion usually does not occur for the first 24 h (9, 99, 100). Vascular insult, hemorrhage and ischemia ultimately lead to cell death and tissue destruction through multiple mechanisms, including oxygen deprivation, loss of adenosine triphosphate (ATP), excitotoxicity, ionic imbalance, free radical formation, and necrotic cell death. Cellular necrosis and release of cytoplasmic content increase the extracellular level of glutamate causing glutamate excitotoxicity (93, 101). Moreover, re-establishment of blood flow in ischemic tissue leads to further damage through generating free radicals and eliciting an inflammatory response (93, 102) that will be discussed in this review.

Within few minutes after primary SCI, the combination of direct cellular damage and ischemia/hypoxia triggers a significant rise of extracellular glutamate, the main excitatory neurotransmitter in the CNS (7). Glutamate binds to ionotropic (NMDA, AMPA, and Kainate receptors) as well as metabotropic receptors resulting in calcium influx inside the cells (103105) (93). The effect of glutamate is not restricted to neurons as its receptors are vastly expressed on the surface of all glia and endothelial cells (103106). Astrocytes can also release excess glutamate extracellularly upon elevation of their intracellular Ca2+ levels. Reduced ability of activated astrocytes for glutamate re-uptake from the interstitial space due to lipid peroxidation results in further accumulation of glutamate in the SCI milieu (93). Using microdialysis, elevated levels of glutamate have been detected in the white matter in the acute stage of injury (107). Based on a study by Panter and colleagues, glutamate increase is detected during the first 2030 min post SCI and returns to the basal levels after 60 min (108).

Under normal condition, concentration of free Ca2+ can considerably vary in different parts of the cell (109). In the cytosol, Ca2+ ranges from 50100 nM while it approaches 0.51.0 mM in the lumen of endoplasmic reticulum (110112). A long-lasting abnormal increase in Ca2+ concentration in cytosol, mitochondria or endoplasmic reticulum has detrimental consequences for the cell (109113). Mitochondria play a central role in calcium dependent neuronal death (113). In neurons, during glutamate induced excitotoxicity, NMDA receptor over-activity leads to mitochondrial calcium overload, which can cause apoptotic or necrotic cell death (113). Shortly after SCI, Ca2+ enters mitochondria through the mitochondrial calcium uniporter (MCU) (114). While the amount of mitochondrial calcium is limited during the resting state of a neuron, they can store a high amount of Ca2+ following stimulation (113). Calcium overload also activates a host of protein kinases and phospholipases that results in calpain mediated protein degradation and oxidative damage due to mitochondrial failure (93). In the injured white matter, astrocytes, oligodendrocytes and myelin are also damaged by the increased release of glutamate and Ca2+-dependent excitotoxicity (115). Within the first few hours after injury, oligodendrocytes show signs of caspase-3 activation and other apoptotic features, and their density declines (116). Interestingly, while glutamate excitotoxicity is triggered by ionic imbalance in the white matter, in the gray matter, it is largely associated with the activity of neuronal NMDA receptors (117, 118). Altogether, activation of NMDA receptors and consequent Ca2+ overload appears to induce intrinsic apoptotic pathways in neurons and oligodendrocytes and causes cell death in the first week of SCI in the rat (119, 120). Administration of NMDA receptor antagonist (MK-801) shortly following SCI has been associated with improved functional recovery and reduced edema (121).

Mitochondrial calcium overload also impedes mitochondrial respiration and results in ATP depletion disabling Na+/K+ ATPase and increasing intracellular Na+ (119, 122124). This reverses the function of the Na+ dependent glutamate transporter that normally utilizes Na+ gradient to transfer glutamate into the cells (119, 125, 126). Moreover, the excess intracellular Na+ reverses the activity of Na+/Ca2+ exchanger allowing more Ca+ influx (127). Cellular depolarization activates voltage gated Na+ channels that results in entry of Cl and water into the cells along with Na+ causing swelling and edema (128). Increased Na+ concentration over-activates Na+/H+ exchanger causing a rise in intracellular H+ (101, 129). Resultant intracellular acidosis increases membrane permeability to Ca2+ that exacerbates the injury-induced ionic imbalance (101, 129). Axons are more susceptible to the damage caused by ionic imbalance due to their high concentration of voltage gated Na+ channels in the nodes of Ranvier (7). Accumulating evidence shows that administration of Na+ channel blockers such as Riluzole attenuates tissue damage and improves functional recovery in SCI underlining sodium as a key player in secondary injury mechanisms (130133).

SCI results in production of free radicals and nitric oxide (NO) (114). Mitochondrial Ca2+ overload activates NADPH oxidase (NOX) and induces generation of superoxide by electron transport chain (ETC) (114). Reactive oxygen and nitrogen species (ROS and RNS) produced by the activity of NOX and ETC activates cytosolic poly (ADP ribose) polymerase (PARP). PARP consumes and depletes NAD+ causing failure of glycolysis, ATP depletion and cell death (114). Moreover, PAR polymers produced by PARP activity, induce the release of apoptosis inducing factor (AIF) from mitochondria and induce cell death (114). On the other hand, acidosis caused by SCI results in the release of intracellular iron from ferritin and transferrin (93). Spontaneous oxidation of Fe2+ to Fe3+ gives rise to more superoxide radicals (93). Subsequently, the Fenton reaction between Fe3+ and hydrogen peroxide produces highly reactive hydroxyl radicals (134). The resultant ROS and RNS react with numerous targets including lipids in the cell membrane with the most deleterious effects (93, 135). Because free radicals are short-lived and difficult to assess, measurements of their activity and final products, such as Malondialdehyde (MDA), are more reliable following SCI. Current evidence indicates that MDA levels are elevated as early as 1 h and up to 1 week after SCI (136, 137).

Oxidation of lipids and proteins is one of the key mechanisms of secondary injury following SCI (93). Lipid peroxidation starts when ROSs interact with polyunsaturated fatty acids in the cell membrane and generate reactive lipids that will then form lipid peroxyl radicals upon interacting with free superoxide radicals (138, 139). Each lipid peroxyl radical can react with a neighboring fatty acid, turn it into an active lipid and start a chain reaction that continues until no more unsaturated lipids are available or terminates when the reactive lipid quenches with another radical (93). The final products of this termination step of the lipid peroxidation is 4-hydroxynonenal (HNE) and 2-propenal, which are highly toxic to the cells (138140). Lipid peroxidation is also an underlying cause of ionic imbalance through destabilizing cellular membranes such as cytoplasmic membrane and endoplasmic reticulum (93). Moreover, lipid peroxidation leads to Na+/K+ ATPase dysfunction that exacerbates the intracellular Na+ overload (141). In addition to ROS associated lipid peroxidation, amino acids are subject to significant RNS associated oxidative damage following SCI (93). RNSs (containing ONOO) can nitrate the tyrosine residues of amino acids to form 3-nitrotyrosine (3-NT), a marker for peroxynitrite (ONOO) mediated protein damage (139). Lipid and protein oxidation following SCI has a number of detrimental consequences at cellular level including mitochondrial respiratory and metabolic failure as well as DNA alteration that ultimately lead to cell death (141).

Cell death is a major event in the secondary injury mechanisms that affects neurons and glia after SCI (142145). Cell death can happen through various mechanisms in response to various injury-induced mediators. Necrosis and apoptosis were originally identified as two major cell death mechanisms following SCI (146148). However, recent research has uncovered additional forms of cell death. In 2012, the Nomenclature Committee on Cell Death (NCCD) NCCD defined 12 different forms of cell death such as necroptosis, pyroptosis, and netosis (149). Among the identified modes of cell death, to date, necrosis, necroptosis, apoptosis, and autophagy have been studied more extensively in the context of SCI and will be discussed in this review.

Following SCI, neurons and glial cells die through necrosis as the result of mechanical damage at the time of primary injury that also continues to the acute and subacute stages of injury (7, 150). Necrosis occurs due to a multitude of factors including accumulation of toxic blood components (151), glutamate excitotoxicity and ionic imbalance (152), ATP depletion (153), pro-inflammatory cytokine release by neutrophils and lymphocytes (154, 155), and free radical formation (142, 156158). It was originally thought that necrosis is caused by a severe impact on a cell that results in rapid cell swelling and lysis. However, follow up evidence showed that in the case of seizure, ischemia and hypoglycemia, necrotic neurons show signs of shrunken, pyknotic, and condensed nuclei, with swollen, irreversibly damaged mitochondria and plasma membrane that are surrounded by astrocytic processes (159). Moreover, necrosis was conventionally viewed as instantaneous energy-independent non-programmed cell death (142, 156). However, recent research has identified another form of necrosis, termed as necroptosis, that is executed by regulated mechanisms.

Programmed necrosis or necroptosis has been described more recently as a highly regulated, caspase-independent cell death with similar morphological characteristics as necrosis (160). Necroptosis is a receptor-mediated process. It is induced downstream of the TNF receptor 1 (TNFR1) and is dependent on the activity of the receptor interacting protein kinase 1 (RIPK1) and RIPK3. Recent studies has uncovered a key role for RIPK1 as the mediator of necroptosis and a regulator of the innate immune response involved in both inflammation and cell death (161). Evidence from SCI studies show that lysosomal damage can potentiate necroptosis by promoting RIPK1 and RIPK3 accumulation (161). Interestingly, inhibition of necroptosis by necrostatin-1, a RIPK1 inhibitor, improves functional outcomes after SCI (150). These initial findings suggest that modulation of necroptosis pathways seems to be a promising target for neuroprotective strategies after SCI.

Apoptosis is the most studied mechanism of cell death after SCI. Apoptosis represents a programmed, energy dependent mode of cell death that begins within hours of primary injury (7). This process takes place in cells that survive the primary injury but endure enough insult to activate their apoptotic pathways (142). In apoptosis, the cell shrinks and is eventually phagocytosed without induction of an inflammatory response (156). Apoptosis typically occurs in a delayed manner in areas more distant to the injury site and most abundantly affects oligodendrocytes. In rat SCI, apoptosis happens as early as 4 h after the injury and reaches a peak at 7 day (156). At the site of injury majority of oligodendrocytes are lost within 7 days after SCI (162). However, apoptosis can be observed at a diminished rate for weeks after SCI (162, 163). Microglia and astrocytes also undergo apoptosis (156, 164). Interestingly, apoptotic cell death occurs in the chronically injured spinal cord in rat, monkey and human models of SCI, which is thought to be due to loss of trophic support from degenerating axons (146, 165).

Apoptosis is induced through extrinsic and intrinsic pathways based on the triggering mechanism (166). The extrinsic pathway is triggered by activation of death receptors such as FAS and TNFR1, which eventually activates caspase 8 (167). The intrinsic pathway, however, is regulated through a balance between intracellular pro- and anti-apoptotic proteins and is triggered by the release of cytochrome C from mitochondria and activating caspase 9 (167). In SCI lesion, apoptosis primarily happens due to injury induced Ca2+ influx, which activates caspases and calpain; enzymes involved in breakdown of cellular proteins (7). Moreover, it is believed that the death of neurons and oligodendrocytes in remote areas from the lesion epicenter can be mediated through cytokines such as TNF-, free radical damage and excitotoxicity since calcium from damaged cells within the lesion barely reaches these remote areas (8, 168). Fas mediated cell death has been suggested as a key mechanism of apoptosis following SCI (144, 169172). Post-mortem studies on acute and chronic human SCI and animal models revealed that Fas mediated apoptosis plays a role in oligodendrocyte apoptosis and inflammatory response at acute and subacute stages of SCI (173). Fas deficient mice exhibit a significant reduction in apoptosis and inflammatory response evidenced by reduced macrophage infiltration and inflammatory cytokine expression following SCI (173). Interestingly, Fas deficient mice show a significantly improved functional recovery after SCI (173) suggesting the promise of anti-apoptotic strategies for SCI.

SCI also results in a dysregulated autophagy (174). Normally, autophagy plays an important role in maintaining the homeostasis of cells by aiding in the turnover of proteins and organelles. In autophagy, cells degrade harmful, defective or unnecessary cytoplasmic proteins and organelles through a lysosomal dependent mechanism (175, 176). The process of autophagy starts with the formation of an autophagosome around the proteins and organelles that are tagged for autophagy (176). Next, fusion of the phagosome with a lysosome form an autolysosome that begins a recycling process (176). In response to cell injury and endoplasmic reticulum (ER) stress, autophagy is activated and limits cellular loss (177, 178). Current evidence suggests a neuroprotective role for autophagy after SCI (175, 179). Dysregulation of autophagy contributes to neuronal loss (174, 180). Accumulation of autophagosomes in ventral horn motor neurons have been detected acutely following SCI (181). Neurons with dysregulated autophagy exhibit higher expression of caspase 12 and become more prone to apoptosis (174). Moreover, blocking autophagy has been associated with neurodegenerative diseases such as Parkinson's and Alzheimer's disease (182184). Autophagy promotes cell survival through elimination of toxic proteins and damaged mitochondria (185, 186). Interestingly, autophagy is crucial in cytoskeletal remodeling and stabilizes neuronal microtubules by degrading SCG10, a protein involved in microtubule disassembly (179). Pharmacological induction of autophagy in a hemi-section model of SCI in mice has been associated with improved neurite outgrowth and axon regeneration, following SCI (179). Altogether, although further studies are needed, autophagy is currently viewed as a beneficial mechanism in SCI.

Neuroinflammation is a key component of the secondary injury mechanisms with local and systemic consequences. Inflammation was originally thought to be detrimental for the outcome of SCI (187). However, now it is well-recognized that inflammation can be both beneficial and detrimental following SCI, depending on the time point and activation state of immune cells (188). There are multiple cell types involved in the inflammatory response following injury including neutrophils, resident microglia, and astrocytes, dendritic cells (DCs), blood-born macrophages, B- and T-lymphocytes (189) (). The first phase of inflammation (02 days post injury) involves the recruitment of resident microglia and astrocytes and blood-born neutrophils to the injury site (190). The second phase of inflammation begins approximately 3 days post injury and involves the recruitment of blood-born macrophages, B- and T-lymphocytes to the injury site (189, 191193). T lymphocytes become activated in response to antigen presentation by macrophages, microglia and other antigen presenting cells (APCs) (194). CD4+ helper T cells produce cytokines that stimulate B cell antibody production and activate phagocytes (195) (). In SCI, B cells produce autoantibodies against injured spinal cord tissue, which exacerbate neuroinflammation and cause tissue destruction (196). While inflammation is more pronounced in the acute phase of injury, it continues in subacute and chronic phase and may persist for the remainder of a patients' life (193). Interestingly, composition and phenotype of inflammatory cells change based on the injury phase and the signals present in the injury microenvironment. It is established that microglia/macrophages, T cells, B cells are capable of adopting a pro-inflammatory or an anti-inflammatory pro-regenerative phenotype in the injured spinal cord (191, 197199). The role of each immune cell population in the pathophysiology of SCI will be discussed in detail in upcoming sections.

Immune response in spinal cord injury. Under normal circumstances, there is a balance between pro-inflammatory effects of CD4+ effector T cells (Teff) and anti-inflammatory effects of regulatory T and B cells (Treg and Breg). Treg and Breg suppress the activation of antigen specific CD4+ Teff cells through production of IL-10 and TGF-. Injury disrupts this balance and promote a pro-inflammatory environment. Activated microglia/macrophages release pro-inflammatory cytokines and chemokines and present antigens to CD4+ T cells causing activation of antigen specific effector T cells. Teff cells stimulate antigen specific B cells to undergo clonal expansion and produce autoantibodies against spinal cord tissue antigens. These autoantibodies cause neurodegeneration through FcR mediated phagocytosis or complement mediated cytotoxicity. M1 macrophages/microglia release pro-inflammatory cytokines and reactive oxygen species (ROS) that are detrimental to neurons and oligodendrocytes. Breg cells possess the ability to promote Treg development and restrict Teff cell differentiation. Breg cells could also induce apoptosis in Teff cells through Fas mediate mechanisms.

Astrocytes are not considered an immune cell per se; however, they play pivotal roles in the neuroinflammatory processes in CNS injury and disease. Their histo-anatomical localization in the CNS has placed them in a strategic position for participating in physiological and pathophysiological processes in the CNS (200). In normal CNS, astrocytes play major roles in maintaining CNS homeostasis. They contribute to the structure and function of blood-brain-barrier (BBB), provide nutrients and growth factors to neurons (200), and remove excess fluid, ions, and neurotransmitters such as glutamate from synaptic spaces and extracellular microenvironment (200). Astrocytes also play key roles in the pathologic CNS by regulating BBB permeability and reconstruction as well as immune cell activity and trafficking (201). Astrocytes contribute to both innate and adaptive immune responses following SCI by differential activation of their intracellular signaling pathways in response to environmental signals (201).

Astrocytes react acutely to CNS injury by increasing cytokine and chemokine production (202). They mediate chemokine production and recruitment of neutrophils through an IL-1R1-Myd88 pathway (202). Activation of the nuclear factor kappa b (NF-B) pathway, one of the key downstream targets of interleukin (IL)1R-Myd88 axis, increases expression of intracellular adhesion molecule (ICAM) and vascular cell adhesion molecule (VCAM), which are necessary for adhesion and extravasation of leukocytes in inflammatory conditions such as SCI (201, 202). Within minutes of injury, production of IL-1 is significantly elevated in astrocytes and microglia (203). Moreover, chemokines such as monocyte chemoattractant protein (MCP)-1, chemokine C-C motif ligand 2 (CCL2), C-X-C motif ligand 1 (CXCL1), and CXCL2 are produced by astrocytes, and enhance the recruitment of neutrophils and pro-inflammatory macrophages following injury (201, 202). Astrocytes also promote pro-inflammatory M1-like phenotype in microglia/macrophages in the injured spinal cord through their production of TNF-, IL-12, and IFN- (204206). Interestingly, astrocytes also produce anti-inflammatory cytokines, such as TGF- and IL-10, which can promote a pro-regenerative M2-like phenotype in microglia/macrophages (201, 207, 208).

Immunomodulatory role of astrocytes is defined by activity of various signaling pathways through a wide variety of surface receptors (200). For example, gp130, a member of IL-6 cytokine family, activates SHP2/Ras/Erk signaling cascade in astrocytes and limits neuroinflammation in autoimmune rodent models (209). TGF- signaling in astrocytes has been implicated in modulation of neuroinflammation through inhibition of NF-B activity and nuclear translocation (201, 210). STAT3 is another key signaling pathway in astrocytes with beneficial properties in neuroinflammation. Increase in STAT3 phosphorylation enhances astrocytic scar formation and restricts the expansion of inflammatory cells in mouse SCI, which is associated with improved functional recovery (211). Detrimental signaling pathways in astrocytes are known to be activated by cytokines, sphingolipids and neurotrophins (200). As an example, IL-17 is a key pro-inflammatory cytokine produced by effector T cells that can bind to IL-17R on the astrocyte surface (200). Activation of IL-17R results in the activation of NF-B, which enhances expression of pro-inflammatory mediators, activation of oxidative pathways and exacerbation of neuroinflammation (200, 212). This evidence shows the significance of astrocytes in the inflammatory processes following SCI and other neuroinflammatory diseases of the CNS.

Neutrophils infiltrate the spinal cord from the bloodstream within the first few hours after injury (213). Their population increases acutely in the injured spinal cord tissue and reaches a peak within 24 h post-injury (214). The presence of neutrophils is mostly limited to the acute phase of SCI as they are rarely found sub-acutely in the injured spinal cord (214). The role of neutrophils in SCI pathophysiology is controversial. Evidence shows that neutrophils contribute to phagocytosis and clearance of tissue debris (48). They release inflammatory cytokines, proteases and free radicals that degrade ECM, activate astrocytes and microglia and initiate neuroinflammation (48). Although neutrophils have been conventionally associated with tissue damage (48, 215), their elimination compromises the healing process and impedes functional recovery (216).

To elucidate the role of neutrophils in SCI, Stirling and colleagues used a specific antibody to reduce circulating LyG6/Gr1+ neutrophils in a mouse model of thoracic contusive SCI (216). This approach significantly reduced neutrophil infiltration in the injured spinal cord by 90% at 24 and 48 h after SCI (216). Surprisingly, neutrophil depletion aggravated the neurological and structural outcomes in the injured animals suggesting a beneficial role for neutrophils in the acute phase of injury (216). It is shown that simulated neutrophils release IL-1 receptor antagonist that can exert neuroprotective effects following SCI (217). Moreover, ablation of neutrophils results in altered expression of cytokines and chemokines and downregulation of growth factors such as fibroblast growth factors (FGFs), vascular endothelial growth factors (VEGFs) and bone morphogenetic proteins (BMPs) in the injured spinal cord that seemingly disrupt the normal healing process (216). Altogether, neutrophils play important roles in regulating neuroinflammation at the early stage of SCI that shapes the immune response and repair processes at later stages. While neutrophils were originally viewed as being detrimental in SCI, emerging evidence shows their critical role in the repair process. Further investigations are required to elucidate the role of neutrophils in SCI pathophysiology.

Following neutrophil invasion, microglia/macrophages populate the injured spinal cord within 23 days post-SCI. Macrophage population is derived from invading blood-borne monocytes or originate from the CNS resident macrophages that reside in the perivascular regions within meninges and subarachnoid space (218, 219). The population of microglia/macrophages reaches its peak at 710 days post-injury in mouse SCI, followed by a decline in the subacute and chronic phases (20, 220). While macrophages and microglia share many functions and immunological markers, they have different origins. Microglia are resident immune cells of the CNS that originate from yolk sac during the embryonic period (221). Macrophages are derived from blood monocytes, which originate from myeloid progeny in the bone marrow (222, 223). Upon injury, acute disruption of brain-spinal cord barrier (BSB) enables monocytes, to infiltrate the spinal cord tissue and transform into macrophages (222). Macrophages populate the injury epicenter, while resident microglia are mainly located in the perilesional area (222). Once activated, macrophages, and microglia are morphologically and immunohistologically indistinguishable (224). Macrophages and microglia play a beneficial role in CNS regeneration. They promote the repair process by expression of growth promoting factors such as nerve growth factor (NGF), neurotrophin-3 (NT-3) and thrombospondin (225, 226). Macrophages and microglia are important for wound healing process following SCI due to their ability for phagocytosis and scavenging damaged cells and myelin debris following SCI (222, 227).

Based on microenvironmental signals, macrophages/microglia can be polarized to either pro-inflammatory (M1-like) or anti-inflammatory pro-regenerative (M2-like) phenotype, and accordingly contribute to injury or repair processes following SCI (191, 224, 228230). Whether both microglia and macrophages possess the ability to polarize or it is mainly the property of monocyte derived macrophages is still a matter of debate and needs further elucidation (231233). Some evidence show that Proinflammatory M1-like microglia/macrophages can be induced by exposure to Th1 specific cytokine, interferon (IFN)- (224, 230). Moreover, the SCI microenvironment appears to drive M1 polarization of activated macrophages (231). SCI studies have revealed that increased level of the proinflammatory cytokine, TNF-, and intracellular accumulation of iron drives an M1-like proinflammatory phenotype in macrophages after injury (231). Importantly, following SCI, activated M1-like microglia/macrophages highly express MHCII and present antigens to T cells and contribute to the activation and regulation of innate and adaptive immune response () (224, 228). Studies on acute and subacute SCI and experimental autoimmune encephalomyelitis (EAE) models have shown that M1-like macrophages are associated with higher expression of chondroitin sulfate proteoglycans (CSPGs) and increased EAE severity and tissue damage (234237). In vitro, addition of activated M1-like macrophages to dorsal root ganglion (DRG) neuron cultures leads to axonal retraction and failure of regeneration as the expression of CSPGs is much higher in M1-like compared to M2-like macrophages (237, 238). M1-like macrophages also produce other repulsive factors such as repulsive guidance molecule A (RGMA) that is shown to induce axonal retraction following SCI (239, 240). Interestingly, recent evidence shows that IFN- and TNF polarized M1 microglia show reduced capacity for phagocytosis (241), a process that is critical for tissue repair after SCI.

Pro-regenerative M2-like microglia/macrophages, are polarized by Th2 cytokines, IL-4 and IL-13 and exhibit a high level of IL-10, TGF-, and arginase-1 with reduced NF-B pathway activity (224). IL-10 is a potent immunoregulatory cytokine with positive roles in repair and regeneration following CNS injury (242244). IL-10 knock-out mice show higher production of pro-inflammatory and oxidative stress mediators after SCI (245). Lack of IL-10 is also correlated with upregulated levels of pro-apoptotic factors such as Bax and reduced expression of anti-apoptotic factors such as Bcl-2 (245). SCI mice that lacked IL-10 exhibited poorer recovery of function compared to wild-type mice (245). Our recent studies show that IL-10 polarized M2 microglia show enhanced capacity for phagocytosis (241). We have also found that M2 polarized microglia enhance the ability of neural precursor cells for oligodendrocyte differentiation through IL-10 mediated mechanisms (241). In addition to immune modulation, M2-like microglia/macrophages promote axonal regeneration (224). However, similar to the detrimental effects of prolonged M1 macrophage response, excessive M2-like activity promotes fibrotic scar formation through the release of factors such as TGF-, PDGF, VEGF, IGF-1, and Galectin-3 (224, 246248). Hence, a balance between proinflammatory M1 and pro-regenerative M2 macrophage/microglia response is beneficial for the repair of SCI (249).

T and B lymphocytes play pivotal role in the adaptive immune response after SCI (194). Lymphocytes infiltrate the injured spinal cord acutely during the first week of injury and remain chronically in mouse and rat SCI (47, 193, 194, 196). In contrast to the innate immune response that can be activated directly by foreign antigens, the adaptive immune response requires a complex signaling process in T cells elicited by antigen presenting cells (250). Similar to other immune cells, T and B lymphocytes adopt different phenotypes and contribute to both injury and repair processes in response to microenvironmental signals (194, 251). SCI elicits a CNS-specific autoimmune response in T and B cells, which remains active chronically (196). Autoreactive T cells can exert direct toxic effects on neurons and glial cells (194, 252). Moreover, T cells can indirectly affect neural cell function and survival through pro-inflammatory cytokine and chemokine production (e.g. IL-1, TNF-, IL-12, CCL2, CCL5, and CXCL10) (194, 252). Genetic elimination of T cells (in athymic nude rats) or pharmacological inhibition of T cells (using cyclosporine A and tacrolimus) leads to improved tissue preservation and functional recovery after SCI (194, 253) signifying the impact of T cells in SCI pathophysiology and repair.

Under normal circumstances, systemic autoreactive effector CD4+ helper T cells (Teff) are suppressed by CD4+FoxP3+ regulatory T cells (Treg) () (194, 254). This inhibition is regulated through various mechanisms such as release of anti-inflammatory cytokines IL-10 and TGF- by the Treg cells () (194). Moreover, it is known that Treg mediated inhibition of antigen presentation by dendritic cells (DCs) prevent Teff cell activation (194). Following SCI, this Treg -Teff regulation is disrupted. Increased activity of autoreactive Teff cells contributes to tissue damage through production of pro-inflammatory cytokines and chemokines, promoting M1-like macrophage phenotype and induction of Fas mediated neuronal and oligodendroglial apoptosis () (173). Moreover, autoreactive Teff cells promote activation and differentiation of antigen specific B cells to autoantibody producing plasma cells that contribute to tissue damage after SCI (255). In SCI and MS patients, myelin specific proteins such as myelin basic protein (MBP) significantly increase the population of circulating T cells (256, 257). Moreover, serological assessment of SCI patients has shown high levels of CNS reactive IgM and IgG isotypes confirming SCI-induced autoimmune activity of T and B cells () (196, 258, 259). In animal models of SCI, serum IgM level increases acutely followed by an elevation in the levels of IgG1 and IgG2a at later time-points (196). In addition to autoantibody production, autoreactive B cells contribute to CNS injury through pro-inflammatory cytokines that stimulate and maintain the activation states of Teff cells (194, 260). B cell knockout mice (BCKO) that have no mature B cell but with normal T cells, show a reduction in lesion volume, lower antibody levels in the cerebrospinal fluid and improved recovery of function following SCI compared to wild-type counterparts (255). Of note, antibody mediated injury is regulated through complement activation as well as macrophages/microglia that express immunoglobulin receptors (193, 255).

The effect of SCI on systemic B cell response is controversial. Evidence shows that SCI can suppress B cell activation and antibody production (261). Studies in murine SCI have shown that B cell function seems to be influenced by the level of injury (262). While injury to upper thoracic spinal cord (T3) suppresses the antibody production, a mid-thoracic (T9) injury has no effect on B cell antibody production (262). An increase in the level of corticosterone in serum together with elevation of splenic norepinephrine found to be responsible for the suppression of B cell function acutely following SCI (261). Elevated corticosterone and norepinephrine leads to upregulation of lymphocyte beta-2 adrenergic receptors eliciting lymphocyte apoptosis (194). This suggests a critical role for sympathetic innervation of peripheral lymphoid tissues in regulating B cell response following CNS injury (261). Despite their negative roles, B cells also contribute to spinal cord repair following injury through their immunomodulatory Breg phenotype () (263). Breg cells control antigen-specific T cell autoimmune response through IL-10 production (264).

Detrimental effects of SCI-induced autoimmunity are not limited to the spinal cord. Autoreactive immune cells contribute to the exacerbation of post-SCI sequelae such as cardiovascular, renal and reproductive dysfunctions (194). For example, presence of an autoantibody against platelet prostacyclin receptor has been associated with a higher incidence of coronary artery disease in SCI patients (265). Collectively, evidence shows the critical role of adaptive immune system in SCI pathophysiology and repair. Thus, treatments that harness the pro-regenerative properties of the adaptive immune system can be utilized to reduce immune mediated tissue damage, improve neural tissue preservation and facilitate repair following SCI.

Traumatic SCI triggers the formation of a glial scar tissue around the injury epicenter (266, 267). The glial scar is a multifactorial phenomenon that is contributed f several populations in the injured spinal cord including activated astrocytes, NG2+ oligodendrocyte precursor cells (OPCs), microglia, fibroblasts, and pericytes (268271). The heterogeneous scar forming cells and associated ECM provides a cellular and biochemical zone within and around the lesion () (272). Resident and infiltrating inflammatory cells contribute to the process of glial activation and scar formation by producing cytokines (e.g., IL-1 and IL-6) chemokines and enzymes that activate glial cells or disrupt BSB (267). Activated microglia/macrophages produce proteolytic enzymes such as matrix metalloproteinases (MMPs) that increase vascular permeability and further disruption of the BSB (273). Inhibition of MMPs improves neural preservation and functional recovery in animal models of SCI (273275). In addition to glial and immune cells, fibroblasts, pericytes and ependymal cells also contribute to the structure of the glial scar (267). In penetrating injuries where meninges are compromised, meningeal fibroblasts infiltrate the lesion epicenter (276). Fibroblasts contribute to the production of fibronectin, collagen, and laminin in the ECM of the inured spinal cord (267) and are a source of axon-repulsing molecules such as semaphorins that influence axonal regeneration following SCI (277). Fibroblasts have also been found in contusive injuries where meninges are intact (268, 270). Studies using genetic fate mapping in these injuries have unraveled that perivascular pericytes and fibroblasts migrate to the injury site and form a fibrotic core in the scar which matures within 2 weeks post-injury (268, 270). SCI also triggers proliferation and migration of the stem/progenitor cell pool of the spinal cord parenchyma and ependyma. These cells can give rise to new scar forming astrocytes and OPCs (278280). In a mature glial scar, activated microglia/macrophages occupy the innermost portion closer to the injury epicenter surrounded by NG2+ OPCs () (267), while reactive astrocytes reside in the injury penumbra and form a cellular barrier (267). Of note, in human SCI, the glial scar begins to form within the first hours after the SCI and remains chronically in the spinal cord tissue (281). The glial scar has been found within the injured human spinal cord up to 42 years after the injury (267).

Activated astrocytes play a leading role in the formation of the glial scar (267). Following injury, astrocytes increase their expression of intermediate filaments, GFAP, nestin and vimentin, and become hypertrophied (282, 283). Reactive astrocytes proliferate and mobilize to the site of injury and form a mesh like structure of intermingled filamentous processes around the injury epicenter (284, 285). The astrocytic glial scar has been shown to serve as a protective barrier that prevents the spread of infiltrating immune cells into the adjacent segments (267, 284, 286). Attenuating astrocyte reactivity and scar formation by blockade of STAT3 activation results in poorer outcomes in SCI (211, 286). Reactive astrogliosis is also essential for reconstruction of the BBB, and blocking this process leads to exacerbated leukocyte infiltration, cell death, myelin damage, and reduced functional recovery (211, 285, 286). Despite the protective role of the astrocytic glial scar in acute SCI, its evolution and persistence in the sub-acute and chronic stages of injury has been considered as a potent inhibitor for spinal cord repair and regeneration (267, 287). A number of inhibitory molecules have been associated with activated astrocytes and their secreted products such as proteoglycans and Tenascin-C (288). Thus, manipulation of the astrocytic scar has been pursued as a promising treatment strategy for SCI (267, 289).

Chondroitin sulfate proteoglycans (CSPGs) are well-known for their contribution to the inhibitory role of the glial scar in axonal regeneration (290295), sprouting (296299), conduction (300302), and remyelination (241, 303307). In normal condition, basal levels of CSPGs are expressed in the CNS that play critical roles in neuronal guidance and synapse stabilization (90, 308). Following injury, CSPGs (neurocan, versican, brevican, and phosphacan) are robustly upregulated and reach their peak of expression at 2 weeks post-SCI and remain upregulated chronically (309, 310). Mechanistically, disruption of BSB and hemorrhage following traumatic SCI triggers upregulation of CSPGs in the glial scar by exposing the scar forming cells to factors in plasma such as fibrinogen (311). Studies in cortical injury have shown that fibrinogen induces CSPG expression in astrocytes through TGF/Smad2 signaling pathway (311). The authors show that intracellular Smad2 translocation is essential for Smad2 signal transduction process and its inhibition reduces scar formation (312). In contrast, another study has identified that TGF induces CSPGs production in astrocytes through a SMAD independent pathway (313). This study showed a significant upregulation of CSPGs in SMAD2 and SMAD4 knockdown astrocytes. Interestingly, CSPG upregulation was found to be mediated by the activation of the phosphoinositide 3-kinase (PI3K)/Akt and mTOR axis (313). Further studies are required to confirm these findings.

Extensive research in the past few decades has demonstrated the inhibitory effect of CSPGs on axon regeneration (314, 315). The first successful attempt on improving axon outgrowth and/or sprouting by enzymatic degradation of CSPGs using chondroitinase ABC (ChABC) in a rat SCI model was published in 2002 by Bradbury and colleagues (291). This study showed significant improvement in recovery of locomotor and proprioceptive functions following intrathecal delivery of ChABC in a rat model of dorsal column injury (291). This observation was followed by several other studies demonstrating the promise of CSPGs degradation in improvement of axon regeneration and sprouting of the serotonergic (295, 297, 299, 303), sensory (293, 298, 316), corticospinal (291, 297, 303, 317), and rubrospinal fibers (318) in animal models of CNS injury. Additionally, ChABC treatment is shown to be neuroprotective by preventing CSPG induced axonal dieback and degeneration (303, 319, 320). Studies by our group also showed that degradation of CSPGs using ChABC attenuates axonal dieback in corticospinal fibers in chronic SCI model in the rat (303). ChABC also blocks macrophage-mediated axonal degeneration in neural cultures and after SCI (238).

The inhibitory effects of astrocytic glial scar on axonal regeneration has been recently challenged after SCI (321). Using various transgenic mouse models, a study by Sofroniew's and colleagues has shown that spontaneous axon regrowth failed to happen following the ablation or prevention of astrocytic scar in acute and chronic SCI. They demonstrated that when the intrinsic ability of dorsal root ganglion (DRG) neurons for growth was enhanced by pre-conditioning injury as well as local delivery of a combination of axon growth promoting factors into the SCI lesion, the axons grew to the wall of the glial scar and CSPGs within the lesion. However, when astrocyte scarring was attenuated, the pre-conditioned/growth factor stimulated DRG neurons showed a reduced ability for axon growth (321). From these observations, the authors suggested a positive role for the astrocytic scar in axonal regeneration following SCI (321). Overall, this study points to the importance of reactive and scar forming astrocytes and their pivotal role in the repair process following SCI (322). This is indeed in agreement with previous studies by the same group that showed a beneficial role for activated astrocytes in functional recovery after SCI by limiting the speared of infiltrated inflammatory cells and tissue damage in SCI (285). It is also noteworthy that the glial scar is contributed by various cell populations and not exclusively by astrocytes (269, 271). Therefore, the outcomes of this study need to be interpreted in the context of astrocytes and astrocytic scar. Moreover, the reduced capacity of the injured spinal cord for regeneration is not solely driven by the glial scar as other factors including inflammation and damaged myelin play important inhibitory role in axon regeneration (323, 324). Taken together, further investigation is needed to delineate the mechanisms of the glial scar including the contribution of astrocyte-derived factors on axon regeneration in SCI.

While CSPGs were originally identified as an inhibitor of axon growth and plasticity within the glial scar, emerging evidence has also identified them as an important regulator of endogenous cell response. Emerging evidence has identified CSPGs as an inhibitor of oligodendrocytes (241, 272, 306). Replacement of oligodendrocytes is an important repair process in SCI and other demyelinating conditions such as MS (90). SCI and MS triggers activation of endogenous OPCs and their mobilization to the site of injury (143, 162, 306, 325). In vitro and in vivo evidence shows that CSPGs limit the recruitment of NPCs and OPCs to the lesion and inhibit oligodendrocyte survival, differentiation and maturation (145, 272, 305, 306, 326). Our group and others have shown that targeting CSPGs by ChABC administration or xyloside, or through inhibition of their signaling receptors enhances the capacity of NPCs and OPCs for proliferation, oligodendrocyte differentiation and remyelination following SCI and MS-like lesions (145, 303, 304, 306).

Mechanistically, the inhibitory effects of CSPGs on axon growth and endogenous cell differentiation is mainly governed by signaling through receptor protein tyrosine phosphatase sigma (RPTP) and leukocyte common antigen-related phosphatase receptor (LAR) (327). RPTP is the main receptor mediating the inhibition of axon growth by CSPGs (327, 328). Improved neuronal regeneration has been demonstrated in RPTP/ mice model of SCI and peripheral nerve injury (328, 329). Blockade of RPTP and LAR by intracellular sigma peptide (ISP) and intracellular LAR peptide (ILP), facilitates axon regeneration following SCI (327, 330). Inhibition of RPTP results in significant improvement in locomotion and bladder function associated with serotonergic re-innervation below the level of injury in rat SCI (327). Our group has also shown that CSPGs induce caspase-3 mediated apoptosis in NPCs and OPCs in vitro and in oligodendrocytes in the injured spinal cord that is mediated by both RPTP and LAR (241). Inhibition of LAR and RPTP sufficiently attenuates CSPG-mediated inhibition of oligodendrocyte maturation and myelination in vitro and attenuated oligodendrocyte cell death after SCI (241).

CSPGs have been implicated in regulating immune response in CNS injury and disease. Interestingly, our recent studies indicated that CSPGs signaling appears to restrict endogenous repair by promoting a pro-inflammatory immune response in SCI (241, 331). Inhibition of LAR and RPTP enhanced an anti-inflammatory environment after SCI by promoting the populations of pro-regenerative M2-like microglia/macrophages and regulatory T cells (241) that are known to promote repair process (224). These findings are also in agreement with recent studies in animal models of MS that unraveled a pro-inflammatory role for CSPGs in autoimmune demyelinating conditions (332). In MS and EAE, studies by Stephenson and colleagues have shown that CSPGs are abundant within the leucocyte-containing perivascular cuff, the entry point of inflammatory cells to the CNS tissue (332). Presence of CSPGs in these perivascular cuffs promotes trafficking of immune cells to induce a pro-inflammatory response in MS condition. In contrast to these new findings, early studies in SCI described that preventing CSPG formation with xyloside treatment at the time of injury results in poor functional outcome, while manipulation of CSPGs at 2 days after SCI was beneficial for functional recovery (333). These differential outcomes were associated with the modulatory role of CSPGs in regulating the response of macrophages/microglia. Disruption in CSPG formation immediately after injury promoted an M1 pro-inflammatory phenotype in macrophages/microglia, whereas delayed manipulation of CSPGs resulted in a pro-regenerative M2 phenotype (333). In EAE, by products of CSPG degradation also improve the outcomes by attenuating T cell infiltration and their expression of pro-inflammatory cytokines IFN- and TNF (334).

These emerging findings suggest an important immunomodulatory role for CSPGs in CNS injury and disease; further investigations are needed to elucidate CSPG mechanisms in regulating neuroinflammation. Altogether, current evidence has identified a multifaceted inhibitory role for CSPGs in regulating endogenous repair mechanisms after SCI, suggesting that targeting CSPGs may present a promising treatment strategy for SCI.

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Traumatic Spinal Cord Injury: An Overview of ...

Abstract

Stem cells or mother or queen of all cells are pleuropotent and have the remarkable potential to develop into many different cell types in the body. Serving as a sort of repair system for the body, they can theoretically divide without limit to replenish other cells as long as the person or animal is alive. When a stem cell divides, each new cell has the potential to either remain a stem cell or become another type of cell with a more specialized function, such as a muscle cell, a red blood cell, or a brain cell. Stem cells differ from other kinds of cells in the body. All stem cells regardless of their source have three general properties:

They are unspecialized; one of the fundamental properties of a stem cell is that it does not have any tissue-specific structures that allow it to perform specialized functions.

They can give rise to specialized cell types. These unspecialized stem cells can give rise to specialized cells, including heart muscle cells, blood cells, or nerve cells.

They are capable of dividing and renewing themselves for long periods. Unlike muscle cells, blood cells, or nerve cells which do not normally replicate themselves - stem cells may replicate many times. A starting population of stem cells that proliferates for many months in the laboratory can yield millions of cells. Today, donated organs and tissues are often used to replace those that are diseased or destroyed. Unfortunately, the number of people needing a transplant far exceeds the number of organs available for transplantation. Pleuropotent stem cells offer the possibility of a renewable source of replacement cells and tissues to treat a myriad of diseases, conditions, and disabilities including Parkinsons and Alzheimers diseases, spinal cord injury, stroke, Cerebral palsy, Battens disease, Amyotrophic lateral sclerosis, restoration of vision and other neuro degenerative diseases as well.

Stem cells may be the persons own cells (a procedure called autologous transplantation) or those of a donor (a procedure called allogenic transplantation). When the persons own stem cells are used, they are collected before chemotherapy or radiation therapy because these treatments can damage stem cells. They are injected back into the body after the treatment.

The sources of stem cells are varied such as pre-implantation embryos, children, adults, aborted fetuses, embryos, umbilical cord, menstrual blood, amniotic fluid and placenta

New research shows that transplanted stem cells migrate to the damaged areas and assume the function of neurons, holding out the promise of therapies for Alzheimers disease, Parkinsons, spinal cord injury, stroke, Cerebral palsy, Battens disease and other neurodegenerative diseases.

The therapeutic use of stem cells, already promising radical new treatments for cancer, immune-related diseases, and other medical conditions, may someday be extended to repairing and replenishing the brain. In a study published in the February 19, 2002, Proceedings of the National Academy of Sciences, researchers exposed the spinal cord of a rat to injury, paralyzing the animals hind limbs and lower body. Stem cells grown in exponential numbers in the laboratory were then injected into the site of the injury. It was seen that week after the injury, motor function improved dramatically,

The following diseases have been treated by various stem cell practitioners with generally positive results and the spectrum has ever since been increasing.

Cerebral palsy is a disorder caused by damage to the brain during pregnancy, delivery or shortly after birth. It is often accompanied by seizures, hearing loss, difficulty speaking, blindness, lack of co-ordination and/or mental retardation. Studies in animals with experimentally induced strokes or traumatic injuries have indicated that benefit is possible by stem cell therapy. The potential to do these transplants via injection into the vasculature rather than directly into the brain increases the likelihood of timely human studies. As a result, variables appropriate to human experiments with intravascular injection of cells, such as cell type, timing of the transplant and effect on function, need to be systematically performed in animal models Studies in animals with experimentally induced strokes or traumatic injuries have indicated that benefit is possible with injury, with the hope of rapidly translating these experiments to human trials.(1)

Cerebral palsy produces chronic motor disability in children. The causes are quite varied and range from abnormalities of brain development to birth-related injuries to postnatal brain injuries. Due to the increased survival of very premature infants, the incidence of cerebral palsy may be increasing. While premature infants and term infants who have suffered neonatal hypoxic-ischemic (HI) injury represent only a minority of the total cerebral palsy population, this group demonstrates easily identifiable clinical findings, and much of their injury is to oligodendrocytes and the white matter (2)

Alzheimers is a complex, fatal disease involving progressive cell degeneration, beginning with the loss of brain cells that control thought, memory and language. The disease, which currently has no cure, was first described by German physician Dr. Alzheimer, who discovered amyloid plaques and neurofibrillary tangles in the brain of a woman who died of an unusual mental illness. A compound similar to the components of DNA may improve the chances that stem cells transplanted from a patients bone marrow to the brain will take over the functions of damaged cells and help treat Alzheimers disease and other neurological illnesses. A research team led by University of Central Florida professor Kiminobu Sugaya found that treating bone marrow cells in laboratory cultures with bromodeoxyuridine, a compound that becomes part of DNA, made adult human stem cells more likely to develop as brain cells after they were implanted in adult rat brains.

It has long been recognized that Alzheimers disease (AD) patients present an irreversible decline of cognitive functions as consequence of cell deterioration in a structure called nucleus basalis of Meynert The reduction of the number of cholinergic cells causes interference in several aspects of behavioral performance including arousal, attention, learning and emotion. It is also common knowledge that AD is an untreatable degenerative disease with very few temporary and palliative drug therapies. Neural stem cell (NSC) grafts present a potential and innovative strategy for the treatment of many disorders of the central nervous system including AD, with the possibility of providing a more permanent remedy than present drug treatments. After grafting, these cells have the capacity to migrate to lesioned regions of the brain and differentiate into the necessary type of cells that are lacking in the diseased brain, supplying it with the cell population needed to promote recovery. (3)

Malignant multiple sclerosis (MS) is a rare but clinically important subtype of MS characterized by the rapid development of significant disability in the early stages of the disease process. These patients are refractory to conventional immunomodulatory agents and the mainstay of their treatment is plasmapheresis or immunosuppression with mitoxantrone, cyclophosphamide, cladribine or, lately, bone marrow transplantation. A report on the case of a 17-year old patient with malignant MS who was treated with high-dose chemotherapy plus anti-thymocyte globulin followed by autologous stem cell transplantation. This intervention resulted in an impressive and long-lasting clinical and radiological response (4).

In other experiment treatment of 24 patients (14 women, 10 men) with relapsing-remitting Multiple Sclerosis, in the course of 28 years was done For treatment, used were embryonic stem cell suspensions (ESCS) containing stem cells of mesenchymal and ectodermal origin obtained from active growth zones of 48 weeks old embryonic cadavers organs. Suspensions were administered in the amount of 13 ml, cell count being 0,1-100x105/ml. In the course of treatment, applied were 24 different suspensions, mode of administration being intracavitary, intravenous, and subcutaneous. After treatment, syndrome of early post-transplant improvement was observed in 70% of patients, its main manifestations being decreased weakness, improved appetite and mood, decreased depression. In the course of first post-treatment months, positive dynamics was observed in the following aspects: Nystagmus, convergence disturbances, spasticity, and coordination. In such symptoms as dysarthria, dysphagia, and ataxia, positive changes occurred at much slower rate. In general, the treatment resulted in improved range and quality of motions in the extremities, normalized muscle tone, decreased fatigue and general weakness, and improved quality of life. Forth, 87% of patients reported no exacerbations, no aggravation of neurological symptoms, and no further progression of disability. MRI performed in 12 years after the initial treatment, showed considerable subsidence of focal lesions, mean by 31%, subsidence of gadolinium enhanced lesions by 48%; T2-weighted images showed marked decrease of the focis relative density.

Doctors firstly isolated adult stem cells from the patients brain, they were then cultured in vitro and encouraged to turn into dopamine-producing neurons. As soon as tests showed that the cells were producing dopamine they were then re-injected into the mans brain. After the transplant, the mans condition was seen to improve and he experienced a reduction in the trembling and muscle rigidity associated with the disease. Brain scans taken 3-months after the transplant revealed that dopamine production had increased by 58%, however it later dropped but the Parkinsons symptoms did not return. The study is the first human study to show that stem cell transplants can help to treat Parkinsons.

The use of fetal-derived neural stem cells has shown significant promise in rodent models of Parkinsons disease, and the potential for tumorigenicity appears to be minimal. The authors report that undifferentiated human neural stem cells (hNSCs) transplanted into severely Parkinsonian 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated primates could survive, migrate, and induce behavioral recovery of Parkinsonian symptoms, which were directly related to reduced dopamine levels in the nigrostriatal system(5). Working with these cells, the researchers created dopamine neurons deficient in DJ-1, a gene mutated in an inherited form of Parkinsons. They report that DJ-1-deficient cells -- and especially DJ-1-deficient dopamine neurons -- display heightened sensitivity to oxidative stress, caused by products of oxygen metabolism that react with and damage cellular components like proteins and DNA. In a second paper, they link DJ-1 dysfunction to the aggregation of alpha-synuclein, a hallmark of Parkinsons neuropathology. (6,7)

In summary most of studies using aborted human embryonic tissue indicate that:

Clinical benefit does occur; however, the benefit is not marked and there is a delay of many months before the clinical change.

Postmortem examinations show that tissue grafts do survive and innervate the striatum.

PET scans show that there is an increase in dopamine uptake after transplantation.

Followup studies show that long term benefit does occur with transplantation.(8)

During and after a stroke, certain cellular events take place that lead to the death of brain cells. Compounds that inhibit a group of enzymes called histone deacetylases can modulate gene expression, and in some cases produce cellular proteins that are actually neuroprotective -- they are able to block cell death. Great deal of research has gone into developing histone deacetylase inhibitors as novel therapeutics (9)

One Mesenchymal stem cell (MSC) transplantation improves recovery from ischemic stroke in animals. The Researchers examined the feasibility, efficacy, and safety of cell therapy using culture-expanded autologous MSCs in patients with ischemic stroke. They prospectively and randomly allocated 30 patients with cerebral infarcts within the middle cerebral arterial territory Serial evaluations showed no adverse cell-related, serological, or imaging-defined effects. In patients with severe cerebral infarcts, the intravenous infusion of autologous MSCs appears to be a feasible and safe therapy that may improve functional recovery.(10)

Early intravenous stem cell injection displayed anti-inflammatory functionality that promoted neuroprotection, mainly by interrupting splenic inflammatory responses after intra cranial Haemorrage.

In summary, early intravenous NSC injection displayed anti-inflammatory functionality that neural stem cell (NSC) transplantation has been investigated as a means to reconstitute the damaged brain after stroke. In this study, however, was investigated the effect on acute cerebral and peripheral inflammation after intracerebral haemorrhage (ICH). STEM CELLS from fetal human brain were injected intravenously (NSCs-iv, 5 million cells) or intracerebrally (NSCs-ic, 1 million cells) at 2 or 24 h after collagenase-induced ICH in a rat model. Only NSCs-iv-2 h resulted in fewer initial neurologic deteriorations and reduced brain edema formation, inflammatory infiltrations and apoptosis. (11)

Emerging cell therapies for the restoration of sight have focused on two areas of the eye that are critical for visual function, the cornea and the retina. The relatively easy access of the cornea, the homogeneity of the cells forming the different layers of the corneal epithelium and the improvement of cell culture protocols are leading to considerable success in corneal epithelium restoration. Rebuilding the entire cornea is however still far from reality. The restoration of the retina has recently been achieved in different animal models of retinal degeneration using immature photoreceptors (12)

Bone marrow contains stem cells, which have the extraordinary abilities to home in on injuries and possibly regenerate other cell types in the body. In this case, the cells were transplanted to confirm that bone marrow does regenerate the injured RPE. Damage to RPE is present in many diseases of the retina, including age-related macular degeneration, which affects more than 1.75 million people in the United States. (13)

Neural stem cells (NSCs) offer the potential to replace lost tissue after nervous system injury. Thus, stem cells can promote host neural repair in part by secreting growth factors, and their regeneration-promoting activities can be modified by gene delivery.

Attempted repair of human spinal cord injury by transplantation of stem cells depends on complex biological interactions between the host and graft

Extrapolating results from experimental therapy in animals to humans with spinal cord injury requires great caution.

There is great pressure on surgeons to transplant stem cells into humans with spinal cord injury. However, as the efficacy of and exact indications for this therapy are still uncertain, and morbidity (such as rejection or late tumour development) may result, only carefully designed studies based on sound experimental work which attempts to eliminate placebo effects should proceed.

Premature application of stem cell transplantation in humans with spinal cord injury should be discouraged. 14, 15, 16)

Attempted repair of human spinal cord injury by transplantation of stem cells depends on complex biological interactions between the host and graft

Extrapolating results from experimental therapy in animals to humans with spinal cord injury requires great caution.

There is great pressure on surgeons to transplant stem cells into humans with spinal cord injury. However, as the efficacy of and exact indications for this therapy are still uncertain, and morbidity (such as rejection or late tumour development) may result, only carefully designed studies based on sound experimental work which attempts to eliminate placebo effects should proceed.

Premature application of stem cell transplantation in humans with spinal cord injury should be discouraged.

Mesenchymal stem cells have also been identified and are currently being developed for bone, cartilage, muscle, tendon, and ligament repair and regeneration. These MSCs are typically harvested, isolated, and expanded from bone marrow or adipose tissue, and they have been isolated from rodents, dogs, and humans. Interestingly, these cells can undergo extensive sub cultivation in vitro without differentiation, magnifying their potential clinical use.(17) Human MSCs can be directed toward osteoblastic differentiation by adding dexamethasone, ascorbic acid, and -glycerophosphate to the tissue culture media. This osteoblastic commitment and differentiation can be clearly documented by analyzing alkaline phosphatase activity, the expression of bone matrix proteins, and the mineralization of the extracellular matrix.(18)

Children with Battens disease suffer seizures, motor control disturbances, blindness and communication problems. As many as 600 children in the US are currently diagnosed with the condition.(19)

Death can occur in children as young as 8 years old. The children lack an enzyme for breaking down complex fat and protein compounds in the brain, explains Robert Steiner, vice chair of paediatric research at the hospital. The material accumulates and interferes with tissue function, ultimately causing brain cells to die. Tests on animals demonstrated that stem cells injected into the brain secreted the missing enzyme. And the stem cells were found to survive well in the rodent brain. Once injected, the purified neural cells may develop into neurons or other nervous system tissue, including oligodendrocytes, or glial cells, which support the neurons(20).

In a study that demonstrates the promise of cell-based therapies for diseases that have proved intractable to modern medicine, a team of scientists from the University of Wisconsin-Madison has shown it is possible to rescue the dying neurons characteristic of amyotrophic lateral sclerosis (ALS), a fatal neuromuscular disorder also known as Lou Gehrigs disease. Previously there was no effective treatments for ALS, which afflicts roughly 40,000 people in the United States and which is almost always fatal within three to five years of diagnosis. Patients gradually experience progressive muscle weakness and paralysis as the motor neurons that control muscles are destroyed by the disease

In the new Wisconsin study, nascent brain cells known as neural progenitor cells derived from human fetal tissue were engineered to secrete a chemical known as glial cell line derived neurotrophic factor (GDNF), an agent that has been shown to protect neurons but that is very difficult to deliver to specific regions of the brain. The engineered cells were then implanted in the spinal cords of rats afflicted with a form of ALS. The implanted cells, in fact, demonstrated an affinity for the areas of the spinal cord where motor neurons were dying. The cells after being injected to the area of damage where they just sit and release GDNF. At the early stages of disease, almost 100 percent protection of motor neurons was seen. (21)

In other study MSCs were isolated from bone marrow of 9 patients with definite ALS. Growth kinetics, immunophenotype, telomere length and karyotype were evaluated during in vitro expansion. No significant differences between donors or patients were observed. The patients received intraspinal injections of autologous MSCs at the thoracic level and monitored for 4 years. No significant acute or late side effects were evidenced. No modification of the spinal cord volume or other signs of abnormal cell proliferation were observed. The results seem to demonstrate that MSCs represent a good chance for stem cell cell-based therapy in ALS and that intraspinal injection of MSCs is safe also in the long term. A new phase 1 study is carried out to verify these data in a larger number of patients. (22)

Stem-cell-based technology offers amazing possibilities for the future. These include the ability to reproduce human tissues and potentially repair damaged organs (such as the brain, spinal cord, vertebral column the eye), where, at present, we mainly provide supportive care to prevent the situation from becoming worse. This potential almost silences the sternest critics of such technology, but the fact remains that the ethical challenges are daunting. It is encouraging that, in tackling these challenges, we stand to reflect a great deal about the ethics of our profession and our relationships with patients, industry, and each other. The experimental basis of stem-cell or OEC transplantation should be sound before these techniques are applied to humans with neurological disorders.

1. Stem cell therapy for cerebral palsy. Bartley J, Carroll JE. Department of Pediatrics of the Medical College of Georgia, Augusta, Georgia, USA

8. Department of Neurology, Mt. Sinai School of Medicine, New York, NY, Medscape journal. Stem Cell Transplantation for Parkinsons Disease

9. Journal of Medicinal Chemistry. Future Therapies For Stroke May Block Cell Death 16 Jun 2007

10. Neurosurg Focus. 2005;19(6) 2005 American Association of Neurological Surgeons

11. Brain Advance Access originally published online on December 20, 2007 Brain 2008 Anti-inflammatory mechanism of intravascular neural stem cell transplantation in haemorrhagic stroke.

13. University of Florida(2006, June 8). Bone Marrow May Restore Cells Lost In Vision Diseases. ScienceDaily.

18. Autologous mesenchymal stem cell transplantation in stroke patients Oh Young Bang, MD, PhD 1, Jin Soo Lee, MD Department of Neurology, School of Medicine, Ajou University, Suwon, South Korea Brain Disease Research Center, School of Medicine, Ajou University, Suwon, South Korea.

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Role of Stem Cells in Treatment of Neurological Disorder

Every week there are numerous scientific studies published. Heres a look at some of the more interesting ones.

T-Cell Immune Response to COVID-19 Vaccines and Natural Infections

Much of the discussions and news reports about immune responses to vaccines and COVID-19 revolve around antibody levels. Much less has been said about T-cells, which provide longer-term protection. Researchers atGladstone Institutesconducteda detailed T-cell survey before and after COVID-19 immunization, which they published ineLife. They concluded that the Pfizer-BioNTech and Moderna mRNA vaccines create long-term populations of T-cells that recognize multiple SARS-COV-2 virus variants. They also found key differences in the T-cell responses in people who had COVID-19 infections before vaccination compared to people who had never been infected.

Overall, our data support the idea that vaccines are eliciting a very robust T-cell response in healthy individuals, said Nadia Roan, senior author of the study and Gladstone Associate Investigator. But they also suggest there may be some ways to improve them further, by getting more of the vaccine-elicited T-cells to park themselves in the respiratory tract.

Antibodies produced by B-cells quickly recognize viruses, target them, and prevent infection by destroying the viruses. T-cells, however, identify and destroy cells that are already infected. Antibodies are better at stopping initial infection, but T-cells typically last longer after an initial infection or vaccine. At that point they are better at fighting off disease in its early stages, which prevents severe symptoms. But T-cells are very diverse and difficult to analyze. Some subsets respond differently to infected cells and behave differently, while others have different functions within the overall T-cell immune response.

One key finding was that in people who had not been previously infected, the T-cell responses become stronger in quantity and quality after the second dose of the vaccine. But in people who had previously had COVID-19, there was not much of a change between the first and second vaccine dose.

Blood Biomarkers Provide Warning Signs of Dementia

Investigators at theGerman Center for Neurodegenerative Diseases (DZNE)identifiedmolecules in the blood that potentially warn of impending dementia. The research study included several university hospitals across Germany. The biomarkers were based on measuring levels of microRNAs. They say that the technique isnt ready yet for practical use, but they hope to develop a simple blood test. MicroRNAs have regulatory properties, influencing protein production and metabolism. In tests in humans, mice and cell cultures, they found three microRNAs whose levels were linked to mental performance. The three microRNAs also influence neuro-inflammation and neuroplasticity, including the ability of neurons to establish connections with each other.

Stem Cell Population Essential for Bone Regeneration

Researchers at theUniversity of Tsukuba, Japan,identifieda subpopulation of mesenchymal stem cells that play a major role in bone healing. The stem cells are found in the bone marrow and express the marker CD73. When a bone fracture heals, it moves through a series of stages, including clotted blood forming at the fracture. This clot is replaced by fibrous tissue and cartilage, then by a hard bony callus. The bone is then remodeled, with regular bone replacing the hard callus. They found that the generation of the callus is critically dependent on recruiting MSCs from the surrounding tissue and bone marrow. They observed the CD73-positive MSCs migrating toward the fracture site and forming new cartilage and bone cells. When they grafted CD73-positive MSCs into the fracture, they noted enhanced healing processes.

Antiviral Molecule Prevents SARS-CoV-2 from Entering Cells

Scientists atWashington University School of Medicinein St. Louisdevelopeda compound that prevents the SARS-CoV-2 virus, which causes COVID-19, from entering cells. The compound is called MM3122 and has been studied in cell cultures and in mice. MM3122 targets a key human protein called transmembrane serine protease 2 (TMPRSS2), which coronaviruses use to enter and infect human cells. Once the virus attached onto a cell in the epithelia of the airway, the TMPRSS2 protein cuts the viral spike protein, which activates the spike protein to mediate fusion of the viral and cellular membranesstarting the infection process. In cell cultures, MM3122 protected cells from viral damage better than remdesivir,Gilead Sciences antiviral against COVID-19; and an acute safety assay in mice demonstrated that large doses of MM3122 given for seven days did not cause noticeable issues. The compound also was effective against SARS-CoV, the virus behind SARS, and MERS-CoV, the coronavirus that causes MERS. The researchers are now working with researchers at the NIH to test it in animal models of COVID-19. They are also working on an oral version of the injectable compound.

Specific Personality Traits Might Signal Pending Alzheimers

Researchers atFlorida State Universityfoundthat specific changes in the brain linked with Alzheimers disease are often visible earlier in people with personality traits associated with the disease. The research focused on two traits: neuroticism, or a predisposition for negative emotions, and conscientiousness, linked to a tendency to be careful, organized, goal-directed and responsible. They found that people with amyloid and tau deposits, proteins linked to Alzheimers disease in the brain, were identified in participants who scored higher in neuroticism levels and lower in conscientiousness. The study suggests that personality traits might help protect against Alzheimers and other brain diseases by delaying or preventing the neuropathology for people strong in conscientiousness and low in neuroticism.

Why We Overeat

Astudyfrom theUniversity of Washington School of Medicine/UW Medicinereported on the function of glutamatergic neurons in mice. These neurons communicate to the lateral habenula, a brain region associated with the pathophysiology of depression, and the ventral tegmental area, which is involved in motivation, reward and addiction. They found that when mice are eating, the neurons in the lateral habenula are more responsive than the neurons in the ventral tegmental area. They suggest that these neurons might play a bigger role in guiding feeding. In addition, they studied the influence of the leptin and ghrelin hormones, which are believed to regulate behavior via the mesolimbic dopamine system, part of the reward pathway. The research adds additional insight into satiety and why people or at least mice overeat.

We found these cells are not a monolithic group, and that different flavors of these cells do different things, said Garret Stuber, a joint UW professor of anesthesiology and pain medicine and pharmacology, the papers senior author.

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Research Roundup: T-Cell Immune Response to COVID-19 Vaccines and More - BioSpace

NEW YORK, Oct. 14, 2021 /PRNewswire/ --BrainStorm Cell Therapeutics Inc. (NASDAQ: BCLI), a leading developer of cellular therapies for neurodegenerative diseases, will present findings from a multicenter, open label clinical trial of NurOwn in progressive multiple sclerosis. The study, "Phase 2 Safety and Efficacy Study of Intrathecal MSC-NTF cells in Progressive Multiple Sclerosis," will be delivered in an oral presentation today at the fully digital37thCongress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS).

The Phase 2 clinical trial was designed to evaluate intrathecal administration of NurOwn (autologous MSC-NTF cells) in participants with progressive MS. The study achieved the primary endpoint of safety and tolerability. It demonstrated a reduction of neuroinflammatory biomarkers and an increase in neuroprotective biomarkers in the cerebrospinal fluid (CSF) and consistent improvement across MS functional outcome measures, including measures of walking, upper extremity function, vision and cognition.

"We were pleased that this study demonstrated safety, preliminary evidence of efficacy and relevant biomarker outcomes in patients with progressive multiple sclerosis, in an area of high unmet need," said Jeffrey Cohen, M.D., Director of Experimental Therapeutics at the Cleveland Clinic Mellen Center for MS and principal investigator for the trial. "These results should be confirmed in a randomized placebo-controlled trial."

The study was sponsored by Brainstorm Cell Therapeutics with additional financial support for biomarker analyses from the National Multiple Sclerosis Society Fast-Forward Program. It was conducted at four U.S. MS centers of excellence:

"We very much appreciate the tremendous collaboration among many premier organizations, for their generous sharing of expertise, support and data, which enabled the important balance between scientific rigor and ethical treatment of progressive MS participants in the trial," said Ralph Kern, M.D., MHSc., President and Chief Medical Officer, Brainstorm Cell Therapeutics. "We are holding discussions with key MS experts, and seeking guidance from the FDA to determine next steps for the development of NurOwn in progressive MS."

"The National MS Society is pleased to support the biomarker portion of this study through our commercial funding program Fast Forward," said Mark Allegretta, Ph.D., Vice President, Research. "We're encouraged to see evidence that the biomarker analysis showed proof of concept for detecting neuroprotection and reduced inflammation."

About the trial

The Phase 2 open-label studyevaluated the safety and efficacy of intrathecal administration of autologous MSC-NTF cells in patients with primary or secondary progressive MS. The primary study endpoint was safety and tolerability. Secondary efficacy endpoints included: timed 25-foot walk (T25FW); 9-Hole Peg Test (9-HPT); Low Contrast Letter Acuity (LCLA); Symbol Digit Modalities Test (SDMT); 12 item MS Walking Scale (MSWS-12); as well as cerebrospinal fluid (CSF) and blood biomarkers. Clinical efficacy outcomes were compared with matched (n=48) participants in the Comprehensive Longitudinal Investigation of Multiple Sclerosis (CLIMB) registry, Tanuja Chitnis, MD Brigham and Women's Hospital and the Ann Romney Center for Neurologic Diseases, and 255 patient randomized double blind placebo controlled NN-102 SPRINT-MS Study, courtesy NIH/NINDS, PI: Robert J. Fox, MD, MS, FAAN, Cleveland Clinic, CTR: NCT01982942. Baseline characteristics from these two cohorts were similar allowing for comparison of efficacy results, comparisons with SPRINT-MS were with the placebo arm of this study.

Mean age of participants was 47 years, 56% were female, and mean baseline EDSS score was 5.4. 18 participants were treated, 16 (80%) received all 3 treatments and completed the entire study; 2 study discontinuations were due to procedure-related adverse events. No deaths or treatment-related adverse events due to worsening of MS were observed.

In responder analyses, 14% and 13% of MSC-NTF treated participants showed at least a 25% improvement in T25FW and 9-HPT (combined hands) respectively, compared to 5% and 0% in matched CLIMB patients and 9% and 3% in SPRINT. Twenty-seven percent (27%) showed at least an 8-letter improvement in LCLA (binocular, 2.5% threshold) and 67% showed at least a 3-point improvement in SDMT, compared to 6% and 18% in CLIMB and 13% and 35% in SPRINT, respectively.

Mean improvements of +0.10 ft/sec in T25FW and -0.23 sec in 9-HPT (combined hands), were observed in MSC-NTF treated participants, compared to a mean worsening of -0.07 ft/sec and +0.49 sec in CLIMB and -0.06 ft/sec and +0.28 sec in SPRINT, respectively. MSC-NTF treated participants showed a mean improvement of +3.3 letters in LCLA (binocular, 2.5% threshold) and 3.8 points in SDMT, compared to a mean worsening of -1.07 letters in LCLA (binocular, 2.5% threshold) and mean improvement of +0.10 in SDMT, in CLIMB and -0.6 and -0.1 in SPRINT. In addition the MSFC-4 Composite Z-score of T25W, 9-HPT, SDMT and LCLA showed a 0.18 point improvement in MSC-NTF treated participants, while CLIMB and SPRINT showed decreases of -0.02 and -0.05.

Furthermore, 38% of treated patients showed at least a 10-point improvement in the MSWS-12 a patient reported outcome that evaluates the impact of MS on walking function, whereas this outcome was not evaluated in CLIMB or SPRINT.

CSF biomarkers obtained at 3 consecutive time points, showed increases in neuroprotective molecules (VEGF, HGF, NCAM-1,Follistatin, Fetuin-A) and decreases in neuroinflammatory biomarkers (MCP-1, SDF-1, sCD27 and Osteopontin).

About NurOwn

The NurOwntechnology platform (autologous MSC-NTF cells) represents a promising investigational therapeutic approach to targeting disease pathways important in neurodegenerative disorders. MSC-NTF cells are produced from autologous, bone marrow-derived mesenchymal stem cells (MSCs) that have been expanded and differentiated ex vivo. MSCs are converted into MSC-NTF cells by growing them under patented conditions that induce the cells to secrete high levels of neurotrophic factors (NTFs). Autologous MSC-NTF cells are designed to effectively deliver multiple NTFs and immunomodulatory cytokines directly to the site of damage to elicit a desired biological effect and ultimately slow or stabilize disease progression.

About BrainStorm Cell Therapeutics Inc.

BrainStorm Cell Therapeutics Inc. is a leading developer of innovative autologous adult stem cell therapeutics for debilitating neurodegenerative diseases. The Company holds the rights to clinical development and commercialization of the NurOwntechnology platform used to produce autologous MSC-NTF cells through an exclusive, worldwide licensing agreement. Autologous MSC-NTF cells have received Orphan Drug designation status from the U.S. Food and Drug Administration (FDA) and the European Medicines Agency (EMA) for the treatment of amyotrophic lateral sclerosis (ALS). BrainStorm has completed a Phase 3 pivotal trial in ALS (NCT03280056); this trial investigated the safety and efficacy of repeat-administration of autologous MSC-NTF cells and was supported by a grant from the California Institute for Regenerative Medicine (CIRM CLIN2-0989). BrainStorm completed under an investigational new drug application a Phase 2 open-label multicenter trial (NCT03799718) of autologous MSC-NTF cells in progressive multiple sclerosis (MS) and was supported by a grant from the National MS Society (NMSS).

For more information, visit the company's website atwww.brainstorm-cell.com.

Safe-Harbor Statement

Statements in this announcement other than historical data and information, including statements regarding future NurOwnmanufacturing and clinical development plans, constitute "forward-looking statements" and involve risks and uncertainties that could cause BrainStorm Cell Therapeutics Inc.'s actual results to differ materially from those stated or implied by such forward-looking statements. Terms and phrases such as "may," "should," "would," "could," "will," "expect,""likely," "believe," "plan," "estimate," "predict," "potential," and similar terms and phrases are intended to identify these forward-looking statements. The potential risks and uncertainties include, without limitation, BrainStorm's need to raise additional capital, BrainStorm's ability to continue as a going concern, the prospects for regulatory approval of BrainStorm's NurOwntreatment candidate, the initiation, completion, and success of BrainStorm's product development programs and research, regulatory and personnel issues, development of a global market for our services, the ability to secure and maintain research institutions to conduct our clinical trials, the ability to generate significant revenue, the ability of BrainStorm's NurOwntreatment candidate to achieve broad acceptance as a treatment option for ALS or other neurodegenerative diseases, BrainStorm's ability to manufacture, or to use third parties to manufacture, and commercialize the NurOwntreatment candidate, obtaining patents that provide meaningful protection, competition and market developments, BrainStorm's ability to protect our intellectual property from infringement by third parties, heath reform legislation, demand for our services, currency exchange rates and product liability claims and litigation; and other factors detailed in BrainStorm's annual report on Form 10-K and quarterly reports on Form 10-Q available athttp://www.sec.gov. These factors should be considered carefully, and readers should not place undue reliance on BrainStorm's forward-looking statements. The forward-looking statements contained in this press release are based on the beliefs, expectations and opinions of management as of the date of this press release. We do not assume any obligation to update forward-looking statements to reflect actual results or assumptions if circumstances or management's beliefs, expectations or opinions should change, unless otherwise required by law. Although we believe that the expectations reflected in the forward-looking statements are reasonable, we cannot guarantee future results, levels of activity, performance or achievements.

Contacts:

Investor Relations:Eric GoldsteinLifeSci Advisors, LLCPhone: +1 (646) 791-9729egoldstein@lifesciadvisors.com

Media:Mariesa Kemble kemblem@mac.com

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Phase 2 Clinical Trial Data of NurOwn in Progressive MS Will Be Presented at the 37th Congress of the European Committee for Treatment and Research in...

KENILWORTH, N.J. & TOKYO--(BUSINESS WIRE)--Merck (NYSE: MRK), known as MSD outside the United States and Canada, and Eisai today announced that the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency has adopted positive opinions recommending approval of the combination of KEYTRUDA, Mercks anti-PD-1 therapy, plus LENVIMA (marketed as KISPLYX in the European Union [EU] for the treatment of advanced renal cell carcinoma [RCC]), the orally available multiple receptor tyrosine kinase inhibitor discovered by Eisai, for two different indications. One positive opinion is for the first-line treatment of adult patients with advanced RCC, and the other is for the treatment of adult patients with advanced or recurrent endometrial carcinoma (EC) who have disease progression on or following prior treatment with a platinum-containing therapy in any setting and are not candidates for curative surgery or radiation. Decisions on the CHMPs recommendations will be given by the European Commission for marketing authorization in the EU, and are expected in the fourth quarter of 2021. If approved, this would be the first combination of an anti-PD-1 therapy with a tyrosine kinase inhibitor approved for the treatment of two different types of cancer in the EU.

The positive CHMP opinions are based on data from two pivotal Phase 3 trials: CLEAR (Study 307)/KEYNOTE-581 evaluating the combination in adult patients with advanced RCC and KEYNOTE-775/Study 309 evaluating the combination in certain patients with advanced EC.

In CLEAR/KEYNOTE-581, KEYTRUDA plus LENVIMA demonstrated statistically significant improvements versus sunitinib in the efficacy outcome measures of overall survival (OS), reducing the risk of death by 34% (HR=0.66 [95% CI, 0.49-0.88]; p=0.0049) versus sunitinib, and progression-free survival (PFS), reducing the risk of disease progression or death by 61% (HR=0.39 [95% CI, 0.32-0.49]; p<0.0001) with a median PFS of 23.9 months versus 9.2 months for sunitinib. Additionally, the confirmed objective response rate was 71% (95% CI: 66-76) (n=252) for patients who received KEYTRUDA plus LENVIMA versus 36% with sunitinib (95% CI: 31-41) (n=129).

In KEYNOTE-775/Study 309, KEYTRUDA plus LENVIMA demonstrated statistically significant improvements in the studys dual efficacy outcome measures of OS, reducing the risk of death by 38% (HR=0.62 [95% CI, 0.51-0.75]; p<0.0001) with a median OS of 18.3 months versus 11.4 months for chemotherapy (investigators choice of doxorubicin or paclitaxel), and PFS, reducing the risk of disease progression or death by 44% (HR=0.56 [95% CI, 0.47-0.66]; p<0.0001), with a median PFS of 7.2 months versus 3.8 months for chemotherapy (investigators choice of doxorubicin or paclitaxel).

KEYTRUDA plus LENVIMA demonstrated a survival benefit for advanced renal cell carcinoma in the first-line setting and represents an important potential new treatment option for these patients. Additionally, KEYTRUDA plus LENVIMA is the first anti-PD-1 and tyrosine kinase inhibitor combination to demonstrate a survival benefit in advanced endometrial carcinoma patients, and the benefit was shown regardless of mismatch repair status, said Dr. Gregory Lubiniecki, Vice President, Clinical Research, Merck Research Laboratories. We are pleased that the CHMP has recognized the important role of the combination therapy in these difficult-to-treat cancers.

We appreciate the positive opinions rendered by the EU CHMP recommending approval of KEYTRUDA plus LENVIMA in advanced renal cell carcinoma and advanced endometrial carcinoma, underscoring the potential significance of the outcomes observed in the CLEAR/KEYNOTE-581 and KEYNOTE-775/Study 309 trials, said Dr. Takashi Owa, President, Oncology Business Group at Eisai. We are grateful to the patients who participated in these studies, their families and clinicians. Their commitment made these meaningful milestones possible.

The safety of KEYTRUDA in combination with axitinib or LENVIMA in advanced RCC, and in combination with LENVIMA in advanced EC has been evaluated in a total of 1,456 patients with advanced RCC or advanced EC. In these patient populations, the most frequent adverse reactions were diarrhea (58%), hypertension (54%), hypothyroidism (46%), fatigue (41%), decreased appetite and nausea (40% each), arthralgia (30%), vomiting, weight decreased, dysphonia and abdominal pain (28% each), proteinuria (27%), palmar plantar erythrodysesthesia syndrome and rash (26% each), stomatitis and constipation (25% each), musculoskeletal pain and headache (23% each) and cough (21%).

About Renal Cell Carcinoma (RCC)

Worldwide, it is estimated there were more than 431,000 new cases of kidney cancer diagnosed and more than 179,000 deaths from the disease in 2020. In Europe, it is estimated there were more than 138,000 new cases of kidney cancer diagnosed and more than 54,000 deaths from the disease in 2020. Renal cell carcinoma is by far the most common type of kidney cancer; about nine out of 10 kidney cancer diagnoses are RCC. Renal cell carcinoma is about twice as common in men as in women. Most cases of RCC are discovered incidentally during imaging tests for other abdominal diseases. Approximately 30% of patients with RCC will have metastatic disease at diagnosis. Survival is highly dependent on the stage at diagnosis, and the five-year survival rate is 13% for patients diagnosed with metastatic disease.

About Endometrial Cancer

Endometrial cancer begins in the inner lining of the uterus, which is known as the endometrium and is the most common type of cancer in the uterus. Worldwide, it was estimated there were more than 417,000 new cases and more than 97,000 deaths from uterine body cancers in 2020 (these estimates include both endometrial cancers and uterine sarcomas; more than 90% of uterine body cancers occur in the endometrium, so the actual numbers for endometrial cancer cases and deaths are slightly lower than these estimates). In Europe, it is estimated there were more than 130,000 new cases and more than 29,000 deaths in 2020. The five-year relative survival rate for metastatic endometrial cancer (stage IV) is estimated to be approximately 17%.

About KEYTRUDA (pembrolizumab) Injection, 100 mg

KEYTRUDA is an anti-programmed death receptor-1 (PD-1) therapy that works by increasing the ability of the bodys immune system to help detect and fight tumor cells. KEYTRUDA is a humanized monoclonal antibody that blocks the interaction between PD-1 and its ligands, PD-L1 and PD-L2, thereby activating T lymphocytes which may affect both tumor cells and healthy cells.

Merck has the industrys largest immuno-oncology clinical research program. There are currently more than 1,600 trials studying KEYTRUDA across a wide variety of cancers and treatment settings. The KEYTRUDA clinical program seeks to understand the role of KEYTRUDA across cancers and the factors that may predict a patient's likelihood of benefitting from treatment with KEYTRUDA, including exploring several different biomarkers.

Selected KEYTRUDA (pembrolizumab) Indications in the U.S.

Melanoma

KEYTRUDA is indicated for the treatment of patients with unresectable or metastatic melanoma.

KEYTRUDA is indicated for the adjuvant treatment of patients with melanoma with involvement of lymph node(s) following complete resection.

Non-Small Cell Lung Cancer

KEYTRUDA, in combination with pemetrexed and platinum chemotherapy, is indicated for the first-line treatment of patients with metastatic nonsquamous non-small cell lung cancer (NSCLC), with no EGFR or ALK genomic tumor aberrations.

KEYTRUDA, in combination with carboplatin and either paclitaxel or paclitaxel protein-bound, is indicated for the first-line treatment of patients with metastatic squamous NSCLC.

KEYTRUDA, as a single agent, is indicated for the first-line treatment of patients with NSCLC expressing PD-L1 [tumor proportion score (TPS) 1%] as determined by an FDA-approved test, with no EGFR or ALK genomic tumor aberrations, and is:

KEYTRUDA, as a single agent, is indicated for the treatment of patients with metastatic NSCLC whose tumors express PD-L1 (TPS 1%) as determined by an FDA-approved test, with disease progression on or after platinum-containing chemotherapy. Patients with EGFR or ALK genomic tumor aberrations should have disease progression on FDA-approved therapy for these aberrations prior to receiving KEYTRUDA.

Head and Neck Squamous Cell Cancer

KEYTRUDA, in combination with platinum and fluorouracil (FU), is indicated for the first-line treatment of patients with metastatic or with unresectable, recurrent head and neck squamous cell carcinoma (HNSCC).

KEYTRUDA, as a single agent, is indicated for the first-line treatment of patients with metastatic or with unresectable, recurrent HNSCC whose tumors express PD-L1 [combined positive score (CPS 1)] as determined by an FDA-approved test.

KEYTRUDA, as a single agent, is indicated for the treatment of patients with recurrent or metastatic HNSCC with disease progression on or after platinum-containing chemotherapy.

Classical Hodgkin Lymphoma

KEYTRUDA is indicated for the treatment of adult patients with relapsed or refractory classical Hodgkin lymphoma (cHL).

KEYTRUDA is indicated for the treatment of pediatric patients with refractory cHL, or cHL that has relapsed after 2 or more lines of therapy.

Primary Mediastinal Large B-Cell Lymphoma

KEYTRUDA is indicated for the treatment of adult and pediatric patients with refractory primary mediastinal large B-cell lymphoma (PMBCL), or who have relapsed after 2 or more prior lines of therapy. KEYTRUDA is not recommended for treatment of patients with PMBCL who require urgent cytoreductive therapy.

Urothelial Carcinoma

KEYTRUDA is indicated for the treatment of patients with locally advanced or metastatic urothelial carcinoma (mUC):

Non-muscle Invasive Bladder Cancer

KEYTRUDA is indicated for the treatment of patients with Bacillus Calmette-Guerin (BCG)-unresponsive, high-risk, non-muscle invasive bladder cancer (NMIBC) with carcinoma in situ (CIS) with or without papillary tumors who are ineligible for or have elected not to undergo cystectomy.

Microsatellite Instability-High or Mismatch Repair Deficient Cancer

KEYTRUDA is indicated for the treatment of adult and pediatric patients with unresectable or metastatic microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) solid tumors that have progressed following prior treatment and who have no satisfactory alternative treatment options.

This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials. The safety and effectiveness of KEYTRUDA in pediatric patients with MSI-H central nervous system cancers have not been established.

Microsatellite Instability-High or Mismatch Repair Deficient Colorectal Cancer

KEYTRUDA is indicated for the treatment of patients with unresectable or metastatic MSI-H or dMMR colorectal cancer (CRC).

Gastric Cancer

KEYTRUDA, in combination with trastuzumab, fluoropyrimidine- and platinum-containing chemotherapy, is indicated for the first-line treatment of patients with locally advanced unresectable or metastatic HER2-positive gastric or gastroesophageal junction (GEJ) adenocarcinoma.

This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials.

KEYTRUDA, as a single agent, is indicated for the treatment of patients with recurrent locally advanced or metastatic gastric or gastroesophageal junction (GEJ) adenocarcinoma whose tumors express PD-L1 (CPS 1) as determined by an FDA-approved test, with disease progression on or after 2 or more prior lines of therapy including fluoropyrimidine- and platinum-containing chemotherapy and if appropriate, HER2/neu-targeted therapy.

This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials.

Esophageal Cancer

KEYTRUDA is indicated for the treatment of patients with locally advanced or metastatic esophageal or GEJ (tumors with epicenter 1 to 5 centimeters above the GEJ) carcinoma that is not amenable to surgical resection or definitive chemoradiation either:

Cervical Cancer

KEYTRUDA, in combination with chemotherapy, with or without bevacizumab, is indicated for the treatment of patients with persistent, recurrent, or metastatic cervical cancer whose tumors express PD-L1 (CPS 1) as determined by an FDA-approved test.

KEYTRUDA, as a single agent, is indicated for the treatment of patients with recurrent or metastatic cervical cancer with disease progression on or after chemotherapy whose tumors express PD-L1 (CPS 1) as determined by an FDA-approved test.

Hepatocellular Carcinoma

KEYTRUDA is indicated for the treatment of patients with hepatocellular carcinoma (HCC) who have been previously treated with sorafenib. This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials.

Merkel Cell Carcinoma

KEYTRUDA is indicated for the treatment of adult and pediatric patients with recurrent locally advanced or metastatic Merkel cell carcinoma (MCC). This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials.

Renal Cell Carcinoma

KEYTRUDA, in combination with axitinib, is indicated for the first-line treatment of adult patients with advanced renal cell carcinoma (RCC).

KEYTRUDA, in combination with LENVIMA, is indicated for the first-line treatment of adult patients with advanced RCC.

Endometrial Carcinoma

KEYTRUDA, in combination with LENVIMA, is indicated for the treatment of patients with advanced endometrial carcinoma that is not MSI-H or dMMR, who have disease progression following prior systemic therapy in any settings and are not candidates for curative surgery or radiation.

Tumor Mutational Burden-High Cancer

KEYTRUDA is indicated for the treatment of adult and pediatric patients with unresectable or metastatic tumor mutational burden-high (TMB-H) [10 mutations/megabase] solid tumors, as determined by an FDA-approved test, that have progressed following prior treatment and who have no satisfactory alternative treatment options. This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials. The safety and effectiveness of KEYTRUDA in pediatric patients with TMB-H central nervous system cancers have not been established.

Cutaneous Squamous Cell Carcinoma

KEYTRUDA is indicated for the treatment of patients with recurrent or metastatic cutaneous squamous cell carcinoma (cSCC) or locally advanced cSCC that is not curable by surgery or radiation.

Triple-Negative Breast Cancer

KEYTRUDA is indicated for the treatment of patients with high-risk early-stage triple-negative breast cancer (TNBC) in combination with chemotherapy as neoadjuvant treatment, and then continued as a single agent as adjuvant treatment after surgery.

KEYTRUDA, in combination with chemotherapy, is indicated for the treatment of patients with locally recurrent unresectable or metastatic TNBC whose tumors express PD-L1 (CPS 10) as determined by an FDA-approved test.

Selected Important Safety Information for KEYTRUDA

Severe and Fatal Immune-Mediated Adverse Reactions

KEYTRUDA is a monoclonal antibody that belongs to a class of drugs that bind to either the PD-1 or the PD-L1, blocking the PD-1/PD-L1 pathway, thereby removing inhibition of the immune response, potentially breaking peripheral tolerance and inducing immune-mediated adverse reactions. Immune-mediated adverse reactions, which may be severe or fatal, can occur in any organ system or tissue, can affect more than one body system simultaneously, and can occur at any time after starting treatment or after discontinuation of treatment. Important immune-mediated adverse reactions listed here may not include all possible severe and fatal immune-mediated adverse reactions.

Monitor patients closely for symptoms and signs that may be clinical manifestations of underlying immune-mediated adverse reactions. Early identification and management are essential to ensure safe use of antiPD-1/PD-L1 treatments. Evaluate liver enzymes, creatinine, and thyroid function at baseline and periodically during treatment. For patients with TNBC treated with KEYTRUDA in the neoadjuvant setting, monitor blood cortisol at baseline, prior to surgery, and as clinically indicated. In cases of suspected immune-mediated adverse reactions, initiate appropriate workup to exclude alternative etiologies, including infection. Institute medical management promptly, including specialty consultation as appropriate.

Withhold or permanently discontinue KEYTRUDA depending on severity of the immune-mediated adverse reaction. In general, if KEYTRUDA requires interruption or discontinuation, administer systemic corticosteroid therapy (1 to 2 mg/kg/day prednisone or equivalent) until improvement to Grade 1 or less. Upon improvement to Grade 1 or less, initiate corticosteroid taper and continue to taper over at least 1 month. Consider administration of other systemic immunosuppressants in patients whose adverse reactions are not controlled with corticosteroid therapy.

Immune-Mediated Pneumonitis

KEYTRUDA can cause immune-mediated pneumonitis. The incidence is higher in patients who have received prior thoracic radiation. Immune-mediated pneumonitis occurred in 3.4% (94/2799) of patients receiving KEYTRUDA, including fatal (0.1%), Grade 4 (0.3%), Grade 3 (0.9%), and Grade 2 (1.3%) reactions. Systemic corticosteroids were required in 67% (63/94) of patients. Pneumonitis led to permanent discontinuation of KEYTRUDA in 1.3% (36) and withholding in 0.9% (26) of patients. All patients who were withheld reinitiated KEYTRUDA after symptom improvement; of these, 23% had recurrence. Pneumonitis resolved in 59% of the 94 patients.

Pneumonitis occurred in 8% (31/389) of adult patients with cHL receiving KEYTRUDA as a single agent, including Grades 3-4 in 2.3% of patients. Patients received high-dose corticosteroids for a median duration of 10 days (range: 2 days to 53 months). Pneumonitis rates were similar in patients with and without prior thoracic radiation. Pneumonitis led to discontinuation of KEYTRUDA in 5.4% (21) of patients. Of the patients who developed pneumonitis, 42% interrupted KEYTRUDA, 68% discontinued KEYTRUDA, and 77% had resolution.

Immune-Mediated Colitis

KEYTRUDA can cause immune-mediated colitis, which may present with diarrhea. Cytomegalovirus infection/reactivation has been reported in patients with corticosteroid-refractory immune-mediated colitis. In cases of corticosteroid-refractory colitis, consider repeating infectious workup to exclude alternative etiologies. Immune-mediated colitis occurred in 1.7% (48/2799) of patients receiving KEYTRUDA, including Grade 4 (<0.1%), Grade 3 (1.1%), and Grade 2 (0.4%) reactions. Systemic corticosteroids were required in 69% (33/48); additional immunosuppressant therapy was required in 4.2% of patients. Colitis led to permanent discontinuation of KEYTRUDA in 0.5% (15) and withholding in 0.5% (13) of patients. All patients who were withheld reinitiated KEYTRUDA after symptom improvement; of these, 23% had recurrence. Colitis resolved in 85% of the 48 patients.

Hepatotoxicity and Immune-Mediated Hepatitis

KEYTRUDA can cause immune-mediated hepatitis. Immune-mediated hepatitis occurred in 0.7% (19/2799) of patients receiving KEYTRUDA, including Grade 4 (<0.1%), Grade 3 (0.4%), and Grade 2 (0.1%) reactions. Systemic corticosteroids were required in 68% (13/19) of patients; additional immunosuppressant therapy was required in 11% of patients. Hepatitis led to permanent discontinuation of KEYTRUDA in 0.2% (6) and withholding in 0.3% (9) of patients. All patients who were withheld reinitiated KEYTRUDA after symptom improvement; of these, none had recurrence. Hepatitis resolved in 79% of the 19 patients.

KEYTRUDA with Axitinib

KEYTRUDA in combination with axitinib can cause hepatic toxicity. Monitor liver enzymes before initiation of and periodically throughout treatment. Consider monitoring more frequently as compared to when the drugs are administered as single agents. For elevated liver enzymes, interrupt KEYTRUDA and axitinib, and consider administering corticosteroids as needed. With the combination of KEYTRUDA and axitinib, Grades 3 and 4 increased alanine aminotransferase (20%) and increased aspartate aminotransferase (13%) were seen at a higher frequency compared to KEYTRUDA alone. Fifty-nine percent of the patients with increased ALT received systemic corticosteroids. In patients with ALT 3 times upper limit of normal (ULN) (Grades 2-4, n=116), ALT resolved to Grades 0-1 in 94%. Among the 92 patients who were rechallenged with either KEYTRUDA (n=3) or axitinib (n=34) administered as a single agent or with both (n=55), recurrence of ALT 3 times ULN was observed in 1 patient receiving KEYTRUDA, 16 patients receiving axitinib, and 24 patients receiving both. All patients with a recurrence of ALT 3 ULN subsequently recovered from the event.

Immune-Mediated Endocrinopathies

Adrenal Insufficiency

KEYTRUDA can cause primary or secondary adrenal insufficiency. For Grade 2 or higher, initiate symptomatic treatment, including hormone replacement as clinically indicated. Withhold KEYTRUDA depending on severity. Adrenal insufficiency occurred in 0.8% (22/2799) of patients receiving KEYTRUDA, including Grade 4 (<0.1%), Grade 3 (0.3%), and Grade 2 (0.3%) reactions. Systemic corticosteroids were required in 77% (17/22) of patients; of these, the majority remained on systemic corticosteroids. Adrenal insufficiency led to permanent discontinuation of KEYTRUDA in <0.1% (1) and withholding in 0.3% (8) of patients. All patients who were withheld reinitiated KEYTRUDA after symptom improvement.

Hypophysitis

KEYTRUDA can cause immune-mediated hypophysitis. Hypophysitis can present with acute symptoms associated with mass effect such as headache, photophobia, or visual field defects. Hypophysitis can cause hypopituitarism. Initiate hormone replacement as indicated. Withhold or permanently discontinue KEYTRUDA depending on severity. Hypophysitis occurred in 0.6% (17/2799) of patients receiving KEYTRUDA, including Grade 4 (<0.1%), Grade 3 (0.3%), and Grade 2 (0.2%) reactions. Systemic corticosteroids were required in 94% (16/17) of patients; of these, the majority remained on systemic corticosteroids. Hypophysitis led to permanent discontinuation of KEYTRUDA in 0.1% (4) and withholding in 0.3% (7) of patients. All patients who were withheld reinitiated KEYTRUDA after symptom improvement.

Thyroid Disorders

KEYTRUDA can cause immune-mediated thyroid disorders. Thyroiditis can present with or without endocrinopathy. Hypothyroidism can follow hyperthyroidism. Initiate hormone replacement for hypothyroidism or institute medical management of hyperthyroidism as clinically indicated. Withhold or permanently discontinue KEYTRUDA depending on severity. Thyroiditis occurred in 0.6% (16/2799) of patients receiving KEYTRUDA, including Grade 2 (0.3%). None discontinued, but KEYTRUDA was withheld in <0.1% (1) of patients.

Hyperthyroidism occurred in 3.4% (96/2799) of patients receiving KEYTRUDA, including Grade 3 (0.1%) and Grade 2 (0.8%). It led to permanent discontinuation of KEYTRUDA in <0.1% (2) and withholding in 0.3% (7) of patients. All patients who were withheld reinitiated KEYTRUDA after symptom improvement. Hypothyroidism occurred in 8% (237/2799) of patients receiving KEYTRUDA, including Grade 3 (0.1%) and Grade 2 (6.2%). It led to permanent discontinuation of KEYTRUDA in <0.1% (1) and withholding in 0.5% (14) of patients. All patients who were withheld reinitiated KEYTRUDA after symptom improvement. The majority of patients with hypothyroidism required long-term thyroid hormone replacement. The incidence of new or worsening hypothyroidism was higher in 1185 patients with HNSCC, occurring in 16% of patients receiving KEYTRUDA as a single agent or in combination with platinum and FU, including Grade 3 (0.3%) hypothyroidism. The incidence of new or worsening hypothyroidism was higher in 389 adult patients with cHL (17%) receiving KEYTRUDA as a single agent, including Grade 1 (6.2%) and Grade 2 (10.8%) hypothyroidism.

Type 1 Diabetes Mellitus (DM), Which Can Present With Diabetic Ketoacidosis

Monitor patients for hyperglycemia or other signs and symptoms of diabetes. Initiate treatment with insulin as clinically indicated. Withhold KEYTRUDA depending on severity. Type 1 DM occurred in 0.2% (6/2799) of patients receiving KEYTRUDA. It led to permanent discontinuation in <0.1% (1) and withholding of KEYTRUDA in <0.1% (1) of patients. All patients who were withheld reinitiated KEYTRUDA after symptom improvement.

Immune-Mediated Nephritis With Renal Dysfunction

KEYTRUDA can cause immune-mediated nephritis. Immune-mediated nephritis occurred in 0.3% (9/2799) of patients receiving KEYTRUDA, including Grade 4 (<0.1%), Grade 3 (0.1%), and Grade 2 (0.1%) reactions. Systemic corticosteroids were required in 89% (8/9) of patients. Nephritis led to permanent discontinuation of KEYTRUDA in 0.1% (3) and withholding in 0.1% (3) of patients. All patients who were withheld reinitiated KEYTRUDA after symptom improvement; of these, none had recurrence. Nephritis resolved in 56% of the 9 patients.

Immune-Mediated Dermatologic Adverse Reactions

KEYTRUDA can cause immune-mediated rash or dermatitis. Exfoliative dermatitis, including Stevens-Johnson syndrome, drug rash with eosinophilia and systemic symptoms, and toxic epidermal necrolysis, has occurred with antiPD-1/PD-L1 treatments. Topical emollients and/or topical corticosteroids may be adequate to treat mild to moderate nonexfoliative rashes. Withhold or permanently discontinue KEYTRUDA depending on severity. Immune-mediated dermatologic adverse reactions occurred in 1.4% (38/2799) of patients receiving KEYTRUDA, including Grade 3 (1%) and Grade 2 (0.1%) reactions. Systemic corticosteroids were required in 40% (15/38) of patients. These reactions led to permanent discontinuation in 0.1% (2) and withholding of KEYTRUDA in 0.6% (16) of patients. All patients who were withheld reinitiated KEYTRUDA after symptom improvement; of these, 6% had recurrence. The reactions resolved in 79% of the 38 patients.

Other Immune-Mediated Adverse Reactions

The following clinically significant immune-mediated adverse reactions occurred at an incidence of <1% (unless otherwise noted) in patients who received KEYTRUDA or were reported with the use of other antiPD-1/PD-L1 treatments. Severe or fatal cases have been reported for some of these adverse reactions. Cardiac/Vascular: Myocarditis, pericarditis, vasculitis; Nervous System: Meningitis, encephalitis, myelitis and demyelination, myasthenic syndrome/myasthenia gravis (including exacerbation), Guillain-Barr syndrome, nerve paresis, autoimmune neuropathy; Ocular: Uveitis, iritis and other ocular inflammatory toxicities can occur. Some cases can be associated with retinal detachment. Various grades of visual impairment, including blindness, can occur. If uveitis occurs in combination with other immune-mediated adverse reactions, consider a Vogt-Koyanagi-Harada-like syndrome, as this may require treatment with systemic steroids to reduce the risk of permanent vision loss; Gastrointestinal: Pancreatitis, to include increases in serum amylase and lipase levels, gastritis, duodenitis; Musculoskeletal and Connective Tissue: Myositis/polymyositis, rhabdomyolysis (and associated sequelae, including renal failure), arthritis (1.5%), polymyalgia rheumatica; Endocrine: Hypoparathyroidism; Hematologic/Immune: Hemolytic anemia, aplastic anemia, hemophagocytic lymphohistiocytosis, systemic inflammatory response syndrome, histiocytic necrotizing lymphadenitis (Kikuchi lymphadenitis), sarcoidosis, immune thrombocytopenic purpura, solid organ transplant rejection.

Infusion-Related Reactions

KEYTRUDA can cause severe or life-threatening infusion-related reactions, including hypersensitivity and anaphylaxis, which have been reported in 0.2% of 2799 patients receiving KEYTRUDA. Monitor for signs and symptoms of infusion-related reactions. Interrupt or slow the rate of infusion for Grade 1 or Grade 2 reactions. For Grade 3 or Grade 4 reactions, stop infusion and permanently discontinue KEYTRUDA.

Complications of Allogeneic Hematopoietic Stem Cell Transplantation (HSCT)

See the rest here:
Merck and Eisai Receive Positive EU CHMP Opinions for KEYTRUDA (pembrolizumab) Plus LENVIMA (lenvatinib) in Two Different Types of Cancer - Business...

Every person, every mouse, every dog, has one unmistakable sign of aging: hair loss. But why does that happen?

Rui Yi, a professor of pathology at Northwestern University, set out to answer the question.

A generally accepted hypothesis about stem cells says they replenish tissues and organs, including hair, but they will eventually be exhausted and then die in place. This process is seen as an integral part of aging.

Instead Dr. Yi and his colleagues made a surprising discovery that, at least in the hair of aging animals, stem cells escape from the structures that house them.

Its a new way of thinking about aging, said Dr. Cheng-Ming Chuong, a skin cell researcher and professor of pathology at the University of Southern California, who was not involved in Dr. Yis study, which was published on Monday in the journal Nature Aging.

The study also identifies two genes involved in the aging of hair, opening up new possibilities for stopping the process by preventing stem cells from escaping.

Charles K.F. Chan, a stem cell researcher at Stanford University, called the paper very important, noting that in science, everything about aging seems so complicated we dont know where to start. By showing a pathway and a mechanism for explaining aging hair, Dr. Yi and colleagues may have provided a toehold.

Stem cells play a crucial role in the growth of hair in mice and in humans. Hair follicles, the tunnel-shaped miniature organs from which hairs grow, go through cyclical periods of growth in which a population of stem cells living in a specialized region called the bulge divide and become rapidly growing hair cells.

Sarah Millar, director of the Black Family Stem Cell Institute at the Icahn School of Medicine at Mount Sinai, who was not involved in Dr. Yis paper, explained that those cells give rise to the hair shaft and its sheath. Then, after a period of time, which is short for human body hair and much longer for hair on a persons head, the follicle becomes inactive and its lower part degenerates. The hair shaft stops growing and is shed, only to be replaced by a new strand of hair as the cycle repeats.

But while the rest of the follicle dies, a collection of stem cells remains in the bulge, ready to start turning into hair cells to grow a new strand of hair.

Dr. Yi, like most scientists, had assumed that with age the stem cells died in a process known as stem cell exhaustion. He expected that the death of a hair follicles stem cells meant that the hair would turn white and, when enough stem cells were lost, the strand of hair would die. But this hypothesis had not been fully tested.

Together with a graduate student, Chi Zhang, Dr. Yi decided that to understand the aging process in hair, he needed to watch individual strands of hair as they grew and aged.

Ordinarily, researchers who study aging take chunks of tissue from animals of different ages and examine the changes. There are two drawbacks to this approach, Dr. Yi said. First, the tissue is already dead. And it is not clear what led to the changes that are observed or what will come after them.

He decided his team would use a different method. They watched the growth of individual hair follicles in the ears of mice using a long wavelength laser that can penetrate deep into tissue. They labeled hair follicles with a green fluorescent protein, anesthetized the animals so they did not move, put their ear under the microscope and went back again and again to watch what was happening to the same hair follicle.

What they saw was a surprise: When the animals started to grow old and gray and lose their hair, their stem cells started to escape their little homes in the bulge. The cells changed their shapes from round to amoeba-like and squeezed out of tiny holes in the follicle. Then they recovered their normal shapes and darted away.

Sometimes, the escaping stem cells leapt long distances, in cellular terms, from the niche where they lived.

If I did not see it for myself I would not have believed it, Dr. Yi said. Its almost crazy in my mind.

The stem cells then vanished, perhaps consumed by the immune system.

Dr. Chan compared an animal's body to a car. If you run it long enough and dont replace parts, things wear out, he said. In the body, stem cells are like a mechanic, providing replacement parts, and in some organs like hair, blood and bone, the replacement is continual.

But with hair, it now looks as if the mechanic the stem cells simply walks off the job one day.

But why? Dr. Yi and his colleagues next step was to ask if genes are controlling the process. They discovered two FOXC1 and NFATC1 that were less active in older hair follicle cells. Their role was to imprison stem cells in the bulge. So the researchers bred mice that lacked those genes to see if they were the master controllers.

By the time the mice were 4 to 5 months old, they started losing hair. By age 16 months, when the animals were middle-aged, they looked ancient: They had lost a lot of hair and the sparse strands remaining were gray.

Now the researchers want to save the hair stem cells in aging mice.

This story of the discovery of a completely unexpected natural process makes Dr. Chuong wonder what remains to be learned about living creatures.

Nature has endless surprises waiting for us, he said. You can see fantastic things.

Excerpt from:
Losing Your Hair? You Might Blame the Great Stem Cell Escape. - The New York Times

A recent article in the journal Nature credits Stanford physician-neuroscientist Sergiu Pasca, MD, with blazing a trail toward a more profound understanding of early brain development, and of what can go wrong in the process, using a cell-based research innovation he named "assembloids."

In 2015, Pasca and his colleagues published a paper in Nature Methods describing a fascinating feat: His tinkering with induced pluripotent stem cells, or iPS cells -- former skin cells transformed so that they've acquired an almost magical capacity to generate all the tissues in the body -- had borne a three-dimensional product. From these "magic" iPS cells grew a complex conglomerate of cells capable of modeling specific organs.

Pasca's particular interest was in the brain, and in the experiments detailed in the study, his lab had caused human iPS cells to multiply and differentiate into small spherical clusters of brain tissue suspended in laboratory glassware.

These clusters recapitulated the architecture and physiology of the human cerebral cortex -- the outermost layer of brain tissue, critical to perception, cognition and action. Pasca named these clusters, which grew to several millimeters in diameter and contained millions of cells, "cortical spheroids." Today, researchers around the world are using similar methodology to create models, broadly known as "organoids," to study other parts of the human body.

Two years later, in a study published in Nature, Pasca upped the ante by, first, generating a second kind of neural spheroid -- this time, representative of a deeper part of the developing forebrain called the subpallium -- and, second, by growing this kind of spheroid in conjunction with cortical spheroids, in the same dish.

To the researchers' amazement, spheroids of both types fused together, with nerve cells from subpallial spheroids migrating and poking extensions into the cortical spheroids and establishing working connections with nerve cells of a different type in the latter spheroids, just as occurs in fetal development.

"It's amazing that these cells already self-organize and know what they need to do," Pasca marveled in "Brain Balls," an article I wrote for our magazine, Stanford Medicine, a few years ago.

Pasca sensibly dubbed the two-fused-spheroid combos "assembloids," the Nature recap notes.

But why stop at two? Pasca has since created three-element assembloids composed of spheroids representative of cerebral cortex, spinal cord and skeletal muscle in order to model the circuitry of voluntary movement. He's also shown that stimulating the "cerebral cortex" spheroid can result in contraction of the "muscle" spheroid. (This accomplishment was published in Cell in late 2020.) He has explored other assembloid combinations, as well, such as the fusing of cortical spheroids with spheroids representing the striatum, a brain structure implicated in regulating our movements and responses to rewarding and aversive stimuli.

Because each spheroid begins with skin cells, they can be grown on a personalized basis -- and can therefore be extracted from patients with neurological disorders known or suspected to spring from early developmental aberrations (such as autism or schizophrenia). The cells can then be used to create models to probe these disorders' molecular, cellular and circuit-based deviations from the pathways of normal brain development, allowing scientists to study the brain in way they could never do with a living patient.

From the Nature article:

Assembloids are now at the leading edge of stem-cell research. Scientists are using them to investigate early events in organ development as tools for studying not only psychiatric disorders, but other types of disease as well.

An assembloid is by no means a complete, working brain. But, the article notes, "Pasca stands by the aphorism that all models are wrong, and some are useful. 'There's been important progress in the field in a short period of time,' he says."

Photo courtesy of the Pasca laboratory

Originally posted here:
Stanford neuroscientist's 'assembloids' pave the way for innovative brain research - Scope

Introduction

The growing burden of ischemic heart disease (IHD) is a major public health issue. The most harmful type of IHD is acute myocardial infarction (MI), which leads to loss of tissue and impaired cardiac performance, accounting for two in five deaths in China.1 Timely revascularization after MI, including percutaneous coronary intervention, thrombolytic treatment and bypass surgery, is key to improving cardiac function and preventing post-infarction pathophysiological remodeling.2 However, these effective but invasive approaches cannot be used in all patients owing to their applicability, which is limited based on specific clinical characteristics, and the possibility of severe complications such as bleeding and reperfusion injury.2,3 Attempts to limit infarct size and improve prognosis using pharmacotherapy (including antiplatelet and antiarrhythmic drugs and angiotensin-converting enzyme inhibitors) without reperfusion has been proven generally inefficient, due to non-targeted drug distribution and side effects, and short half-life of some drugs.1,3,4 Consequently, many patients in which this approach is used still progress to cardiac hypertrophy and heart failure.1 Growth and rupture of atherosclerotic plaques and the ensuing thrombosis are the major causes of acute MI.4 Currently available interventions for atherosclerosis (AS) including statins can reduce acute MI, but the effects vary between individuals, and leave significant residual risks.58 Some chemotherapies, such as docetaxel9 and methotrexate,10,11 also seem to have beneficial effects in AS; however, systemic administration of these drugs is limited because of their adverse effects.12 The demand for safer and more efficient therapies and prevention strategies for MI is therefore increasing.

Several optimized strategies have so far been explored, one of which is the application of nanoparticles (NPs). These nanoscale particles have been widely used in the treatment of tumors and neural diseases.13,14 NPs enable delivery of therapeutic compounds to target sites with high spatial and temporal resolution, enhancement of tissue engineering processes and regulation of the behaviour of transplants such as stem cells. The application of NPs improves the therapeutic effects and minimizes the adverse effects of traditional or novel therapies, increasing the likelihood that they can be successfully translated to clinical settings.1518 However, research on NPs in this field is still in its infancy.5,1921 This review summarizes the latest NP-based strategies for managing acute MI, mostly published within the past 7 years, with a particular focus on effects and mechanisms rather than particle types, which have been extensively covered in other reviews (Figure 1). In addition, we offer an initial viewpoint on the value of function-based systems over those based on materials, and discuss future prospects in this field.

Figure 1 Overview of nanoparticle-based strategies for the treatment and prevention of myocardial infarction. Nanoparticles are capable of delivering therapeutic agents and nucleic acids in a stable and targeted manner, improving the properties of tissue engineering scaffolds, labeling transplanted cells and regulating cell behaviors, thus promoting the cardioprotective effects of traditional or novel therapies.

A multitude of NP types are currently under investigation, including lipid-based NPs, polymeric NPs, micelles, inorganic NPs, and exosomes. Virus can also be considered as NPs; however they will not be discussed in this review.22 NPs made from different materials show similar in vivo metabolic kinetic characteristics and protective effects on infarcted heart.19,20 Function-based NP types, oriented towards a specific purpose, may be preferable compared with traditional types, on account of their practicality in basic research and clinical translation. In this review, we discuss NPs used in the treatment and prevention of MI that fall into the following four categories: 1) circulation-stable nanocarriers (polymeric, lipid or inorganic particles); 2) targeted delivery vectors (magnetic or particles modified to improve target specificity); 3) enhancers of tissue engineering; and 4) regulators of cell behavior (Figure 1). We propose that the choice of each NP for any given application should be primarily based on the roles or mechanisms they perform.

Many NPs, whether composed of either naturally occurring or synthetic materials, act as nanocarriers to improve the circulating stability of therapeutic agents.15,16 Polymeric NPs comprise one of the most widely employed types, with excellent biocompatibility, tunable mechanical properties, and the ability be easily modified with therapeutic agents using a broad range of chemical techniques.23,24 The most commonly used polymer for these NPs is polylactide-co-glycolide (PLGA), which has Food and Drug Administration approval.25,26 Recently, there has been a therapeutic emphasis on polydopamine (PDA), from which several related nanomaterials have been created, including PDA NPs and PDA NP-knotted hydrogels.27,28 NPs made from polylactic acid (PLA),29,30 poly--caprolactone (PCL),31 polyoxalates,32 polyacrylonitrile,33 chitosan29,34 and hollow mesoporous organosilica35 have also been constructed and administered in vitro in cells and in vivo in animal models.

Lipid NPs or liposomes are also considered promising candidates for the delivery of therapeutic agents, due to their morphology, which is similar to that of cellular membranes and ability to carry both lipophilic and hydrophilic drugs. These non-toxic, non-immunogenic and biodegradable amphipathic nanocarriers can be designed to reduce capture by reticuloendothelial cells, increase circulation time, and achieve satisfactory targeting.36,37 Solid lipid NPs (SLNs) combine the advantages of polymeric NPs, fat emulsions, and liposomes, remaining in a solid state at room temperature. Active key components of SLNs are mainly physiological lipids, dispersed in aqueous solution containing a stabilizer (surfactant).38 Micelles are made by colloidal aggregation in a solution through self-assembly of amphiphilic polymers, or a simple lipidic layer of transfer vehicles;39 these have been used in cellular and molecular imaging40 and treatment41 for a long time.

Inorganic NPs used in basic IHD research are classified as metal, metal compounds, carbon,42 or silicon NPs;43 these are relatively inert, stable, and biocompatible. Gold (Au),44 silver (Ag)45 and copper (Cu)46 are commonly used materials in their production. These NPs can be delivered orally,47 or injected intravenously48 or intraperitoneally.56 However, they are more widely used to construct electrically conductive myocardial scaffolds in tissue engineering.49,50 Myocardial patches and scaffolds are promising therapeutic approaches to repairing heart tissue after IHD; incorporating conductive NPs can further improve functionality, introducing beneficial physical properties and electroconductivity. Some organic particles, such as liposomes anchored with poly(N-isopropylacrylamide)-based copolymer groups, are also suitable for the production of effective nanogels or patches for this purpose.37

Several metal compounds have been used for treatment of IHD.5154 The application of magnetic particles made from iron oxide has been of particular interest in recent research. These NPs are more prone to manipulation with an external magnetic field, and thus serve as powerful tools for targeted delivery of therapeutics. In addition, modification with targeted peptides or antibodies is another approach to the construction of targeted delivery systems.

Another strategy to protect cardiac performance after MI is the transplantation of cells; however, the beneficial effects of this are currently limited.58 Many NPs can improve the behavior of cells; in this context, they may stimulate cardioprotective potential. In particular, exosomes a major subgroup of extracellular vesicles (EVs) with a diameter of 30150nm, which are secreted via exocytosis55 represent novel, heterogeneous, biological NPs with an endogenous origin. They are able to carry a variety of proteins, lipids, nucleic acids, and other bioactive substances.5557 Mechanistic studies have confirmed that exosomes offer a cell-free strategy to rescue ischemic cardiomyocytes (CMs).59,60

The physical properties of NPs, including size, shape, and surface charge, impact on how biological processes behave, and consequently, responses in the body.61 The recommended definition of NPs in pharmaceutical technology and biomedicine includes a limitation that more than 50% of particles should be in a size distribution range of 10100 nm.39 However, this is not strictly distinguished in studies, so for the purposes of this review, we have relaxed this definition. Small NPs have a faster uptake and processing speed and longer blood circulation half-lives than larger ones; a decreased surface area results in increased reactivity to the microenvironment and greater speed of release of the compounds they carry.6163 However, an exception to this principle is that, among particles of less than 50 nm diameter, larger NPs have longer circulatory half-lives.64,65 NPs can be spherical, discoidal, tubular or dendritic.61,63 The impact of NP shape on uptake and clearance has also been revealed;66,67 for instance, spheres endocytose more easily,20 while micelles and filomicelles target aortic macrophages, B cells, and natural killer (NK) cells in the immune system more effectively than polymersomes.68 In terms of charge, cationic NPs are more likely to interact with cells than negatively charged or neutral particles because the mammalian cell membrane is negatively charged.62 As a result, positively charged particles are reported to be more likely to destabilize blood cell membranes and cause cell lysis.61 Additionally, the rate of drug release is largely determined by the diameter of the pore. Motivated by the idea, Palma-Chavez et al developed a multistage delivery system by encapsulating PLGA NPs in micron-sized PLGA outer shells.69

Some types of NPs, such as micelles, possess coreshell morphological structures: a core composed of hydrophobic block segments is surrounded by hydrophilic polymer blocks in a shell that stabilizes the entire micelle. The core provides enough space to accommodate compounds, while the shell protects drug molecules from hydrolysis and enzymatic degradation.36 Surface chemical composition largely governs the chemical interactions between NPs and molecules in the body. Appropriate surface coatings can create a defensive layer, protect encapsulated cargo, and affect biological behaviors. Coating with inert polymers like polyethylene glycol (PEG) is the most commonly used method, which hinders interactions with proteins, alters the composition of the protein corona, attenuate NP recognition by opsonins which tag particles for phagocytosis, and extend the half-life of particles.36,70 Additionally, PEG coating helps the therapeutic agents reach ischemic sites, because PEGylated macromolecules tend to diffuse in the interstitial space of the heart.71 Functionalization of gangliosides can further attenuate the immunogenicity of PEGylated liposomes without damaging therapeutic efficacy.72 Removal of detachable PEG conjugates in the microenvironment of the target sites improves capture by cells. Wang and colleagues synthesized PDA-coated tanshinone IIA NPs by spontaneous hydrophobic self-assembly.73 Polyethyleneimine (PEI) is capable of condensing nucleic acid and overcoming hamper of cell membrane. Therefore, modification with PEI is mainly used for the transport of DNA and RNA.74 Of note, despite their inertness, novel NPs composed of metals can also be modified with compounds such as PEG, thiols, and disulfides.48,75 Hydrogels mixed with peptide-coated Au NPs attain greater viscosity than hydrogels mixed with Au NPs.24

Targeted delivery is a primary goal in the development of nanocarriers. Passive targeting is based on enhanced permeability in ischemic heart tissue, which does not meet the needs of clinical application.76 This fact has prompted work on targeting agent modification and magnetic guidance. Conjugation with specific monoclonal antibodies is a feasible method for delivering drug payloads targeted to ischemic lesions. Copper sulfide (CuS) NPs coupled to antibodies targeting transient receptor potential vanilloid subfamily 1 (TRPV1), permit specific binding to vascular smooth muscle cells (SMCs), and can also act as a switch for photothermal activation of TRPV1 signaling.52 In another study conducted by Liu and colleagues, two types of antibodies, binding CD63 (expressed on the surface of exosomes) or myosin light chain (MLC, expressed on injured CMs) are utilized to allow NPs to capture exosomes and accumulate in ischemic heart tissue. These NPs have a unique structure comprising an ferroferric oxide core and PEG-decorated silica shell, which simultaneously enables magnetic manipulation and molecule conjugation via hydrazone bonds.21 Targeted peptides such as atrial natriuretic peptide (ANP),43 S2P peptide (plague-targeting peptide),77 and stearyl mannose (type 2 macrophage-targeting ligand)16 allow NPs to precisely target atherosclerotic tissue and ischemic heart lesions. Modification with EMMPRIN-binding peptide (AP9) has been shown to enable more rapid uptake of micelles by H9C2 myoblasts and primary CMs and to deliver drug payloads targeted to lesions in vivo.78,79 Another strategy for targeted nanocarriers is to produce cell mimetic carriers. Using the inflammatory response as a marker after MI,76 Boada and colleagues synthesized biomimetic NPs (leukosomes) by integrating membrane proteins purified from activated J774 macrophages into the phospholipid bilayer of NPs. Local chronic inflammatory lesions demonstrated overexpression of adhesion molecules, which bound leukosomes efficiently.80

The biocompatibility of NPs is difficult to predict because any interaction with molecules or cells can cause toxic effects. Generally, NPs remain in blood, but can also extravasate from vasculature with enhanced permeability, or accumulate in the mononuclear phagocyte system.81 Important causes of NP-associated toxicity include: oxidative stress injury and cell apoptosis secondary to the production of free radicals, lack of anti-oxidants, phagocytic cell responses, and the composition of some types of particles.61 Hepatotoxicity, nephrotoxicity and any other potential off-target organ damage caused by accumulation of particles, especially those with poor degradability and slow clearance, are also essential to explore in toxicity tests.82 Additionally, the evaluation of evoked immune responses according to the expression of inflammatory factors and stimulation of leukocytes in cell lines and animal models is also important.83

A few studies have reported NP-associated acute and chronic hazards in pharmacological applications, although some of these observations may be contentious. Specifically, aggregation of non-functionalized carbon nanotubes (CNTs) has been observed owing to inherent hydrophobicity of these particles.61 Aside from inflammation and T lymphocyte apoptosis, multi-walled CNTs can rupture cell membranes, resulting in macrophage cytotoxic effects.84,85 Silica NPs induce vascular endothelial dysfunction and promoted the release of proinflammatory and procoagulant factors, mediated by miR-451a negative regulation of the interleukin 6 receptor/signal transducer and activator of transcription/transcription factor (IL6R/STAT/TF) signaling pathway.8688 Metal NPs, such as Au and Ag, can also penetrate the cell membrane, increase oxidative stress and decrease cell viability.89,90 Consequently, exposure to Au may cause nephrotoxicity91 and reversible cardiac hypertrophy.92 El-Hussainy and colleagues observed myocardial dysfunction in rats given alumina NPs.93,94 Nemmar and colleagues investigated the toxicity of ultrasmall superparamagnetic iron oxide nanoparticles (SPIONs) administered intravenously, which resulted in cardiac oxidative stress and DNA damage as well as thrombosis.95 Cell-derived exosomes and a majority of natural polymers are considered relatively safe;83 however, Babiker and colleagues demonstrated that dendritic polyamidoamine NPs compromise recovery from ischemia/reperfusion (I/R) injury in isolated rat hearts.96 The effects of degradation byproducts are also of concern.83 An advantage of the nanoscale size of NPs is that their injection is unlikely to block the microvascular system; however, it remains controversial whether NPs give rise to arrhythmias.97 These factors highlight that examining the biocompatibility of NPs both in vitro and in vivo is a vital component of preclinical or clinical research.

NP toxicity depends on many parameters, including material composition, coating, size, shape, surface charges and concentration.39 For instance, larger particles seem to be more favorable from a toxicology standpoint.83 However, single-walled CNTs are considered more harmful than multi-walled CNTs, due to their smaller size resulting in less aggregation and increased uptake by macrophages.61 Cationic AuNPs are more toxic compared with anionic AuNPs, which appear to be nontoxic.98 Generally speaking, NP-associated toxicity can be lowered by functionalization with nontoxic surface molecules, stabilization and localization in the region of interest by using scaffolds.24,99 The toxicity of CNTs mediated by oxidative stress and inflammation was reduced using these strategies in several studies.24,100 Local application and targeted delivery also enabled dose reduction and concurrently decreased the incidence of adverse effects. Administration of therapeutic agents directly into the infarcted or peri-infarcted myocardium is a conventional approach with a low risk of inducing embolization.

NP is a suitable method for the administration of therapeutic agents in terms of the minimization of side effects, enhanced stability of cargo, and possibility of controlled delivery and release.76 Detailed information on the experimental design and results of the latest studies on the use of NPs as therapeutic vectors are provided in Table 1. Recently, several drugs approved for clinical use as immunosuppressants have been suggested as potentially effective cardioprotective agents. For example, NPs containing cyclosporine A inhibited apoptosis and inflammation in ischemic myocardium by improving mitochondrial function.25,101 Commercial methotrexate also showed minor cardioprotective effects; additionally, when loaded into lipid core NPs, adenosine bioavailability and echocardiographic and morphometric results were all improved a rats model of MI.102 Margulis and colleagues developed a method to fabricate NPs via a supercritical fluids setup, which loaded and transferred celecoxib, a lipophilic nonsteroidal anti-inflammatory drug, into the NPs. These celecoxib-containing NPs alleviated ejection function damage and ventricular dilation by inducing significant levels of neovascularization.103 Furthermore, a series of investigations indicated that drugs used for hypoglycemia (eg pioglitazone, exenatide and liraglutide)104106 and lipid lowering (statins)107 attenuate the progression of post-MI heart failure, and are therefore also potential therapeutic cargoes for NPs in the treatment of MI.

NP systems also offer an alternative method for delivering plant-derived therapeutic agents, most of which belong to traditional Chinese medicine. Its of vital importance because of the criticization on adverse reactions caused by direct injection of such complexes. Cheng and colleagues designed a dual-shell polymeric NP as a multistage, continuous, targeted vehicle of resveratrol, a reactive oxygen species (ROS) scavenger. Due to the severe oxide stress in areas of infarction, the proposed antioxidant-delivery NPs represent a new method to effectively treat MI. These NPs are modified with two peptides, targeting ischemic myocardium and mitochondria, respectively; cardioprotective effects have been confirmed in both hypoxia/reoxygenated (H/R) H9C2 cells and I/R rats.108 In addition, Dong and colleagues also demonstrated that puerarin-SLNs produced smaller areas of infarction in a MI rat model, evaluated by 2,3,5-triphenyltetrazolium chloride (TTC) staining. These particles were modified with cyclic arginyl-glycyl-aspartic acid peptide, a specific targeting moiety to v3 integrin receptors, which are highly expressed on endothelial cells (ECs) during angiogenesis.109 In a recent study, quercetin was loaded into mesoporous silica NPs, which enhanced the inhibition of cell apoptosis and oxidative stress, improving ventricular remodeling and promoting the recovery of cardiac function by activating the janus kinase 2 (JAK2)/STAT3 pathway.110 Similarly, curcuminpolymer NPs, administered by gavage, improved serum inflammatory cytokine levels compared with direct administration of curcumin.111

Translation of novel bioactive agents into clinical practice has been limited, owing to lack of sufficient bioavailability and systemic toxicity.76 Encapsulating small molecules such as 3i-1000 (an inhibitor of the GATA4NKX2-5 interaction),43 TAK-242 (inhibitor of toll-like receptor 4, TLR4)112 and C143 (inhibitor of ERK1/2)113 in NPs promotes myocardial repair after MI without the risk of uncontrolled and off-target adverse effects. Administration of vascular endothelial growth factor (VEGF) causes elevated vascular permeability and tissue edema. The cardioprotective effects of VEGF-loaded polymeric NPs injected either intravenously114 or intramyocardially115 eliminated vascular leakage due to promotion of lymphangiogenesis. Further studies have confirmed these results and add to the evidence that combined delivery of VEGF with other growth factors is recommended, since VEGF primarily drives the formation of new capillaries.116 Furthermore, in line with previous research, similar therapeutic effects have been demonstrated in studies using polymeric NPs loaded with stromal cell derived factor 1 (SDF-1) and insulin-like growth factor 1 (IGF-1).117,118

We also notice that some novel payloads in NPs-based therapy for MI have been studied. For example, deoxyribozyme-AuNP can silence tumor necrosis factor- (TNF-).119 A target that is implicated in irreversible heart damage after MI; its effects are mediated by free radical production, downregulation of contractile proteins, and initiation of pro-inflammatory cytokine cascades. Mesoporous iron oxide NPs containing the hydrogen sulfide donor compound diallyl trisulfide act as a platform for the controlled and sustained release of this therapeutic gas molecule. The application of these NPs at appropriate concentrations, resulted in the preservation of cardiac systolic performance without any observable detrimental effects on homeostasis in vivo.15

With increasing insight into the molecular mechanisms of MI, a particular emphasis on gene therapy has emerged. Gene expression can be modulated by DNA fragments, messenger RNA (mRNA), microRNA (miRNA) and small interfering RNA (siRNA), which thus represent new approaches for treating ischemia. Currently available nucleic acid delivery systems are mainly divided into viral and non-viral systems. However, virus-based approaches are limited by their potential for uncontrollable mutagenesis.36 From a clinical point of view, NP represents a suitable choice as novel non-viral nucleic acid vector, which could feasibly transfect in a stable, targeted, and sustained manner (as shown in Table 2).

Table 2 NPs-Based Nucleic Acid Delivery Systems for Treatment for MI Reported in the Last 7 Years

As a common gene vehicle, plasmids face the risk of being destroyed by DNase and immunoreactivity in the serum, and transduction in non-target organs.120 A recent study by Kim and colleagues aligns with current research trends focused on virus-free therapies, in which carboxymethylcellulose NPs were designed to transfer 5-azacytidine to halt proliferation, and deliver plasmid DNA containing GATA4, myocyte enhancer factor 2C (MEF2C), and TBX5 to induce reprogramming and cardiogenesis of mature normal human dermal fibroblasts.121 In a methodological study, lipidoid NPs were used to successfully deliver pseudouridine-modified mRNA, encoding enhanced green fluorescent protein.122

MiRNAs act as essential regulators of cellular processes through post-transcriptional suppression; increasing evidence reveals miRNAs play critical roles in cardiovascular diseases. An miRNA-transferring platform with self-accelerating nucleic acid release, containing a heparin core and an ethanolamine-modified poly(glycidyl methacrylate) shell, has been constructed and used as an efficient vector of miR-499, which inhibits cardiomyocyte apoptosis.123 Intravenous administration of anionic hyaluronan-sulfate NPs (mean diameter 130 nm) enable the stable delivery of miR-21 mimics, thus modulating the expression of TNF, transforming growth factor (TGF), and suppressor of cytokine signaling 1 (SOCS1). Consequently, these NPs switch the phenotype of macrophages from pro-inflammatory to reparative, promote neovascularization and reduced collagen deposition.124 Interestingly, silencing miR-21 using antagomiR-21a-5p in a nanoparticle formulation has also been shown to reduce expression of pro-inflammatory cytokines in vitro, and attenuate inflammation and fibrosis in mice with autoimmune myocarditis.125 A number of other potentially therapeutic miRNAs have also been successfully transferred to CMs in recent works, including miR-146a, miR-146b-5p, miR-181b, miR-199-3p, miR-214-3p, miR-194-5p and miR-122-5p.126128 Evaluation of angiogenesis, cardiac function, and scar size in these studies indicated that injectable miRNANPs can deliver miRNA to restore injured myocardium efficiently and safely. Yang and colleagues developed an in vivo miRNA delivery system incorporating a shear-thinning hydrogel and NPs characterized by surface presence of miRNA and cell-penetrating peptide (CPP).126 Additionally, angiotensin II type 1 receptor-targeting peptide-modified NPs serve as targeted carriers for anti-miR-1 antisense oligonucleotide, significantly reducing apoptosis and infarct size.129

SiRNAs inhibit gene expression by mediating mRNA cleavage in a sequence-specific manner, highlighting NP-based RNA interference as another viable approach to modulate cellular phenotype and attenuate cardiac failure. Dosta and colleagues demonstrated that poly(-amino ester) particles modified by adding lysine-/histidine-oligopeptides could represent a system for the transfer of siRNA.130 Studies have now revealed that chemokine CC motif ligand 2 (CCL2) and its cognate receptor CC chemokine receptor 2 (CCR2) promoted excessive Ly6Chigh inflammatory monocyte infiltration in infarcted area and aggravate myocardial injury.131 Photoluminescent mesoporous silicon nanoparticles (MSNPs) carrying siCCR2 have been reported to improve the effectiveness of transplanted mesenchymal stem cells (MSCs) in reducing myocardial remodeling after acute MI.131 Targeted transportation and enhanced uptake with minimum leakage improved the efficiency of delivery via NPs, significantly outperforming the control group. Taken together, these studies demonstrate that NPs act as promising drug delivery systems in the treatment of MI.

Myocardial patches and scaffolds, consisting of either bioactive hydrogels or nanofibers, are minimally invasive, relatively localized, and targeted approaches to repair the heart after IHD. Those biomaterials must have an anisotropic structure, mechanical elasticity, electrical conductivity, and the ability to promote ischemic heart repair.132 A variety of NPs have been applied in this field, among which inorganic NPs have been the focus of most research efforts.42 These investigations of inorganic NPs can be divided into four categories based on their effects and the mechanisms involved, which are described in this section.

NPs enhance physical properties and electroconductivity, which is essential for the biomaterials to properly accommodate cardiac cells and subsequently resulted in cell retention, cell-cell coupling and robust synchronized beating behavior. CNTs are able to increase the required physical properties of scaffolds, such as maximum load, elastic modulus, and toughness.133,134 Gelatin methacrylate (GelMA) also has decreased impedance, hydrogel swelling ratio, and pore diameter, as well as increased Youngs modulus when combined with gold nanorods (AuNRs).135 Given this insight, highly electroconductive NPs have been increasingly investigated.34,99 Specifically, Ahadian and colleagues revealed that a higher integrated CNT concentration in gels resulted in greater conductivity.136 Zhou and colleagues verified the therapeutic effects of patches incorporating single-walled CNT for myocardial ischemia, which halted progressive cardiac dysfunction and regenerated the infarcted myocardium.137 Spherical AuNPs have also been shown to increase the conductivity of chitosan hydrogels in a concentration-dependent manner.138 Interestingly, silicon NPs mimic the effects of AuNRs without affecting conductivity or stiffness, as reported by Navaei and colleagues.139

Several studies demonstrate the effects of CNT on CM functions. When CMs are cultured on multi-walled CNT substrates or treated with CNT-integrated patches, these cells show spontaneous electrical activity.34,99,140 Brisa and colleagues functionalized reverse thermal gels with AuNPs, investigating the phenotype of CMs in vitro; the growth of cells with a CM phenotype was observed, along with gap junction formation.141 CMs exposed to AuNR-containing GelMa show higher affinity, leading to packed and uniform tissue structure.135 These conductive scaffolds also facilitate the robustness and synchrony of spontaneous beating in CMs without damaging their viability and metabolic activity.

Combined incorporation of inorganic NPs and cells represents a feasible strategy to promote therapeutic effects. Despite some reports on the cytotoxicity of Au,89,90 no significant loss of viability, metabolism, migration, or proliferation of MSCs in scaffolds containing AuNP is reported. A CNT-embedded, electrospun chitosan/polyvinyl alcohol mesh is reported to promote the differentiation of MSCs to CMs.142 In another approach, Baei and colleagues added AuNPs to chitosan thermosensitive hydrogels seeded with MSCs.138 There was a significant increase in expression of early and mature cardiac markers, indicating enhanced cardiomyogenic differentiation of MSCs compared to the matrix alone, while no difference in growth was observed. Gao et al created a fibrin scaffold, in which cells and AuNPs were suspended simultaneously; these bioactive patches were shown to promote left ventricular function and decrease infarct size and apoptosis in the periscar boarder zone myocardium in swine models of acute MI.97 These studies of AuNP-containing scaffolds demonstrated reduced infarct and fibrotic size, as well as facilitated angiogenesis and cardiac function, which can be attributed at least in part to the enhanced expression of connexin 43 and atrial natriuretic peptide, and activation of the integrin-linked kinase(ILK)/serine-threonine kinase (p-AKT)/GATA4 pathway.49,143,144 Scaffolds containing Ag NPs evoke M2 polarization of macrophages in vitro;145 which may also play a role in cardioprotective action because M2 macrophages are capable of promoting cardiac recovery via the secretion of anti-inflammatory cytokines, collagen deposition, and neovascularization.146

Similarly, CNT also act synergically with poly(N-isopropylacrylamide) scaffolds containing adipose-derived stem cells;147 significant improvement of cardiac function and increased implantation and proliferation of stem cells has been observed with these scaffolds, compared with scaffolds without CNT.147 Selenium NPs148 and titania NPs53 have been shown to improve the mechanical and conductive properties of chitosan patches, promoting their ability to support proliferation and the synchronous activity of cells growing on these patches.

Mounting evidence demonstrates the unique benefits of using cardiac scaffolds with magnetic NPs such as SPIONs; these benefits include, but are not limited to, significant improvements in cell proliferation149 and assembly of electrochemical junctions.150 Given that magnetic manipulation enhances the therapeutic efficacy of iron oxide NPs in cardiac scaffolds, Chouhan and colleagues designed a magnetic actuator device by incorporating magnetic iron oxide NPs (MIONs) in silk nanofibers; this resulted in more controlled drug release properties, as well as the promotion of proliferation and maturation in CMs.151 Magnetic NPs can be used to label induced pluripotent stem cell (iPSC)-derived CMs via conjugation with antibodies against signal-regulatory protein . Zwi-Dantsis and colleagues reported the construction of tailored cardiac tissue microstructures, achieved by orienting MION-labelled cells along the applied field to impart different shapes without any mechanical support.152 However, the interactions between and effects of NPs and cells in scaffolds, and the cardioprotective efficacy of patches in which NP-labelled cells are suspended, require further elucidation.

Polymeric nanomaterials have also been investigated in the context of cardiac bioengineering materials; for instance, water-swollen polymer NPs have been used to prepare nanogels. With a 3D structure containing cross-linked biopolymer networks, nanogels can encapsulate, protect, and deliver various agents.83,153 PDA-coated tanshinone IIA NPs suspended in a ROS-sensitive, injectable hydrogel via PDA-thiol bonds significantly improved cardiac performance, accompanied by inhibition of the expression of inflammation factors in rat model.73 After implanting cryogel patches consisting of GelMa and linked conductive polypyrrole NPs154 or scaffolds of electrospun GelMA/polycaprolactone with GelMA-polypyrrole NPs,155 left ventricular (LV) ejection fraction (EF) has been shown to increase, with a concurrent decrease in infarct size, in MI animal models.

Progenitor or stem cell-based therapy in the form of injections and engineered cardiac patches, discussed in the previous section, has been recognized as a promising strategy to improve the cardiac niche and ameliorate adverse remodeling processes and fibrosis after acute MI.56,156,157 However, poor survival and low engraftment rates for transplanted cells are still major challenges in this field.157 Among possible optimization strategies, combining NPs with stem cell therapy is of great interest (Table 3).

Table 3 Studies Combining NPs and Cell Therapy Reported in the Last 7 Years

Accumulating evidence has shown two main mechanisms for NP-loaded cell therapy in the context of MI treatment. Firstly, various NP types could efficiently improve survival and cell proliferation, modulating differentiation of implanted cells in the ischemic microenvironment.62,158 Specifically, electrically driven nanomanipulators could guide cardiomyogenic differentiation of MSCs: in a previous study, electroactuated gold NPs were administrated with pulsed electric field stimulation, and tube-like morphological alterations were observed, along with upregulation of cardiac specific markers.143 Adipose-derived stem cells that load PLGA-simvastatin NPs promoted differentiation of these cells into SMCs and ECs, and had cardioprotective effects in a mouse model of MI induced by left anterior descending ligation.17 Secondly, engraftment rate is another important factor affecting treatment efficacy in this context.159 Zhang and colleagues designed silica-coated, MION-labelled endothelial progenitor cells; intravenous administration of these cells in a rat model of MI significantly improved cardiac performance, as indicated by echocardiogram, morphological, and histological evidence, and neovascularization. This indicates magnetic guidance may potentially address the problem of low levels of stem cell retention, which has typically been observed.51 In particular, NPs can link the therapeutic cells to injured CMs, thereby promoting cell anchorage and engraftment. To this end, Cheng and colleagues established a magnetic, bifunctional cell connector by conjugating NPs with two antibodies: one against cell determinant (CD)45, which is expressed on bone marrow-derived stem cells, and one against MLC. The magnetic core of this NP also enabled physical enrichment in ischemic heart tissue using external magnets.160 More than one mechanism may be involved in a study. Chen and colleagues fabricated a sustained release carrier of insulin-like growth factor (IGF), a pro-survival agent, via in situ growth of Fe3O4 NPs on MSNPs. In this study, the NPs promoted both the survival and retention of MSCs, and intramyocardial injection of the NP-labeled MSCs was able to ameliorate functional and histological damage without any obvious toxicity in vivo.161 However, SPION labeling does not seem to improve therapeutic efficiency, as demonstrated by Wang and colleagues in a study using hypoxia-preconditioned SPION-labeled adipose-derived stem cells (ASCs).162

Primary criticisms of cell-based therapies include their potential immunogenicity, arrhythmogenicity and tumorigenicity. It is widely accepted that the beneficial effects of cell-based therapy are mainly attributable to paracrine effects rather than directly replenishing lost CMs;56 researchers are therefore investigating of cell-free approaches. Exosomes have attractive properties including stable transport, homing to target tissues or cells, and penetration of biological barriers, as well as being more biocompatible with lower immunogenicity than cell-based approaches. Interestingly, post-MI circulating exosomes serve as important cardioprotective messengers.163,164 Manipulating their biodistribution has proven to be a viable strategy to reduce infarct size, promoting angiogenesis and ejection functions.21 However, from a therapeutic standpoint, the lack of control over endogenous exosome production and cargo encapsulation limits the use of this naturally-present mechanism for therapeutic enhancement. The low purity and weak targeting of natural exosomes are two further obstacles to overcome before clinical application. Strategies to address these include finding robust sources; optimized isolation methods for higher yields, efficiency and purity; and improving therapeutic payloads. These have been systematically summarized in other reviews.165167

AS is considered a low-grade, chronic inflammatory disease, characterized by accumulation and deposition of cholesterol in arteries, as well as remodeling of the extracellular matrix in the intima and inner media.12,168 Inflammation of ECs, proliferation of SMCs, and recruitment of monocytes and macrophages play a critical role in the development of AS. NPs allow for the packaging of large amounts of therapeutic compounds in a compact nanostructure, specifically targeting pathological mechanisms and attenuating atherogenesis. Optimization of the loaded drug and NP target together lead to enhanced efficacy while minimizing side effects.169 In this section, we summarize recent breakthroughs in the order of pathological progression, as shown in Table 4.

Primary prevention refers to control of the risk factors of AS, one of which is hypertension.170 PLA NPs have been shown to improve the efficacy of aliskiren, the first oral direct renin inhibitor and the first in a new class of antihypertensive agents.29 Encapsulation in nanocarriers also renders the application of anandamide viable, which was once limited; recent research revealed that this new therapy could lower blood pressure and LV mass index in rats.171 Similar results were observed in a study in which angiotensinogen was silenced using small hairpin RNA.172 NPs may also help to make more anti-hypertensive drugs available, reduce side effects such as asthma, and lessen the effective dosage by providing sustained drug release over time. The link between AS and diabetes mellitus, which describes a group of metabolic disorders, has also been investigated in numerous studies.173 Possible mechanisms include oxidative stress, altered protein kinase signaling, and epigenetic modifications. Cetin and colleagues successfully constructed NP-based drug delivery systems for the administration of metformin, an oral antihyperglycemic agent with low oral bioavailability and short biological half-life.174 NPs are also promising tools for improving the oral bioavailability of insulin, which is of great interest because oral insulin will significantly increase patients compliance.175,176

The inflammatory hypothesis of AS is now widely established, making selective targeting and accumulation of NPs in inflammatory lesions attractive therapeutic strategies. Targeting macrophages in apoE-/- mice has been shown to result in decreased phagocytosis and suppression of inflammatory genes in lesional macrophages, thus lessening burden of atherosclerotic plaques.177 Tom and colleagues used NPs consisting of high-density lipoprotein (HDL), a known atheroprotective bionanomaterial, as carriers for TNF receptor-associated factor in mice, and observed reductions in both leukocyte recruitment and macrophage activation.178 Both single-walled CNT and HDL-NPs have a favorable safety profile. In a pathological context, activated endothelial tissue expresses more adhesion molecules, such as selectins, than usual. These molecules are thus potential targets for cardiovascular nanomedicine. Glycoprotein Ib (GPIb)179 and biotinylated Sialyl Lewis A (sLeA)69 specifically bind to selectins, leading to the accumulation of conjugated NPs in injured vessels; an in vitro study demonstrated that GPIb-conjugated NPs could bind to target surfaces, where they were taken up by activated ECs under shear stress conditions. In another study, Sager and colleagues simultaneously inhibited five adhesion molecules associated with leukocyte recruitment in post-MI apoE-/- mice. Inflammation in plaque and ischemic heart, rendering acute coronary events and post-MI complications less likely to occur.180 However, targeting inflammatory process may have heterogeneous effects in humans because the targeting moieties and target receptors may be overexpressed in several different pathologic conditions in addition to AS. Oxidation is another factor involved in the development of AS. Upregulation of endothelial nitric oxide synthase (eNOS) leads to vascular construction and other AS-promoting effects. Pechanova and colleagues observed that the application of PLA NPs resulted in larger decreases in NOS than direct administration.29

Aside from these processes, avoiding plaque rupture and thrombosis could be another therapeutic aim. Nakashiro and colleagues showed that delivering pioglitazone via NPs inhibited plaque rupture in apoE-/- mice.181 The integrin 3 is upregulated in angiogenic vasculature, which is ubiquitous in plaque ruptures, which may lead to MI.182 3 integrin-targeted NPs provide a site-specific drug delivery platform that has been shown to successfully stabilize plaques in rabbits.182 Ji and colleagues used NPs composed of albumin with an average diameter of 225.6 nm to deliver a plasmid containing the tissue-type plasminogen activator gene (t-PA); this system plays a role in preventing thrombosis in addition to attenuating intimal thickness and proliferation of vascular SMCs.183 NPs consisting of engineered amphipathic cationic peptide and serine/threonine protein kinase JNK2 siRNA also reduces thrombotic risk, plaque necrotic area, and vascular barrier disorder in mice given the equivalent of a 14-week western diet.184

Innovation and development of therapies based on NPs in recent years has led to significant advances towards complete repair of the injured myocardium following acute MI. Nevertheless, developing clinically relevant solutions remains difficult for several reasons. Firstly, as shown in tables, there is little consistency among studies regarding the characteristics of NPs, their payloads, and their methods of administration, as well as methods used for evaluating cardiac repair. It can be difficult to control characteristics such as the size of the synthesized particles in a narrow range, even within single studies. Such significant heterogeneity can lead to differences in observed results in repeated experiments, or under different conditions. Secondly, although many studies have focused on the health effects of unintentional exposure to NPs by inhalation or ingestion,185,186 most of the studies on medical applications of NPs have not reported on toxicity of NP systems until recently.73 Remarkably, there has not been a consensus on NP-associated adverse effects in existing reports, making assessments of biocompatibility a priority for NP characterization.

NPs have emerged as a powerful tool for controlling cell signaling pathways in regenerative strategies using novel therapeutics and drugs that are unsuitable for direct administration. One advantage of the application of NP systems is the ability to release the drug payload or regulate gene expression in a stable and controlled manner. Therefore, many otherwise serious side effects, such as sudden arrhythmic deaths resulting from persistent and uncontrolled expression of miRNA by viral vectors, may be completely avoided.187 More research is required to develop stable and efficient methods of NP production, improve encapsulation efficiency of drugs, and achieve satisfactory targeting. In particular, a greater focus on investigating NP-based switches, including optical, electrical and magnetic methods, has enabled the regulation of cell signaling, exemplified by the development of a CuS NP-based photothermal switch.52 Optimizing tissue engineering scaffolds containing conductive NPs is a promising strategy for the protection of the myocardium after ischemia by mimicking the myocardial extracellular matrix. Improvements in understanding of cardiac repair mechanisms, and how these biomaterials may interfere with them, is therefore urgently needed. Furthermore, heart repair is complex and involves many processes, including apoptosis, angiogenesis, inflammatory infiltration, and fibrosis. Therefore, novel treatments should be designed using NP-based integrative strategies based on these multiple different mechanisms. However, its important to highlight that synergistic effects of different drug payloads, NPs, and NPcell combined strategies should be addressed, as not all may be compatible with one another. Future research should focus on these aspects to translate NP-based therapeutic strategies for MI into practical and effective clinical use.

The authors report no conflicts of interest in this work.

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55. Xiong YY, Gong ZT, Tang RJ, Yang YJ. The pivotal roles of exosomes derived from endogenous immune cells and exogenous stem cells in myocardial repair after acute myocardial infarction. Theranostics. 2021;11(3):10461058. doi:10.7150/thno.53326

56. Huang P, Wang L, Li Q, et al. Atorvastatin enhances the therapeutic efficacy of mesenchymal stem cells-derived exosomes in acute myocardial infarction via up-regulating long non-coding RNA H19. Cardiovasc Res. 2020;116(2):353367. doi:10.1093/cvr/cvz139

57. Zhang LL, Xiong YY, Yang YJ. The vital roles of mesenchymal stem cells and the derived extracellular vesicles in promoting angiogenesis after acute myocardial infarction. Stem Cells Dev. 2021;30(11):561577. doi:10.1089/scd.2021.0006

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Therapy and Prevention Strategies for Myocardial Infarction | IJN - Dove Medical Press

Learn how these advanced 3D tissue models generated on the Mantarray platform can improve the physiological relevance of preclinical cardiac and skeletal muscle models, accelerating the discovery of new medicines.

TORONTO (PRWEB) October 05, 2021

3D cellular models and organs-on-chips are poised to add tremendous value by providing human data earlier in the drug discovery pipeline. There is intense interest in adopting these 3D models in preclinical and translational research, but their complex implementation has remained a roadblock for many labs.

In this webinar, Curi Bio will present its Mantarray platform, which represents an easy-to-use, flexible, and scalable system for generating 3D EMTs at high-throughput with the ability to measure contractility in parallel. The platform features a novel method of casting 3D tissues that can be easily performed by nearly any cell biology researcher and can be readily adapted to a variety of cell lines and extracellular matrices. In addition, Mantarrays novel magnetic sensing modality permits contractility measurement of 24 tissues in parallel and in real time, while the cloud data analysis portal takes the guesswork out of analyzing and comparing results across experiments.

Register for this webinar to hear an overview of the technology, along with application examples across various use cases, including:

Learn how these advanced 3D tissue models generated on the Mantarray platform can improve the physiological relevance of preclinical cardiac and skeletal muscle models, accelerating the discovery of new medicines.

Join Dr. Nicholas Geisse, Chief Science Officer at Curi Bio, for the live webinar on Friday, October 22, 2021 at 1pm EDT.

For more information, or to register for this event, visit Mantarray: Scalable Human-Relevant 3D-Engineered Cardiac and Skeletal Muscle Tissues for Safety and Efficacy Studies.

ABOUT XTALKS

Xtalks, powered by Honeycomb Worldwide Inc., is a leading provider of educational webinars to the global life science, food and medical device community. Every year, thousands of industry practitioners (from life science, food and medical device companies, private & academic research institutions, healthcare centers, etc.) turn to Xtalks for access to quality content. Xtalks helps Life Science professionals stay current with industry developments, trends and regulations. Xtalks webinars also provide perspectives on key issues from top industry thought leaders and service providers.

To learn more about Xtalks visit http://xtalks.comFor information about hosting a webinar visit http://xtalks.com/why-host-a-webinar/

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Mantarray: Scalable Human-relevant 3D Engineered Cardiac and Skeletal Muscle Tissues for Therapeutics Discovery Upcoming Webinar Hosted by Xtalks -...

Trained as a chemist, biophysicist, internist, and cardiologist, Mark Yeager is eager to propel the Frost Institute for Chemistry and Molecular Science into a leading research center.

Even in his youth Mark Yeager could picture the door to his future. Scuffed, chipped, and almost black from layers of varnish, the old, wooden door had a frosted window with five words stenciled in glossy black: Laboratory of Dr. Mark Yeager.

Yet Yeager, the inaugural executive director of the University of Miamis Frost Institute for Chemistry and Molecular Science (FICMS), is quite happy that his new lab in the 94,000-square-foot building slated to open late next year wont even have a door. The $60 million facilitys open floor plan was designed to encourage the free flow of people and ideasand help transform the University into one of the worlds premier research centers for improving the health of humans and that of our planet.

That is the vision, but its not a fantastical vision, said Yeager, a distinguished biophysicist and cardiologist whose top priority is attracting a diverse and elite group of scientists as the institutes first faculty. It is achievable, and it will happen because the University has not wavered in its commitment to elevate STEM (science, technology, engineering, and mathematics) to advance scientific discovery. Theres something going on here thats organic and alive and excitingand Im thrilled to be part of it.

Yeager, whose own groundbreaking research focuses on the molecular causes of heart disease and viral infections, trained as a chemist at Carnegie-Mellon University, as a physician and biophysicist at Yale University and as an internist and cardiologist at Stanford University. He spent two decades at Scripps Research in California, where he established his first independent laboratory, served as the director of research in cardiology, and helped launch the Skaggs Clinical Scholars Program in Translational Research. He has also served as a consultant and scientific and clinical advisor to several biotech companies.

Now he is transitioning to the University from the University of Virginia School of Medicine (UVA), where he chaired the Department of Molecular Biophysics and Biochemistry for nearly a dozen years and helped establish the Sheridan G. Snyder Translational Research Building. At UVA, he also established one of the nations five regional centers for cryo-electron microscopy (cryoEM)the technique he advanced for flash-freezing, imaging, and studying proteins and other macromolecules in their near-natural state.

It is exciting to see the progress being made on the evolution of our Frost Institutes, starting with Data Science and Computing and now the emergence of Chemistry and Molecular Science. We are fortunate to have Mark overseeing our Frost Institute for Chemistry and Molecular Science and working across the entire institutionhis interdisciplinary knowledge and perspective on chemistry are essential for our success, said Jeffrey Duerk, executive vice president for academic affairs and provost. Mark brings a wealth of knowledge and experience to the University of Miami and we are looking forward to his impactful leadership continuing as we move forward.

Yeager said he knew he was making the right career move on his first visit to the University last November. Although the COVID-19 pandemic had curtailed in-person learning and suspended new construction, he heard the unmistakable sound of heavy equipment as he walked past the royal palms and fountain at the end of Memorial Drive, where the five-story FICMS now stands.

I could see an excavation area and heard a cacophony of construction noise where I had a hunch the institute should be, he recalled. That told me that the University was all in. They had made this commitment to fortify STEM and to do transformational science and nothing was going to stop them. In spite of the pandemic, it was all systems go.

The Universitys longtime benefactors, Phillip and Patricia Frost, enabled that commitment in 2017, when they announced their landmark $100 million gift to establish the Frost Institutes for Science and Engineering, now a key initiative of the Roadmap to Our New Centurythe strategic plan guiding the University toward its centennial mark. The umbrella organization for a group of multidisciplinary research centers patterned after the National Institutes of Health and its network of affiliated institutes, the Frost Institutes were envisioned to translate interdisciplinary research into solutions for real-world problems.

Though Yeager officially started his new role on June 1, he has been heavily involved in planning the FICMS' interior for months. He recently placed a $20 million order to equip the facility with five different electron microscopy instruments that chemists, molecular scientists, and engineers will use to explore the molecular structure of exquisitely beam-sensitive soft materials like proteins, hard materials such as metal alloys, as well as nanomaterials comprised of soft and hard components. Along with the buildings state-of-the-art technology and the Universitys research infrastructure, hes confident its location in the heart of the Coral Gables campus will help him recruit a diverse and elite group of scientists who are exploring challenging avenues of impactful researchsomething he has been driven to do almost his entire life.

An occasional songwriter, guitar player, and jogger who in his younger days ran 18 marathons, Yeager was always fascinated by scientific discoveries that illuminated unknown and unseen worlds. A child of the Sputnik era who began entering science fairs in junior high, he began forging his own career as a physician-scientist while in high school in Colorado Springs, Colorado, where his father, an agricultural economist, settled his family after a number of job-related moves.

Inspired by an experiment in Scientific American magazine, he convinced physicians in the therapeutic radiology department at Penrose Hospital to irradiate his fruit flies so he could compare the effects of administering different doses of radiation on their eye pigments. Delivered in Styrofoam cups, his experiments on what is now called dose fractionationand used to reduce tissue damage during cancer treatmentswon him first place in the U.S. Department of Agricultures 1967 International Science Fair and a research stint in an insect toxicology lab in Berkeley, California.

The following summer, when Yeager returned to Penrose Hospital to work as an orderly, he realized that he loved patient care as much as laboratory research and began plotting how he could pursue both careers.

I just got incredible satisfaction from helping patients get out of bed and into a wheelchair, transfer to a gurney, learn to use crutches, recalled Yeager, who joins the University as one of its 100 Talents for 100 Years, a Roadmap initiative to add 100 new endowed chairs to the faculty by the Universitys 2025 centennial. But I also loved chemistry. I loved physics. I loved too many things.

After earning his undergraduate degree in chemistry from Carnegie-Mellon, he was accepted to the Medical Scientist Training Program at Yale University, where, along with his medical degree, he earned his masters degree and doctorate in molecular biophysics and biochemistry. There, he encountered the first of many trailblazing scientists, including two future Nobel laureates, who would influence his lifes work. His Ph.D. advisor, Lubert Stryer, was particularly influential. Stryer authored a premier textbook of biochemistry, pioneered fluorescence-based techniques to explore the motions of biological macromolecules, and made fundamental discoveries on the molecular basis of vision. Yeagers graduate work on rhodopsin, a photoreceptor membrane protein, triggered his fascination with elucidating the molecular bases for such diseases as sudden cardiac death, heart attacks, HIV-1, and other viral infections.

Yeager completed his medical residency and specialized fellowship training in cardiovascular medicine at Stanford University Medical Center, where he managed the pre- and post-operative care of heart transplant patients and wrote 13 chapters in the book Handbook of Difficult Diagnoses.

He also continued exploring cellular biology in the laboratory of Nigel Unwin, who had collaborated with future Nobel laureate Richard Henderson to pioneer the use of cryoEM to determine the molecular structure of membrane proteinsand inspired Yeagers groundbreaking research on gap junction channels. The electrical conduits that connect every cell in the body to its neighbor, gap junction channels play a critical role in maintaining the normal heartbeat.

That research, which Yeager continued at Scripps and at UVA, explained how gap junction channels behave in their normal state, and during an injured state, such as a heart attack. His quest to answer another question particularly relevant todayhow viruses enter host cells, replicate, and assemble infectious particlesis exemplified by his breakthrough research on the assembly, structure, and maturation of HIV-1, the virus that causes AIDS.

Today, those insights, which Yeager humbly calls a few bricks in the edifice of science, hold important clues for developing new, more effective therapies to prevent HIV-1 infection, repair injured tissue, and treat cancer and cardiovascular diseasethe kind of impactful research that the FICMS was designed to advance with collaborative partners across the University, and beyond.

As a pioneer in the field of cryo-transmission electron microscopy, a forefront technology in materials and biological research, Marks expertise and knowledge will position the University as aleader in these cutting-edge fields, said Leonidas Bachas, dean of the College of Arts and Sciences who served as the initial interim director of the FICMS. We look forward to having him lead the Frost Institute for Chemistry and Molecular Science as we continue to advance the sciences, innovate, and expand research collaborations with our faculty and industry partners.

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Distinguished physician-scientist takes the helm of first Frost Institute - University of Miami

TUCSON, Ariz., Oct. 5, 2021 /PRNewswire/ --On November 15th, 2021, healthcare professionals and the general public are invited to participate in World Cord Blood Day 2021 (www.WorldCordBloodDay.org) via a free online conference and live educational events being held around the globe. Registration is now open (free, public welcome).

Cord blood is the blood left in the umbilical cord and placenta following the birth of a child. It is rich in life-saving stem cells. While cord blood has been used for over 30 years, Covid-19 has renewed interest in this medical resource given its unique regenerative qualities and the fact that most cord blood currently stored was collected prior to the pandemic. These units are naturally Covid-free, an advantage over many other stem cell sources. Yet, cord blood is still thrown away as medical waste in the majority of births worldwide. Education is key to changing this practice and World Cord Blood Day 2021 will provide the perfect opportunity for OBGYNs, midwives, transplant doctors, nurses, parents and students to learn about this vital medical resource.

During World Cord Blood Day 2021, participants will learn how cord blood is used to treat over 80 life-threatening diseases such as leukemia and lymphoma, bone marrow failure, immune deficiency diseases and inherited blood disorders such as thalassemia and sickle cell disease. Leading transplant doctors and researchers will also highlight cord blood's role in the emerging fields of gene therapy and regenerative medicine to potentially treat cerebral palsy, autism, stroke and more.

Organized by Save the Cord Foundation, a 501c3 non-profit, World Cord Blood Day 2021 is officially sponsored by QuickSTAT Global Life Science Logistics, recognized leader in medical shipping and healthcare logistics. Inspiring Partners include Be the Match (NMDP), World Marrow Donor Association (WMDA-Netcord), AABB Center for Cellular Therapies, Cord Blood Association, and the Foundation for the Accreditation of Cellular Therapy (FACT).

"QuickSTAT, part of Kuehne+Nagel, is proud to sponsor the 5th annual World Cord Blood Day to help support and educate the healthcare community and expectant parents about the life-saving value of cord blood stem cells. We're excited to play a role in the research and development of cord blood derivative therapies by providing logistics supply chain solutions to cord blood, biotech and pharmaceutical companies worldwide," said Monroe Burgess, VP Life Science Commercial Marketing, QuickSTAT.

Visit http://www.WorldCordBloodDay.org to learn how you can participate. Show your support on social media: @CordBloodDay, #WorldCordBloodDay, #WCBD21

About Save the Cord FoundationSave the Cord Foundation (a 501c3 non-profit) was established to advance cord blood education providing non-commercial information to health professionals and the public regarding methods for saving cord blood, as well as current applications and the latest research. http://www.SaveTheCordFoundation.org.

About QuickSTAT Global Life Science LogisticsEvery day, QuickSTAT, a part of Kuehne+Nagel, safely and reliably moves thousands of critical shipments around the world. For over forty years, QuickSTAT has been entrusted with transporting human organs and tissue for transplant or research, blood, blood products, cord blood, bone marrow, medical devices, and personalized medicine, 24/7/365. QuickSTAT's specially trained experts work with hospitals, laboratories, blood banks and medical processing centers, and utilize the safest routes to ensure integrity, temperature control and chain of custody throughout the transportation process. Learn more at http://www.quickstat.aero.

Contact:Charis Ober(520) 419-0269[emailprotected]

SOURCE Save the Cord Foundation

http://www.SaveTheCordFoundation.org

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Ready to Treat Over 80 Life-Threatening Diseases, Discover the Potential of Cord Blood during World Cord Blood Day 2021 - PRNewswire

Published: Oct. 4, 2021 at 6:00 AM EDT

NEW YORK, Oct. 4, 2021 /PRNewswire/ -- BrainStorm Cell Therapeutics Inc. (NASDAQ: BCLI), a leading developer of cellular therapies for neurodegenerative diseases, announced today that Stacy Lindborg, Ph.D., Executive Vice President and Head of Global Clinical Research, will deliver a presentation at the2021 Cell & Gene Meeting on the Mesa, being held as a hybrid conferenceOctober 12-14, and October 19-20, 2021.

Dr. Lindborg's presentation highlights the expansion of Brainstorm's technology portfolio to include autologous and allogeneic product candidates, covering multiple neurological diseases. The most progressed clinical development program, which includes a completed phase 3 trial of NurOwn in ALS patients, remains the highest priority for Brainstorm. Brainstorm is committed to pursuing the best and most expeditious path forward to enable patients to access NurOwn.

Dr. Lindborg's presentation will be in the form of an on-demand webinar that will be available beginning October 12. Those who wish to listen to the presentation are required to registerhere. At the conclusion of the 2021 Cell & Gene Meeting on the Mesa, a copy of the presentation will also be available in the "Investors and Media" section of the BrainStorm website underEvents and Presentations.

About the 2021 Cell & Gene Meeting on the Mesa

The meeting will feature sessions and workshops covering a mix of commercialization topics related to the cell and gene therapy sector including the latest updates on market access and reimbursement schemes, international regulation harmonization, manufacturing and CMC challenges, investment opportunities for the sector, among others. There will be over 135 presentations by leading public and private companies, highlighting technical and clinical achievements over the past 12 months in the areas of cell therapy, gene therapy, gene editing, tissue engineering and broader regenerative medicine technologies.

The conference will be delivered in a hybrid format to allow for an in-person experience as well as a virtual participation option. The in-person conference will take place October 12-14 in Carlsbad, CA. Virtual registrants will have access to all content via livestream during program dates. Additionally, all content will be available on-demand within 24 hours of the live program time. Virtual partnering meetings will take place October 19-20 via Zoom.

About NurOwn

The NurOwntechnology platform (autologous MSC-NTF cells) represents a promising investigational therapeutic approach to targeting disease pathways important in neurodegenerative disorders. MSC-NTF cells are produced from autologous, bone marrow-derived mesenchymal stem cells (MSCs) that have been expanded and differentiated ex vivo. MSCs are converted into MSC-NTF cells by growing them under patented conditions that induce the cells to secrete high levels of neurotrophic factors (NTFs). Autologous MSC-NTF cells are designed to effectively deliver multiple NTFs and immunomodulatory cytokines directly to the site of damage to elicit a desired biological effect and ultimately slow or stabilize disease progression.

About BrainStorm Cell Therapeutics Inc.

BrainStorm Cell Therapeutics Inc. is a leading developer of innovative autologous adult stem cell therapeutics for debilitating neurodegenerative diseases. The Company holds the rights to clinical development and commercialization of the NurOwntechnology platform used to produce autologous MSC-NTF cells through an exclusive, worldwide licensing agreement. Autologous MSC-NTF cells have received Orphan Drug designation status from the U.S. Food and Drug Administration (FDA) and the European Medicines Agency (EMA) for the treatment of amyotrophic lateral sclerosis (ALS). BrainStorm has completed a Phase 3 pivotal trial in ALS (NCT03280056); this trial investigated the safety and efficacy of repeat-administration of autologous MSC-NTF cells and was supported by a grant from the California Institute for Regenerative Medicine (CIRM CLIN2-0989). BrainStorm completed under an investigational new drug application a Phase 2 open-label multicenter trial (NCT03799718) of autologous MSC-NTF cells in progressive multiple sclerosis (MS) and was supported by a grant from the National MS Society (NMSS).

For more information, visit the company's website atwww.brainstorm-cell.com.

Safe-Harbor Statement

Statements in this announcement other than historical data and information, including statements regarding future NurOwnmanufacturing and clinical development plans, constitute "forward-looking statements" and involve risks and uncertainties that could cause BrainStorm Cell Therapeutics Inc.'s actual results to differ materially from those stated or implied by such forward-looking statements. Terms and phrases such as "may," "should," "would," "could," "will," "expect,""likely," "believe," "plan," "estimate," "predict," "potential," and similar terms and phrases are intended to identify these forward-looking statements. The potential risks and uncertainties include, without limitation, BrainStorm's need to raise additional capital, BrainStorm's ability to continue as a going concern, the prospects for regulatory approval of BrainStorm's NurOwntreatment candidate, the initiation, completion, and success of BrainStorm's product development programs and research, regulatory and personnel issues, development of a global market for our services, the ability to secure and maintain research institutions to conduct our clinical trials, the ability to generate significant revenue, the ability of BrainStorm's NurOwntreatment candidate to achieve broad acceptance as a treatment option for ALS or other neurodegenerative diseases, BrainStorm's ability to manufacture, or to use third parties to manufacture, and commercialize the NurOwntreatment candidate, obtaining patents that provide meaningful protection, competition and market developments, BrainStorm's ability to protect our intellectual property from infringement by third parties, heath reform legislation, demand for our services, currency exchange rates and product liability claims and litigation; and other factors detailed in BrainStorm's annual report on Form 10-K and quarterly reports on Form 10-Q available athttp://www.sec.gov. These factors should be considered carefully, and readers should not place undue reliance on BrainStorm's forward-looking statements. The forward-looking statements contained in this press release are based on the beliefs, expectations and opinions of management as of the date of this press release. We do not assume any obligation to update forward-looking statements to reflect actual results or assumptions if circumstances or management's beliefs, expectations or opinions should change, unless otherwise required by law. Although we believe that the expectations reflected in the forward-looking statements are reasonable, we cannot guarantee future results, levels of activity, performance or achievements.

ContactsInvestor Relations:Eric GoldsteinLifeSci Advisors, LLCPhone: +1 646.791.9729egoldstein@lifesciadvisors.com

Media:Paul TyahlaSmithSolvePhone: + 1.973.713.3768Paul.tyahla@smithsolve.com

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BrainStorm to Present at the 2021 Cell & Gene Meeting on the Mesa - WWNY

StemExpress to use utilize the Thermo Fisher Accula rapid PCR testing system to provide event attendees with accurate results in 30 minutes.

Published: Oct. 5, 2021 at 2:33 PM CDT|Updated: 4 hours ago

SACRAMENTO, Calif., Oct. 5, 2021 /PRNewswire/ --StemExpress is proud to announce that they will be the official COVID-19 testing provider for 2021's Meeting on the Mesa, a hybrid event bringing together great minds in the cell and gene biotech sphere. It has partnered with Alliance for Regenerative Medicine to comply with the newly implemented California state COVID-19 vaccination and testing policy regarding gatherings with 1,000 or more attendees. This partnership will allow the vital in-person networking aspect of the event to commence while protecting the health and safety of participants and attendees.

In-person networking commences at the 2021 Cell and Gene Meeting on the Mesa with COVID-19 testing options provided by StemExpress.

As a leading global provider of human biospecimen products, StemExpress understands the incredible impact that Meeting on the Mesa has on the industry and has been a proud participant for many years. For over a decade, StemExpress has provided the cell and gene industry with vital research products and holds valued partnerships with many of this year's participants. As such, it understands the immense value that in-person networking provides and is excited to help bring this element back to the meeting safely and responsibly.

StemExpress has been a trusted provider of widescale COVID-19 testing solutions since early 2020 - providing testing for government agencies, public health departments, private sector organizations, and the public nationwide. For Meeting on the Mesa, StemExpress is offering convenient testing options for unvaccinated attendees and those traveling from outside of the country. Options will include take-home RT-PCR COVID Self-Testing Kits and on-site, rapid PCR testing for the duration of the event. The self-testing kit option allows attendees to test for COVID in the days leading up to the event for a seamless admission and the days following the event to confirm they haven't been exposed. The on-site rapid testing option utilizes the new Thermo Fisher Accula, offering in-person testing at the event with results in around 30 minutes. StemExpress is excited to bring these state-of-the-art COVID testing solutions to the frontlines of the Cell & Gene industry to allow for safe in-person connections.

The StemExpress partnership with Alliance for Regenerative Medicine seeks to empower the entire cell and gene industry with a long-awaited opportunity to return to traditional networking practices. It is well known that innovation doesn't exist in a vacuum - allowing great minds to come together is a sure way to spur scientific growth and advance cutting-edge research, giving hope for future cures.

Cell and Gene Meeting on the Mesa will take place October 12th, 2021, through October 14th, 2021, at Park Hyatt Aviara,7100 Aviara Resort Drive Carlsbad, CA 92011. To learn more about the event, please visit MeetingOnTheMesa.com.

For more information about COVID testing solutions for businesses and events, visit https://www.stemexpress.com/covid-19-testing/.

About StemExpress:

Founded in 2010 and headquartered in Sacramento, California, StemExpress is a leading global biospecimen provider of human primary cells, stem cells, bone marrow, cord blood, peripheral blood, and disease-state products. Its products are used for research and development, clinical trials, and commercial production of cell and gene therapies by academic, biotech, diagnostic, pharmaceutical, and contract research organizations (CRO's).

StemExpress has over a dozen global distribution partners and seven (7) brick-and-mortar cellular clinics in the United States, outfitted with GMP certified laboratories. StemExpress runs its own non-profit supporting STEM initiatives, college and high school internships, and women-led organizations. It is registered with the U.S. Food and Drug Administration (FDA) and is continuously expanding its network of healthcare partnerships, which currently includes over 50 hospitals in Europe and 3 US healthcare systems - encompassing 31 hospitals, 35 outpatient facilities, and over 200 individual practices and clinics.

StemExpress has been ranked by Inc. 500 as one of the fastest-growing companies in the U.S.

About the Alliance for Regenerative Medicine:

The Alliance for Regenerative Medicine (ARM) is the leading international advocacy organization dedicated to realizing the promise of regenerative medicines and advanced therapies. ARM promotes legislative, regulatory, reimbursement and manufacturing initiatives to advance this innovative and transformative sector, which includes cell therapies, gene therapies and tissue-based therapies. Early products to market have demonstrated profound, durable and potentially curative benefits that are already helping thousands of patients worldwide, many of whom have no other viable treatment options. Hundreds of additional product candidates contribute to a robust pipeline of potentially life-changing regenerative medicines and advanced therapies. In its 12-year history, ARM has become the voice of the sector, representing the interests of 400+ members worldwide, including small and large companies, academic research institutions, major medical centers and patient groups. To learn more about ARM or to become a member, visit http://www.alliancerm.org.

Media Contact: Anthony Tucker, atucker@stemexpress.com

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The above press release was provided courtesy of PRNewswire. The views, opinions and statements in the press release are not endorsed by Gray Media Group nor do they necessarily state or reflect those of Gray Media Group, Inc.

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StemExpress Partners with the Alliance for Regenerative Medicine to Provide COVID-19 Testing for the Cell and Gene Meeting on the Mesa - WSAW

NEW YORK, Aug. 30, 2021 (GLOBE NEWSWIRE) -- Mesoblast Limited (Nasdaq:MESO; ASX:MSB), global leader in allogeneic cellular medicines for inflammatory diseases, today reported operational highlights and financial results for the fourth quarter and full-year ended June 30, 2021 (FY2021).

During this calendar year we made significant progress in both regulatory and clinical outcomes for our lead product candidate, remestemcel-L, after experiencing a disappointing set-back last year said Silviu Itescu, Chief Executive of Mesoblast. We are pleased with recent recommendations by FDAs CBER to meet with the review team and address remaining CMC items for remestemcel-L in the treatment of steroid-refractory acute graft versus host disease in children. Additionally, our most recent meeting with the FDA has provided clarity on the pathway towards an emergency use authorization for remestemcel-L in the treatment of COVID ARDS.

Operational Highlights

Remestemcel-L Outcome of recent meeting with FDA on regulatory pathway for emergency use authorization in the treatment of COVID-19 ARDS:

Remestemcel-L in the treatment of steroid-refractory acute graft versus host disease (SR-aGVHD) in children:

Rexlemestrocel-L in the treatment of chronic heart failure and chronic low back pain:

Manufacturing

Financial Highlights

DETAILED CLINICAL ACTIVITIES FOR THE FISCAL YEAR FY2021

Remestemcel-L

Acute Respiratory Distress Syndrome due to COVID-19

Mesoblast recently presented results from the randomized controlled trial of remestemcel-L in 222 ventilator-dependent COVID-19 patients with moderate/severe acute respiratory distress syndrome (ARDS) at the biennial Stem Cells, Cell Therapies, and Bioengineering in Lung Biology and Diseases conference hosted by the University of Vermont, Burlington, VT, and at the International Society for Cell & Gene Therapy (ISCT) Scientific Signatures Series event on Cell and Gene-Based Therapies in Lung Diseases and Critical Illnesses.

The presented data included improved respiratory function in patients treated with remestemcel-L, as well as 90-day survival outcomes showing remestemcel-L significantly reduced mortality by 48% at 90 days compared to controls in a pre-specified exploratory analysis of 123 treated patients under 65 years old. The trial had been halted after the third interim analysis since the 30-day primary endpoint would not be attained.

Key presentation findings were:

Mesoblast plans to move forward with an additional Phase 3 trial in COVID-19 ARDS with the next step being to agree with the FDA the final protocol and potency assay.

Inflammatory Bowel Disease Crohns Disease and Ulcerative Colitis

A randomized, controlled study of remestemcel-L delivered by an endoscope directly to areas of inflammation and tissue injury in up to 48 patients with medically refractory Crohns disease and ulcerative colitis commenced at Cleveland Clinic in October 2020. The investigator-initiated study is the first in humans using local cell delivery in the gut and will enable Mesoblast to compare clinical outcomes using this delivery method with results from an ongoing randomized, placebo-controlled trial in patients with biologic-refractory Crohns disease where remestemcel-L was administered intravenously.

Rexlemestrocel-L

Chronic Heart Failure

The results from the landmark DREAM-HF randomized controlled trial in 537 treated patients with chronic heart failure with reduced left ventricular ejection fraction (HFrEF) who received rexlemestrocel-L (REVASCOR) or control sham, demonstrated that a single dose of rexlemestrocel-L resulted in substantial and durable reductions in heart attacks, strokes, and cardiac deaths. The trials primary endpoint of reduction in volume overload related hospitalizations was not achieved. The results of this trial identify New York Heart Association (NYHA) class II HFrEF patients as the optimal target population for greatest rexlemestrocel-L treatment effect, and therefore a focus for developing rexlemestrocel-L in the largest market in heart failure.

The incidence of heart attacks and strokes were reduced by 60% over a median follow-up period of 30 months following a single dose of rexlemestrocel-L in the entire population of 537 treated patients. The incidence of death from cardiovascular causes was reduced by 60% in the 206 patients with NYHA class II disease, a significant reduction which was evident in both ischemic and non-ischemic subgroups as well as diabetic and nondiabetic patients.

The results also show that the NYHA class II patients in the control group, following an initial period of approximately 20 months of disease stability, progressed to cardiac death rates in-line with NYHA class III patients. NYHA class II patients treated with a single dose of rexlemestrocel-L did not show such cardiac death progression.

The combination of the three pre-specified outcomes of cardiac death, heart attack or stroke into a single composite outcome - called the three-point major adverse cardiovascular events (MACE) is a well-established endpoint used by the FDA to determine cardiovascular risk. Rexlemestrocel-L reduced this three-point MACE by 30% compared to controls across the entire population of 537 treated patients. In the NYHA class II subgroup of 206 patients, rexlemestrocel-L reduced the three-point MACE by 55% compared to controls.

Mesoblast expects feedback from the FDA in the next quarter on the potential pathway to US regulatory approval for rexlemestrocel-L in patients with chronic heart failure.

Chronic Low Back Pain due to Degenerative Disc Disease

The results from the randomized controlled trial of its allogeneic mesenchymal precursor cell (MPC) therapy rexlemestrocel-L in 404 enrolled patients with chronic low back pain (CLBP) due to degenerative disc disease (DDD) refractory to conventional treatments indicate that a single injection of rexlemestrocel-L+hyaluronic acid (HA) carrier may provide a safe, durable, and effective opioid-sparing therapy for patients with chronic inflammatory back pain due to degenerative disc disease, and that greatest benefits are seen when administered earlier in the disease process before irreversible fibrosis of the intervertebral disc has occurred. The trial's composite outcomes of pain reduction together with functional responses to treatment were not met by either MPC group.

The rexlemestrocel-L+HA treatment group achieved substantial and durable reductions in CLBP compared to control through 24 months across the entire evaluable study population (n=391) compared with saline controls. Greatest pain reduction was observed in the pre-specified population with CLBP of shorter duration than the study median of 68 months (n=194) and subjects using opioids at baseline (n=168) with the rexlemestrocel-L+HA group having substantially greater reduction at all time points (1, 3, 6, 12, 18 and 24 months) compared with saline controls. There was no appreciable difference in the safety of MPC groups compared to saline control over the 24-month period of follow-up in the entire study population. In subjects using opioids at baseline, the MPC+HA demonstrated a reduction in the average opioid dose over 24 months, while saline control subjects had essentially no change.

There is a significant need for a safe, efficacious, and durable opioid-sparing treatment in patients with chronic low back pain due to severely inflamed degenerative disc disease. Mesoblast has filed a request and expects to receive feedback from the FDA on the pathway to US regulatory approval in patients with chronic low back pain due to degenerative disc disease.

Intellectual Property

Mesoblast has an extensive patent portfolio with over 1,000 patents and patent applications across 77 patent families, and patent terms extending through 2041. These patents cover composition of matter, manufacturing, and therapeutic applications of mesenchymal lineage cells, and provide strong commercial protection for our products in all major markets, including the United States, Europe, Japan and China. During the fiscal year Mesoblast has significantly expanded its patent portfolio, focusing on areas of its strategic commercial interests.

Licensing agreements with JCR, Grnenthal, Tasly and Takeda highlight the strength of Mesoblast's extensive intellectual property portfolio covering mesenchymal lineage cells. Mesoblast will continue to use its patents to prosecute its commercial rights as they relate to its core strategic product portfolio. When consistent with the Companys strategic objectives, it may consider providing third parties with commercial access to its patent portfolio.

DETAILED FINANCIAL RESULTS

Financial Results for the Year Ended June 30, 2021 (FY2021)

In August we entered into a contractual amendment to extend the interest-only period of its current senior debt facility to at least January 2022 and as a result no loan repayments will be required prior to January 2022. Mesoblast is in active discussions to refinance the facility.

We expect to recognize the existing US$21.9 million of remestemcel-L pre-launch inventory on the balance sheet if we receive FDA approval.

As a result of the above and other remeasurements on revaluation of assets and liabilities, the loss after tax for FY2021 was US$98.8 million compared to US$77.9 million for FY2020. The net loss attributable to ordinary shareholders was 16.33 US cents per share for FY2021, compared with 14.74 US cents per share for FY2020.

Conference Call

There will be a webcast today, beginning at 7.00pm EDT (Monday, August 30, 2021); 9.00am AEST (Tuesday, August 31). It can be accessed via:https://webcast.boardroom.media/mesoblast-limited/20210826/NaN61036c41df5665001c97fc67

The archived webcast will be available on the Investor page of the Companys website: http://www.mesoblast.com

About Mesoblast

Mesoblast is a world leader in developing allogeneic (off-the-shelf) cellular medicines for the treatment of severe and life-threatening inflammatory conditions. The Company has leveraged its proprietary mesenchymal lineage cell therapy technology platform to establish a broad portfolio of late-stage product candidates which respond to severe inflammation by releasing anti-inflammatory factors that counter and modulate multiple effector arms of the immune system, resulting in significant reduction of the damaging inflammatory process.

Mesoblast has a strong and extensive global intellectual property portfolio with protection extending through to at least 2041 in all major markets. The Companys proprietary manufacturing processes yield industrial-scale, cryopreserved, off-the-shelf, cellular medicines. These cell therapies, with defined pharmaceutical release criteria, are planned to be readily available to patients worldwide.

Mesoblast has completed Phase 3 trials of rexlemestrocel-L for advanced chronic heart failure and chronic low back pain. Remestemcel-L is being developed for inflammatory diseases in children and adults including steroid refractory acute graft versus host disease and moderate to severe acute respiratory distress syndrome. Two products have been commercialized in Japan and Europe by Mesoblasts licensees, and the Company has established commercial partnerships in Europe and China for certain Phase 3 assets.

Mesoblast has locations in Australia, the United States and Singapore and is listed on the Australian Securities Exchange (MSB) and on the Nasdaq (MESO). For more information, please see http://www.mesoblast.com, LinkedIn: Mesoblast Limited and Twitter: @Mesoblast

References / Footnotes

Forward-Looking Statements

This announcement includes forward-looking statements that relate to future events or our future financial performance and involve known and unknown risks, uncertainties and other factors that may cause our actual results, levels of activity, performance or achievements to differ materially from any future results, levels of activity, performance or achievements expressed or implied by these forward-looking statements. We make such forward-looking statements pursuant to the safe harbor provisions of the Private Securities Litigation Reform Act of 1995 and other federal securities laws. Forward-looking statements should not be read as a guarantee of future performance or results, and actual results may differ from the results anticipated in these forward-looking statements, and the differences may be material and adverse. Forward-looking statements include, but are not limited to, statements about the initiation, timing, progress and results of Mesoblasts preclinical and clinical studies, and Mesoblasts research and development programs; Mesoblasts ability to advance product candidates into, enroll and successfully complete, clinical studies, including multi-national clinical trials; Mesoblasts ability to advance its manufacturing capabilities; the timing or likelihood of regulatory filings and approvals, manufacturing activities and product marketing activities, if any; the commercialization of Mesoblasts product candidates, if approved; regulatory or public perceptions and market acceptance surrounding the use of stem-cell based therapies; the potential for Mesoblasts product candidates, if any are approved, to be withdrawn from the market due to patient adverse events or deaths; the potential benefits of strategic collaboration agreements and Mesoblasts ability to enter into and maintain established strategic collaborations; Mesoblasts ability to establish and maintain intellectual property on its product candidates and Mesoblasts ability to successfully defend these in cases of alleged infringement; the scope of protection Mesoblast is able to establish and maintain for intellectual property rights covering its product candidates and technology; estimates of Mesoblasts expenses, future revenues, capital requirements and its needs for additional financing; Mesoblasts financial performance; developments relating to Mesoblasts competitors and industry; and the pricing and reimbursement of Mesoblasts product candidates, if approved. You should read this press release together with our risk factors, in our most recently filed reports with the SEC or on our website. Uncertainties and risks that may cause Mesoblasts actual results, performance or achievements to be materially different from those which may be expressed or implied by such statements, and accordingly, you should not place undue reliance on these forward-looking statements. We do not undertake any obligations to publicly update or revise any forward-looking statements, whether as a result of new information, future developments or otherwise.

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Operational Highlights and Financial Results for the Year Ended June 30, 2021 - GlobeNewswire

Abstract: Global Induced Pluripotent Stem Cell ((iPSC) Market to Reach $2. 3 Billion by 2026 . Induced pluripotent stem cells (iPSCs) hold tremendous clinical potential to transform the entire therapeutic landscape by offering treatments for various medical conditions and disorders.

New York, Aug. 05, 2021 (GLOBE NEWSWIRE) -- Reportlinker.com announces the release of the report "Global Induced Pluripotent Stem Cell (iPSC) Industry" - https://www.reportlinker.com/p05798831/?utm_source=GNW These cells are derived from somatic cells like blood or skin cells that are genetically reprogrammed into embryonic stem cell-like state for developing an unlimited source of a diverse range of human cells for therapeutic applications. The global market is propelled by increasing demand for these cells, rising focus on researchers in the field, and their potential application in treatment of various diseases. The market growth is supplemented by rising prevalence of several chronic disorders such as diabetes, heart disease, stroke and cancer. Moreover, increasing awareness about stem cells and associated research, potential clinical applications and rising financial assistance by governments and private players are expected to contribute significantly to the market expansion. The iPSC technique is anticipated to find extensive adoption in the pharmaceutical industry for developing efficient cell sources like iPSC-derived functional cells to support drug screening and toxicity testing.

Amid the COVID-19 crisis, the global market for Induced Pluripotent Stem Cell ((iPSC) estimated at US$1.6 Billion in the year 2020, is projected to reach a revised size of US$2.3 Billion by 2026, growing at a CAGR of 6.6% over the analysis period. Vascular Cells, one of the segments analyzed in the report, is projected to record a 7.2% CAGR and reach US$835.8 Million by the end of the analysis period. After a thorough analysis of the business implications of the pandemic and its induced economic crisis, growth in the Cardiac Cells segment is readjusted to a revised 7.9% CAGR for the next 7-year period. The demand for iPSC-derived cardiac cells is attributed to diverse applications including cardiotoxicity testing, drug screening and drug validation along with metabolism studies and electrophysiology applications.

The U.S. Market is Estimated at $767.1 Million in 2021, While China is Forecast to Reach $82.4 Million by 2026

The Induced Pluripotent Stem Cell ((iPSC) market in the U.S. is estimated at US$767.1 Million in the year 2021. China, the world`s second largest economy, is forecast to reach a projected market size of US$82.4 Million by the year 2026 trailing a CAGR of 8.5% over the analysis period. Among the other noteworthy geographic markets are Japan and Canada, each forecast to grow at 5.5 % and 6.8% respectively over the analysis period. Within Europe, Germany is forecast to grow at approximately 6.5% CAGR. North America leads the global market, supported by continuing advances related to iPSC technology and access to functional cells used in pre-clinical drug screening. The market growth is supplemented by increasing insights into the iPSC platform along with high throughput analysis for drug toxicity. The iPSC market in Asia-Pacific is estimated to post a fast growth due to increasing R&D projects across countries like Australia, Japan and Singapore.

Neuronal Cells Segment to Reach $336.9 Million by 2026

In the global Neuronal Cells segment, USA, Canada, Japan, China and Europe will drive the 6.4% CAGR estimated for this segment. These regional markets accounting for a combined market size of US$202.9 Million in the year 2020 will reach a projected size of US$308 Million by the close of the analysis period. China will remain among the fastest growing in this cluster of regional markets. Led by countries such as Australia, India, and South Korea, the market in Asia-Pacific is forecast to reach US$19.8 Million by the year 2026. Select Competitors (Total 51 Featured)

Story continues

Axol Bioscience Ltd.

Cynata Therapeutics Limited

Evotec SE

Fate Therapeutics, Inc.

FUJIFILM Cellular Dynamics, Inc.

Ncardia

Pluricell Biotech

REPROCELL USA, Inc.

Sumitomo Dainippon Pharma Co., Ltd.

Takara Bio, Inc.

Thermo Fisher Scientific, Inc.

ViaCyte, Inc.

Read the full report: https://www.reportlinker.com/p05798831/?utm_source=GNW

I. METHODOLOGY

II. EXECUTIVE SUMMARY

1. MARKET OVERVIEW Influencer Market Insights Impact of Covid-19 and a Looming Global Recession Induced Pluripotent Stem Cells (iPSCs) Market Gains from Increasing Use in Research for COVID-19 Studies Employing iPSCs in COVID-19 Research Stem Cells, Application Areas, and the Different Types: A Prelude Applications of Stem Cells Types of Stem Cells Induced Pluripotent Stem Cell (iPSC): An Introduction Production of iPSCs First & Second Generation Mouse iPSCs Human iPSCs Key Properties of iPSCs Transcription Factors Involved in Generation of iPSCs Noteworthy Research & Application Areas for iPSCs Induced Pluripotent Stem Cell ((iPSC) Market: Growth Prospects and Outlook Drug Development Application to Witness Considerable Growth Technical Breakthroughs, Advances & Clinical Trials to Spur Growth of iPSC Market North America Dominates Global iPSC Market Competition Recent Market Activity Select Innovation/Advancement

2. FOCUS ON SELECT PLAYERS Axol Bioscience Ltd. (UK) Cynata Therapeutics Limited (Australia) Evotec SE (Germany) Fate Therapeutics, Inc. (USA) FUJIFILM Cellular Dynamics, Inc. (USA) Ncardia (Belgium) Pluricell Biotech (Brazil) REPROCELL USA, Inc. (USA) Sumitomo Dainippon Pharma Co., Ltd. (Japan) Takara Bio, Inc. (Japan) Thermo Fisher Scientific, Inc. (USA) ViaCyte, Inc. (USA)

3. MARKET TRENDS & DRIVERS Effective Research Programs Hold Key in Roll Out of Advanced iPSC Treatments Induced Pluripotent Stem Cells: A Giant Leap in the Therapeutic Applications Research Trends in Induced Pluripotent Stem Cell Space EXHIBIT 1: Worldwide Publication of hESC and hiPSC Research Papers for the Period 2008-2010, 2011-2013 and 2014-2016 EXHIBIT 2: Number of Original Research Papers on hESC and iPSC Published Worldwide (2014-2016) Concerns Related to Embryonic Stem Cells Shift the Focus onto iPSCs Regenerative Medicine: A Promising Application of iPSCs Induced Pluripotent: A Potential Competitor to hESCs? EXHIBIT 3: Global Regenerative Medicine Market Size in US$ Billion for 2019, 2021, 2023 and 2025 EXHIBIT 4: Global Stem Cell & Regenerative Medicine Market by Product (in %) for the Year 2019 EXHIBIT 5: Global Regenerative Medicines Market by Category: Breakdown (in %) for Biomaterials, Stem Cell Therapies and Tissue Engineering for 2019 Pluripotent Stem Cells Hold Significance for Cardiovascular Regenerative Medicine EXHIBIT 6: Leading Causes of Mortality Worldwide: Number of Deaths in Millions & % Share of Deaths by Cause for 2017 EXHIBIT 7: Leading Causes of Mortality for Low-Income and High -Income Countries Growing Importance of iPSCs in Personalized Drug Discovery Persistent Advancements in Genetics Space and Subsequent Growth in Precision Medicine Augur Well for iPSCs Market EXHIBIT 8: Global Precision Medicine Market (In US$ Billion) for the Years 2018, 2021 & 2024 Increasing Prevalence of Chronic Disorders Supports Growth of iPSCs Market EXHIBIT 9: Worldwide Cancer Incidence: Number of New Cancer Cases Diagnosed for 2012, 2018 & 2040 EXHIBIT 10: Number of New Cancer Cases Reported (in Thousands) by Cancer Type: 2018 EXHIBIT 11: Fatalities by Heart Conditions: Estimated Percentage Breakdown for Cardiovascular Disease, Ischemic Heart Disease, Stroke, and Others EXHIBIT 12: Rising Diabetes Prevalence Presents Opportunity for iPSCs Market: Number of Adults (20-79) with Diabetes (in Millions) by Region for 2017 and 2045 Aging Demographics Add to the Global Burden of Chronic Diseases, Presenting Opportunities for iPSCs Market EXHIBIT 13: Expanding Elderly Population Worldwide: Breakdown of Number of People Aged 65+ Years in Million by Geographic Region for the Years 2019 and 2030 Growth in Number of Genomics Projects Propels Market Growth EXHIBIT 14: Genomic Initiatives in Select Countries EXHIBIT 15: New Gene-Editing Tools Spur Interest and Investments in Genetics, Driving Lucrative Growth Opportunities for iPSCs: Total VC Funding (In US$ Million) in Genetics for the Years 2014, 2015, 2016, 2017 and 2018 Launch of Numerous iPSCs-Related Clinical Trials Set to Benefit Market Growth EXHIBIT 16: Number of Induced Pluripotent Stem Cells based Studies by Select Condition: As on Oct 31, 2020 iPSCs-based Clinical Trial for Heart Diseases Induced Pluripotent Stem Cells for Stroke Treatment ?Off-the-shelf? Stem Cell Treatment for Cancer Enters Clinical Trial iPSCs for Hematological Disorders Market Benefits from Growing Funding for iPSCs-Related R&D Initiatives EXHIBIT 17: Stem Cell Research Funding in the US (in US$ Million) for the Years 2016 through 2021 Human iPSC Banks: A Review of Emerging Opportunities and Drawbacks EXHIBIT 18: Human iPSC Banks Worldwide: An Overview EXHIBIT 19: Cell Sources and Reprogramming Methods Used by Select iPSC Banks Innovations, Research Studies & Advancements in iPSCs Key iPSC Research Breakthroughs for Regenerative Medicine Researchers Develop Novel Oncogene-Free and Virus-Free iPSC Production Method Scientists Study Concerns of Genetic Mutations in iPSCs iPSCs Hold Tremendous Potential in Transforming Research Efforts Researchers Highlight Potential Use of iPSCs for Developing Novel Cancer Vaccines Scientists Use Machine Learning to Improve Reliability of iPSC Self-Organization STEMCELL Technologies Unveils mTeSR? Plus Challenges and Risks Related to Pluripotent Stem Cells A Glance at Issues Related to Reprogramming of Adult Cells to iPSCs A Note on Legal, Social and Ethical Considerations with iPSCs

4. GLOBAL MARKET PERSPECTIVE Table 1: World Current & Future Analysis for Induced Pluripotent Stem Cell (iPSC) by Geographic Region - USA, Canada, Japan, China, Europe, Asia-Pacific and Rest of World Markets - Independent Analysis of Annual Sales in US$ Thousand for Years 2020 through 2027 and % CAGR

Table 2: World 7-Year Perspective for Induced Pluripotent Stem Cell (iPSC) by Geographic Region - Percentage Breakdown of Value Sales for USA, Canada, Japan, China, Europe, Asia-Pacific and Rest of World Markets for Years 2020 & 2027

Table 3: World Current & Future Analysis for Vascular Cells by Geographic Region - USA, Canada, Japan, China, Europe, Asia-Pacific and Rest of World Markets - Independent Analysis of Annual Sales in US$ Thousand for Years 2020 through 2027 and % CAGR

Table 4: World 7-Year Perspective for Vascular Cells by Geographic Region - Percentage Breakdown of Value Sales for USA, Canada, Japan, China, Europe, Asia-Pacific and Rest of World for Years 2020 & 2027

Table 5: World Current & Future Analysis for Cardiac Cells by Geographic Region - USA, Canada, Japan, China, Europe, Asia-Pacific and Rest of World Markets - Independent Analysis of Annual Sales in US$ Thousand for Years 2020 through 2027 and % CAGR

Table 6: World 7-Year Perspective for Cardiac Cells by Geographic Region - Percentage Breakdown of Value Sales for USA, Canada, Japan, China, Europe, Asia-Pacific and Rest of World for Years 2020 & 2027

Table 7: World Current & Future Analysis for Neuronal Cells by Geographic Region - USA, Canada, Japan, China, Europe, Asia-Pacific and Rest of World Markets - Independent Analysis of Annual Sales in US$ Thousand for Years 2020 through 2027 and % CAGR

Table 8: World 7-Year Perspective for Neuronal Cells by Geographic Region - Percentage Breakdown of Value Sales for USA, Canada, Japan, China, Europe, Asia-Pacific and Rest of World for Years 2020 & 2027

Table 9: World Current & Future Analysis for Liver Cells by Geographic Region - USA, Canada, Japan, China, Europe, Asia-Pacific and Rest of World Markets - Independent Analysis of Annual Sales in US$ Thousand for Years 2020 through 2027 and % CAGR

Table 10: World 7-Year Perspective for Liver Cells by Geographic Region - Percentage Breakdown of Value Sales for USA, Canada, Japan, China, Europe, Asia-Pacific and Rest of World for Years 2020 & 2027

Table 11: World Current & Future Analysis for Immune Cells by Geographic Region - USA, Canada, Japan, China, Europe, Asia-Pacific and Rest of World Markets - Independent Analysis of Annual Sales in US$ Thousand for Years 2020 through 2027 and % CAGR

Table 12: World 7-Year Perspective for Immune Cells by Geographic Region - Percentage Breakdown of Value Sales for USA, Canada, Japan, China, Europe, Asia-Pacific and Rest of World for Years 2020 & 2027

Table 13: World Current & Future Analysis for Other Cell Types by Geographic Region - USA, Canada, Japan, China, Europe, Asia-Pacific and Rest of World Markets - Independent Analysis of Annual Sales in US$ Thousand for Years 2020 through 2027 and % CAGR

Table 14: World 7-Year Perspective for Other Cell Types by Geographic Region - Percentage Breakdown of Value Sales for USA, Canada, Japan, China, Europe, Asia-Pacific and Rest of World for Years 2020 & 2027

Table 15: World Current & Future Analysis for Cellular Reprogramming by Geographic Region - USA, Canada, Japan, China, Europe, Asia-Pacific and Rest of World Markets - Independent Analysis of Annual Sales in US$ Thousand for Years 2020 through 2027 and % CAGR

Table 16: World 7-Year Perspective for Cellular Reprogramming by Geographic Region - Percentage Breakdown of Value Sales for USA, Canada, Japan, China, Europe, Asia-Pacific and Rest of World for Years 2020 & 2027

Table 17: World Current & Future Analysis for Cell Culture by Geographic Region - USA, Canada, Japan, China, Europe, Asia-Pacific and Rest of World Markets - Independent Analysis of Annual Sales in US$ Thousand for Years 2020 through 2027 and % CAGR

Table 18: World 7-Year Perspective for Cell Culture by Geographic Region - Percentage Breakdown of Value Sales for USA, Canada, Japan, China, Europe, Asia-Pacific and Rest of World for Years 2020 & 2027

Table 19: World Current & Future Analysis for Cell Differentiation by Geographic Region - USA, Canada, Japan, China, Europe, Asia-Pacific and Rest of World Markets - Independent Analysis of Annual Sales in US$ Thousand for Years 2020 through 2027 and % CAGR

Table 20: World 7-Year Perspective for Cell Differentiation by Geographic Region - Percentage Breakdown of Value Sales for USA, Canada, Japan, China, Europe, Asia-Pacific and Rest of World for Years 2020 & 2027

Table 21: World Current & Future Analysis for Cell Analysis by Geographic Region - USA, Canada, Japan, China, Europe, Asia-Pacific and Rest of World Markets - Independent Analysis of Annual Sales in US$ Thousand for Years 2020 through 2027 and % CAGR

Table 22: World 7-Year Perspective for Cell Analysis by Geographic Region - Percentage Breakdown of Value Sales for USA, Canada, Japan, China, Europe, Asia-Pacific and Rest of World for Years 2020 & 2027

Table 23: World Current & Future Analysis for Cellular Engineering by Geographic Region - USA, Canada, Japan, China, Europe, Asia-Pacific and Rest of World Markets - Independent Analysis of Annual Sales in US$ Thousand for Years 2020 through 2027 and % CAGR

Table 24: World 7-Year Perspective for Cellular Engineering by Geographic Region - Percentage Breakdown of Value Sales for USA, Canada, Japan, China, Europe, Asia-Pacific and Rest of World for Years 2020 & 2027

Table 25: World Current & Future Analysis for Other Research Methods by Geographic Region - USA, Canada, Japan, China, Europe, Asia-Pacific and Rest of World Markets - Independent Analysis of Annual Sales in US$ Thousand for Years 2020 through 2027 and % CAGR

Table 26: World 7-Year Perspective for Other Research Methods by Geographic Region - Percentage Breakdown of Value Sales for USA, Canada, Japan, China, Europe, Asia-Pacific and Rest of World for Years 2020 & 2027

Table 27: World Current & Future Analysis for Drug Development & Toxicology Testing by Geographic Region - USA, Canada, Japan, China, Europe, Asia-Pacific and Rest of World Markets - Independent Analysis of Annual Sales in US$ Thousand for Years 2020 through 2027 and % CAGR

Table 28: World 7-Year Perspective for Drug Development & Toxicology Testing by Geographic Region - Percentage Breakdown of Value Sales for USA, Canada, Japan, China, Europe, Asia-Pacific and Rest of World for Years 2020 & 2027

Table 29: World Current & Future Analysis for Academic Research by Geographic Region - USA, Canada, Japan, China, Europe, Asia-Pacific and Rest of World Markets - Independent Analysis of Annual Sales in US$ Thousand for Years 2020 through 2027 and % CAGR

Table 30: World 7-Year Perspective for Academic Research by Geographic Region - Percentage Breakdown of Value Sales for USA, Canada, Japan, China, Europe, Asia-Pacific and Rest of World for Years 2020 & 2027

Table 31: World Current & Future Analysis for Regenerative Medicine by Geographic Region - USA, Canada, Japan, China, Europe, Asia-Pacific and Rest of World Markets - Independent Analysis of Annual Sales in US$ Thousand for Years 2020 through 2027 and % CAGR

Table 32: World 7-Year Perspective for Regenerative Medicine by Geographic Region - Percentage Breakdown of Value Sales for USA, Canada, Japan, China, Europe, Asia-Pacific and Rest of World for Years 2020 & 2027

Table 33: World Current & Future Analysis for Other Applications by Geographic Region - USA, Canada, Japan, China, Europe, Asia-Pacific and Rest of World Markets - Independent Analysis of Annual Sales in US$ Thousand for Years 2020 through 2027 and % CAGR

Table 34: World 7-Year Perspective for Other Applications by Geographic Region - Percentage Breakdown of Value Sales for USA, Canada, Japan, China, Europe, Asia-Pacific and Rest of World for Years 2020 & 2027

III. MARKET ANALYSIS

UNITED STATES Table 35: USA Current & Future Analysis for Induced Pluripotent Stem Cell (iPSC) by Cell Type - Vascular Cells, Cardiac Cells, Neuronal Cells, Liver Cells, Immune Cells and Other Cell Types - Independent Analysis of Annual Sales in US$ Thousand for the Years 2020 through 2027 and % CAGR

Table 36: USA 7-Year Perspective for Induced Pluripotent Stem Cell (iPSC) by Cell Type - Percentage Breakdown of Value Sales for Vascular Cells, Cardiac Cells, Neuronal Cells, Liver Cells, Immune Cells and Other Cell Types for the Years 2020 & 2027

Table 37: USA Current & Future Analysis for Induced Pluripotent Stem Cell (iPSC) by Research Method - Cellular Reprogramming, Cell Culture, Cell Differentiation, Cell Analysis, Cellular Engineering and Other Research Methods - Independent Analysis of Annual Sales in US$ Thousand for the Years 2020 through 2027 and % CAGR

Table 38: USA 7-Year Perspective for Induced Pluripotent Stem Cell (iPSC) by Research Method - Percentage Breakdown of Value Sales for Cellular Reprogramming, Cell Culture, Cell Differentiation, Cell Analysis, Cellular Engineering and Other Research Methods for the Years 2020 & 2027

Table 39: USA Current & Future Analysis for Induced Pluripotent Stem Cell (iPSC) by Application - Drug Development & Toxicology Testing, Academic Research, Regenerative Medicine and Other Applications - Independent Analysis of Annual Sales in US$ Thousand for the Years 2020 through 2027 and % CAGR

Table 40: USA 7-Year Perspective for Induced Pluripotent Stem Cell (iPSC) by Application - Percentage Breakdown of Value Sales for Drug Development & Toxicology Testing, Academic Research, Regenerative Medicine and Other Applications for the Years 2020 & 2027

CANADA Table 41: Canada Current & Future Analysis for Induced Pluripotent Stem Cell (iPSC) by Cell Type - Vascular Cells, Cardiac Cells, Neuronal Cells, Liver Cells, Immune Cells and Other Cell Types - Independent Analysis of Annual Sales in US$ Thousand for the Years 2020 through 2027 and % CAGR

Table 42: Canada 7-Year Perspective for Induced Pluripotent Stem Cell (iPSC) by Cell Type - Percentage Breakdown of Value Sales for Vascular Cells, Cardiac Cells, Neuronal Cells, Liver Cells, Immune Cells and Other Cell Types for the Years 2020 & 2027

Table 43: Canada Current & Future Analysis for Induced Pluripotent Stem Cell (iPSC) by Research Method - Cellular Reprogramming, Cell Culture, Cell Differentiation, Cell Analysis, Cellular Engineering and Other Research Methods - Independent Analysis of Annual Sales in US$ Thousand for the Years 2020 through 2027 and % CAGR

Table 44: Canada 7-Year Perspective for Induced Pluripotent Stem Cell (iPSC) by Research Method - Percentage Breakdown of Value Sales for Cellular Reprogramming, Cell Culture, Cell Differentiation, Cell Analysis, Cellular Engineering and Other Research Methods for the Years 2020 & 2027

Table 45: Canada Current & Future Analysis for Induced Pluripotent Stem Cell (iPSC) by Application - Drug Development & Toxicology Testing, Academic Research, Regenerative Medicine and Other Applications - Independent Analysis of Annual Sales in US$ Thousand for the Years 2020 through 2027 and % CAGR

Table 46: Canada 7-Year Perspective for Induced Pluripotent Stem Cell (iPSC) by Application - Percentage Breakdown of Value Sales for Drug Development & Toxicology Testing, Academic Research, Regenerative Medicine and Other Applications for the Years 2020 & 2027

JAPAN Table 47: Japan Current & Future Analysis for Induced Pluripotent Stem Cell (iPSC) by Cell Type - Vascular Cells, Cardiac Cells, Neuronal Cells, Liver Cells, Immune Cells and Other Cell Types - Independent Analysis of Annual Sales in US$ Thousand for the Years 2020 through 2027 and % CAGR

Table 48: Japan 7-Year Perspective for Induced Pluripotent Stem Cell (iPSC) by Cell Type - Percentage Breakdown of Value Sales for Vascular Cells, Cardiac Cells, Neuronal Cells, Liver Cells, Immune Cells and Other Cell Types for the Years 2020 & 2027

Table 49: Japan Current & Future Analysis for Induced Pluripotent Stem Cell (iPSC) by Research Method - Cellular Reprogramming, Cell Culture, Cell Differentiation, Cell Analysis, Cellular Engineering and Other Research Methods - Independent Analysis of Annual Sales in US$ Thousand for the Years 2020 through 2027 and % CAGR

Table 50: Japan 7-Year Perspective for Induced Pluripotent Stem Cell (iPSC) by Research Method - Percentage Breakdown of Value Sales for Cellular Reprogramming, Cell Culture, Cell Differentiation, Cell Analysis, Cellular Engineering and Other Research Methods for the Years 2020 & 2027

Table 51: Japan Current & Future Analysis for Induced Pluripotent Stem Cell (iPSC) by Application - Drug Development & Toxicology Testing, Academic Research, Regenerative Medicine and Other Applications - Independent Analysis of Annual Sales in US$ Thousand for the Years 2020 through 2027 and % CAGR

Table 52: Japan 7-Year Perspective for Induced Pluripotent Stem Cell (iPSC) by Application - Percentage Breakdown of Value Sales for Drug Development & Toxicology Testing, Academic Research, Regenerative Medicine and Other Applications for the Years 2020 & 2027

CHINA Table 53: China Current & Future Analysis for Induced Pluripotent Stem Cell (iPSC) by Cell Type - Vascular Cells, Cardiac Cells, Neuronal Cells, Liver Cells, Immune Cells and Other Cell Types - Independent Analysis of Annual Sales in US$ Thousand for the Years 2020 through 2027 and % CAGR

Table 54: China 7-Year Perspective for Induced Pluripotent Stem Cell (iPSC) by Cell Type - Percentage Breakdown of Value Sales for Vascular Cells, Cardiac Cells, Neuronal Cells, Liver Cells, Immune Cells and Other Cell Types for the Years 2020 & 2027

Table 55: China Current & Future Analysis for Induced Pluripotent Stem Cell (iPSC) by Research Method - Cellular Reprogramming, Cell Culture, Cell Differentiation, Cell Analysis, Cellular Engineering and Other Research Methods - Independent Analysis of Annual Sales in US$ Thousand for the Years 2020 through 2027 and % CAGR

Table 56: China 7-Year Perspective for Induced Pluripotent Stem Cell (iPSC) by Research Method - Percentage Breakdown of Value Sales for Cellular Reprogramming, Cell Culture, Cell Differentiation, Cell Analysis, Cellular Engineering and Other Research Methods for the Years 2020 & 2027

Table 57: China Current & Future Analysis for Induced Pluripotent Stem Cell (iPSC) by Application - Drug Development & Toxicology Testing, Academic Research, Regenerative Medicine and Other Applications - Independent Analysis of Annual Sales in US$ Thousand for the Years 2020 through 2027 and % CAGR

Table 58: China 7-Year Perspective for Induced Pluripotent Stem Cell (iPSC) by Application - Percentage Breakdown of Value Sales for Drug Development & Toxicology Testing, Academic Research, Regenerative Medicine and Other Applications for the Years 2020 & 2027

EUROPE Table 59: Europe Current & Future Analysis for Induced Pluripotent Stem Cell (iPSC) by Geographic Region - France, Germany, Italy, UK and Rest of Europe Markets - Independent Analysis of Annual Sales in US$ Thousand for Years 2020 through 2027 and % CAGR

Table 60: Europe 7-Year Perspective for Induced Pluripotent Stem Cell (iPSC) by Geographic Region - Percentage Breakdown of Value Sales for France, Germany, Italy, UK and Rest of Europe Markets for Years 2020 & 2027

Table 61: Europe Current & Future Analysis for Induced Pluripotent Stem Cell (iPSC) by Cell Type - Vascular Cells, Cardiac Cells, Neuronal Cells, Liver Cells, Immune Cells and Other Cell Types - Independent Analysis of Annual Sales in US$ Thousand for the Years 2020 through 2027 and % CAGR

Table 62: Europe 7-Year Perspective for Induced Pluripotent Stem Cell (iPSC) by Cell Type - Percentage Breakdown of Value Sales for Vascular Cells, Cardiac Cells, Neuronal Cells, Liver Cells, Immune Cells and Other Cell Types for the Years 2020 & 2027

Table 63: Europe Current & Future Analysis for Induced Pluripotent Stem Cell (iPSC) by Research Method - Cellular Reprogramming, Cell Culture, Cell Differentiation, Cell Analysis, Cellular Engineering and Other Research Methods - Independent Analysis of Annual Sales in US$ Thousand for the Years 2020 through 2027 and % CAGR

Table 64: Europe 7-Year Perspective for Induced Pluripotent Stem Cell (iPSC) by Research Method - Percentage Breakdown of Value Sales for Cellular Reprogramming, Cell Culture, Cell Differentiation, Cell Analysis, Cellular Engineering and Other Research Methods for the Years 2020 & 2027

Table 65: Europe Current & Future Analysis for Induced Pluripotent Stem Cell (iPSC) by Application - Drug Development & Toxicology Testing, Academic Research, Regenerative Medicine and Other Applications - Independent Analysis of Annual Sales in US$ Thousand for the Years 2020 through 2027 and % CAGR

Table 66: Europe 7-Year Perspective for Induced Pluripotent Stem Cell (iPSC) by Application - Percentage Breakdown of Value Sales for Drug Development & Toxicology Testing, Academic Research, Regenerative Medicine and Other Applications for the Years 2020 & 2027

FRANCE Table 67: France Current & Future Analysis for Induced Pluripotent Stem Cell (iPSC) by Cell Type - Vascular Cells, Cardiac Cells, Neuronal Cells, Liver Cells, Immune Cells and Other Cell Types - Independent Analysis of Annual Sales in US$ Thousand for the Years 2020 through 2027 and % CAGR

Table 68: France 7-Year Perspective for Induced Pluripotent Stem Cell (iPSC) by Cell Type - Percentage Breakdown of Value Sales for Vascular Cells, Cardiac Cells, Neuronal Cells, Liver Cells, Immune Cells and Other Cell Types for the Years 2020 & 2027

Table 69: France Current & Future Analysis for Induced Pluripotent Stem Cell (iPSC) by Research Method - Cellular Reprogramming, Cell Culture, Cell Differentiation, Cell Analysis, Cellular Engineering and Other Research Methods - Independent Analysis of Annual Sales in US$ Thousand for the Years 2020 through 2027 and % CAGR

Table 70: France 7-Year Perspective for Induced Pluripotent Stem Cell (iPSC) by Research Method - Percentage Breakdown of Value Sales for Cellular Reprogramming, Cell Culture, Cell Differentiation, Cell Analysis, Cellular Engineering and Other Research Methods for the Years 2020 & 2027

Table 71: France Current & Future Analysis for Induced Pluripotent Stem Cell (iPSC) by Application - Drug Development & Toxicology Testing, Academic Research, Regenerative Medicine and Other Applications - Independent Analysis of Annual Sales in US$ Thousand for the Years 2020 through 2027 and % CAGR

Table 72: France 7-Year Perspective for Induced Pluripotent Stem Cell (iPSC) by Application - Percentage Breakdown of Value Sales for Drug Development & Toxicology Testing, Academic Research, Regenerative Medicine and Other Applications for the Years 2020 & 2027

GERMANY Table 73: Germany Current & Future Analysis for Induced Pluripotent Stem Cell (iPSC) by Cell Type - Vascular Cells, Cardiac Cells, Neuronal Cells, Liver Cells, Immune Cells and Other Cell Types - Independent Analysis of Annual Sales in US$ Thousand for the Years 2020 through 2027 and % CAGR

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Global Induced Pluripotent Stem Cell ((iPSC) Market to Reach $2.3 Billion by 2026 - Yahoo Finance UK

DUBLIN, Aug. 4, 2021 /PRNewswire/ -- The "Asia Pacific Cell Therapy Market Size, Share & Trends Analysis Report by Use-type (Clinical-use, Research-use), by Therapy Type (Autologous, Allogeneic) and Segment Forecasts, 2021-2028" report has been added to ResearchAndMarkets.com's offering.

The Asia Pacific cell therapy market size is expected to reach USD 2.9 billion by 2028. The market is expected to expand at a CAGR of 14.9% from 2021 to 2028.

Rapid advancements in regenerative medicine are anticipated to provide effective solutions for chronic conditions. A substantial number of companies in the growing markets, such as India and South Korea, are striving to capitalize on the untapped opportunities in the market, thereby driving the market.

The growth is greatly benefitted by the fund and regulatory support from government bodies and regulatory agencies. For instance, in August 2020, the government of South Korea passed an Act on the Safety and Support of Advanced Regenerative Medical Treatment and Medicine to establish a regulatory system for patient safety during quality control and clinical trials and to strengthen the regulatory support for regenerative medicine development.

The implementation of the act is expected to enhance clinical studies and approvals of regenerative medicine in South Korea. Furthermore, CAR-T and TCR T-cell therapies have already revolutionized hematologic cancer treatment. With the onset of the COVID-19 pandemic, scientists are deciphering its potential against the novel coronavirus. The concept of using T cells against chronic viral infections, such as HIV and hepatitis B, has already been proposed.

Based on the previous research insights, Singapore-based Duke-NUS medical school's emerging infectious diseases research program demonstrated the utility of these immunotherapies in treating patients with COVID-19 infection.

Thus, an increase in research for use of cell therapies for COVID-19 treatment is expected to drive the market in Asian countries. In April 2021, a team of researchers from Japan used induced pluripotent stem cells (iPS) to find drugs that can effectively inhibit the coronavirus and other RNA viruses.

Key Topics Covered:

Chapter 1 Methodology and Scope

Chapter 2 Executive Summary2.1 Market Snapshot

Chapter 3 Cell Therapy Market Variables, Trends, and Scope3.1 Market Trends and Outlook3.2 Market Segmentation and Scope3.3 Market Dynamics3.3.1 Market driver analysis3.3.1.1 Rise in number of clinical studies for cellular therapies in Asia Pacific3.3.1.2 Expanding regenerative medicine landscape in Asian countries3.3.1.3 Introduction of novel platforms and technologies3.3.2 Market restraint analysis3.3.2.1 Ethical concerns3.3.2.2 Clinical issues pertaining to development & implementation of cell therapy3.3.2.2.1 Manufacturing issues3.3.2.2.2 Genetic instability3.3.2.2.3 Condition of stem cell culture3.3.2.2.4 Stem cell distribution after transplant3.3.2.2.5 Immunological rejection3.3.2.2.6 Challenges associated with allogeneic mode of transplantation3.3.3 Market opportunity analysis3.3.3.1 Approval of Kymriah and Yescarta across various Asian countries3.3.3.2 Developments in CAR T-cell therapy for solid tumors3.3.4 Market challenge analysis3.3.4.1 Operational challenges associated with cell therapy development & usage3.3.4.1.1 Volume of clinical trials for cell and gene therapy vs accessible qualified centers3.3.4.1.2 Complex patient referral pathway3.3.4.1.3 Patient treatment, selection, and evaluation3.3.4.1.4 Availability of staff vs volume of cell therapy treatments3.4 Penetration and Growth Prospect Mapping for Therapy Type, 20203.5 Business Environment Analysis3.5.1 SWOT Analysis; By factor (Political & Legal, Economic and Technological)3.5.2 Porter's Five Forces Analysis3.6 Regulatory Framework3.6.1 China3.6.1.1 Regulatory challenges & risk of selling unapproved cell therapies3.6.2 Japan

Chapter 4 Cell Therapy Market: COVID-19 Impact analysis4.1 Challenge's analysis4.1.1 Manufacturing & supply challenges4.1.2 Troubleshooting the manufacturing & supply challenges associated to COVID-194.2 Opportunities analysis4.2.1 Need for development of new therapies against SARS-CoV-24.2.1.1 Role of T-cell based therapeutics in COVID-19 management4.2.1.2 Role of mesenchymal cell-based therapeutics in COVID-19 management4.2.2 Rise in demand for supply chain management solutions4.3 Challenges in manufacturing cell therapies against COVID-194.4 Clinical Trial Analysis4.5 Key Market Initiatives

Chapter 5 Asia Pacific Cell Therapy CDMOs/CMOs Landscape5.1 Role of Cell Therapy CDMOs5.2 Key Trends Impacting Asia Cell Therapy CDMO Market5.2.1 Regulatory reforms5.2.2 Expansion strategies5.2.3 Rising investments5.3 Manufacturing Volume Analysis5.3.1 Wuxi Biologics5.3.2 Samsung Biologics5.3.3 GenScript5.3.4 Boehringer Ingelheim5.3.5 Seneca Biopharma, Inc.5.3.6 Wuxi AppTech5.4 Competitive Milieu5.4.1 Regional network map for major players

Chapter 6 Asia Pacific Cell Therapy Market: Use Type Business Analysis6.1 Market (Stem & non-stem cells): Use type movement analysis6.2 Clinical Use6.2.1 Market (stem & non-stem cells) for clinical use, 2017 - 2028 (USD Million)6.2.2 Market (stem & non-stem cells) for clinical use, by therapeutic area6.2.2.1 Malignancies6.2.2.1.1 Market (stem & non-stem cells) for malignancies, 2017 - 2028 (USD Million)6.2.2.2 Musculoskeletal disorders6.2.2.3 Autoimmune disorders6.2.2.4 Dermatology6.2.3 Market (stem & non-stem cells) for clinical use, by cell type6.2.3.1 Stem cell therapies6.2.3.1.1 Market, 2017 - 2028 (USD Million)6.2.3.1.2 BM, blood, & umbilical cord-derived stem cells/mesenchymal stem cells6.2.3.1.3 Adipose-derived stem cell therapies6.2.3.1.4 Other stem cell therapies6.2.3.2 Non-stem cell therapies6.3 Research Use

Chapter 7 Asia Pacific Cell Therapy Market: Therapy Type Business Analysis7.1 Market (Stem & Non-stem Cells): Therapy type movement analysis7.2 Allogeneic Therapies7.3 Autologous Therapies

Chapter 8 Asia Pacific Cell Therapy Market: Country Business Analysis8.1 Market (Stem & Non-stem Cells) Share by Country, 2020 & 2028

Chapter 9 Asia Pacific Cell Therapy Market: Competitive Landscape

For more information about this report visit https://www.researchandmarkets.com/r/3hdt1c

Media Contact: Research and Markets Laura Wood, Senior Manager [emailprotected]

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Asia-Pacific Cell Therapy Market 2021-2028 - Opportunities in the Approval of Kymriah and Yescarta - PRNewswire

A study released inSTEM CELLS Translational Medicinehas confirmed the safety of a novel type of cellular therapy for knee pain caused by osteoarthritis. Conducted by a multi-institutional team of researchers in Japan who had developed the new therapy, the study was designed to confirm that their treatment which involves transplanting the patients own mesenchymal stem cells (MSCs) into the affected knee did not cause tumors.

The results showed that five years after transplantation, osteoarthritis-related tears to the knee meniscus had healed and, just as importantly, none of the patients experienced any serious side effects from the treatment. The meniscus is a crescent-shaped cartilage in the knee joint that plays a role in shock absorption. Age-related damage to the meniscus often leads to the progression of osteoarthritis of the knee.

Chronic knee pain is a major issue for the aging, affecting approximately 25 percent of all adults, according to the Centers for Disease Control and Prevention (CDC). Osteoarthritis is the most common cause of this condition in people aged 50 and older. Along with pain, which can be debilitating, knee problems can significantly affect the persons mobility and quality of life.

Knee replacement surgery is the gold standard of treatment, with the majority of people experiencing a dramatic reduction in pain and, thus, improvement in their ability to live a normal life. However, though rare, such surgery does come with risks such as the possibility of infection.

Lead investigator Mitsuru Mizuno, DVM, Ph.D. and corresponding author Ichiro Sekiya, M.D., Ph.D. Credit: AlphaMed Press

Cellular therapies are showing great potential as a less invasive way to treat difficult-to-heal knee injuries. The team behind the current study, which included researchers from Tokyo Medical and Dental University, Kyoto University and Kazusa DNA Research Institute, recently developed a therapy involving the transplantation of MSCs derived from the knees soft tissue (the synovium) into the injured meniscus. MSCs are multipotent adult stem cells present in the umbilical cord, bone marrow, fat, dental and other body tissues. Their ability to secrete biologically active molecules that exert beneficial effects on injured tissues makes them a promising target in regenerative medicine.

But some stem cell treatments have been known to cause tumors, which is why the team wanted to ensure that their therapy was free of any negative side effects. In particular, they wanted to investigate the safety of any MSCs that might show a type of chromosomal disorder called trisomy 7.

Trisomy 7 occurs frequently in patients with severe knee disease such as osteoarthritis. The detection of trisomy 7 in epithelial cells has been associated with tumor formation. However, the safety of these cells after transplantation has not been investigated. Thats what we wanted to learn from this study, said corresponding author Ichiro Sekiya, M.D., Ph. D., director and professor of the Center for Stem Cell and Regenerative Medicine (CSCRM) at Tokyo Medical and Dental University.

Mitsuru Mizuno, DVM, Ph.D., assistant professor with CSCRM, served as the studys lead investigator. He reported on the results. We recruited 10 patients for the study and transplanted their own stem cells into the affected knee joints, then followed up with MRIs over the next five years. The images revealed that tears in the patients knee meniscus were obscured three years after transplantation. We also identified trisomy 7 in three of the patients, yet no serious adverse events including tumor formation were observed in any of them.

Dr. Sekiya added, Keep in mind that these were autologous MSCs used in our study, which means that the transplanted MSCs came from the patients themselves. Any problems that might arise in the case of allogeneic cells, which are donated by someone other than the patient, still need to be determined.

Nevertheless, we believe that these data suggest that MSCs with trisomy 7 are safe for transplantation into human knees and show much promise in treating osteoarthritis.

This study highlights the ability of a patients own stem cells to potentially heal torn cartilage in the knee, said Anthony Atala, M.D., Editor-in-Chief ofSTEM CELLS Translational Medicineand director of the Wake Forest Institute for Regenerative Medicine. These outcomes suggest a potential approach that could change the overall physical health of patients who suffer from osteoarthritis and experience debilitating joint pain. We look forward to the continuation of this research to further document clinical efficacy.

Reference: Transplantation of human autologous synovial mesenchymal stem cells with trisomy 7 into the knee joint and 5 years of follow-up by Mitsuru Mizuno, Kentaro Endo, Hisako Katano, Naoki Amano, Masaki Nomura, Yoshinori Hasegawa, Nobutake Ozeki, Hideyuki Koga, Naoko Takasu, Osamu Ohara, Tomohiro Morio and Ichiro Sekiya, 3 August 2021, STEM CELLS Translational Medicine.DOI: 10.1002/sctm.20-0491

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Safety of Stem Cell Therapy for Chronic Knee Pain Confirmed in New Study - SciTechDaily

Q: Im considering having my own stem cells injected into me to improve physical and mental problems that I am having post-COVID-19 infection. What do you think?

James D., Huntington, N.Y.

A: Theres been a lot of talk about using what are called autologous stem cells (your own) to fight off COVID-19 long-haul symptoms, as well as to treat everything from torn ligaments to Alzheimers disease. None is approved by the Food and Drug Administration. The only stem-cell-based products that are FDA-approved come from blood-forming stem cells (hematopoietic progenitor cells) derived from cord blood and theyre for treating disorders involving production of blood (the hematopoietic system). A list is at fda.gov; search for Approved Cellular and Gene Therapy Products.

In fact, stem cell/regenerative medicine treatment scams are so prevalent that this spring the FDA finally told manufacturers and marketers that they had to comply with regulations on human cell and tissue products. Unfortunately, a June report from Pew Trust found compliance by the companies and enforcement from the FDA to be anemic.

What the report did find was that more than 700 clinics in the U.S. offer unapproved stem-cell and regenerative medicine interventions for conditions such as Alzheimers, muscular dystrophy, autism, spinal cord injuries and, most recently, COVID-19. They also found post-injection infection happens frequently and is likely because of sloppily manufactured products and failure to properly screen for diseases such as HIV and hepatitis B and C.

If youre considering stem-cell treatment, the FDA urges you to ask the clinic for the following info before getting it even if the stem cells are your own:

Proof the FDA has reviewed and approved the treatment. Have your primary care doc confirm the information.

If the clinic is claiming it has an FDA-issued Investigational New Drug application number, ask for it and ask to review the FDA communication acknowledging the IND.

Stem-cell treatment has great potential, but when used for unapproved therapies outside a clinical trial, its risky (and expensive). To search for a trial, go to clinicaltrials.gov.

Q: My doctor says my high blood pressure puts me at increased risk for dementia. I think hes just trying to get me on one more med. Is there really a connection?

Lacie R., Sacramento, Calif.

A: Dementia means that you have cognition problems that cause trouble with memory, thought and everyday tasks. That could result from mini- or regular strokes, and we know that high blood pressure increases your stroke risk. In fact, one Harvard study found that high blood pressure increases a mans risk of stroke by 220 percent; another found that each 10 mmHg rise in systolic pressure (the top number) boosts your risk of ischemic stroke by 28 percent and of hemorrhagic stroke by 38 percent.

Even if your high blood pressure doesnt trigger a stroke, it can lead to impaired cognition and dementia. The 2018 SPRINT-MIND trial found that intensive control of high blood pressure (getting the top number below 120) lowered the risk of mild cognitive impairment by 19 percent compared with standard blood pressure control. Now, a new study in the journal Hypertension indicates that certain antihypertensive medications ACE inhibitors and ARBs (and angiotensin II receptor blockers) can cross the blood-brain barrier and lower dementia risk. Tracking almost 13,000 people for three years, the researchers found that folks taking those meds showed less memory loss than folks taking other sorts of antihypertensive medications.

You dont indicate how high your blood pressure is, but if it is only slightly elevated you may be able to bring it down through changing your diet, losing weight if you need to and exercising for 30 to 60 minutes five days a week. If it is above 125 (top number) or above 85 (bottom number), a combo of those self-care techniques and medication may be the safest choice. But either way, bringing your blood pressure to around 115/75 will protect your brain, as well as your heart, kidneys and eyes.

Contact Drs. Oz and Roizen at sharecare.com.

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Stemming the tide of stem-cell treatment scams - Houston Chronicle

Researchers at the Chinese Academy of Sciences and University of Science and Technology of China have devised a novel bioprinting-based method of curing previously untreatable spinal cord injuries.

Using a custom bio-ink, the Chinese team have managed to 3D bioprint neural stem cell-loaded tissues capable of carrying instructions via impulses from the brain, much like those seen in living organisms. Once implanted into disabled rats, the scaffolds have shown the ability to restore movement in paralyzed limbs, and the scientists now believe their approach could find human applications in future.

There is no known effective cure for spinal cord injury, Zhijun Zhang, a nanobiomedical engineer at the Chinese Academy of Sciences told the Scientist. The 3D bioprinting strategy weve developed, may represent a general and versatile strategy for rapid and precise engineering of the central nervous system (CNS), and other neuronal tissues for regenerative medicine.

The SCI injury conundrum

A Spinal Cord Injury or SCI is a blanket term used to describe any damage caused to the bundle of cells and nerves that send signals to and from the brain along the human spinal cord. While the damage itself can be caused either by direct injury, or from bruising to the surrounding vertebrae, the result is often the same: a partial or complete loss of sensory and locomotor function below the affected area.

While theres no current known cure for SCI, a number of promising cell-based therapies are now being developed, with the regeneration of functional neurons seen as central to their future success. In effect, such approaches involve re-establishing links between neurons throughout the injured area in order to restore nerve functionality, but repairing damaged cells continues to be problematic.

Where neural stem cells have previously been implanted into SCI sites, theyve also shown poor viability and uncontrolled differentiation, leading to low therapeutic efficacy. More recent efforts have seen scientists bioprint cell-loaded scaffolds, capable of creating a suitable microenvironment in which neurons can flourish, yet this has raised further issues around printability and initiating cellular interaction.

To get around these problems, the Chinese researchers have now developed a novel bio-ink that gels together at body temperature to prevent neurons from differentiating into cells that dont produce electrical impulses, and can be 3D bioprinted into scaffolds that not only mimic the white matter appearance of the spine, but encourage cell-to-cell interactions.

A paralysis cure in-action

To begin with, Zhang and his team formulated their bio-ink from natural chitosan sugars, as well as a mixture of hyaluronic acids and matrigel, before combining them with rat neural stem cells. The scientists then used a BioScaffolder 3D bioprinter to deposit the resulting concoction into cell-laden scaffolds, which were later stored in culture plates for further testing.

Prior to their implantation, the teams different samples were incubated for three, five and seven days respectively, during which they proliferated and formed connections. Interestingly though, the researchers found that the higher the concentration of hyaluronic acid, the lower levels of interaction they observed, showing that their bio-ink can be tweaked to achieve desired tissue characteristics.

When injected into paraplegic lab rats, the scaffolds exhibited a cell viability of 95% while promoting neuron regeneration to the point that they enabled the rats to regain control over their hind legs. Over a 12-week observation period, the treated animals also showed a revived ability to move their hips, knees and ankles without support, and kick pressure sensors with markedly enhanced muscle strength.

As a result, the scientists have concluded that their approach offers a versatile and powerful platform for building precisely-controlled complex neural tissues with potential human applications, although they concede that more precise regulation of cell differentiation will be needed to achieve this, in addition to further testing on more clinically-relevant injury models.

Overall, this study clearly demonstrated for the first time the feasibility of the 3D bioprinted neural stem cell-laden scaffolds for SCI repair in-vivo, concluded the team in their paper, which, we expect, may move toward clinical applications in the neural tissue engineering, such as SCI and other regenerative medicine fields in the near future.

3D bioprinting in CNS treatments

Thanks to constant advances in flexible electronics and 3D bioprinting technologies, its now becoming increasingly possible to produce neural implants, with the potential to treat complex CNS injuries. Last year, a project started at TU Dresden led to the creation of 3D printed neural implants, capable of linking the human brain to computers as a means of treating neurological conditions such as paralysis.

In a similar study, engineering firm Renishaw has worked with pharmaceuticals expert Herantis Pharma to assess the performance of its 3D printed neuroinfuse drug delivery device. Designed to deliver intermittent infusions into the parenchyma, an organs functional tissue, the platform could be used as a future treatment for Parkinsons disease.

With regards to treating spinal injuries specifically, researchers at the University of California San Diego have also managed to repair spinal cord injuries in rats. By implanting 3D printed two-millimeter-wide grafts into test subjects, the team have been able to facilitate neural stem cell growth, restore nerve connections and ultimately help recover limb functionality in rodent test subjects.

The researchers findings are detailed in their paper titled 3D bioprinted neural tissue constructs for spinal cord injury repair. The study was co-authored by Xiaoyun Liu, Mingming Hao, Zhongjin Chen, Ting Zhang, Jie Huang, Jianwu Dai and Zhijun Zhang.

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Featured image shows the researchers 3D bioprinted scaffolds after 7 and 21 days culturing. Images via the Biomaterials journal.

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Introducing the 3D bioprinted neural tissues with the potential to 'cure' human paralysis - 3D Printing Industry

Our cells have abilities that go far beyond the fastest, smartest computer. They generate mechanical forces to propel themselves around the body and sense their local surroundings through a myriad of channels, constantly recalibrating their actions.

The idea of using cells as medicine emerged with bone marrow transplants, and then CAR-T therapy for blood cancers. Now, scientists are beginning to engineer much more complex living therapeutics by tapping into the innate capabilities of living cells to treat a growing list of diseases.

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UCSF launched a Living Therapeutics Initiative to accelerate the development and delivery of revolutionary treatments.

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That includes solid tumors like cancers of the brain, breast, lung, or prostate, and also inflammatory diseases like diabetes, Crohns, and multiple sclerosis. One day, this work may extend to regenerating tissues outside or even inside the body.

Taking a page from computer engineers, biologists are trying their hands at programming cells by building DNA circuits to guide their protein-making machinery and behavior.

We need cells with GPS that never make mistakes in where they need to go, and with sensors that give them real-time information before they deliver their payload, said Hana El-Samad, PhD, a professor of biochemistry and biophysics. Maybe they kill a little bit and then deliver a therapeutic payload that cleans up. And the next program over encourages the rejuvenation of healthy cells.

These engineered cell therapies would be a huge leap from traditional therapies, like small molecules and biologics, which can only be controlled through dose, or combination, or by knowing the time it takes for the body to get rid of it.

If you put in drugs, you can block things and push things one way or the other, but you can't read and monitor whats going on, said Wendell Lim, PhD, a professor of cellular and molecular pharmacology who directs the Cell Design Institute at UCSF. A living cell can get into the disease ecosystem and sense what's going on, and then actually try to restore that ecosystem.

Like people, cells live in communities and share duties. They even take on new identities when the need arises, operating through unseen forces that biologists term, self-organizing.

We need cells with GPS that never make mistakes in where they need to go, and with sensors that give them real-time information before they deliver their payload.

Hana El-Samad, PhD

Some living cell therapies could be controlled even after they enter the body.

Lim and others say it is possible to begin adapting cells into therapy, even when so much has yet to be learned about human biology, because cells already know so much.

Their built-in power includes dormant embryonic abilities, so a genetic nudge in the right place could enable a cell to assume a new function, even something it has never done before.

When a cell, a building block thats 10 microns in diameter can do that, and you have 10 trillion of them in your body, its a whole new ballgame, said Zev Gartner, PhD, a professor of pharmaceutical chemistry who studies how tissues form. Were not talking about engineering in the same way that somebody working at Ford or Intel or Apple or anywhere else thinks about engineering. Its a whole new way of thinking about engineering and construction.

For several years now, synthetic biologists have been building rudimentary feedback circuits in model organisms like yeast by inserting engineered DNA programs. Recently, Lim and El-Samad put these circuits into mice to see if they could tamp down the excess inflammation from traumatic brain injury.

They demonstrated that engineered T-cells could get into the sites of injury in the brain and perform an immune-modulating function. But its just a prototype of what synthetic circuits could do.

You can imagine all kinds of scenarios of therapies that dont cause any side effects, and do not have any collateral damage, said El-Samad.

UCSF researchers are building ever more complex circuits to move cells around the body and sense their surroundings. They hope to load them with DNA programs that trigger the cells protein-making machinery to do things like remove cancerous cells, then repair the damage caused by the tumors haphazard growth.

Or they could make cells that send signals to finetune the immune system when it overreacts to a threat or mistakenly attacks healthy cells. Or build new tissue and organs from our bodys own cells to repair damage associated with trauma, disease, or aging.

The fact that biological systems and cellular systems can self-organize is a huge part of biology, and thats something were starting to program, Lim said. Then we can make cells that do the functions that we want. We aspire to not only have immune cells be better at killing and detecting cancer but also to suppress the immune system for autoimmunity and inflammation or go to the brain to fight degeneration.

These UCSF scientists are on their way to engineering cell-based solutions to different diseases.

Tejal Desai, PhD, a professor and chair of the Department of Bioengineering and Therapeutic Sciences, is employing nanotechnology to create tiny depots where cells that have been engineered to treat Type 1 diabetes or cancer can refuel with oxygen and nutrients.

Having growth factors or other factors that keep them chugging along is very helpful, she said. Certain cytokines help specific immune cells proliferate in the body. We can design synthetic particles that present cytokines and have a signal that says, Come over to me. Basically, a homing signal.

Ophir Klein, MD, PhD, a professor of orofacial sciences and pediatrics, employs stem cell biology to research treatments for birth defects and conditions like inflammatory bowel disease. He is working with Lim and Gartner to create circuits that induce cells to grow in new ways, for example to repair the damage to intestines in Crohns disease.

Cells and tissues are able to do things that historically we thought they were incapable of doing, Klein said. We dont assume that the way things happen or dont happen is the best way that they can happen, and were trying to figure out if there are even better ways.

Faranak Fattahi, PhD, a Sandler Faculty Fellow, is developing cell replacement therapy for damaged or missing enteric neurons, which regulate the muscles that move food through the GI tract. She generated these gut neurons using iPS cell technology.

What we want to do in the lab is see if we can figure out how these nerves are misbehaving and reverse it before transplanting them inside the tissue, she said. Now, she is working with Lim to refine the cells, so they integrate into tissues more efficiently without being killed off by the immune system and work better in reversing the disease.

Matthias Hebrok, PhD, a professor in the Diabetes Center, has created pancreatic islets, a complex cellular ecosystem containing insulin-producing beta cells, glucagon-producing alpha cells and delta cells.

Now, he is working on how to make islet transplants that dont trigger the immune system, so diabetes patients can receive them without immune-suppressing drugs.

We might be able to generate stem-cell derived organs that the recipients immune system will either recognize as self or not react to in a way that would disrupt their function.

In health, the community of cells in these islets perform the everyday miracle of keeping your blood sugar on an even keel, regardless of what you ate or drank, or how little or how much you exercised or slept.

To me, at least, thats the most remarkable thing about our cells, Gartner said. All of this stuff just happens on its own.

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Beyond CAR-T: New Frontiers in Living Cell Therapies - UCSF News Services