Your heart and lungs share a close relationship, each relying on the other to replenish your blood with oxygen, remove wastes, and move blood and nutrients around your body.

When one of these players is underperforming or damaged, the other is quickly affected.

Pneumonia is an infection in one or both lungs. The tiny air sacs (alveoli) that move gases like oxygen in and out of your blood fill with fluid or pus.

This article will explore how pneumonia can affect how well your heart works and what can happen if you already have heart disease and then develop pneumonia.

Coronary artery disease is the most common form of heart disease in the United States. It develops when cholesterol and other substances build up in your blood vessels specifically the coronary arteries that supply blood to your heart.

Many things can lead to this buildup, including diet, lifestyle choices, and genetics.

The buildup of substances in your blood vessels is dangerous on its own since it can restrict blood flow to the heart and other body parts. But its even more serious when pieces of this buildup called plaques break off from the walls of your blood vessels.

When these pieces break off, they can travel to other areas of the body like the brain or heart, cutting off the blood supply to these organs resulting in a stroke or heart attack.

On its own, pneumonia is not a heart disease. Its a lung infection caused by bacteria or viruses.

However, heart disease complications like congestive heart failure can cause a condition similar to pneumonia.

Certain types of heart failure can lead to pulmonary edema. In this case, the heart is too weak to effectively pump blood out to the body, so the blood backs up into the heart and eventually into the lungs.

As this backed-up blood builds up in the lungs, pressure in the blood vessels of your lungs increases, and it can cause fluid buildup in the alveoli.

This results in an effect similar to pneumonia, where these air sacs fill with fluid.

Pneumonia is an infection that can cause inflammation throughout the body. This inflammation can lead to other complications, including an increased risk that bits of plaque can break free from your vessel walls and lead to heart attack or stroke.

Even without existing coronary artery disease or plaque buildup, the body-wide inflammation that pneumonia triggers can cause its own problems.

Inflammation can interfere with the normal function of all kinds of systems in your body especially the heart. This makes heart failure one of the most common complications of pneumonia.

About 30% of people hospitalized with community-acquired pneumonia develop heart failure and other cardiovascular problems, but the risk isnt always immediate. Research indicates that the greatest risk of heart complications occurs in the month after a pneumonia diagnosis, and the risk can continue for up to a decade.

It can be difficult to tell when pneumonia is affecting your heart, as pneumonia and heart disease can share symptoms including:

Additional symptoms you may experience with pneumonia that are not as common with heart disease include:

Inflammation in response to a pneumonia infection has some of the greatest impact on your heart.

Although heart damage from pneumonia can happen in anyone, it affects people with preexisting heart disease the most.

Among people who develop pneumonia with preexisting heart failure, about 1.4% who are treated in the outpatient setting find their heart failure gets worse after pneumonia. That percentage increases to 24% in people with more severe pneumonia that requires hospitalization.

Aside from inflammation, some individual cardiac symptoms or complications that can develop after a bout with pneumonia include:

The relationship between pneumonia and cardiovascular disease goes both ways: Pneumonia can increase the risk of heart disease, and a history of heart disease can increase the risk of pneumonia.

One 2018 study found that people with cardiovascular diseases heart failure in particular are three times more likely than others to develop community-acquired pneumonia.

Generally, the best way to prevent problems like pneumonia and heart failure is to take care of your overall health.

This means:

People with heart disease are generally recommended to stay up-to-date on various vaccinations, too. This can prevent acute infection and its complications.

However, there may be little difference in mortality rates among people with heart failure and pneumonia who had been vaccinated against things like influenza and pneumonia.

With every heartbeat and every breath, your lungs and heart work in tandem. Infections and chronic diseases that affect one organ can affect the other.

Pneumonia can increase your risk of developing heart disease or having your existing heart disease worsen. Likewise, heart disease can increase your risk of developing several types of pneumonia.

Talk with your doctor about your overall health and how to avoid chronic heart disease and acute infections like pneumonia.

Vaccines are one part of the equation, but the best strategy involves other health and diet strategies, too.

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Pneumonia and Heart Disease: What You Should Know - Healthline

Cardiac Stem Cells Comments Off on Pneumonia and Heart Disease: What You Should Know – Healthline | July 16th, 2022

After reading this article, you should be able to:

A wound is any injury that disrupts the structure of healthy skin tissue caused by chemical, mechanical, biological or thermal trauma. Wounds can be classified as acute or chronic, depending on their period of healing[1]. Acute wounds usually heal without complication within ten days; however, chronic wounds do not undergo normal healing processes, commonly have exaggerated inflammation, persistent infections or microbial biofilm formation and persist longer than six weeks[24]. The most frequent causes of chronic wounds are pressure, diabetes and vascular diseases[5].

Chronic wounds are a global problem, with annual cases rising dramatically owing to the ageing population and increased prevalence of diabetes and obesity[6]. It is estimated that up to 7% of the UK adult population has a chronic wound, costing the NHS 8.3bn each year in staff costs, wound dressings and medication[7]. Individual costs for wound management have been reported to vary, from 358 to 4,684 per patient for a wound that follows the normal healing trajectory, increasing to 831 to 7,886 per patient for a chronic, non-healing wound[7]. The majority of the costs account for GP and nursing time, with infected wounds costing an additional 1.39bn on antibiotics[7].

Results from one study, published in 2020, found that 59% of chronic wounds healed if there was no evidence of infection, compared with 45% if infection was present or suspected[7].Health conditions, such as diabetes mellitus and vascular disease, can predispose people to wounds that are difficult to heal, which can become chronic unless the underlying causes are addressed. For example, people with diabetes are prone to have a high incidence of wounds on their feet, which are slow to heal because of the impact of diabetes on the immune system, circulation and diabetic neuropathy. Complex chronic wounds, such as venous leg ulcers and diabetic ulcers, can significantly impact quality of life, morbidity and mortality[7].

Wound healing is a complex series of physiological reactions and interactions between numerous cell types and chemical mediators[8,9]. It comprises four coordinated and overlapping phases: haemostasis, inflammation, proliferation and remodelling[10].

The Figure below shows the phases of wound healing[11].

The first stage, haemostasis, is instantly activated after injury to stop bleeding at the site and prevent the entry of pathogens. In primary haemostasis, within seconds of an injury occurring, damaged blood vessels vasoconstrict to reduce blood flow through the wound area and diminish blood loss. Platelets adhere to the sub-endothelium of the impaired vessels, initiated by the presence of von Willebrand factor. This binds to glycoprotein Ib receptors on the surface of platelets, causing a conformational change on the platelet surface, activating platelets. These activated platelets release chemicals, such as adenosine diphosphate,serotonin andthromboxane A2, from their dense granules to stimulate platelet recruitment and adhesion to form a platelet plug[12,13]. Secondary haemostasis is a sequence of events, described as a coagulation cascade, that consequently converts soluble fibrinogen into insoluble fibrin. A fibrin mesh sticks to the platelet plug producing a haemostatic plug to seal the inside of wound[12,14].

At the beginning of the inflammatory phase, activated platelets also release pro-inflammatory cytokines and growth factors to stimulate the recruitment of immune cells to clean the wound area, initially involving infiltration of neutrophils and monocytes[15]. Monocytes undergo a phenotypic change to become macrophages. The previously constricted blood vessels also vasodilate because of increased prostaglandins, facilitating the chemotaxis of inflammatory cells[16,17]. The proliferation phase is charactered by re-epithelialization, capillary regeneration and the formation of granulation tissue(18). Fibroblasts and endothelial cells proliferate during this phase, stimulated by the numerous cytokines and growth factors released by the platelets and macrophages. This leads to the formation of new blood vessels in a process called angiogenesis[18].

After migration to the wound site, fibroblasts begin to proliferate and synthesize collagen and extracellular matrix components, such as proteoglycans, hyaluronic acid, glycosaminoglycans, and fibronectin, to form granulation tissue[1618]. The final stage is remodelling, which can last for several years. The formation of new capillaries slows, facilitating maturation of blood vessels in the wound. Type III collagen is replaced by type I collagen in the extracellular matrix to create a denser matrix with a higher tensile strength. The differentiation of fibroblasts into myofibroblasts causes the wound to physically contract. However, owing to differences in collagen type, new tissue after healing does not fully regain its original strength[1618].

Delayed wound healing can be caused by local and/or systemic factors. Local factors in the wound site include oxygen deficiency (causing chronic hypoxia), excessive exudate (causing maceration) or insufficient exudate (leading to desiccation), local infection, foreign bodies intensifying the inflammatory response, repetitive trauma, pressure/shear, and impaired vascular supply to the injury area[16,19].

Systemic factors that delay the healing process include the following[16,19]:

Oestrogen insufficiency, for instance in postmenopausal women, is known to impair all stages of wound repair process, especially inflammation and regranulation, with improved wound healing being a potential benefit of hormone replacement therapy. Androgens can repress cutaneous repair in both acute and chronic wounds, retarding the healing process and increasing inflammation[20].

The process can also be delayed in people with immunocompromised conditions, such as acquired immunodeficiency syndrome, cancer and malnutrition, with deficiencies in protein, carbohydrates, amino acids, vitamins A, C and E, zinc, iron, magnesium all having an effect[16,19,21]. Certain medicines can also delay the process, such as glucocorticoid steroids, chemotherapeutic drugs and non-steroidal anti-inflammatory drugs[19,21].

The most common causes of delayed chronic wound healing are infection and biofilm formation: biofilms are microscopically identifiable in up to 60% of chronic and recurrent wounds,leading to significant morbidity and mortality and an escalated healthcare cost[5,22,23].

A wound is considered infected when there are sufficiently large numbers of microbes presenting in wound environment or sufficient virulence to raise either a local or systemic immune response.

The wound-infection continuum has three stages: contamination, colonisation and infection. In the contamination phase, micro-organisms are unlikely to replicate because of an unfavourable environment. Colonisation happens when microbes successfully multiply, but not in sufficient levels to destroy host defences. However, the accelerated loads and persistence of microbes in wound environments may prolong the inflammatory phase and delay wound healing. When bacteria invade deeper into the wound bed and proliferate speedily, they can provoke an immune reaction and initiate local infection. As pathogens proliferate beyond the boundaries of the wound, infection may spread into deeper tissues, adjacent tissues, fascia, muscle or local organs. Eventually, systemic infection, such as sepsis, can occur when microbes invade into the body via vascular vessels or lymphatic systems, affecting the entirety of the body[24,25].

Biofilm is an extracellular polymeric substance produced by bacteria that acts as a physical barrier, enveloping bacteria and protecting them from host defences and antimicrobial agents. Several pathogens isolated from chronic wounds are typically capable of forming biofilms, such asStaphylococcus aureusandPseudomonas spp[5,23,24,26]. Biofilms persisting within chronic wounds can continuously stimulate host immunity, resulting in the prolonged release of nitric oxide, pro-inflammatory cytokines such as interleukin-1 and TNF-, and free radicals, and activation of immune complexes and complement, causing the healing process to fail and convert to a chronic state[23,27]. Sustained inflammatory reactions also trigger an escalated level of matrix metalloproteases, which can disrupt the extracellular matrix[16].

Most of the time, wound infection is diagnosed via visual inspection based on clinical signs and symptoms, including the classic signs of heat, pain, swelling, suppuration, erythema and fever. Typical characteristics of an acute infected wound are pain, erythema, swelling, purulent drainage, heat and malodour. In addition, a chronic wound may display signs of delayed healing, wound breakdown, friable granulation, epithelial bridging and pocketing in granulation tissue, increasing pain and serious odour.

Microbiological analysis of a specimen from wound cultures (using tissue biopsy or wound swab, pus collection or debrided viable tissue) is performed to identify causative microorganisms and guide the choice of antimicrobial therapy. Traditional diagnostics can be time consuming, and some organisms can be difficult to culture, so molecular techniques including DNA sequencing may help with characterising genetic markers[25]. Other laboratory markers, such as C-reactive protein, have also been used as markers and imaging techniques, such as CT scanning and autofluorescence imaging, may help with real-time diagnosis[25,28].

In clinical practice, the evaluation and identification of underlying conditions that affect wound healing are vital to optimising wound care. Accurate assessment of causes and comorbidities will inform the best course of treatment, such as compression therapy for venous leg ulcers or offloading (relief of pressure points) for people with diabetic foot ulcers[29]. The underlying pathologies of wounds are numerous and failure to address them can lead to a failure in healing[2,29].

Once any underlying conditions are identified, the wound bed should be prepared to optimise the chance of healing. A wound hygiene approach should be considered; its core principle is to remove or minimise unwanted materials, such as biofilm, devitalised tissue and foreign debris, from the wound bed to kickstart the healing process[30]. A holistic patient and wound assessment will ensure wound pathology and wound biofilm are managed simultaneously[30]. The TIME framework (tissue, infection/inflammation, moisture balance, edges) is a systematic approach to wound management[31]. Wound-bed preparation and the TIME approach should be used alongside a holistic assessment of other patient factors such as pain, nutrition and hydration[2].

Effective management of infection in chronic wounds involves the removal of necrotic tissue, debris and biofilms using debridement plus the appropriate use of antimicrobials (including topical antiseptics and systemic antibiotics)[1,32].

Antiseptics have a broad spectrum of bactericidal activity and are used externally for the purposes of eliminating bacterial colonisation, preventing infection, and potentially stimulating wound healing. They are less likely to cause antimicrobial resistance (AMR) than antibioticsand inhibit the development of microbes by disrupting cell walls and cytoplasmic membranes, denaturing proteins, and damaging bacterial DNA and RNA[5,23,33,34]. An ideal antiseptic agent should have broad-spectrum activity, a fast onset of action, long-lasting activity, be safe for healthy surrounding tissue, possess minimal allergenicity, be stable in blood and tissue protein, persistently remain within the wound bed, and potentially be active against biofilms[23,35]. Antiseptics, antimicrobial washes or surfactants can be used to clean the wound and peri-wound skin and prepare the wound bed for debridement[30].

A variety of antiseptic agents are used in clinical practice[23,34]:

Antiseptics can also be used as an adjunct to other therapies (e.g. negative pressure therapies) in treating complicated wound types(e.g.diabetic foot ulcers,venous leg ulcers and sternal wounds)[36].

All open wounds will be colonised with bacteria, but antibiotic therapy is only required for those that are clinically infected[37]. Systemic antibiotic therapy should only be considered for the treatment of cellulitis, osteomyelitis, sepsis, lymphangitis, abscess, and invasive tissue infection. Inappropriate use of systemic antibiotics may increase the risk of side effects and contributes to emergence of AMR[5]. The choice of initial therapy and the duration is frequently empirical and should take into account the type of wound, severity of infection, suspected pathogens and local AMR[38]. With severe infections, broad-spectrum antibiotics should be used against both gram-positive and gram-negative organisms, while a relatively narrow spectrum agent is enough for most mild and many moderate infections[5].

A systematic review assessed the clinical and cost-effective efficacy of systemic and topical antibiotic agents in the treatment of chronic skin wounds. The authors of the review suggested that there was insufficient evidence to support any routine use of systemic antibiotics in specific chronic wounds[39].

Appropriate and judicious use of antimicrobials must be considered when managing wounds. The use of topical antibiotics is not recommended for eliminating bacterial colonisation or wound infections because of their limited effectiveness, high risk of resistance and potential to cause contact allergy[5,35].

AMR occurs when microorganisms naturally evolve in ways that cause medicines used to treat infections to become ineffective, and these micro-organisms become resistant to most[40,41]. The misuse and overuse of antibiotics is a major cause of the emergence of AMR, via four main mechanisms[42]:

Moreover, the multicellular nature of biofilm matrix is likely to give extra protection to bacteria communities, makes them resistant to antibiotics. There are several proposed mechanisms for AMR related to biofilm: the alteration of chemical environment within biofilm, slow or inadequate diffusion of the antibiotics into the biofilm, and a differentiated biofilm subpopulation[43].

Topical antimicrobial use plays an important role when the wound is clinically infected or there is a suspected biofilm. The British Society for Antimicrobial Chemotherapy and European Wound Management Association position paper highlighted antimicrobial stewardship (AMS) a set of strategies to improve the appropriateness and minimise the adverse effects of antibiotic use as being central to wound care treatment to improving patient outcomes, reducing microbial resistance and decreasing the spread of infections caused by multidrug-resistant organisms[37]. Effective AMS avoids the use of antimicrobial therapy when not indicated while enabling the prescribing of appropriate antimicrobial interventions when they are indicated to treat infection.

The UK government has outlined a 20-year vision for reducing AMR, proposing a lower burden of infection through better treatment of resistant infections[44]. This includes the optimal use of antimicrobials and good stewardship across all sectors and appropriate use of new diagnostics, therapies, vaccines and interventions in use, combined with a full AMR research and development pipeline for antimicrobials, alternatives, diagnostics, vaccines and infection prevention across all sectors.

The use of alternatives to traditional antibiotic therapy is of huge interest for combating increasing AMR, including bacteriophage therapy, phage-encoded products, monoclonal antibodies and immunotherapy[45]. Among these, endolysins phage-encoded peptidoglycan hydrolases selectively targeting bacterial taxa have been identified as promising antimicrobial agents because of their ability to kill antimicrobial-resistant bacteria and lack of reported resistance However, challenges restrict the widespread use of endolysin therapy, such as limited drug-delivery methods, their specificity to particular bacteria types, and bioavailability via IV administration[46,47].

Debridement is the physical removal of biofilm, devitalisedtissue, debris and organic matter and is a crucial component of wound care. The presence of non-viable tissue in the wound bed prevents the formation of granulation tissue and delays the wound healing process. The removal of non-viable tissue encourages wound healing. The type of tissue found in the wound bed (e.g. whether necrotic or sloughy) will determine whether debridement is required. Factors such as bioburden, wound edges and the condition of peri-wound skin can also influence whether debridement is required[48]. A range of techniques can be used, dependent on the clinicians ability level: these include autolytic, larval, mechanical, sharp and surgical methods[49,50].

The concept of moist wound healing is not newand can lead to healing up to 23 times quicker than that of dry wound healing[51,52].Wound dressings such as cotton wool, gauze, plasters, bandages, tulle or lint should not be used, as they do not promote a moist wound healing environment, require excessive changes, and can cause skin damage and pain during dressing changes. They have therefore been replaced by newer types of wound dressingsthat can play a role in autolysis and debridement, maintain a relatively stable local temperature, keep the wound hydrated, promote wound repair and prevent bacterial infection[14,53,54].

Wound dressings should keep the wound free from infections, excessive slough, contaminants and poisons, keep the wound at the ideal temperature and optimum pH for healing, be permeable to water, but not microbes, come away from wound trauma during dressing changes, not be painful and be comfortable[55]. There are a variety of dressings available for managing chronic wounds, such as hydrogels, hydrocolloids, alginates, foams, and film dressings[56]. Dressings can also be used carriers for active agents including growth factors, antimicrobial agents, anti-inflammatory agents, monoterpenes, silver sulfadiazine or silver nanoparticles[57].

Potential factors that may influence dressing selection include:

Antimicrobial dressings impregnated with iodine, silver and honey are available[58]. They can be divided into two categories: those that release an antimicrobial into the wound and those that bind bacteria and remove them from the wound into the dressing. A more detailed overview can be found in a recent consensus document on wound care and dressing selection for pharmacists[57].

It is essential wound dressings do not inadvertently lead to moisture-associated skin damage an umbrella term encapsulating incontinence-associated dermatitis, intertriginous dermatitis (or intertrigo), peri-wound maceration and peristomal dermatitis. Practitioners should ensure the dressing can manage any exudate and protects the peri-wound area. Skin barriers can be used to protect the peri-wound area and prevent skin damage[59].

Widely used to aid the healing of acute, chronic and traumatic wounds, negative-pressure wound therapy (NPWT) removes interstitial fluid/oedema and excessive exudate, provides a moist environment, improves blood flow and tissue perfusion, and stimulates angiogenesis and granulation tissue formation[4,60]. Results from several studies have demonstrated the selective effect of NPWT in eliminating non-fermentative gram-negative bacilli in wounds[36]. Additionally, NPWT can be combined with additional topical antimicrobial solutions, reducing bacteria load, stimulating wound closure and decreasing wound size faster than conventional NPWT[36,61,62].

Hyperbaric oxygen therapy wasfirst proposed as an additional treatment for chronic wounds in the mid-1960s. Treatment involves the intermittent exposure of the body within a large chamber to 100% oxygen at a pressure between 2.0 and 2.5 atmosphere absolute, leading to an increase in oxygen levels within haemoglobin and elevating oxygen tissue tension at the wound site[63].A Cochrane reviewpublished in 2015 reported a significant improvement in the healing of diabetes ulcers in the short term when treated with hyperbaric oxygen therapy. However, further high-quality studies are needed before clinical benefits can be proven[64].

For chronic wound healing, electrical stimulation is the most frequently studied biophysical therapy[4]. It uses direct current, alternative current, and pulsed current. Electrical stimulation has been shown to benefit every stage of the wound-healing process, both at cellular and systemic levels. During the inflammation phase, electrical stimulation promotes vasodilation and increases the permeability of blood vessels, thereby facilitating cellular movement to the wound site and so promoting a shorter inflammatory response.

Studies have reported an inhibition in bacterial proliferation after electric stimulation. In the proliferation phase, electrical stimulation raises the migration, proliferation and differentiation of endothelial cells, keratinocytes, myofibroblasts and fibroblasts. At the systemic level, it promotes revascularisation, angiogenesis, collagen matrix organisation, wound contraction, and re-epithelialisation. Ultimately,electrical stimulation promotes the contractility of myofibroblast and converts type III collagen into type I, along with rearranging collagen fibres to optimise the scars tensile strength[8,65,66].

A prospective clinical study conducted across the UK suggested that using an externally applied electroceutical device, combined with compression bandaging and dressings, was a cost-effective treatment for venous leg ulcers, compared with conventional treatments[67].

Low-frequency ultrasound has been used as an adjunct treatment for chronic wounds. It has a debriding effect, removing debris and necrotic tissue (primarily via cavitational and acoustic streaming phenomena). Ultrasound is also reported to disrupt biofilmin vitro, thus increasing the sensitivity of bacteria to antimicrobials[68]. It is proposed to be effective instimulating collagen synthesis, increasing angiogenesis,diminishing the inflammatory phase as well as promoting cellular proliferation[69].Several clinical studies have shown a reduction in wound size when wounds are treated with low-frequency ultrasound therapy[7072].

Extracorporeal shock wave therapy (ESWT) has been proposed to aid wound healing by transmitting acoustic pulsed energy to tissues. ESWT seems to promote angiogenesis, stimulate circulation, reduce anti-inflammatory response, and upregulate cytokine and growth-factor reactions[4]. A clinical trial demonstrated the feasibility and tolerability of ESWT in wounds with different aetiologies[73]. Furthermore, a review concluded that ESWT brings more benefits for patients with diabetic foot ulcers than hyperbaric oxygen therapy, based on increased angiogenesis, tissue perfusion and cellular reactions with reduced cell apoptosis, as well as a higher ulcer healing rate[74].

More recent developments include introducing nanomedicine to wound-healing approaches. It has been used to achieve controlled delivery, stimulate chronic wound healing and control microbial infections[14,75]. Nanotechnology-based wound dressings like nanogels and nanofibers offer a larger surface area and greater porosity, potentially enhancing absorption of wound exudate. They can also facilitate collagen synthesis and ultimately re-epithelisation through supporting the migration and proliferation of fibroblasts and keratinocytes.

Nanomedicines also seem to aid healing through molecular and cellular pathways[75]. For example, a methacrylated gelatin (MeGel)/poly(L-lactic acid) hybrid nanofiber synthesised has been reported to stimulate the recruitment and proliferation of human dermal fibroblasts, thereby promoting wound healing[76]. Nanoparticles can not only act as carriers of antimicrobial agents, they can also have an intrinsic antimicrobial effect[75,77,78]. In 2021, Qiu et al. successfully developed an antibacterial photodynamic gold nanoparticle (AP-AuNPs) that demonstrated antibacterial effects on both Gram-negativeEscherichia coliand Gram-positiveStaphylococcus aureus,as well as potentially inhibiting biofilm formationin vitro[79].

Growth factors such as vascular endothelial growth factor (VEGF), platelet-derived growth factor (PDGF), and fibroblast growth factor (FGF) are down-regulated in chronic wounds, suggesting that topical administration of growth factors and cytokines could improve wound healing[80].

Growth factors can improve wound repair through several mechanisms[81]:

Growth factors that have been studied in wound healing are EGF, VEGF, FGF, PDGF, transforming growth factor-beta 1 (TGF-1) and granulocyte-macrophage colony stimulating factor[82]. Becaplermin (rhPDGF-BB) was the first growth-factor therapy approved by the US Food and Drug Administration, after it demonstrated effectiveness in treating complex wounds when combined with standard wound care[80]. A systematic review and meta-analysis indicated that growth factors were effective in healing venous stasis ulcers, increasing wound healing by 48.8% compared with placebo and showing no difference in adverse effects compared with controls[83].

Stem cells may have certain advantages in wound healing because of their ability to differentiate into specialised cells and secrete numerous mediators including cytokines, chemokines, and growth factors[84,85]. This makes them a promising approach for treating chronic wounds.

Mesenchymal stem cells can be extracted from bone marrow, adipose tissue, umbilical cord blood, nerve tissue, or dermis and used both systemically and locally[86]. They release growth factors that stimulate blood-vessel and granulation tissue formation, fibroblast and keratinocyte migration, collagen synthesis, and fibroblast activation, increase re-epithelialisation, exert immunomodulatory properties, regulate inflammatory responses, and display antibacterial activities[85,8789].

Many studies have investigated the efficacy of stem-cell therapies for a variety of wounds, including burns, non-healing ulcers, and critical limb ischemia[9096]. A systematic review published in 2020 that investigated the clinical application of stem-cell therapy for the treatment of chronic wounds showed the potential of a variety of stem cells in the restoration of impaired wound healing, bothin vitroandin vivo, despite the clinical evidence being very limited. As the recorded studies were on case-by-case basis, there is a lack of comprehensive guidelines for the use of stem cells in different wounds[97].

Auto-transplantationof adipose tissue-derived mesenchymal stromal cells has been proposed as a safe, alternative method to treat chronic venous ulcers[96]. Bioscaffold matrices comprising hyaluronic acid, collagen or other bio-polymeric materials have increasingly been applied for stem-cell transplantation. These matrices not only provide wound coverage, but also offer protection for stem cells and controlled delivery[86].

Skin equivalents are polymeric biomaterials increasingly adopted for both acute and non-healing ulcers, such as venous ulcers, diabetic foot ulcers or pressure ulcers, to temporarily or permanently substitute the structure and function of human skin. Skin substitutes are designed to increase wound healing, provide a physical barrier that protects the wound from trauma or bacteria, provide a moist environment for the repair process, replace impaired skin components and decrease morbidity from more invasive treatments like skin grafting[98,99].

They can usually be classified as one of three major types: dermal replacement, epidermal replacement, and dermal/epidermal replacement[98]. Epidermal replacements (substitutes) comprising isolated autogeneous keratinocytes cultured on top of fibroblasts include Myskin (Regenerys), Laserskin(Fidia Advanced Biopolymers) and Epicel(Genzyme Tissue Repair Corporation). Dermal replacements include Dermagraft (Smith and Nephew) and Transcyte(Shire Regenerative Medicine)[98].

Epidermal/dermal skin replacements (also called composite skin substitutes) contain both epidermal and dermal layers that mimic the histological structure of original skin. The bi-layered bioengineering skin Apligraf (Organogenesis) was the first living skin equivalent for the management of complex chronic wounds like diabetic foot ulcers and venous leg ulcers. It is made up of a dermal layer of human fibroblasts embedded in a bovine type I collagen matrix and an epidermal layer generated by human keratinocytes[100]. Some other commercial products of composite substitutes are OrCel(Forticell Bioscience) andPermaDerm(Regenicin)[98]. In general, the current high cost of such dressings and limited evidence on effectiveness restricts them from being widely adopted[101]. Recently, technologies such as electrospinning or 3D-printing have been used to fabricate skin substitutes. Electrospinning can create nanofibers with high oxygen permeability, variable porosity, a large, exposed surface area and a morphology similar to the extracellular matrix, making them interesting candidates for skin substitutes[102,103].

TheNational Wound Care Strategy Programme, which was implemented by NHS England in 2018, has made progress in reducing unwanted variation in care and addressing suboptimal wound care.

Through its workstreams, the involvement of stakeholders, patients and carers, and the publication of the core capabilities for educating a multi-professional workforce, wound care has become a national priority. There are still many challenges in the management of chronic wounds the complexity of wound environment, limited knowledge of the biological, biochemical, and immunological healing processes, and the increasing complexity of disease pathophysiology that comes with ageing populations.

The development of standardised and clinically relevant testing for wound dressings, along with high-quality clinical trials, would enable useful comparisons of treatments. The whole episode of care should be considered in assessments of the cost-effectiveness of different dressings and devices, rather the simple cost of the individual entity. All these complex concerns restrict success in wound management, which in turn negatively impacts the quality of life of the patients and places a burden on global healthcare systems[75,104]. Organisations and healthcare providers should share best practice and education of healthcare professionals is needed to get the best outcomes for patients with preventable chronic wounds.

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Current and advanced therapies for chronic wound infection - The Pharmaceutical Journal

Cardiac Stem Cells Comments Off on Current and advanced therapies for chronic wound infection – The Pharmaceutical Journal | July 16th, 2022

Have something to say? Lookout welcomes letters to the editor, within our policies, from readers. Guidelines here.

Like many moms, UC Santa Cruz stem cell biologist Lindsay Hinck struggled to make enough milk to feed her infant daughter.

Frustrated by her low supply, she went to a lactation consultant, who advised her to wake up every night at 3 a.m. an optimal time in the hormone cycle to pump precious drops of liquid gold for her baby.

Hinck did it, but she also wondered, why was she having so much trouble and losing so much sleep while other moms had no problem feeding their newborns?

After many exhausting early hours with the pump, Hinck did what she does best: research. She found something remarkable: More than 25% of women worldwide struggle to produce enough milk to feed their infant children.

But when she looked to scientific literature for an explanation, it came up empty.

Hinck, who got a masters degree in biochemistry from UC Davis and her Ph.D. in cancer biology from Stanford University, was shocked to realize scientists have barely studied human lactation. There was almost no information for scientists or moms about how human breast tissue makes milk.

Hinck decided to change that.

She switched her UCSC labs research focus from breast cancer to lactation, specifically looking into how stem cells in breast tissue create milk and why some womens supply comes out low.

Its a topic some view with skepticism; lactation and breastfeeding are still treated by many as uncomfortable or inappropriate. In fact, in the early days of her research, Hinck had to get funding from an animal health firm interested in increasing milk production in cows.

We sexualize breasts in the most amazing ways, and people dont seem to have a problem talking about that, says Hinck, who has been at UCSC since 1998 and serves as co-director of the universitys Institute for the Biology of Stem Cells. Yet when it gets down to their biological function which is to provide nutrition for infants somehow the world clams up.

With the a nationwide baby formula shortage having affected millions of families, Hincks work funded by the National Institutes of Health takes on even greater importance. Parents whose infants have allergies or metabolic conditions rely on formula, and women particularly those who are already struggling to breastfeed cant suddenly build a milk supply overnight when formula is not available.

Hinck spoke with Lookout from her office at UCSC; this interview has been edited for clarity.

Lookout: What is lactation insufficiency?

Lindsay Hinck: Lactation insufficiency is the inability of a woman to produce the breast milk in daily volumes that meet the nutritional needs of her infant.

The statistics that we have are very broad. Somewhere between 25% and 67% of women will experience this worldwide. And this statistic is so broad because lactation insufficiency is understudied, and its hard to study.

A lot of scientists would agree that breast milk does confer an immunological advantage, and that it is filled with immune cells that the mother is giving to her infant; milk is also filled with microbes. Those are two of the major deliveries to children that come through breast milk, not to mention all the comfort of the breastfeeding cycle, psychological comfort and connectedness through the skin on skin feeling of being fed that way.

Lookout: How do you feel about your research in the context of the baby formula shortage?

Hinck: A lot of women rely on formula because they have trouble building a milk supply. Currently there are no FDA (U.S. Food and Drug Administration)-approved drugs in the United States for lactation insufficiency. My research is identifying therapeutically relevant drug targets, so that maybe we will be able to address this issue. We hope that one day women can take a drug to better build a milk supply.

Were working on a nonhormonal drug. The current drugs work on the hormone prolactin, whereas my lab studies stem cells. None of the drugs targeting prolactin have been approved, because they have terrible side effects.

Hormones have wide-ranging effects. Theyre released and they spread throughout the body. I think maybe we have an opportunity to identify a therapeutic that wont have so many deleterious side effects.

(Mel Melcon / Los Angeles Times)

Lookout: Because of the baby formula shortage, an easy answer might be to tell mothers they should just breastfeed. Why might that not be a compassionate or realistic response?

Hinck: No, thats not a compassionate or realistic response. I mean, especially if you havent built your milk supply, its not a trivial thing. If you didnt build a milk supply from the beginning, and even if you are breastfeeding, if you cant meet the daily needs of your infant, you simply dont have the milk. Its just not there.

Building a milk supply doesnt occur over 24 hours, you cant just latch the child on more often and have more milk in a day. Eventually the milk supply will increase, but its complicated. Its hard for some women to initiate and build a milk supply.

Lookout: In the U.S., lactation and breastfeeding seem to be treated as somewhat taboo or uncomfortable topics. How do you respond to that?

Hinck: We dont want to see women doing it. It seems to make people uncomfortable, so at best we provide women a room somewhere, and at worst there are no accommodations. We certainly dont appear as a society that welcomes breastfeeding in public. I am bemused at this, and find it tragic at the same time.

I myself, when I breastfed, I just breastfed. I just got to the point where tough, you know? I know I made people uncomfortable. My mother-in-law would try to drape a huge blanket over me and my child in the summer in the heat, and it was like 100 degrees underneath that blanket. I would just be like, This is crazy! Its just an infant at my breast eating. Seems fine to me. And I dont think the climate has dramatically changed in many places in the world. My daughter is 22 years old, and in 22 years I have not seen that needle budge. It still seems like breastfeeding makes people uncomfortable, and I dont know why.

Lookout: Have you faced any skepticism about this as a research topic, or faced any particular challenges in studying lactation compared to other topics, like cancer?

Hinck: I would say that I have had a harder time getting my lactation research funded. But recently, I received a NIH grant from the National Institutes for Child Health and Human Development, so thats been terrific. There has been a gaining interest in a number of whats been classified as womens diseases that have been understudied for a long time.

But in the early days, I got money from an animal health firm because they were interested in increasing milk supply in cows. The biology is the same, however. So that worked out for me, and we were able to have a project that involves looking to see if this would work for building milk supply in cows, and then we were able to unravel the basic pathways, and now were applying that.

Lookout: What would you say are the big questions driving your current research?

Hinck: How does the breast tissue know how many progenitor cells to release or recruit to expand and to build the milk supply?

Breast stem/progenitor cells have to last a whole lifetime, and they have limited potential. Theyre stemlike in that they undergo an asymmetric cell division, which is a special type of cell division that recreates the stem/progenitor cells and gives rise to daughter cells that can go on to expand and become the milk producing cells.

So how many of those asymmetric cell divisions occur? How many cells are recruited to undergo those asymmetric cell divisions? All of that is unknown. Remember, the stem cell, the progenitor cell, wants to divide as infrequently as possible. Every time they replicate their DNA, it is opening up the possibility of damage that could lead to cancer.

Lookout: How would understanding these progenitor cell pathways help improve peoples lives, or pursue a solution to lactation insufficiency?

Hinck: Its early days. We dont understand a lot, and of course giving drugs to women who are pregnant is tough. There are drugs on the market for lactation domperidone is the best medicine to build milk supply, but its not approved by the FDA in America. It has side effects, cardiac side effects.

So its not unheard of that there would be drugs that could help build a milk supply. I think that would be the ultimate goal of our research, to understand if there is any pharmacological intervention that could help.

Lookout: What do you think nursing mothers who are struggling with lactation need? What can we do as a society to support them?

Hinck: Well, in the short term, certainly make workplace rules that change the climate. I mean, even if the rules are in place, if women dont feel welcome to take the breaks to pump then it doesnt happen. I mean, we all know how that goes.

Give mothers more time off. Create more welcoming environments when they come back to work to support them and their desire to breastfeed their child.

And in the longer term, we could understand the biology of building milk supply, which is still quite mysterious in humans. What are some of the factors that may impinge on that during pregnancy or after pregnancy?

Lookout: What did you have to do in order to feed your child when you were having trouble making enough milk?

Hinck: I saw the lactation consultant and I was told to pump at 3 a.m. when prolactin levels are the highest. I would set the alarm and get up and pump every night. I was also working full time, pumping every four hours. But I could barely pump the amount of milk for the next day.

Thats a burden, you know? Its just hard to balance. Youve got an infant, and youve got this other role, but youre also providing all the food for them. It doesnt always work seamlessly, thats for sure. I went to work to do my science, and I did the best I could.

It was a lot of work. Its so much to expect of mothers. And we just dont give parents, mothers, the space and time to breastfeed at work. Its also underappreciated that there could be other people who want to breastfeed, and we need to open doors for them for non-birth moms, trans people. Why do we keep lactation in just the realm of women? I think that if we understood lactation physiology better, we could help people breastfeed.

Guanan Gmez-Van Cortright is a 2022 graduate of the UC Santa Cruz Science Communication masters program. She has written for Good Times, KQED radio and the San Jose Mercury News.

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Why do some women struggle to breastfeed? A UCSC researcher on what we know, and don't - Lookout Santa Cruz

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Stem Cells. Author manuscript; available in PMC 2020 Jul 1.

Published in final edited form as:

PMCID: PMC6658105

NIHMSID: NIHMS1024291

1NeuroRepair Department, Mossakowski Medical Research Centre, Polish Academy of Sciences, Warsaw, Poland

1NeuroRepair Department, Mossakowski Medical Research Centre, Polish Academy of Sciences, Warsaw, Poland

1NeuroRepair Department, Mossakowski Medical Research Centre, Polish Academy of Sciences, Warsaw, Poland

2Russell H. Morgan Department of Radiology and Radiological Science, Johns Hopkins University School of Medicine, Baltimore, MD, USA

3Cellular Imaging Section and Vascular Biology Program, Institute for Cell Engineering, Johns Hopkins University, Baltimore, MD, USA

1NeuroRepair Department, Mossakowski Medical Research Centre, Polish Academy of Sciences, Warsaw, Poland

2Russell H. Morgan Department of Radiology and Radiological Science, Johns Hopkins University School of Medicine, Baltimore, MD, USA

3Cellular Imaging Section and Vascular Biology Program, Institute for Cell Engineering, Johns Hopkins University, Baltimore, MD, USA

Author contributions:

Barbara Lukomska: Conception and design, financial support, collection and/or assembly of data, final approval of manuscript

Miroslaw Janowski: Conception and design, financial support, collection and/or assembly of data, manuscript writing, final approval of manuscript

It was shown as long as half a century ago that bone marrow is a source of not only hematopoietic stem cells, but also stem cells of mesenchymal tissues. Then the term of mesenchymal stem cells (MSCs) has been coined in early 1990s and over a decade later the criteria for defining MSCs have been released by International Society for Cellular Therapy. The easy derivation from a variety of fetal and adult tissues and not demanding cell culture conditions made MSCs an attractive research object. It was followed by the avalanche of reports from preclinical studies on potentially therapeutic properties of MSCs such as immunomodulation, trophic support and capability for a spontaneous differentiation into connective tissue cells, and differentiation into majority of cell types upon specific inductive conditions. While ontogenesis, niche and heterogeneity of MSCs are still under investigation, there is a rapid boost of attempts in clinical applications of MSCs, especially for a flood of civilization-driven conditions in so quickly aging societies in not only developed countries, but also very populous developing world. The fields of regenerative medicine and oncology are particularly extensively addressed by MSC applications, in part due to paucity of traditional therapeutic options for these highly demanding and costly conditions. There are currently almost 1000 clinical trials from entire world registered at clinicaltrials.gov and it seems that we are starting to witness the snowball effect with MSCs becoming a powerful global industry, however spectacular effects of MSCs in clinic still need to be shown.

Keywords: Mesenchymal stem cells, clinical, differentiation, immunomodulation, paracrine activity, history

Friedenstein was one of the pioneers of the theory that bone marrow is a reservoir of stem cells of mesenchymal tissues in adult organisms. It was based on his observation at the turn of the 1960s and 1970s., that ectopic transplantation of bone marrow into the kidney capsule, results not only the proliferation of bone marrow cells, but also the formation of bone [1] (). This indicated the existence in the bone marrow of a second, in addition to hematopoietic cells, stem cell population giving rise to bone precursors. Due to the ability of these cells to create osteoblasts, Friedenstein gave them the name of osteogenic stem cells. Friedenstein was also the first to isolate from bone marrow adherent fibroblast-like cells with the ability to grow rapidly in vitro in the form of clonogenic colonies (CFU-F; colony forming unit-fibroblast). These cells derived from CFU-F colonies were characterized by the ability to differentiate in vitro not only to osteocytes, but also to chondrocytes and adipocytes. After transplantation of CFU-F colonies into the recipient, they were capable of co-formation of the bone marrow micro-environment [2,3]. The term mesenchymal stem cells has been proposed by Caplan in 1991 because of their ability to differentiate into more than one type of cells that form connective tissue in many organs [4]. This name has become very popular and is currently the most commonly used, even though it raised doubts about the degree of their stemness [5]. Today, there are many substitutes in the literature for the abbreviation of MSCs, including Multipotent Stromal Cells, Marrow Stromal Cells, Mesodermal Stem Cells, Mesenchymal Stromal Cells and many more. In its latest work, Caplan recommends renaming these cells to Medicinal Signaling Cells due to the emphasis on the mechanism of their therapeutic effects after transplantation, which is believed to be based mainly on the secretion of factors facilitating regenerative processes [6].

The roots of research on bone marrow-derived stem cells of connective tissue, which has been then named: mesenchymal stem cells

Due to the growing controversy regarding the nomenclature, the degree of stemness and the characteristics of the cells discovered by Friedenstein, the International Society for Cellular Therapy (ISCT) in 2006 published its position specifying the criteria defining the population of MSCs, which was accepted by the global scientific community. These guidelines recommend the use of the name multipotent mesenchymal stromal cells, however, the name mesenchymal stem cells still remains the most-used. The condition for the identification of MSCs is the growth of cells in vitro as a population adhering to the substrate, as well as in the case of cells of human origin, a phenotype characterized by the presence of CD73, CD90, CD105 surface antigens and the lack of expression of proteins such as: CD45, CD34, CD14, CD11b, CD79a or CD19 or class II histocompatibility complex antigens (HLA II, human leukocyte antigens class II). Moreover, these cells must have the ability to differentiate towards osteoblasts, adipocytes and chondroblasts [7,8]. In addition to the markers mentioned in the ISCT guidelines, the following antigens turned out to be useful in isolating the human MSCs from the bone marrow: STRO-1 (antigen of the bone marrow stromal-1 antigen, cell surface antigen expressed by stromal elements in human bone marrow-1), VCAM / CD106 (vascular cell adhesion molecule 1) and MCAM / CD146 (melanoma cell adhesion molecule), which characterizes cells growing in vitro in a adherent form, with a high degree of clonogenicity and multidirectional differentiation ability [911].

The common mesenchymal core in both versions of MSC abbreviation comes from the term mesenchyme, which is synonymous with mesenchymal tissue or embryonic connective tissue. It is used to refer to a group of cells present only in the developing embryo derived mainly from the third germ layer - mesoderm. During the development these cells migrate and diffuse throughout the body of the embryo. They give rise to cells that build connective tissue in adult organisms, such as bones, cartilage, tendons, ligaments, muscles and bone marrow. The view about the differentiation of MSCs during embryonic development from mesenchymal cells is widely spread [4]. This is due, inter alia, to the observed convergence in the expression of markers such as: vimentin, laminin 1, fibronectin and osteopontin, which are typical for mesoderm cells during embryonic development, as well as characteristic for in vitro adherent bone marrow stroma cells [12]. However, the true origin of MSCs is unknown. In the literature, we can find also reports indicating that they are ontogenetically associated with a group of cells derived from ectoderm, which originate from Sox1 + cells (SRY - sex determining region Y) that appear during the development of embryonic neuroectoderm and neural crest. These cells inhabit newborn bone marrow and meet the criteria corresponding to their designation as MSCs. However, with the development of animals, the population of these cells disappears and is replaced by cells with a different, unidentified origin [13]. It has also been shown that in the bone marrow of the developing mouse embryo, at least two MSCs populations with distinct expression of the nestin protein and the intensity of cell divisions can be distinguished. The former one originates from mesoderm that does not express nestin, and is characterized by intense proliferation and is involved in the process of creating the embryo skeleton. The latter one is derived from the cells of the neural crest, which expresses nestin and is non-dividing and remains passive during bone formation while in the adult organism contributes to a niche of hematopoietic cells [14]. It seems, therefore, that the ontogenesis of MSCs is associated with cells belonging to different germ layers and their original source determines the role and functions that they play in the adult body.

In 1978, the concept of a niche was defined as a place in the body that is settled by stem cells and whose environment allows them to be maintained in an undifferentiated state [15]. MSCs were first obtained from the bone marrow stroma where they constitute an element of stromal cells, participating in the production of signals modulating the maturation of hematopoietic cells. However, the precise location of the niche for MSCs has not been known so far. In the context of research results indicating that MSCs can be isolated from many mesoderm-derived tissues during embryonic development, a common element was sought for all sources from which MSCs can be isolated and a theory was proposed about the existence of their niche within the blood vessels that are present in all structures from which these cells were isolated.

Crisan and colleagues have shown that cells inhabiting the perivascular space of blood vessels, isolated from human tissues such as skeletal muscle, pancreas, adipose tissue and placenta, with the phenotype CD146 +, NG2 + (neuroglycan-2), PDGF-R + (-type platelet-derived growth factor receptor), ALP + expressing endothelial, hematopoietic and muscle cell markers described as pericytes were precursors for cells that after in vitro expansion meet the criteria for determining them as MSCs [16]. Analogously to the described by Friedenstein MSCs, CD146 + cells colonizing the perivascular space of sinusoidal sinus vessels, are responsible for the production of signals allowing the reconstruction of the bone marrow microenvironment after transplantation to heterotopic location [11]. Whats more, tracing the fate of pericytes in the process of rebuilding a damaged tooth in rodents has shown that they are transforming into odontoblasts, which arise from MSCs found in the pulp. However, the same studies showed that in the process of reconstruction of incisors in mice, a different population of odontoblasts, which is not formed from pericytes, but from MSCs of different origin migrating to the area of damage, prevailed quantitatively [17]. The second cell population associated with blood vessels, proposed as a counterpart of MSCs in the body is advent building cells with the CD34+ CD31- CD146- phenotype, which after isolation and in vitro culture meet the criteria defining the population as MSCs. However, these cells also have the ability to differentiate into pericytes [18,19]. Although pericytes and MSCs have a very similar gene expression profile as well as an analogical capacity for differentiation, it has been shown that the functionality of these cells varies. In vitro studies of endothelial cell interactions in co-culture with MSCs or pericytes have shown that only pericytes are able to form highly branched, dense, cylindrical structures with large diameter, typical for well-organized blood vessels, while isolated from the bone marrow MSCs do not have such abilities. Currently, it is believed that there is a link between pericytes and MSCs, but their mutual relations are not well defined. There are speculations that MSCs are an intermediate form of pericytes or their subpopulation, but there is still no conclusive evidence confirming this hypothesis [20,21].

While the cells fulfilling criteria for MSCs can be harvested from various tissues at all developmental stages (fetal, young, adult and aged) using their plastic adherence property, there are profound differences between obtained MSC populations [22,23]. Bone marrow was historically the first source from which MSCs were obtained, however, over time, there have been reports of the possibility of isolation from other sources of cells with similar properties. Mesenchymal cells are obtained from both tissues and secretions of the adult body, such as adipose tissue, peripheral blood, dental pulp, yellow ligament, menstrual blood, endometrium, milk from mothers, as well as fetal tissues: amniotic fluid, membranes, chorionic villi, placenta, umbilical cord, Wharton jelly, and umbilical cord blood [2437]. MSCs of fetal origin as compared to cells isolated from tissues of adult organisms are characterized by a faster rate of proliferation as well as a greater number of in vitro passages until senescence [38]. However, MSCs derived from bone marrow and adipose tissue are able to create a larger number of CFU-F colonies, which indirectly indicates a higher degree of their stemness. The comparison of gene expression typical for pluripotent cells shows that only in cells isolated from the bone marrow we can observe the expression of the SOX2 gene, the activation of which is associated with the self-renewal process of stem cells as well as with neurogenesis during embryonic development [39]. Discrepancies in the ability of MSCs obtained from various sources to differentiate have also been described. The lack of differentiation of MSCs derived from umbilical cord blood towards adipocytes as well as the greater tendency of MSCs from bone marrow and adipose tissue to differentiate towards osteoblasts were observed [39,40].

In addition to the diverseness observed between MSCs from different sources, there are also differences associated with obtaining them from individual donors. Among the cells isolated from the bone marrow from donors of different ages and sexes, up to 12-fold differences in the rate of their proliferation and osteogenesis were found, combined with a 40-fold difference in the level of bone remodeling marker activity - ALP (alkaline phosphatase). At the same time, no correlations were found resulting from differences in the sex or age of donors [41]. However, the results of studies by other authors indicate that the properties of MSCs isolated from the bone marrow are strongly associated with the age of the donor. Cells collected from older donors are characterized by an increased percentage of apoptotic cells and slower rate of proliferation, which is associated with an increased population doubling time. There is also a weakened ability of MSCs from older donors to differentiate towards osteoblasts [42]. Heo in his work shows the different ability of MSCs to osteogenesis combining it with different levels of DLX5 gene expression (transcription factor with the homeodomain 5 motif) in individual donors, however independent of the type of tissue from which the cells were isolated [39].

The next stage in which we can observe diversity among the MSCs population is in vitro culture. The morphology of cultured cells that originate from the same isolation allows for differentiation into three sub-populations. There are observed spindle-shaped proliferating cells resembling fibroblasts (type I); large, flat cells with a clearly marked cytoskeleton structure, containing a number of granules (type II) and small, round cells with high self-renewal capacity [43,44]. The original hypothesis assumed that all cells that make up the MSCs population are multipotent, and each colony of CFU is capable of differentiating into adipocytes, chondrocytes and osteoblasts, as confirmed by appropriate studies [45]. However, in the literature we can find reports that cell lines derived from a common colony of CFU-F differ in their properties, characterized by uni-, di- or multipotence [46]. Some of the authors showed the division of clonogenic MSCs colonies into as much as eight groups distinct in their potential for differentiation. At the same time, it is suggested that there is a hierarchy within which cells subordinate to each other are increasingly directed towards osteo- chondro- or adipocytes and gradually lose their multipotential properties to di- and unipotential ones. This transformation may also be associated with a decrease in the rate of cell proliferation and the level of CD146 protein expression (CD; cluster of differentiation) - proposed as a marker of multipotency [47].

One of the main advantages of MSCs are their immunomodulatory properties. MSCs grown in vitro have the ability to interact and regulate the function of the majority of effector cells involved in the processes of primary and acquired immune response () [48]. They exert their immunomodulatory effects by inhibiting the complement-mediated effects of peripheral blood mononuclear cell proliferation [49,50], blocking apoptosis of native and activated neutrophils, as well as reducing the number of neutrophils binding to vascular endothelial cells, limiting the mobilization of these cells to the area of damage [51,52]. In addition, cytokines synthesized by activated MSCs stimulate neutrophil chemotaxis and secretion of pro-inflammatory chemokines involved in recruitment and stimulation of phagocytic macrophage properties [53]. Moreover MSCs limit mast cell degranulation, secretion of pro-inflammatory cytokines by these cells as well as their migration towards the chemotactic factors [54]. Native MSCs have the ability to block the proliferation of de novo-induced NK cells, but they are only able to partially inhibit the proliferation of already activated cells [55]. They also contribute to the reduction of cytotoxic activity of NK cells [56]. Moreover MSCs can block the differentiation of CD34 + cells isolated from the bone marrow or blood monocytes into mature dendritic cells both by direct contact as well as by secreted paracrine factors [57,58]. They inhibit the transformation of immature dendritic cells into mature forms and limit the mobilization of dendritic cells to the tissues [59]. Under their influence, M1 (pro-inflammatory) macrophages are transformed into M2 type cells with an anti-inflammatory phenotype, and the IL-10 (IL, interleukin) secreted by them inhibits T-cell proliferation [60,61]. In vitro studies have demonstrated a direct immunomodulatory effect of MSCs on lymphocytes. During the co-culture of MSCs with lymphocytes, suppression of activated CD4 + and CD8 + T cells and B lymphocytes was observed [62]. In addition, MSCs reduce the level of pro-inflammatory cytokines synthesized by T-lymphocytes, such as TNF- (tumor necrosis factor ) and IFN- (interferon ) [63], and increase synthesis of anti-inflammatory cytokines, e.g. IL-4. In the presence of MSCs, the inhibition of the differentiation of naive CD4 + T lymphocytes to Th17 + lymphocytes (Th; T helper cells) was observed, while the percentage of T cells differentiating towards CD4 + CD25 + regulatory T cells was found to increase [64,65]. Glennie et al. described this condition as anergy of activated T cells in the presence of MSCs [62]. MSCs also have the ability to limit the synthesis of immunoglobulins like IgM, IgG and IgA (Ig; immunoglobulin) classes secreted by activated B cells, thereby blocking the differentiation of these cells to plasma cells. They also reduce the expression of chemokines and their receptors on the surface of B lymphocytes, which probably have a negative effect on their ability to migrate [66].

The schematic representation of immunomodulatory capabilities of MSCs

Mesenchymal stem cells secrete a wide range of paracrine factors, collectively referred to as the secretome, which support regenerative processes in damaged tissues. They comprise the components of the extracellular matrix, proteins involved in the adhesion process, enzymes as well as their activators and inhibitors, growth factors and binding proteins, cytokines and chemokines, and probably many more [67]. These factors can have distinct impact on the processes they regulate (). MSCs secrete factors promoting angiogenesis, such as: vascular endothelial growth factor (VEGF) but they may also inhibit this process, through expression of monokine induced by interferon and tissue inhibitors of metalloproteinases 1 and 2 [68,69]. An important role is also played by chemokines secreted by MSCs in the process of blocking or stimulating cell chemotaxis, such as: CCL5 (RANTES, regulated by activation, expression and secretion by normal T lymphocytes), CXCL12 (SDF-1, stromal cell-derived factor 1) or CCL8 (MCP-2; monocyte chemoattractant protein 2). An essential group of factors from the point of view of regeneration processes are growth factors with an anti-apoptotic effect, including: HGF (hepatocyte growth factor), IGF-1 (insulin-like growth factor 1), VEGF, CINC-3 (cytokine induced by a chemoattractant for neutrophil chemoattractant), TIMP-1 (tissue inhibitor of metalloproteinases 1), TIMP-2 (tissue inhibitor of metalloproteinases 2), osteopontin, growth hormone, FGF-BP (bFGF binding protein), and BDNF (brain-derived growth factor; -derived neurotrophic factor) and stimulating proliferation as: TGF- (transforming growth factor ), HGF, EGF (epidermal growth factor), NGF (nerve growth factor; nerve growth factor), bFGF (basic fibroblast growth factor), IGFBP-1, IGFBP-2 (IGFBP; insulin-like growth factor 1 binding protein, IGF-Protein-1 protein) and M-CSF (stimulant factor t molar macrophage colony; macrophage colony-stimulating factor) [68,70,71]. Growth factors secreted by MSCs have also ability to reduce fibrosis of tissues during regeneration. These include KGF (keratinocyte growth factor), HGF, VEGF, and Ang-1 (angiopoietin-1), SDF1, IGF-1, EGF, HGF, NGF, TGF- [71,72]. There are reports about the antibacterial properties and interaction of the MSC secretome with cancer cells. Data on the impact of MSCs on neoplasia are not conclusive, however, it is assumed that both the tumor type and the origin of MSCs are of great importance for the final effect [73]. It was shown that factors enclosed within the MSCs secretome are able to reduce the proliferation, viability and migration of certain types of cancer cells (such as non-small-cell lung carcinoma) [74]. Others have shown that factors released by MSCs may increase motility, invasiveness and the ability to form metastases (including, for example, breast cancer cells) [75]. In response to bacteria, levels of cytokines such as IL- 6, IL-8, CCL5, PGE2, TNF-, IL-1, IL-10, VEGF and SDF-1 secreted by MSCs are subject to change [76]. MSCs contain also substances with antibacterial, anti-parasitic and antiviral activity [77].

The mechanisms mediating MSC-dependent trophic support

Another broad and dynamically developing field in recent years which is related to paracrine MSCs activity is their ability to secrete extracellular vesicles (EVs), which include exosomes, microvesicles and apoptotic bodies. Their composition largely coincides with the components contained in the cells from which they originate. Physiologically they play an important role in the regulation of biological functions, homeostasis and the immune response of the body. It is also postulated that the biological activity of microvesicles is comparable to that of MSCs [78]. Experiments conducted using supernatant derived from in vitro culture of MSCs showed that the factors contained in their secretome are responsible for a large part of the effects exerted by MSCs during the regeneration of the damaged area including the protection of other cells against apoptosis, induction of their proliferation, prevention of excessive fibrosis of tissues, stimulation of the angiogenesis process and immunomodulatory effects, as well as the induction of endogenous stem cells differentiation [65,68,69,7982].

As mentioned above, the ability to differentiate into three types of cells such as: osteocytes, chondrocytes and adipocytes is one of the criterion for MSCs [8]. This phenomenon can be traced in vitro by placing MSCs in a medium containing specific supplements, for the adipogenesis process they are mainly dexamethasone, indomethacin, insulin and isobutylmethylxanthin [83], for chondrogenesis cell culture in DMEM medium (Dulbecco / Vogt Modified Eagles Minimal Essential Medium) supplemented with insulin, transferrin, selenium, linoleic acid, selenium acid, pyruvate, ascorbic phosphate, dexamethasone and TGF- III [84], which may additionally be aided by the addition of IGF-1 and BMP-2 (BMP; bone morphogenetic proteins) [85]. In turn the osteogenesis is induced by the presence of ascorbic acid, -glycerophosphate and dexamethasone [86]. Differentiation of MSCs in the appropriate cell type is assessed by identifying the production of respectively: fat droplets (adipogenesis), proteoglycans and type II collagen synthesis (chondrogenesis) or mineralization of calcium deposits and the increase of alkaline phosphatase expression (osteogenesis). However, many literature reports indicate that by the treatment with appropriate factors MSCs might be also a source of other cell types. Caplan and Dennis in their work from 2006 present a process that they call mesengenesis, in which MSCs give also rise to myoblasts, bone marrow stromal cells, fibroblasts, cells co-creating connective tissue of the body as well as ligaments and tendons [87]. Addition of 5-azacytidine to MSCs allows to obtain muscle cells, including cardiomyocytes and myoblasts having the ability to create multinucleated miotubes and expressing markers such as: -myosin heavy chain, -actin cardiac form and desmin [88]. In addition, in vitro studies have made it possible to obtain from MSCs at least two types of cells derived from the endoderm through their transdifferentiation into hepatocytes and -cells of pancreatic islets. The liver cells are obtained from MSCs in two stages by culturing them in modified Dulbeccos medium supplemented with EGF, bFGF and nicotinamide, and in the next stage with the addition of oncostatin M, dexamethasone, insulin, transferrin and selenium. The resulting cells show the presence of markers typical for hepatocytes such as albumin, -fetoprotein and hepatocyte nuclear factor 4 (HNF-4) [89]. By the treatment with a mixture of growth factors secreted by regenerating cells of the pancreas as well as by the use of acitin A, sodium butyrate, taurine and nicotinamide the pancreatic islets of -cells capable of producing insulin were obtained from MSCs [90,91]. It has also been shown that stimulation with appropriate factors may result in the differentiation of MSCs into cells derived ontogenetically from ectoderm, such as neurons. The use of BME stimulation in vitro (-mercaptoethanol) followed by NGF leads to the differentiation of MSCs into cholinergic nerve cells expressing their typical proteins such as NF-68 neurofilaments (68 kDa Neurofilament protein with 68 kDa molecular mass), NF-200 (neurofilament protein with a molecular weight 200kDa, 200kDa neurofilament protein), NF-160 (neurofilament protein molecular weight 160kDa, 160kDa neurofilament protein), choline acetyltransferase and synapsin I [92]. Other factors mentioned as compounds inducing the transformation of MSCs into nerve cells are insulin, retinoic acid, bFGF, EGF, valproic acid, BME and hydrocortisol [93]. In addition, GNDF (glial cell-derived neurotrophic factor), BDNF (brain-derived neurotrophic factor), retinoic acid, 5-azacytidine, isobutylmethylxanthine and indomethacin stimulate the transformation of MSCs into mature neurons that express markers of nervous systems cells such as: nestin, -III tubulin, microtubule associated protein - MAP2 (microtubule associated protein 2) and neuron-specific enolase (ENO2; enolase 2) [94]. These studies show that under strictly controlled conditions prevailing during in vitro culture, in the presence of chemicals and growth factors, MSCs are able to turn into cells derived from all three embryonic germ layers ().

The differentiation potential of MSCs

It has been more than half a century since the curiosity has been revealed that not only hematopoietic cells, but also those capable of forming connective tissue reside in the bone marrow. Subsequent studies have begun to reveal the increasingly fascinating properties of these cells, which go far beyond forming connective tissue. This, combined with their easy derivation from various tissues, made them an attractive research object. Immunomodulatory properties, aiding repair of various tissues as well as differentiation potential to practically any types of cells stunned a whole host of scientists and established MSCs as a driving force of regenerative medicine and began also to play an increasingly important role in oncology [95]. We are currently observing a flood of clinical trials with the use of MSCs, and their number doubles every few years and currently reaches almost 1000 registered items on the clinicaltrials.gov website.

MSCs compose a negligible fraction of cells derived from in vivo tissues and there is no effective method to capture them directly. Therefore, MSCs need to be subjected to the process of in vitro expansion, which in clinical context is called biomanufacturing and biobanking and both terms are frequently used interchangeably to describe the process from procurement of cell source to deliver cells to the patients bed. The processing of MSCs must be performed according to current Good Manufacturing Practice (cGMP) as any other therapeutic agent and is subjected to extensive regulatory effort. Food and Drug Administration (FDA) is the main authority responsible for acceptance of medical products including those containing living cells such as MSCs in the USA. FDA has issued a perspective on MSC-based product characterization [96] and up-dated it in FDA Grand Round delivered by Steven Bauer, PhD, Chief of Cell and Tissue Therapies Branch at FDA on March 08, 2018. Both sources are an excellent overview of regulatory challenges related to the biobanking of MSCs. In general, any new product must obtain investigational new drug status (INDs) to be used in clinical trial before filing application for marketing, and there were 66 INDs submitted to FDA between 2006 and 2012. Based on that FDA engaged into regulatory research project called MSC consortium to characterize MSC based-products with an output of 16 research papers. The main organ responsible for the regulation of medical market in all Member States is European Medicines Agency (EMA) consisting of seven smaller committees. The MSCs-containing products should be classified as Advanced Therapy Medical Product (ATMP) and in detail considered as Somatic Cell Therapy Medicinal Product (CTMP) [97]. Its release on medical market has to be first accredited by Committee for Advanced Therapies (CAT) which creates the general opinion and evaluates the quality, safety and efficiency of the product. After CAT assessment the final acceptance should be then approved by Committee for the Medicinal Products for Human Use (CHMP). This type of legalization is called Centralized Marketing Authorization and it allows to use ATMP products in all European Union countries. Currently, there is a variety of protocols used for biomanufacturing and biobanking of MSCs, and once the successful stories become strong, the landscape of MSC production will probably solidify with predicted reduction of MSC production approaches due to economic and regulatory pressures.

Summing up, it seems that the MSCs are becoming a powerful global industry, ready to respond to the unmet needs of modern medicine struggling with the proper care and quality of life of rapidly aging societies, which is already affecting not only developed countries, but also very populous developing countries. In conclusion, we are beginning to observe the effect of the snowball in which ever new discoveries related to MSC are increasingly stimulating clinical applications of the MSC, which is beginning to contribute to the transformation of medical care.

Significance Statement

The research on bone marrow-derived stem cells of connective tissue is evolving and continuously expanding with a recent boost of interest in clinical applications reflected by an avalanche of nearly 1000 registered clinical trials. While, the current name: mesenchymal stem cells (MSCs) have been coined as late as early 90-ies, it is important to commemorate of the fiftieth anniversary of research on them and provide a big picture from roots of first paper in 1968, through identification of their various potential therapeutic activities such as immunomodulation, trophic support and capability for differentiation and taking role in cell replacement strategies.

This work was funded by NCR&D grant EXPLORE ME within the STRATEGMED I program and by NIH R01 NS091100-01A1.

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Mesenchymal stem cells: from roots to boost - PMC

Cardiac Stem Cells Comments Off on Mesenchymal stem cells: from roots to boost – PMC | July 8th, 2022

Lab-grown human heart cells provide a powerful tool to understand and potentially treat heart disease. However, the methods to produce human heart cells from pluripotent stem cells are not optimal. Fortunately, a new study out of the University of WisconsinMadison Stem Cell & Regenerative Medicine Center is providing key insight that will aid researchers in growing cardiac cells from stem cells.

The research, published recently in eLife, investigates the role of extracellular matrix (ECM) proteins in the generation of heart cells derived from human pluripotent stem cells (hPSCs). The ECM fills the space between cells, providing structural support and regulating formation of tissues and organs. With a better understanding of ECM and its impact on heart development, researchers will be able to more effectively develop heart muscle cells, called cardiomyocytes, that could be useful for cardiac repair, regeneration and cell therapy.

How the ECM impacts the generation of hPSC-cardiomyocytes has been largely overlooked, says Jianhua Zhang, a senior scientist at the Stem Cell and Regenerative Medicine Center. The better we understand how the soluble factors as well as the ECM proteins work in the cell culture and differentiation, the closer we get to our goals.

Researchers like Zhang have been looking to improve the differentiation of hPSCs into cardiomyocytes, or the ability to take hPSCs, which can self-renew indefinitely in culture while maintaining the ability to become almost any cell type in the human body and turn them into heart muscle cells. To investigate the role of the ECM in promoting this cardiac differentiation of hPSCs, Zhang tested a variety of proteins to see how they impacted stem cell growth and differentiation specifically, ECM proteins including laminin-111, laminin-521, fibronectin and collagen.

Our study showed ECM proteins play significant roles in the hPSC adhesion, growth, and cardiac differentiation. And fibronectin plays an essential role and is indispensable in hPSC cardiac differentiation, says Zhang. By understanding the roles of ECM, this study will help to develop more robust methods and protocols for generation of hPSC-CMs. Furthermore, this study not only helps in the field for cardiac differentiation, but also other lineage differentiation as well.

While the new study provides important insight into heart cell development, it is built upon a 2012 study Zhang led which looked at the most efficient way to develop cardiac differentiation of stem cells.

This study is actually a follow-up paper to the Matrix Sandwich Method that we developed for efficient cardiac differentiation of hPSCs, Zhang says. In order to culture the stem cells, we needed to have an ECM layer on the bottom of the plate. Otherwise, the stem cells would not attach to the plate. We would then add another layer of ECM on top of the growing stem cells, and we found that this helped promote the most effective differentiation.

While it was clear that this layering, or sandwich, method more efficiently and reproducibly differentiated hPSC-cardiomyocytes, researchers did not fully understand why. The new study explains why the ECM layers are crucial and identifies fibronectin as a key ECM protein in the development of hPSC-cardiomyocytes.

The most exciting part of this study is now I understand why the Matrix Sandwich Method worked. We were able to identify the fibronectin and its integrin receptors as well as the downstream signaling pathways in this study, Zhang explains. With a better understanding of ECMs roles in stem cell growth and cardiac differentiation, we now hope to investigate the roles of fibronectin and other ECM proteins in promoting the hPSC-cardiomyocytes transplantation for cell therapy.

The next step could help researchers realize the full potential of using hPSC-cardiomyocytes for disease modeling, drug screening, cardiac regeneration and cell therapy. This is very meaningful to Zhang, who began working in cardiovascular research more than 16 years ago.

I became interested in stem cell and heart research when I began working with the stem cells and saw them turning into heart cells beating in a cell culture dish under a microscope, Zhang says. It was amazing. Ive become more and more dedicated to this research, and I can really see the potential of using the stem cell technologies to cure disease and improve our health.

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New study allows researchers to more efficiently form human heart cells from stem cells - University of Wisconsin-Madison

Cardiac Stem Cells Comments Off on New study allows researchers to more efficiently form human heart cells from stem cells – University of Wisconsin-Madison | July 8th, 2022

He called his wife Ann once in the driver's seat to continue the conversation they'd been having over breakfast.

As he made his way towards Mosman in the usual Sydney traffic, a beat-up Toyota Corona was in the queue directly behind him.

At the intersection of Bardwell Rd and Military Rd, the Corona deliberately swerved into Dr Chang's car and so the two cars pulled over on the side of the road.

It was 8am when Phillip Lim and Chiew Seng Liew - the occupants of the Corona - pulled a pistol on Chang.

They wanted money. Lim planned to extort $3 million from a wealthy Asian businessman living in Australia, so he could set up a gambling den or massage parlour. They'd picked Dr Chang after seeing an article about him in a magazine.

Dr Chang pulled out his wallet immediately, but there were numerous witnesses watching on in horror.

Mosman Collectivequotes Chang as yelling out to someone, "call the police, theyve got guns."

He was shot twice - once in the head, once in the stomach. He died at the scene.

Liew was sentenced to a maximum of 26 years in prison for firing the two shots that killed Dr Chang. After 21 years, he was released and deported back to his home country of Malaysia in 2012.

As The Sydney Morning Heraldreported, it was a decision that "devastated" Dr Chang's family.

"I made a mistake," Liew told the Sevennetwork upon his release. "I did the wrong thing and made the family suffer ... You know I want to apologise for the family."

His co-accused Lim was granted parole after serving his minimum 18-year sentence, which expired in 2009.

Hailed as a "medical genius," Dr Chang was celebrated and admired around the world.

While he personallysaved hundreds of lives, he always had his eye on millions - which could be achieved through medical research.

After his death, the Victor Chang Foundation created by Dr Chang in 1984 with the aim of sharing expertise between Australia and Asia through training in the fields of cardiothoracic surgery, heart and lung transplantation and cardiology, continued on with his work.

But his dream was carried forward even further,with the establishment of The Victor Chang Cardiac Research Institute in 1994. It was opened by Princess Dianawho told those gathered, "Dr Chang was no ordinary cardiac surgeon. He was a visionary."

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Dr Victor Chang saved hundreds of lives. 31 years ago today, he was murdered. - Mamamia

Cardiac Stem Cells Comments Off on Dr Victor Chang saved hundreds of lives. 31 years ago today, he was murdered. – Mamamia | July 8th, 2022

Wilmington, Delaware, United States, Transparency Market Research Inc.: Cell line development is an important technology in life sciences. Stable cell lines are used for various applications including monoclonal antibody and recombinant protein productions, gene functional studies, and drug screening

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Manual screening method is a traditional method used for cell line development. This method is tend to be disadvantageous as it is labor-intensive and time-consuming. Automation in tools used for cell line development is likely to replace manual methods of cell line development.

Cell line development and culturing is being rapidly adopted in areas of biological drug developments for various chronic diseases, regenerative medicines such as stem cells & cell-based therapies, recombinant protein, and other cellular entities for pharmaceuticals, diagnostics, and various other industries.

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Key Drivers and Opportunities of Global Cell Line Development Market

Rise in focus on research & development, owing to increase in prevalence of cancer and other chronic diseases is anticipated to drive the market. Several institutes, such as Cancer Research Institute, National Cancer Institute, Advanced Centre for Treatment, Research and Education in Cancer (Cancer Research Centre [ICRC]), and NCI Community Oncology Research Program (NCORP), are engaged in research & development for cancer diagnosis and treatment. Hence, the initiative of government and non-government organizations is likely boost the growth of the market.

Mammalian cell lines are widely used as production tools for various biologic drugs. Technological advancement in cell line development in mammalian cell culturing is likely to fuel the growth of the market. For instance, according to an article published in Pharmaceuticals (Basel), the U.S. Food and Drug Administered approved 15 novel recombinant protein therapeutics from 2005 to 2011 on an average.

Advances in bioinformatics and recombinant technologies have led to development of new cell lines for synthesis or production of essential peptides, enzymes, saccharides, and other molecules which are being used in pharmaceuticals and various other industries.

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North America to Capture Major Share of Global Cell Line Development Market

North America is expected to account for major share of the global cell line development market due to well-established health care infrastructure and rise in government initiatives. Furthermore, adoption of innovative technologies is likely to augment the market in the region.

The cell line development market in Asia Pacific is expected to grow at a rapid pace during the forecast period, owing to increasing risk of communicable diseases, cancer, and chronic & rare diseases and surge in geriatric population. For instance, according to an article published in BioMed Central Ltd, in 2018, 2.9 million cancer deaths occurred and 4.3 million new cancer cases were recorded in China.

Key Players Operating in Global Cell Line Development Market

The global cell line development market is highly concentrated due to the presence of key players. A large number of manufacturers hold major share in their respective regions. Key players engaged in adopting new strategies are likely to drive the global cell line development market. Key players are developing new, cost-effective biologic products. This is anticipated to augment the market.

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Major players operating in the global cell line development market are:

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Cell Line Development Market: Increase in Prevalence of Cancer and Other Chronic Diseases to Drive the Market - BioSpace

Cardiac Stem Cells Comments Off on Cell Line Development Market: Increase in Prevalence of Cancer and Other Chronic Diseases to Drive the Market – BioSpace | July 8th, 2022

Get PDF Sample on this Market @ https://www.databridgemarketresearch.com/request-a-sample/?dbmr=global-exosome-therapeutic-market&Raj

The global exosome therapeutics market competitive landscape provides details by a competitor. Details included are company overview, company financials, revenue generated, market potential, investment in research and development, new market initiatives, production sites and facilities, company strengths and weaknesses, product launch, product trials pipelines, product approvals, patents, product width, and breadth, application dominance, technology lifeline curve. The above data points provided are only related to the companys focus related to the exosome therapeutics market.

For instance,

Collaboration, joint ventures, and other strategies by the market player are enhancing the company market in the global exosome therapeutics market, which also provides the benefit for an organization to improve their offering for treatment products.

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Some of the major companies influencing this market include:

Some of the major companies providing the global exosome therapeutics market are Stem Cells Group, Exosome Sciences, AEGLE Therapeutics, Capricor Therapeutics, Avalon Globocare Corp, CODIAK, Kimera Labs, Stem Cell Medicine Ltd, Exopharm, Jazz Pharmaceuticals, Inc., evox THERAPEUTICS, ReNeuron Group plc, and EV Therapeutics, among others.

Market Segmentation:-

The global exosome therapeutics market is segmented on the basis of type, source, therapy, transporting capacity, application, route of administration, and end user. The growth among segments helps you analyze niche pockets of growth and strategies to approach the market and determine your core application areas and the difference in your target markets.

The global exosome therapeutics market is categorized into seven notable segments which are based on type, source, therapy, transporting capacity, application, route of administration, and end user.

Regions Covered in Artificial Intelligence in Genomics 2022 Global Market Report:

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Key questions answered in the report include:who are the key market players in the this Market?Which are the major regions for dissimilar trades that are expected to eyewitness astonishing growth for the this Market?What are the regional growth trends and the leading revenue-generating regions for the this Market?What will be the market size and the growth rate by the end of the forecast period?What are the key this Market trends impacting the growth of the market?What are the major Product Types of this Market?What are the major applications of this Market?

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Exosome Therapeutics Market Research Report Size, Share, New Trends and Opportunity, Competitive Analysis and Future Forecast Designer Women -...

Cardiac Stem Cells Comments Off on Exosome Therapeutics Market Research Report Size, Share, New Trends and Opportunity, Competitive Analysis and Future Forecast Designer Women -… | July 8th, 2022

Homology Medicines, Inc.

AAVHSC16 Biodistribution Properties in Preclinical Models Demonstrated Potential for Systemic Delivery of Genetic Medicines to Brain, Heart and Muscle

BEDFORD, Mass., July 05, 2022 (GLOBE NEWSWIRE) -- Homology Medicines, Inc. (Nasdaq: FIXX), a genetic medicines company, announced today the peer-reviewed publication of data showing that AAVHSC16, one of the capsids in its family of 15 naturally occurring AAVHSCs, demonstrated low levels of tropism to the liver while maintaining robust distribution to the central nervous system (CNS) and peripheral organs following a single I.V. administration in preclinical models. The Company believes that its unique properties, with high levels of tropism to the brain, heart and muscle, and no elevations in liver enzymes, could make AAVHSC16 an attractive capsid for new disease indications with Homologys genetic medicines platform.

Our ongoing efforts to fully characterize our family of 15 naturally occurring AAVHSCs as it relates to biodistribution, tissue tropism and the role different features of the capsids play, continues to reveal their unique profiles that allow us to best select capsids for different diseases, said Albert Seymour, Ph.D., President and Chief Scientific Officer of Homology Medicines. In the case of AAVHSC16 with its ability to reach key tissues without targeting the liver in preclinical models, we can potentially expand into additional disease areas where we want to deliver to the CNS, cardiac tissue, or muscle while avoiding exposure in the liver. By continuing to publish our discoveries about the unique structure and function of our AAVHSCs, we believe we can contribute to the fields greater understanding and development of AAV-based therapies that will ultimately benefit more patients.

Homologys AAVHSC capsids differ from each other by one to four amino acids, resulting in differences in biodistribution and transduction efficiencies. As described in the manuscript, AAVHSC16 has two unique amino acids, 501I and 706C, in addition to 505R that is shared across six AAVHSC serotypes. A series of experiments demonstrated that these amino acids contribute to AAVHSC16s unique properties, which include significantly reduced liver tropism compared to other AAVs, no liver enzyme elevations, and high tissue tropism to the CNS and other peripheral organs. Specifically, these data demonstrated:

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Naturally Occurring Variations in AAVHSC16 Alter Cellular Binding Affinity In Vitro

AAVHSC16 does not share the galactose (a type of glycan) binding feature of other AAVHSCs and Clade F AAVs in vitro. AAVHSC16 did not show improved binding or a difference in number of vector genomes (vgs) or eGFP expression in cells with terminally exposed galactose, while other AAVHSCs tested did.

The combination of the unique naturally occurring amino acids at positions 501I and 505R in AAVHSC16 were shown to contribute to reduced galactose-binding.

AAVHSC16 Has Significantly Reduced Liver Transduction in In Vivo and In Vitro Models, with High Tropism to other Tissues Following a Single I.V. Administration

In murine models, a single I.V. administration of AAVHSC16 showed significantly lower levels of liver tropism compared to AAVHSC15 and AAV9. The liver was the only organ with significant differences as AAVHSC16 demonstrated high levels of tropism to all other organs evaluated, including the brain, heart and muscle; these levels were comparable to those observed with AAVHSC15 and AAV9.

Further, in non-human primates (NHPs), a single I.V. administration of AAVHSC16 resulted in substantially lower liver expression than AAVHSC15, while maintaining high and equivalent levels of transduction in the brain, heart and muscle.

In vitro data also showed that AAVHSC16 led to lower expression in primary human liver cells compared to other tested wild type AAVHSCs and AAV9, and it revealed that AAVHSC16s 706 residue was the main contributor to this outcome.

AAVHSC16 Did Not Lead to Elevations in Liver Function Tests

In NHPs, a single I.V. administration of AAVHSC16 at 7E+13 and 1E+14 vg/kg doses did not result in elevated ALT (alanine transaminase) or AST (aspartate transferase) levels at any timepoint post-dose compared to baseline levels or vehicle-treated controls.

Comparing AAVHSC16 liver transduction and ALT and AST levels to AAV9 and other AAVHSCs further suggested that the lack of ALT and AST elevations with AAVHSC16 is associated with its lower liver tropism.

The publication, Natural Variations in AAVHSC16 Significantly Reduce Liver Tropism and Maintain Broad Distribution to Periphery and CNS, was peer-reviewed and published in the journal Molecular Therapy - Methods & Clinical Development. For more information, please click here or http://www.homologymedicines.com/publications.

About Homology Medicines, Inc.Homology Medicines, Inc. is a clinical-stage genetic medicines company dedicated to transforming the lives of patients suffering from rare diseases by addressing the underlying cause of the disease. The Companys clinical programs include HMI-102, an investigational gene therapy for adults with phenylketonuria (PKU); HMI-103, a gene editing candidate for PKU; and HMI-203, an investigational gene therapy for Hunter syndrome. Additional programs focus on metachromatic leukodystrophy (MLD), paroxysmal nocturnal hemoglobinuria (PNH) and other diseases. Homologys proprietary platform is designed to utilize its family of 15 human hematopoietic stem cell-derived adeno-associated virus (AAVHSCs) vectors to precisely and efficiently deliver genetic medicines in vivo through a gene therapy or nuclease-free gene editing modality, as well as to deliver one-time gene therapy to produce antibodies throughout the body through the GTx-mAb platform. Homology has a management team with a successful track record of discovering, developing and commercializing therapeutics with a focus on rare diseases. Homology believes its initial clinical data and compelling preclinical data, scientific and product development expertise and broad intellectual property position the Company as a leader in genetic medicines. For more information, visit http://www.homologymedicines.com.

Forward-Looking Statements This press release contains forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995. All statements contained in this press release that do not relate to matters of historical fact should be considered forward-looking statements, including, without limitation, statements regarding the potential to expand the application of AAVHSC16 to other disease areas; our expectations surrounding the potential, safety, and efficacy of our product candidates; the potential of our gene therapy and gene editing platforms; and our position as a leader in the development of genetic medicines. These statements are neither promises nor guarantees, but involve known and unknown risks, uncertainties and other important factors that may cause our actual results, performance or achievements to be materially different from any future results, performance or achievements expressed or implied by the forward-looking statements, including, but not limited to, the following: the impact of the COVID-19 pandemic on our business and operations, including our preclinical studies and clinical trials, and on general economic conditions; we have and expect to continue to incur significant losses; our need for additional funding, which may not be available; failure to identify additional product candidates and develop or commercialize marketable products; the early stage of our development efforts; potential unforeseen events during clinical trials could cause delays or other adverse consequences; risks relating to the regulatory approval process; interim, topline and preliminary data may change as more patient data become available, and are subject to audit and verification procedures that could result in material changes in the final data; our product candidates may cause serious adverse side effects; inability to maintain our collaborations, or the failure of these collaborations; our reliance on third parties, including for the manufacture of materials for our research programs, preclinical and clinical studies; failure to obtain U.S. or international marketing approval; ongoing regulatory obligations; effects of significant competition; unfavorable pricing regulations, third-party reimbursement practices or healthcare reform initiatives; product liability lawsuits; securities class action litigation; failure to attract, retain and motivate qualified personnel; the possibility of system failures or security breaches; risks relating to intellectual property; risks associated with international operations, such as political and economic instability, including in light of the conflict between Russia and Ukraine; and significant costs incurred as a result of operating as a public company. These and other important factors discussed under the caption Risk Factors in our Quarterly Report on Form 10-Q for the quarter ended March 31, 2022, and our other filings with the Securities and Exchange Commission (SEC) could cause actual results to differ materially from those indicated by the forward-looking statements made in this press release. Any such forward-looking statements represent managements estimates as of the date of this press release. While we may elect to update such forward-looking statements at some point in the future, we disclaim any obligation to do so, even if subsequent events cause our views to change.

Company Contacts:Theresa McNeelyChief Communications Officer and Patient Advocatetmcneely@homologymedicines.com781-301-7277

Media Contact:Cara Mayfield Vice President, Patient Advocacy and Corporate Communications cmayfield@homologymedicines.com 781-691-3510

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Homology Medicines Announces Peer-Reviewed Publication on Novel Discovery of AAVHSC with Robust Distribution to the Central Nervous System and...

Cardiac Stem Cells Comments Off on Homology Medicines Announces Peer-Reviewed Publication on Novel Discovery of AAVHSC with Robust Distribution to the Central Nervous System and… | July 8th, 2022

A paper recently published in the journal Biomaterials reviewed the new advances in three-dimensional bioprinting (3DBP) for regenerative therapy in different organ systems.

Study:Advances in 3D bioprinting of tissues/organs for regenerative medicine and in-vitro models. Image Credit:luchschenF/Shutterstock.com

Organ/tissue shortage has emerged as a significant challenge in the medical field due to patient immune rejections and donor scarcity. Moreover, mimicking or predicting the human disease condition in the animal models is difficult during preclinical trials owing to the differences in the disease phenotype between animals and humans.

3DBP has gained significant attention as a highly-efficient multidisciplinary technology to fabricate 3D biological tissue with complex composition and architecture. This technology allows precise assembly and deposition of biomaterials with donor/patients cells, leading to the successful fabrication of organ/tissue-like structures, preclinical implants, and in vitro models.

In this study, researchers reviewed the 3DBP strategies currently used for regenerative therapy in eight organ systems, including urinary, respiratory, gastrointestinal, exocrine and endocrine, integumentary, skeletal, cardiovascular, and nervous systems. Researchers also focused on the application of 3DBP to fabricate in vitro models. The concept of in situ 3DBP was discussed.

In this extensively used low-cost bioprinting method, rotating screw gear or pressurized air is used without or with temperature to extrude a continuous stream of thermoplastic or semisolid material. Different materials can be printed at a high fabrication speed using this technology. However, low cell viability and the need for post-processing are the major drawbacks of extrusion bioprinting.

In this method, liquid drops are ejected on a substrate by acoustic or thermal forces. High fabrication speed, small droplet volume, and interconnected micro-porosity gradient in the fabricated 3D structures are the main advantages of this technique. However, limited printed materials and clogging are the biggest drawbacks of inkjet bioprinting.

A laser is used to induce the forward transfer of biomaterials on a solid surface in the laser-assisted bioprinting method. High cell viability and nozzle-free noncontact process are the biggest advantages of laser-assisted bioprinting, while metallic particle contamination and the time-consuming nature of the printing process are the major disadvantages.

Several studies were performed involving the development of neuronal tissues using the 3DBP method. The pressure extrusion/syringe extrusion (PE/SE) bioprinting technique was used for central nervous tissue (CNS) tissue replacement. The layered porous structure was fabricated using glial cells derived using human induced pluripotent stem cell (iPSC) and a novel bioink based on agarose, alginate, and carboxymethyl chitosan (CMC) formed synaptic networks and displayed a bicuculline-induced enhanced calcium response.

Similarly, stereolithography (SLA) was used to fabricate a 3D scaffold for CNS and the viability of the scaffold was evaluated for regenerative medicine application. Layered linear microchannels were printed using poly(ethylene glycol) diacrylate-gelatin methacrylate (PEGDA-GelMA) and rat E14 neural progenitor cells (NPCs). The 3D scaffold restored the synaptic contacts and significantly improved the functional outcomes. Cyclohexane was used to bond polystyrene fibers to matrix bundle terminals during crosslinking.

Multiphoton excited 3-dimensional printing (MPE-3DP) was employed for the regeneration of myocardial tissue. A layer-by-layer structure was fabricated using GelMA/ sodium 4-[2-(4-morpholino)benzoyl-2-dimethylamino]-butylbenzenesulfonate (MBS) and human hciPSC-derived cardiomyocytes (CMs), endothelial cells (ECs), and smooth muscle cells (SMCs). The crosslinking was performed by photoactivation. The structure promoted electromechanical coupling and improved cell proliferation, vascularity, and cardiac function.

Fused deposition modeling (FDM) and PE/SE bioprinting method were used for complex tissue and organ regeneration. A micro-fluid network heart shape structure was fabricated using polyvinyl alcohol (PVA), agarose, sodium alginate, and platelet-rich plasma and rat H9c2 cells and human umbilical vein endothelial cells (HUVECs). 2% calcium dichloride was used during the crosslinking mechanism. The fabricated structure possessed a valentine heart with hollow mechanical properties and a self-defined height.

SE printing was utilized to fabricate a capillary-like network using collagen type1/ xanthan gum and human fibroblasts and ECs for applications in blood vessels. The fabricated network possessed endothelial networks and sprouting between the fibroblast layers.

Bone, cartilage, and skeletal muscle tissue can be repaired and regenerated using the 3DBP technique. For instance, FDM printing was used to print multifunctional therapeutic scaffolds for the treatment of bone. Filopodial projections were fabricated using polylactic acid (PLA) platform loaded with hyaluronic acid (HA)/ iron oxide nanoparticles (IONS)/ minocycline and human MG-63 and human bone marrow stromal cells (hBMSCs), which improved the osteogenic stimulation of the IONS and HA.

PE/SE method was used to fabricate disks and cuboid-shaped scaffolds using - tricalcium phosphate (TCP) microgel and human fetal osteoblast (hFOB) and bone marrow-derived mesenchymal stem cell (BM-MSC) for bone repair, multicellular delivery, and disease model. The fabricated structures promoted osteogenesis.

PE/SE bioprinting was also utilized to fabricate complex porous layered cartilage-like structures using alginate/gelatin/HA, rat bone marrow mesenchymal stem cells (BMSCs), and cow cardiac progenitor cells (CPCs) for hyaline cartilage regeneration. The CPCs upregulated gene expression of proteoglycan 4 (PRG4), SRY-box transcription factor 9 (SOX9), and collagen II.

PE/SE printing was also used to fabricate multinucleated, highly-aligned myotube structures using polyurethane (PU), poly(-caprolactone) (PCL), and mouse C2C12 myoblasts and NIH/3T3 fibroblasts for in-situ expansion and differentiation of skeletal muscle tendon. The fabricated constructs demonstrated more than 80% cell viability with initial tissue differentiation and development.

SLA bioprinting technique was used to fabricate bi-layered epidermis-like structure using collagen type I, mouse NIH 3T3 fibroblast cells, and human keratinocyte cells for tissue model and engineering. The fabricated constructs effectively imitated the tissue functions.

Similarly, PE was employed to fabricate microporous structures using human amniotic mesenchymal stem cells (AFSCs) and heparin-HA-PEGDA for wound healing. The construct improved the wound closure and reepithelialization, increased extracellular matrix synthesis and vascularization, and prolonged the cell paracrine activity.

PE technique was utilized to prepare a multilayered cornea-like structure using human keratocytes and methacrylated collagen (ColMA)-alginate. The cell viability of the keratocytes decreased from 90% to 83% after printing.

PE/SE bioprinting was utilized to bioprint multilayered liver-like structures using GeIMA and human HepG2/C3A for liver tissue engineering. Similarly, hepatocytes were also bioprinted to fabricate multiple organ precursors with branching vasculature. A small intestine model with improved intestinal function and high cell proliferation was fabricated using caco-2 cell-loaded polyethylene vinyl acetate (PEVA) scaffold.

Spheroids of mesenchymal stem cells (MSCs) and chondrocytes and lung endothelial cells were utilized to fabricate scaffold-free tracheal transplant. After implantation in the rat model, the matured spheroids displayed excellent vasculogenesis, chondrogenesis, and mechanical strength. FDM technique was used to fabricate a glomerular structure for kidneys using human iPSCs and hydrogel and a hollow porous network using poly(lactic-co-glycolic acid (PLGA)/PCL/tumor-associated endothelial cells (TECs) for the urethra.

In in-situ bioprinting, the tissue is directly printed on the specific defect or wound site in the body for regenerative and reparative therapy. This method provides a well-defined structure and reduces the gap between host-implant interfaces. In-situ bioprinting is better than in vitro bioprinting techniques as the patients body, as a natural bioreactor, provides a natural microenvironment.

Several studies have evaluated this technique for tissue regeneration. For instance, PE/SE method was used for skin tissue regeneration in pigs and mice using fibrin/collagen/HA and human fibroblast cells. Skin-laden sheets of consistent composition, thickness, and width were formed upon rapid crosslinking of biomaterial. PE/SE technique was also used for neural tissue regeneration in mice using agarose/CMC/alginate and human iPSCs.

In vitro models provide significant assistance in understanding the mechanism of therapeutics and disease pathophysiology. Recently, in vitro models of human tissues and organs were engineered using 3DBP technology for safety assessment and drug testing.

In the 3DBP of organs and tissues, biomaterials play a crucial role in maintaining cellular viability, providing support, and long-term acceptance. Specifically, bioinks must possess unique properties, such as cell growth promotion and structural stability, that can be optimized for clinical use. Additionally, bioinks must be compatible with printers for high-precision rapid prototyping.

Bioinks fulfilling all of these requirements are yet to be identified. Moreover, managing the time during the bioprinting of the constructs is another major challenge, as the time required to fabricate them is often more than the survival time of cells. A bioreactor platform that supports organoid growth and provides time for tissue remodeling can be used to overcome this challenge. Ethical challenges and issues are also a hurdle since fabricating internal tissues/organs can lead to liability and biosafety concerns.

In the future, 3DBP can provide novel solutions to engineer organs/tissues and revolutionize modern healthcare and medicine if these challenges can be addressed.

More from AZoM: Building Durable and Sustainable Futures with [emailprotected]

Jain, P., Kathuria, H., Dubey, N. Advances in 3D bioprinting of tissues/organs for regenerative medicine and in-vitro models. Biomaterials 2022. https://www.sciencedirect.com/science/article/abs/pii/S0142961222002794?via%3Dihub

Disclaimer: The views expressed here are those of the author expressed in their private capacity and do not necessarily represent the views of AZoM.com Limited T/A AZoNetwork the owner and operator of this website. This disclaimer forms part of the Terms and conditions of use of this website.

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What New Advances are there in 3D Bioprinting Tissues? - AZoM

Cardiac Stem Cells Comments Off on What New Advances are there in 3D Bioprinting Tissues? – AZoM | June 30th, 2022

Global Surgical Mesh Market Is Estimated To Be Valued At US$ 1.29 Bn In 2022, And Is Forecast To Surpass US$ 2.2 Bn Valuation By The End Of 2032

Sales of surgical meshes are expected to account for more than 21 Mn units by 2032-end, owing to their increasing application in untapped markets, says a Fact.MR analyst.

Fact.MR A Market Research and Competitive Intelligence Provider: The global surgical mesh market is estimated to exceed a valuation of US$ 1.29 Bn in 2022, and expand at a significant CAGR of 5.5% by value over the assessment period (2022-2032).

The availability of surgical meshes in absorbable and non-absorbable forms has expanded their application for temporary as well as permanent reinforcement. In recent years, demand for surgical meshes has escalated in aiding breast reconstruction as they reduce the exposure risk of the implant. Increasing health literacy in North America and Europe will create ample opportunities for surgical mesh manufacturers over the coming years.

Sedentary lifestyle and increasing obesity among the population have resulted in several chronic health issues. The consequent weakening of the muscles extends space for organ prolapse and hernia. Putting these organs back in place by stitching the muscles together can result in muscle tearing and the recurrence of prolapse. However, reinforcing the weakened muscles with the help of a surgical mesh has shown to decrease recurrence and increase the longevity of the repair.

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Winning Strategy

To attract new customers, market players are focusing on portfolio enhancement. Robust investments in R&D are driving product innovation for key market players. Meshes inhibiting the growth of bacterial films and preventing tissue adhesions are luring new consumers. Collaboration of manufacturers with scientific personnel and operating surgeons have enabled bespoke designing of meshes to best fit patients needs.

Manufacturers are also aiming for portfolio expansion through acquisition and partnerships. Partnering with companies that offer a well-aligned portfolio has significantly increased consumer penetration for key manufacturers. However, augmenting relations with local players and operating surgeons will be a key determinant of the products commercial success.

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Scientific collaborations and robust R&D investments have also guided product innovation and became a common strategic approach adopted by leading surgical mesh manufacturing companies to upscale their market presence.

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Fact.MR, in its new offering, presents an unbiased analysis of the global surgical mesh market, presenting historical market data (2017-2021) and forecast statistics for the period of 2022-2032.

The study reveals essential insights on the basis of product type (synthetic, biosynthetic, biologic, hybrid/composite), nature of mesh (absorbable, non-absorbable, partially absorbable), surgical access (open surgery, laparoscopic surgery), use case (hernia repair, pelvic floor disorder treatment, breast reconstruction, others), and raw material (polypropylene, polyethylene terephthalate, expanded polytetrafluoroethylene, polyglycolic acid, decellularized dermis/ECM, others), across seven major regions (North America, Latin America, Europe, East Asia, South Asia & ASEAN, Oceania, MEA).

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Technical Advancements & Innovative Products Likely to Expand Application of Surgical Meshes in Untapped Domains, States Fact.MR - BioSpace

Cardiac Stem Cells Comments Off on Technical Advancements & Innovative Products Likely to Expand Application of Surgical Meshes in Untapped Domains, States Fact.MR – BioSpace | June 30th, 2022

Second-line lisocabtagene maraleucel (liso-cel; Breyanzi) provides an earlier CAR T-cell treatment option that improves survival outcomes and produces a manageable safety profile in patients with relapsed/refractory large B-cell lymphoma (LBCL), including those who are older and have comorbidities, according to Nilanjan Ghosh, MD, PhD.

On June 24, 2022, the FDA approved liso-cel in the second line for patients with relapsed/refractory LBCL, including diffuse large B-cell lymphoma (DLBCL) not otherwise specified, primary mediastinal LBCL, follicular lymphoma grade 3B, and high-grade B-cell lymphoma. This approval was supported by data from the phase 3 TRANSFORM trial (NCT03575351) and the phase 2 TRANSCEND-PILOT-017006 study (NCT03483103).

Liso-cel is a fantastic option, because it has a great efficacy profile and is also a safe product amongst the available CAR T-cell products, with a relatively low incidence of cytokine release syndrome [CRS] and neurological events [NEs], the majority of which are low grade, Ghosh said.

In an interview with OncLive, Ghosh, director of the Lymphoma Program at the Levine Cancer Institute of Atrium Health, discussed the significance of the liso-cel approval in this patient population. He also highlighted how liso-cel will influence current treatment sequencing, which patients might derive the most benefit from this therapy, and the adverse effects (AEs) to be aware of and try to mitigate when prescribing liso-cel.

Ghosh: This approval is highly significant. The majority of patients with primary refractory DLBCL and early relapsed DLBCL do not derive benefit from standard-of-care [SOC] salvage chemotherapy followed by ASCT [autologous stem cell transplant], [which had been the best option until now].

The data from the TRANSFORM study showed liso-cel to be superior to high-dose salvage chemotherapy and ASCT. This approval will allow earlier access to CAR T-cell therapy for this group of patients.

Most patients with LBCL receive frontline therapy in the community setting. In addition to making our community aware of this indication, we need to educate our community about the time it takes to receive CAR T-cell therapy. The process includes many steps, such as gaining financial clearance and setting a date for T-cell collection, or leukapheresis. This date must be acceptable to both the institution [providing the treatment] and the company manufacturing the CAR T cells. [We also need to factor in] the time spent manufacturing the CAR T cells, often known as the vein-to-vein time. This entire process can take 6 weeks or more.

We often focus on just the vein-to-vein time, but there are many other steps even before leukapheresis. These patients are also refractory or have early relapsed disease that must be controlled while they are waiting to receive CAR T-cell therapy. Early referral to a CAR T-cell center is crucial to get the process going while discussing with the referring physician ways and means to control the disease in the interim. Those might include strategies like bridging therapy, which was allowed on the TRANSFORM study.

Insome patients, liso-cel may end up being a third-line therapy, despite its indication as a second-line therapy, because you may have to give another therapy to control the disease while the patients are waiting to receive CAR T cells. That discussion would best be done with the treating center and the referring physician, because some treatments can be toxic to lymphocytes, and you may want to avoid those kinds of treatments prior to collecting the lymphocytes. At the same time, we must make sure we control the disease so the patients can receive the treatment they may benefit from in the future.

Many factors must be taken into account before giving liso-cel. We look at the ECOG performance status [PS], as well as cardiac function and renal function.

Looking at comorbidities, fortunately, the TRANSCEND-PILOT-017006 trial included patients with comorbidities who were not considered good candidates for ASCT. To enroll in the study, the investigators needed to verify that the patients were not good candidates for transplant. [They also needed to meet at least 1 of the criteria], which included being over 70 years of age, having impaired renal function, having impaired cardiac function, or having a decrease in [diffusing capacity of the lungs for carbon monoxide], which is reflective of pulmonary function. The investigators also looked at hepatic function.

The outcomes of this study were good. The bottom line is that patients who are going to receive liso-cel need not only be candidates you would otherwise consider for ASCT. The eligibility for liso-cel is much broader than standard transplanteligibility in terms of age, comorbidities, and disease status. That is the most important thing. A patient who is older, has some comorbidities, and has relapsed or refractory LBCL can still benefit from liso-cel with high efficacy and low toxicity, which is what liso-cel offers in this patient population.

TRANSFORM was a randomized study of patients with DLBCL not otherwise specified, which includes de novo DLBCL and those who have transformed from indolent non-Hodgkin lymphoma; high-grade B cell lymphoma, which includes double-hit and triple-hit lymphoma; follicular lymphoma grade 3B; primary mediastinal B-cell lymphoma; and T-cell or histiocyte-rich DLBCL. Eligible patients needed to have either developed refractory disease from frontline therapy or relapsed within 12 months after frontline therapy. The frontline therapy should have included an anthracycline anda CD20 agent, which is the SOC. In addition, these patients should have been otherwise considered to be eligible for ASCT and had an ECOG PS of 0 to 1.

Eligible patients underwent leukapheresis and then were randomized to receive liso-cel or SOC, which was salvage chemotherapy followed by ASCT for those who responded to salvage chemotherapy. Importantly, this study included crossover from the SOC arm to the liso-cel arm. This was allowed for those who failed to respond to SOC by 9 weeks post-randomization, those who progressedat any time, or those who started a new antineoplastic therapy after transplant.

The primary end point was event-free survival [EFS]. Events were defined as death from any cause, progressive disease, failure to achieve complete response [CR] or partial response by 9 weeks post randomization, or the start of an antineoplastic therapy, whichever occurred first. The median EFS with liso-cel was 10.1 months compared with 2.3 months with SOC. At 12 months, the EFS rates were 44.5% with liso-cel and 23.7% with SOC. That was a significant margin of benefit.

In terms of responses, in this recent population, were most interested in CR. A total of 66% of the patients who received liso-cel achieved a CR compared with 39% of those who received SOC.

Progression-free survival [PFS] was also a secondary end point. The median PFS was 14.8 months with liso-cel and 5.7 months with SOC. Efficacy-wise, liso-cel hit all the marks. Overall survival [OS] data is maturing, so well need some longer follow-up, but we are starting to see trends in the right direction.

We have to remember that this study included crossover. Of the 91 patients in the SOC arm, 50 [crossed over to receive] CAR T-cell therapy with liso-cel. Those data will affect the OS data, but even so, were starting to see some separation of the OS curves in the TRANSFORM study.

The TRANSCEND-PILOT-017006 study is a little different because its a single-arm study. It was not intended for patients who would be otherwise considered transplant candidates. These patients did not need to relapse within 1 year [of frontline therapy], and they could have relapsed or refractory disease. A total of 25% of patients had late relapses as well, which was not the case in TRANSFORM. Otherwise, they all had 1 prior line of therapy, [like in TRANSFORM].

This is also a second-line study but in a different population of patients. This was an elderly population. Compared with the TRANSFORM study, the median age in the TRANSCEND-PILOT-017006 study was 74 years, with the oldest patient being 84 years of age. In total, 33% of patients in this study had double-hit and triple-hit disease, which I want to highlight because this is the toughest group of patients to treat. A total of 54% of the patients had primary refractory disease, [and many patients had comorbidities].

Additionally, 44% of the patients had an HCT-CI [Hematopoietic Cell Transplantation-Specific Comorbidity Index] score of 3 or more. We dont know the relevance [of this score] for CAR T-cell therapy, but outcomes are typically poor in patients who have an HCT-CI score of 3 or higher who undergoallogeneic transplant or ASCT.

[In this trial], the overall response rate was great, at 80%, with 54% achieving CR. Responses were seen in all prespecified subgroups, including patients with high-risk features, with no notable differences in efficacy or safety outcomes based on HCT-CI score. Investigators did separate out patients who had scores of less than 3 vs 3 or higher, and they didnt see any differences.

The median duration of response [DOR] was [11.2 months in patients with an HCT-CI score under 3, and not reached in patients with an HCT-CI score of 3 or higher].In patients who achieved a CR, the median DOR was 21.7 months.

The median PFS was [7.4 months in patients with an HCT-CI score under 3, and NR in patients with an HCT-CI score of 3 or higher]. The median OS was not reached.

Importantly, 32.8% of the patients were monitored as outpatients in this study, and 35% of those needed to be hospitalized for concerns of CRS and neurotoxicity after receiving liso-cel. Most of the patients who received liso-cel as outpatients did not need hospitalization within 3 days of receiving it. These results support liso-cel as a second-line treatment in patients with LBCL in whom transplant is not intended.

In general, the acute AEs that occur with any CAR T-cell therapy, but which are much lower with liso-cel, are CRS and NEs. These occur immediately post-CAR T-cell therapy, within days.

However, the incidence of CRS and NEs was low in both [TRANSFORM and TRANSCEND-PILOT-017006]. Most CRS events were grade 1 or grade 2. In total, 1 patient in each study had grade 3 CRS, and there were no instances of grade 4 CRS [in either study].

The incidence of neurotoxicity was also quite low. [A total of 4% of patients in the TRANSFORM study and 5% of patients in the TRANSCEND-PILOT-017006 study experienced] grade 3 neurotoxicity. Most of the neurotoxicity that was seen was grade 1 or grade 2. Importantly, the utilization of tocilizumab [Actemra] and steroids was also low [in both trials].

However, there are other AEs which we need to monitor. For example, by the time a patient is out of that CRS and neurotoxicity window and thinking of going back to their referring physician, they may still [be at risk for AEs such as] prolonged cytopenias, [which some patients exhibited in these trials]. In the [TRANSFORM] study, prolonged cytopenias were defined as [grade 3 cytopenias that persisted] at day 35 or beyond. [In the TRANSCEND-PILOT-017006 study, prolonged cytopenias were defined as grade 3 or higher cytopenias that persisted at day 29 or beyond.]

We should also monitor for hypogammaglobulinemia. This is important because if a patient has hypogammaglobulinemia or lymphopenia, and neutropenia, they are more prone to infection. Preventing infection, providing supportive care, and giving treatment medications [as early as possible] is important, and monitoring AEs is crucial.

The field of LBCL has exploded with new treatments over the past few years, including what we saw recently in the frontline setting. CAR T-cell therapy, in general, is a huge advancement within this field.

Having said that, its important to be aware of and monitor the AEs. A question that comes up is: How accessible are CAR T-cell therapies going to be? We need to work as a community to make them more accessible to patients, cut down the time from when we first consider CAR T-cell therapy to when we deliver it, and make that process more efficient, so more patients can benefit from it.

We also need to be aware of the many other treatments that have come out in the space, such as bispecific antibodies that are in development and antibody-drug conjugates. Over the next few years, we need to figure out how to sequence thesetherapies so that we can maximize the benefits and help our patients who still have unmet needs. We do have to recognize that even though CAR T-cell therapy has excellent outcomes, there are many patients who are still refractory to CAR T-cell therapy and relapse after CAR T-cell therapy. [We need to find] the best way to sequence the other treatments that are out there to help these patients. Thats an area of active investigation.

I hope we are in a much better place in the years to come. However, weve made huge strides in the past several years, and its been great to be a part of that research.

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Liso-cel Approval Provides Earlier, Expanded Access to CAR T-cell Therapy in Second-line LBCL - OncLive

Cardiac Stem Cells Comments Off on Liso-cel Approval Provides Earlier, Expanded Access to CAR T-cell Therapy in Second-line LBCL – OncLive | June 30th, 2022

Since their first successful derivation in 1998, human embryonic stem cells have received almost unprecedented attention. Hailed as the next revolution for medicine, they have been described as the future of molecular biology and the biggest development since recombinant DNA.1 It has been predicted that their successful derivation will have a more profound impact on health than even the advent of anaesthesia and the development of antibiotics.2 They are set to create a whole new genre of medical therapies.3 Their potential availability has also, however, opened a Pandoras box of ethical dilemmas, ranging from ongoing issues surrounding the moral status of the human embryo to the conflicting claims of alternative stem cell sources. Although integral to ethical discourse, these dilemmas demand understanding and assessment on scientific grounds. It is our contention that the ethical debate is being hindered by failure to appreciate the subtleties of the scientific background.

Since the ethical problems accompanying destruction of human embryos are well recognised, the advantages of bypassing these by employing adult stem cells are obvious. For many, the ethical conflicts would be avoided, while all the potential benefits to patients with severe diseases would be retained. Consequently, perceived ethical problems would be resolved if it could be demonstrated that adult stem cells are superior to embryonic stem cells as therapeutic agents.

Unfortunately, resolution is far from clear, for this research field is in its infancy. Scientific uncertainty abounds, and yet societies are demanding definitive scientific answers on stem cell technology. Since the least controversial course of action would be to use adult stem cells, the pressures on scientists to emerge with evidence demonstrating that their potential is equal to, or even greater than, that of embryonic stem cells are formidable. Scientific data and interpretation have become integral to the ethical debate, perhaps in inappropriate ways.

An understanding of the most fundamental aspects of stem cell identity and function is required, from the identification of stem cells to the role of environmental factors at both the microscopic and macroscopic levels. Recognising the role of environmental factors has ramifications both clinically and ethically. Acknowledgement of these factors will provide for greater understanding of the obstacles that have to be overcome if the clinical potential of stem cells is to be realised. It will also help clarify the notions of totipotency and pluripotency, concepts central to delineating the moral value of embryonic stem cells and their parent blastocysts.

Stem cells are unspecialised cells, which have the ability to renew themselves indefinitely, and under appropriate conditions can give rise to a variety of mature cell types in the human body. Some stem cells can give rise to a wide range of mature cell types, whereas others give rise to only a few. Stem cells can be derived from a variety of sources including early embryos, fetal tissue, and some adult tissues, of which bone marrow and blood are the best known examples. Hence, there are two populations of stem cells: embryonic and adult stem cells. Of these, embryonic stem cells are derived from the inner cell mass (ICM) of the blastocyst at five to seven days after fertilisation. At this point the blastocyst has differentiated into two cell types, ICM cells (some of which will give rise to the future individual) and the surrounding trophectoderm cells (which will later form the placenta).

The distinction between embryonic and adult stem cells raises the issue of accurate identification, a prerequisite to testing the claims frequently made for the abilities of both embryonic and adult stem cells to produce a wide array of cell and tissue types. Scientifically, the problem is a fundamental one: defining stem cells solely on the basis of their structurethat is, the specific markers they carry on their outer surfaces, is inaccurate and potentially misleading. Identification mayfor example, be complicated by some stem cells expressing markers from several kinds of lineages and may be further confused by the possibility that marker expression changes throughout development.4,5 The potential for misidentification is of considerable importance for the scientific community, which has called for functional as well as structural testing.

Placing far more reliance on the functional properties of stem cells opens up a wider debate, namely, the role of the environment in an understanding of stem cell function. The ability of the structure of stem cells to change points to the existence of a dynamic relationship between stem cells and their immediate microenvironment, the stem cell niche.

The niche concept was first developed in blood cells, where proliferation, differentiation, and survival of distinct progenitor populations were found to be dependent on factors secreted by other cell types.6 This microenvironment is characterised by numerous external signals, including those derived from chemical factors, cell/cell interactions, and relationships between cells and the surrounding tissue.6 These, in their various ways, all have an impact on stem cells, affecting the precise directions in which they subsequently develop.

This microenvironment is governed by regulatory mechanisms, the molecular nature of which is complicated and elusive. Schuldiner et al,7 in their study of the effects of eight growth factors on the capacity of human embryonic stem cells to form other cell types, found that while these factors altered developmental outcome, they did not produce uniform differentiation of the stem cells. Consequently, although the structural markers and functions of stem cells appear to be dependent upon their environment, defining the nature of this environment will be far from straightforward.

An increasing awareness of the role of the niche on stem cell structure and function has led to an evolving concept of the stem cell. For instance, there is now the suggestion that stem cells should be viewed, not as undifferentiated cells, but as appropriately differentiated cells with the potential to display diverse cell types in alternative niches.8 An excellent illustration of this point is provided in a recent study by Wu et al9 where human neural stem cells were primed in a cocktail of chemical factors and then implanted into various regions of the adult rat brain. Not only did the implanted stem cells give rise to a larger number of neurons than previously reported, but most significantly they gave rise to different neuronal types depending upon the region of the brain into which they were grafted. It is possible that the distinctive nature of the local environment in each brain region instructed the neural stem cells to adopt such different fates.

Furthermore, stem cells taken out of their original niche and exposed to an entirely new environment can potentially differentiate into the cell type(s) typical of that new environment. Human neural stem cellsfor example, produced muscle cells when introduced into skeletal muscle10 and human bone marrow cells differentiated into neural cells when transplanted into a neural environment.11 The above two studies were carried out in rodents, but more recently Mezey et al12 have demonstrated that a similar scenario is possible in humans. Following bone marrow transplants in patients with various forms of cancer, bone marrow stem cells entered the brain and generated neural cell types including neurons. In many of these studies, where stem cells have been transformed into cells from different lineages, there has been some form of injury to the stem cells new environment or niche. In light of this, it is possible that various factors, signals, or chemicals normally present in damaged or disrupted tissue may play a role in governing stem cell fate.

The above findings reflect the increasing influence being attributed to environmental factors, acknowledgement of which has led to the view that stem cells are dynamic rather than static entities. This view underpins the concept of stem cell plasticity, whereby stem cells from adult sources have the ability to dedifferentiate or redifferentiate into cells from other lineages. This may blur the absolute distinction so frequently made between embryonic and adult stem cells (let alone between specific types of adult stem cells), a determinative factor in much ethical debate.

Adult stem cells include stem cells from bone marrow, blood, fat, and both fetal and adult organs. Plasticity is particularly characteristic of bone marrow. Stem cells from this source can differentiate into neural cells,11,1315 (see above for further discussion) while other research has indicated that such cells can be incorporated into skeletal muscle.16

While these reports indicate that interest in the potential of adult stem cells is justified, they should be interpreted cautiously. It would be unwise to jump to the conclusion that these studies render the use of embryonic stem cells (with destruction of human embryos) unnecessary. There are a number of reasons for this.

First, accurate identification is a prerequisite for determining the presence and extent of plasticity. For instance, although Jackson et al17 presented data to suggest that a group of muscle cells could turn into blood cells, they later found they were dealing with a subpopulation of cells that normally reside in muscle tissue.18 What is required are more rigorous standards for determining stem cell plasticity.1921 Iffor example, cardiac cells developed from stem cells are to contribute to heart function, they would have to demonstrate synchronous contraction within the heart itself. Similarly, neural cells derived from neural stem cells would have to generate electrical impulses and release and respond to chemicals normally found within the brain.19,20

A second issue concerns frequency of occurrence. Failure to replicate previous experimental work showing that blood cells are capable of differentiating into neural cells, suggests that, if transformations are occurring, they are very rare.22 Consistent with this conclusion is the work of Jackson et al,23 who demonstrated plasticity in human blood stem cells, although the change to the desired heart and blood vessel cells occurred in only 0.02% of cells. Thus, as Winston24 notes, even in apparently rich sources, the cells capable of change may be very few in number, and this may ultimately diminish their therapeutic value.

A third point of concern with clinical applications in mind, is that transformations may occur via hybrid cells, that is, by the fusion of two distinct cell types. Such spontaneous fusion was observed when embryonic stem cells were grown in the laboratory in the presence of neural cells25 or bone marrow cells.26 Such hybrids, however, show chromosomal abnormalities that may preclude them from being used in therapeutic applications.

The apparent formation of such hybrid cells may have important implications for interpretations of stem cell plasticity. Such a phenomenon presents an alternate explanation for the claims that stem cells from one tissue type are able to produce the progeny of another tissue typethat is, bone marrow into muscle, blood into brain, and vice versa. In other words, adult stem cells may not be as plastic as early reports have suggested. Thus, as pointed out by Ying et al25 future stem cell plasticity studies should ensure that any transformed cells are examined and tested to see if they display properties of both the original and the introduced cell types.

A final note of caution is that it has become clear that there is far more data to show that embryonic stem cells are capable of indefinite growth and pluripotency than adult stem cells. Mouse embryonic stem cellsfor example, have been renewing for 10 years,27 a capacity yet to be demonstrated in cells from adult sources. If adult cells have a restricted renewal potential, this will have negative implications for therapeutic applications, which rely on the ability to expand cells accurately in the laboratory in order to provide enough material for effective transplantation. Furthermore, embryonic stem cells exhibit high levels of the enzyme telomerase which indicates their immortality,28 whereas adult stem cells grown in the laboratory do not exhibit this in the same way. This property renders embryonic stem cells important in the study of cellular ageing and stem cell renewal. Work with neural stem cells from biopsies and autopsies suggests that embryonic stem cells may be easier to coax into specific cell types than adult stem cells.18

Overall, there are few confirmed reports of truly pluripotential adult human stem cells,3,29 while even apparently convincing reports30 may raise serious queries when assessed in a critical manner.3 Nearly a dozen teams have reported adult stem cell plasticity31 and it seems unlikely that random mutation or hybrid fusion can explain all these results. What is required is far more understanding of the fundamental biological issues raised by this research. Even as Winston24 outlines the advantages of embryonic stem cell researchfor example, he recognises the benefits of adult stem cells in regard to safety, possible efficacy, and accessibility. Adult sources have the added advantage of not requiring an intermediate embryo for immunocompatibility. Similarly, while the UK Department of Health32 argues that the therapeutic potential of embryonic stem cells outweighs that of adult stem cells, it acknowledges that in the long term both may be useful. The UK government reiterated this point in 2002 by stating that it wishes to advance research with stem cells from all sources.33

Scientifically, therefore, research with both adult and embryonic sources should continue, although caution should be exercised in evaluating the results. Currently, however, adult stem cells are more problematic than their embryonic counterparts. In light of this evaluation, considerable care should be employed in advocating on allegedly scientific grounds, the advantages of adult over embryonic cells as the source of replacement tissues. The impetus behind such a sentiment stems principally from a desire to protect the status of the human embryo than from any demonstrated superiority of adult stem cell sources.14,34

Confusion at this point will do nothing to advance the cause of ethical analysis, since the current state of the science and its likely future directions are integral to serious ethical assessment. In other words, it is short sighted to attempt to circumvent discussion of the moral status of the blastocyst by concentrating on the potential of adult stem cells alone. Until it is accepted that this latter approach is a cul de sac for ethical discourse, the imperatives of some ethicists will continue to come into conflict with current scientific perspectives.

It is generally asserted that totipotency denotes the ability of a cell or group of cells to give rise to a complete individual, whereas pluripotency refers to the capacity to give rise to all the cell types constituting the individualbut not the individual as a whole. Helpful as this distinction is, it is limited, in that it neither acknowledges nor emphasises the importance of environmental influences in defining these abilities.

As we have seen, embryonic stem cells are derived from the ICM of the blastocyst. These ICM cells have the capacity to form all three embryonic germ layers: endoderm, which will form the lungs, liver, and gut lining; mesoderm, which will form the bone, blood, and muscle, and ectoderm, which will form the skin, eyes, and nervous system. Outwardly, these cells appear to give rise to a complete individual and are considered by some to be totipotent.35

The claim of totipotency requires a number of conditions, however, whether this be for blastocysts or embryonic stem cells. The latter must be undifferentiated and, hence, capable of giving rise to all three germ layers, a condition that is met when embryonic stem cells are derived from the ICM of the blastocyst. In addition, there is a requirement for trophectoderm cells, which will eventually form the layers of the placenta. The extraembryonic tissues are a crucial source of signalling molecules and must function optimally for the differentiation of both embryonic somatic cells and for the establishment of germlines.36 Since both trophectoderm and ICM cells are required for successful development of the fetus, both cell types are required to establish totipotency.37 Thus, totipotency becomes a function of the immediate environment of the embryonic stem cell. If a viable fetus is to result, totipotency also requires successful implantation and development within the uterus of a woman.

In the absence of all these conditions embryonic stem cells are only pluripotent, since they are capable of creating all the cell lines of the fetus, but not the fetus itself. In the laboratory environment they are incapable of totipotency, since they have been removed from the context of the trophectoderm, let alone that of the uterus. It is inaccurate, therefore, to refer to embryonic stem cells as totipotent rather than pluripotent.38

These criteria for establishing totipotency also have ramifications for the ethical evaluation of the human blastocyst. While the blastocyst has intact trophectoderm cells and, therefore, the capacity to produce all three germ layers, plus the extraembryonic material necessary for its survival, totipotency is still dependent on the wider environmentsuccessful implantation in a uterus. Hence, blastocysts within the laboratory are only potentially totipotent, in contrast to their counterparts within the body.

A blastocyst or even a later embryo in the laboratory lacks the capacity to develop into a human individual. Unfortunately, this simple observation is frequently overlooked, and moral discussion focuses on the potential of an embryo to grow into a fully developed human without any reference to its context. Ignoring context in this manner inevitably overlooks the crucial importance of an appropriate environment necessary for the realisation of totipotency, changes to which may also alter the moral debate. Just as stem cell identity and arguably moral value depend upon the microenvironment, so too the human embryo is intimately dependent upon its wider environment.

Much opposition to the use of embryonic stem cells relies upon the argument that adult stem cells could serve as a viable source of tissues for regeneration and therapy. In the light of this, the argument continues that embryonic stem cells, with their debatable ethical credentials, should no longer feature in attempts to produce replacement tissues. This stance uses alleged scientific evidence to bolster an ethical position, and stands or falls on the strength of the scientific case.

Apart from the validity or otherwise of this approach, definitive evidence will not be forthcoming for some time (possibly years), since the scientific issues are complex on-going ones. As outlined above, the potential of adult stem cells remains a matter for debate and further experimentation. Additionally, the dynamic nature of stem cells, both embryonic and adult, points to a close interrelationship between their potential and the environment in which they are located. The possibility of cell lineage change also has to be taken into account when the suitability of different stem cell types is being advocated. From a scientific perspective none of this is surprising, and yet it fits uneasily alongside any stance that is a mixture of scientific, ethical, and political rhetoric.

The necessity of paying attention to the scientific framework of the debate, such as we are doing, has implications for other stances as well. With the advance of scientific understanding and, specifically, the advent of a genetic level of understanding, has come a tendency to view the life of an individual on the basis of DNA alone. This too, however, ignores the dependence of the embryo upon a competent environment. The context within which the embryo develops, like the niche for the stem cell, is integral to all aspects of its functioning. The environment provides nutritional requirements as well as numerous cues to ensure the healthy development of the embryo and subsequent fetus. Consequently, the preservation of DNA cannot be equated with the preservation of an individuals life, as has been suggested by McGee and Caplan.39 Adherence to such a reductionist mode of thinking is only made possible by ignoring completely the contribution of the environment. Essential as DNA is for development, it requires an appropriate context if its potential is to be realised.

From this it follows that a notion such as totipotency is a function of the environment both at the microscopic and macroscopic levels. This suggests that ethical debate cannot be reduced to potential for life, since inherent within the potential of an embryo is an assumption regarding the appropriateness of its environment. This means that the context of blastocysts and later embryos is crucial, ethically as well as scientifically and clinically.

In light of this, it is appropriate to ask whether it is useful to continue thinking of the blastocyst as an independent entity with a moral status stemming entirely from its organisation and perceived potential. We have argued that neither blastocysts nor stem cells are to be viewed in isolation from their context. Given that the claim is frequently made that moral value and status are closely associated with embryonic potential, recognition of the importance of the environment will have major implications for ethical thinking.

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Stem cells, embryos, and the environment: a context for both science ...

Cardiac Stem Cells Comments Off on Stem cells, embryos, and the environment: a context for both science … | June 20th, 2022

Heart disease is theleading cause of deathamong adults and infants in the U.S. with about 659,000 people dying from heart disease each year, every one in four deaths. Among the many patients with a critical heart condition, about 3,500 are waiting for a heart transplant. Many of them will wait for more than six months, and for some of them time will run out before a transplant becomes available. These alarming statistics illustrate the need for more effective heart tissue replacement strategies.

In contrast to other organs that can repair themselves to various degrees after injury, the heart has limited to no regenerative capacity. When heart cells die during prolonged heart disease or a myocardial infarction, they are replaced by a fibrotic scar that compromises the hearts normal contraction. While modern stem cell technology has enabled production of patient-specific heart cells as a source for tissue engineers, emulating the heart muscles highly structured architecture and complex functionality remains a serious challenge.

The hearts left ventricle pumps blood through our circulatory system by contracting in a torsional wringing motion. This is enabled by layers of cardiomyocytes whose contractile machineries are all aligned in the same direction within an individual layer. Multiple layers are then stacked on top of each other across the 1cm thick heart muscle wall, each oriented at an angle with respect to its neighboring layers. Even though each cardiomyocyte contracts in one direction, the varying alignment of each cardiomyocyte layer causes the ventricle to twist, squeezing the blood within and forcing it to flow to the rest of the body. Tissue engineers have devised different methods to align heart cells on various surfaces but these do not recreate the hearts intricate alignment, nor can they generate myocardial tissue thick enough for use in regenerative heart therapies.

Now, Jennifer Lewis' team at theHarvard John A. Paulson School of Engineering and Applied Sciences(SEAS) and the Wyss Institute for Biologically Inspired Engineering at Harvard University has developed a suite of new heart engineering technologies that has allowed them to mimic the alignment of the hearts contractile elements. Using a bioink with densely packed contractile organ building blocks (OBBs) composed of cardiomyocytes derived from human induced pluripotent stem cells (hiPSCs-CMs), they were able to print aligned cardiac tissue sheets with complex and varied alignment. These sheets have an organization and functionality similar to those in actual human heart muscle layers. The findings are published inAdvanced Materials. In the future, this advance could enable the development of thick multilayered human muscle tissue with more physiological contractile properties.

Being able to effectively mimic the alignment of the hearts contractile system across its entire hierarchy from individual cells to thicker cardiac tissue composed of multiple layers is central to generating functional heart tissue for replacement therapy, said Lewis, senior author of the paper and theHansjrg Wyss Professor of Bioinspired Engineering at SEAS. Lewis is also a Wyss Core Faculty member andco-Lead of the Wyss Institutes 3D Organ Engineering Initiative.

The study builds on Lewis teams 3D bioprinting platform, known assacrificial writing in functional tissue (SWIFT), which allowed them to create cardiac tissue constructs that have the typical high cellular densities of normal heart tissue, usingsophisticated 3D bioprinting capabilities. The approach makes use of preassembled cardiac organ building blocks (OBBs) composed of iPSC-CMs, and allows them to address another grand tissue engineering challenge the introduction of a blood-supporting vascular network using sacrificial inks. However, the resulting tissue constructs did not replicate the complex alignment of the human heart.

To also gain control over directional contractility in engineered layers of heart tissue, we first devised a strategy to program the parallel alignment of iPSC-CMs in developing OBBs, said first-authorJohn Ahrens, who is a graduate student in Lewis group.

To accomplish this, the researchers developed a platform with 1050 individual wells, each containing two micropillars. Into the wells, they seeded hiPSCs-CMs in a mixture with human fibroblast cells and the extracellular matrix (ECM) protein collagen, both of which are essential for heart muscle development. Over time as the cells compact the ECM, they form a dense microtissue in which the cardiomyocytes and their cellular contractile machineries are oriented along the axis connecting the micropillars. The OBBs, called anisotropic OBBs (aOBBs) because they contract in one major direction, are then lifted off the micropillars and used as a feedstock to fabricate a dense bioink. The teams high-throughput approach to the generation of aOBBs also enabled them to fabricate an unprecedented number of contractile building blocks.

The second alignment step is the printing process itself. The mechanical shear forces generated at the print head act on the aOBBs while they are being extruded to give them directionality.

Our lab has previously shown that it was possible to align anisotropic soft materials via 3D printing. Here, we demonstrated that this principle could be applied to cardiac microtissues too, said co-authorSebastien Uzel, who is a Research Associate on Lewis team and mentored Ahrens. To highlight the versatility of their bioprinting process, the researchers printed cardiac tissue sheets with linear, spiral, and chevron geometries in which the contractile aOBBs exhibited significant alignment.

But the team also wanted to be able to measure the contractile features of cardiac constructs printed with aOBBs. For this, they printed long macrofilaments connecting two macropillars, similar to the OBB-generating step using the micropillar platform, only on a larger scale. By measuring the macropillar deflections, they could determine the contractile forces generated by the macrofilaments. The team indeed found that the contractile forces and contraction velocity (speed) increased over a period of seven days which showed that the cardiac filaments kept maturing into actual muscle-like filaments.

With SWIFT, we wanted to address cellular density and tissue scale. Now, by programming alignment, we aimed for mimicking the microarchitecture of the myocardium. One innovation at a time, we are moving closer and closer to engineering functional cardiac tissues for repair or replacement, said Uzel.

For their next order of engineering, the team plans to apply this method to generate more physiological tissues beyond two-dimensional, single layered constructs.

While the holy grail of tissue engineering efforts would be a whole organ heart transplantation, our approach could enable contributions to more immediate applications. It could be used to generate more physiological disease models, and create highly architected myocardial patches that, like LEGO blocks, could match and be used to replace a patient-specific scar after a heart attack, said Ahrens. Similarly, they could be tailored to patch up patient-specific holes in the heart of newborns with congenital heart defects. In theory, these patches could also develop with the child and not have to be replaced as the child grows.

Other authors on the study are present and former members of Lewis team, including Mark Skylar-Scott, who was instrumental in the development of SWIFT, Mariana Mata who assisted with most experiments in this study, as well as Aric Lu and Katharina Kroll. The study was supported by an NSF CELL-MET grant (under grant# EEC-1647837), as well as the Vannevar Bush Faculty Fellowship Program sponsored by the Basic Research Office of the Assistant Secretary of Defense for Research and Engineering through the Office of Naval Research (under grant# N00014-16-1-2823 and N00014-21-1-2958).

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Getting to the heart of engineering a heart - Harvard School of Engineering and Applied Sciences

Cardiac Stem Cells Comments Off on Getting to the heart of engineering a heart – Harvard School of Engineering and Applied Sciences | June 11th, 2022

Stem Cells 101

Every cell type in the body that makes up organs and tissues arose from a more primitive cell type called a stem cell. Stem cells are the foundation of living organisms, with the unique ability to self-renew and differentiate into specialised cell types. There are three different types of stem cell, classified by the number of specialised cell types they can produce: i) pluripotent stem cells (e.g. embryonic stem cells) can generate any specialised cell type; ii) multipotent stem cells (e.g. mesenchymal stem cells) are able to generate multiple, but not all, specialised cell types; and, iii) unipotent stem cells (e.g. epidermal stem cells that produce skin) give rise to only one cell type. It was long believed that stem cell differentiation into specialised cell types only occurs in one direction. There have been many exciting advances in stem cell biology, most notable the discovery of induced pluripotent stem cells (iPSCs) that demonstrated a mature differentiated specialised cell can be reverted to a primitive pluripotent stem cell (Takahashi K, 2006). This discovery transformed our understanding of stem cell biology enabling exciting and substantial advances in stem cell tools, technologies and applications. This article focuses on pluripotent stem cells, as they offer the most promising future applications.

To harness the power of stem cells, they must first be maintained in vitro tissue culture. Culture expansion of stem cells is tricky because they must be maintained in an undifferentiated state and not permitted to differentiate into other cell types until desired. In short, if stem cells are not dividing in log phase growth, they are differentiating. Historically, pluripotent stem cells were notoriously difficult to work with in the lab largely because of the of inherent variability of reagents derived from animal tissues.

An important concept affecting current and future innovations in stem cell technologies is Good Manufacturing Practice (GMP). This is governed by formal regulations administered by drug regulatory agencies (for example the FDA) that control the manufacture processes of medicines. The use of stem cells as therapeutic agents has necessitated specialised drug regulations known as Advanced Therapeutic Medicinal Products (ATMPs). Unlike chemically synthesised medicines where the final product can be defined through chemical analysis, ATMPs are complex biological living entities whereby the entire manufacturing process defines the final product. In simple terms, every reagent that touches the stem cells in the manufacturing process throughout the entire lifetime of the stem cell becomes a component of the final product. As such, in the real world the quality and consistency of the reagents used in a stem cell manufacturing process is paramount for downstream clinical applications, even if the project is still in the R&D or preclinical phase. Once reserved for clinical applications, GMP has become a dominating concept that affects all aspects of stem cell research and applications. Researchers and clinical developers benefit alike from GMP-focused innovations in stem cell technologies that deliver consistent growth properties and high-quality results.

Significant advances that overcome the challenges of the past have been made in all aspects of in vitro stem cell culture. These include advances in tissue culture medium, extracellular matrix, 3D synthetic cell culture plastic, growth factors, dissociation enzymes, cryopreservation agents and differentiation technologies. The workflow to culture stem cells in vitro is not a linear process but rather a continuous circle that can be broken down into 6 steps: 1) Extracellular Matrix coating of tissue culture plasticware; 2) Revival/seeding of tissue culture flasks; 3) Expansion of the cell culture in an incubator; 4) Culture medium change; 5) Subculture or passaging one flask to many; and 6) Cryopreservation of the stem cell culture. The stem cell workflow is shown in Figure 1.

The art of culturing stem cells is a lot easier today than in the past. Stem cells grow as adherent cultures on the surface of tissue culture flasks or dishes (image shown in Figure 1, Step 3). For the stem cells to adhere to the surface it must be coated with extracellular matrix. In the early days, it was an effort to maintain stem cells in culture because the cultures needed to be grown on a feeder layer of fibroblast cells. The requirement for a second cell culture combined with the stem cell culture is laborious to set up and severely limited experiments and applications (due to the contaminating fibroblasts mixed with the stem cells). Extracellular matrix isolated from mouse tumours removed the need for feeder layer cultures but can be variable in consistency and contain contaminants. Today, researchers benefit from recombinantly expressed extracellular matrix containing laminin-511 fragments that provides highly efficient adherence of a broad range of cell types and is easy to use (with only 1 hour coating time required that saves time and cost). Exceptional pluripotent stem cell adherence is achieved with laminin-511 fragments. The recombinant extracellular matrix laminin-511 is expressed in mammalian cell culture (e.g. CHO cells) or insect culture (e.g. silkworm) that eliminates the need for animal derived products in the extracellular matrix. Alternatively, synthetic 3D plastic scaffolds (e.g. Alvetex) are also available that offer a rigid defined matrix that is non-biological.

Early stem cell culture media required the medium to be replenished daily. This means 7 days a week in the lab tending to the stem cell cultures. Optimisation of tissue culture medium composition enables cultures to be maintained over the weekend without a medium change, enabling feeder-free, weekend-free stem cell culture. This may sound insignificant but does have a huge impact on the lifestyle of researchers working with stem cells. Unlike early tissue culture media, the composition of the culture media are fully defined and contain no animal derived products. Removal of animal-derived products offers important advantages by removing variability inherent in animal-derived products and guaranteeing consistent cell growth. Furthermore, animal-free formulations eleminate the risk of infection arising from the animal product (e.g. TSE risk). Growth factors are a critical component of the culture medium to maintain the stem cells in an undifferentiated state. Products available on the market contain growth factors that are expressed and isolated from barley.

Stem cells undergo cellular division in the culture vessel. As they expand, they will eventually outgrow their home and must be subcultured to separate flasks to provide space for further growth. Common practice is to use a digestive enzyme to free the stem cells from the culture surface. Trypsin isolated from bovine is commonplace in the tissue culture laboratory. Advances in the products available today use trypsin expressed in maize that is stable at room temperature in solution. Collagenase is an alternative dissociation reagent that is gentle and efficient on a wide range of cells and is available both animal-free and GMP grade - again enabling robust consistent culture conditions, and removing the dependence on animal derived products that are inherently variable.

The stem cells harvested from cultures can be frozen and stored (or cryopreserved) safely for several decades. When required, the cryopreserved stem cells may be defrosted, revived and expanded in culture providing a renewable source of stem cells. During cryopreservation of stem cells, it is critical to prevent cell death and changes in genotype/phenotype. Todays cryopreservation media can maintain consistent high cell viability after thawing; maintaining cell pluripotency, normal karyotype and proliferation even after long term cell storage. Traditionally, the cryopreservation process involved a rate-controlled freezer or a specialised container to freeze the cells at -1C/min. Advances in cryopreservation agents have removed the need for rate-controlled freezing. The process is now simple - you just place the stem cell suspension into a -80C freezer. Moreover, cryopreservation agents are available in GMP grade and with no animal-derived ingredients.

The power of stem cells lies in their ability both to self-renew and to differentiate into specialised cell types. The process of differentiation removes the stem cells from the workflow towards applications. Directed differentiation of stem cells into specific cell types enables the number of applications to grow. A typical differentiation protocol uses stepwise changes in culture medium, cytokines, growth factors and extracellular matrix over several weeks to direct the stem cells into a particular lineage and fate. Today, innovative technologies use genetic reprogramming factors that rapidly (< 1 week) differentiate stem cells into mature cell phenotypes. This advance significantly reduces time to experiment and increases manufacturing capacity for differentiated cell types.

Table 1. Advances in Stem Cell Technologies.Description Area of Innovation Examples of Innovative ProductsExtracellular Matrix Recombinant Laminin Expressed in CHO and Silkworm iMatrix-511Culture Medium No medium change required over the weekend, GMP grade, animal free StemFit MediumGrowth Factors Recombinant, GMP grade, animal free StemFit PuroteinDissociation Reagents Trypsin enzyme recombinantly expressed in maize. Collagenase & Neutral Protease expressed in Clostridium histolyticum TrypLECollagenase NBNeutral Protease NBCryopreservation Rate-controlled freezing not required. GMP grade, animal free and available for clinical use. Suitable for all cell types. STEM-CELLBANKERDifferentiation Rapid directed differentiation through genetic reprogramming Quick-Skeletal MuscleQuick-EndotheliumQuick-Neuron

There are unlimited applications that arise from a renewable source of mature cell types. One exciting area of innovation using differentiated stem cells is in disease modelling. Studying a disease state in an organ or tissue has in the past been limited to using in vivo animal models; whereas, differentiated stem cells opened the opportunity to create disease states in specific cell types in vitro. In addition, current technologies enable organoids or mini organs to be generated in the laboratory. Disease specific induced pluripotent stem cells can also be used to create disease models in vitro that are valuable tools for the study of disease and drug development without the need for in vivo animal models. In theory, any tissue is possible to create in vitro. In an exciting example of stem cell disease modelling, Dr Takayama from the CiRA in Kyoto, Japan has successfully modelled the life cycle of SARS-CoV-2 in both organoids and undifferentiated pluripotent stem cells (Takayama, 2020) (Sano, 2021) (Figure 2). In another example, the Skeletal Muscle Differentiation Kit was used to produce skeletal muscle myotubes from stem cells to create an in vitro disease model (Figure 3). In a direct application, pluripotent stem cell models of skeletal muscle have also been successfully used to develop a novel treatment for Duchenne muscular dystrophy (Moretti, 2020).

Promising progress is being made to create meat in the laboratory or what is commonly called cultured meat. Environmental concerns are driving the need for more sustainable meat production over traditional farming methods. Stem cell research in itself is reducing the need for the use of animals across multiple aspects as highlighted here. Producing cultured meat is straightforward in principle but faces many challenges in practice, for example maintaining the correct environment and stimuli for cultured cells to produce meat with the correct consistency and characteristics of the animal derived product. Stem cell cultures are expanded at scale in bioreactors and differentiated into skeletal muscle cells. These can be structured, using an edible scaffold for example, or used unstructured as the raw material to produce meat products (Figure 4). Tools and technologies are readily available to achieve this goal: expansion and differentiation of stem cells is highly efficient. However, a key consideration is the cost of goods. Current technologies are too costly but these are pioneering times and research is moving at an exciting pace.

The promise and potential of stem technologies to advance biology, medicine and food production can only be fulfilled if stem cell culture conditions are consistent, and accessible to research scientists and commercial operations alike. Exciting advances across multiple aspects of the stem cell workflow have streamlined processes to deliver products that are fully defined and animal-free. Furthermore, clinical translation of stem cell therapies and drug discovery are accelerated by the availability of GMP compliant reagents. The foundations are set for a bright future of discoveries and applications emerging from stem cell technologies.

Dr William Hadlington-Booth is the business unit manager for stem cell technologies and the extracellular matrix at AMSBIO. Erik Miljan, PhD, is a pioneer in the development of cellular therapies for a range of degenerative and disease conditions. He holds a PhD in biochemistry from Hong Kong University. For further information please contact:William@amsbio.com

Moretti, A. F., et al. (2020). Somatic gene editing ameliorates skeletal and cardiac muscle failure in pig and human models of Duchenne muscular dystrophy. Nature Medicine, 26, 207214.Takahashi K., et al. (2006). Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. . Cell, 126, 663-676.Takayama, K. (2020). In Vitro and Animal Models for SARS-CoV-2 research. Trends in Pharmacological Sciences, 41. 513-517.Sano, E., et al. (2021). Modeling SARS-CoV-2 infection and its individual differences with ACE2-expressing human iPS cells. Iscience, 24(5), 102428.

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Current and Future Innovations in Stem Cell Technologies - Labmate Online

Cardiac Stem Cells Comments Off on Current and Future Innovations in Stem Cell Technologies – Labmate Online | June 11th, 2022

"It actually changed my life," said Taylor, who directed regenerative medicine research at Texas Heart Institute in Houston until 2020. "I said to myself, 'Oh my gosh, that's life.' I wanted to figure out the how and why, and re-create that to save lives."

That goal has become reality. On Wednesday at the Life Itself conference, a health and wellness event presented in partnership with CNN, Taylor showed the audience the scaffolding of a pig's heart infused with human stem cells -- creating a viable, beating human heart the body will not reject. Why? Because it's made from that person's own tissues.

"Now we can truly imagine building a personalized human heart, taking heart transplants from an emergency procedure where you're so sick, to a planned procedure," Taylor told the audience.

"That reduces your risk by eliminating the need for (antirejection) drugs, by using your own cells to build that heart it reduces the cost ... and you aren't in the hospital as often so it improves your quality of life," she said.

Debuting on stage with her was BAB, a robot Taylor painstakingly taught to inject stem cells into the chambers of ghost hearts inside a sterile environment. As the audience at Life Itself watched BAB functioning in a sterile environment, Taylor showed videos of the pearly white mass called a "ghost heart" begin to pinken.

"It's the first shot at truly curing the number one killer of men, women and children worldwide -- heart disease. And then I want to make it available to everyone," said Taylor to audience applause.

"She never gave up," said Michael Golway, lead inventor of BAB and president and CEO of Advanced Solutions, which designs and creates platforms for building human tissues.

"At any point, Dr. Taylor could have easily said 'I'm done, this just isn't going to work. But she persisted for years, fighting setbacks to find the right type of cells in the right quantities and right conditions to enable those cells to be happy and grow."

Giving birth to a heart

"We were putting cells into damaged or scarred regions of the heart and hoping that would overcome the existing damage," she told CNN. "I started thinking: What if we could get rid of that bad environment and rebuild the house?"

Soon, she graduated to using pig's hearts, due to their anatomical similarity to human hearts.

"We took a pig's heart, and we washed out all the cells with a gentle baby shampoo," she said. "What was left was an extracellular matrix, a transparent framework we called the 'ghost heart.'

"Then we infused blood vessel cells and let them grow on the matrix for a couple of weeks," Taylor said. "That built a way to feed the cells we were going to add because we'd reestablished the blood vessels to the heart."

The next step was to begin injecting the immature stem cells into the different regions of the scaffold, "and then we had to teach the cells how to grow up."

"We must electrically stimulate them, like a pacemaker, but very gently at first, until they get stronger and stronger. First, cells in one spot will twitch, then cells in another spot twitch, but they aren't together," Taylor said. "Over time they start connecting to each other in the matrix and by about a month, they start beating together as a heart. And let me tell you, it's a 'wow' moment!"

But that's not the end of the "mothering" Taylor and her team had to do. Now she must nurture the emerging heart by giving it a blood pressure and teaching it to pump.

"We fill the heart chambers with artificial blood and let the heart cells squeeze against it. But we must help them with electrical pumps, or they will die," she explained.

The cells are also fed oxygen from artificial lungs. In the early days all of these steps had to be monitored and coordinated by hand 24 hours a day, 7 days a week, Taylor said.

"The heart has to eat every day, and until we built the pieces that made it possible to electronically monitor the hearts someone had to do it person -- and it didn't matter if it was Christmas or New Year's Day or your birthday," she said. "It's taken extraordinary groups of people who have worked with me over the years to make this happen."

But once Taylor and her team saw the results of their parenting, any sacrifices they made became insignificant, "because then the beauty happens, the magic," she said.

"We've injected the same type of cells everywhere in the heart, so they all started off alike," Taylor said. "But now when we look in the left ventricle, we find left ventricle heart cells. If we look in the atrium, they look like atrial heart cells, and if we look in the right ventricle, they are right ventricle heart cells," she said.

"So over time they've developed based on where they find themselves and grown up to work together and become a heart. Nature is amazing, isn't she?"

Billions and billions of stem cells

As her creation came to life, Taylor began to dream about a day when her prototypical hearts could be mass produced for the thousands of people on transplant lists, many of whom die while waiting. But how do you scale a heart?

"I realized that for every gram of heart tissue we built, we needed a billion heart cells," Taylor said. "That meant for an adult-sized human heart we would need up to 400 billion individual cells. Now, most labs work with a million or so cells, and heart cells don't divide, which left us with the dilemma: Where will these cells come from?"

"Now for the first time we could take blood, bone marrow or skin from a person and grow cells from that individual that could turn into heart cells," Taylor said. "But the scale was still huge: We needed tens of billions of cells. It took us another 10 years to develop the techniques to do that."

The solution? A bee-like honeycomb of fiber, with thousands of microscopic holes where the cells could attach and be nourished.

"The fiber soaks up the nutrients just like a coffee filter, the cells have access to food all around them and that lets them grow in much larger numbers. We can go from about 50 million cells to a billion cells in a week," Taylor said. "But we need 40 billion or 50 billion or 100 billion, so part of our science over the last few years has been scaling up the number of cells we can grow."

Another issue: Each heart needed a pristine environment free of contaminants for each step of the process. Every time an intervention had to be done, she and her team ran the risk of opening the heart up to infection -- and death.

"Do you know how long it takes to inject 350 billion cells by hand?" Taylor asked the Life Itself audience. "What if you touch something? You just contaminated the whole heart."

Once her lab suffered an electrical malfunction and all of the hearts died. Taylor and her team were nearly inconsolable.

"When something happens to one of these hearts, it's devastating to all of us," Taylor said. "And this is going to sound weird coming from a scientist, but I had to learn to bolster my own heart emotionally, mentally, spiritually and physically to get through this process."

Enter BAB, short for BioAssemblyBot, and an "uber-sterile" cradle created by Advance Solutions that could hold the heart and transport it between each step of the process while preserving a germ-free environment. Taylor has now taught BAB the specific process of injecting the cells she has painstakingly developed over the last decade.

"When Dr. Taylor is injecting cells, it has taken her years to figure out where to inject, how much pressure to put on the syringe, and the best speed and pace to add the cells," said BAB's creator Golway.

"A robot can do that quickly and precisely. And as we know, no two hearts are the same, so BAB can use ultrasound to see inside the vascular pathway of that specific heart, where Dr. Taylor is working blind, so to speak," Golway added. "It's exhilarating to watch -- there are times where the hair on the back of my neck literally stands up."

Taylor left academia in 2020 and is currently working with private investors to bring her creation to the masses. If transplants into humans in upcoming clinical trials are successful, Taylor's personalized hybrid hearts could be used to save thousands of lives around the world.

In the US alone, some 3,500 people were on the heart transplant waiting list in 2021.

"That's not counting the people who never make it on the list, due to their age or heath," Taylor said. "If you're a small woman, if you're an underrepresented minority, if you're a child, the chances of getting an organ that matches your body are low.

If you do get a heart, many people get sick or otherwise lose their new heart within a decade. We can reduce cost, we can increase access, and we can decrease side effects. It's a win-win-win."

Taylor can even envision a day when people bank their own stem cells at a young age, taking them out of storage when needed to grow a heart -- and one day even a lung, liver or kidney.

"Say they have heart disease in their family," she said. "We can plan ahead: Grow their cells to the numbers we need and freeze them, then when they are diagnosed with heart failure pull a scaffold off the shelf and build the heart within two months.

"I'm just humbled and privileged to do this work, and proud of where we are," she added. "The technology is ready. I hope everyone is going to be along with us for the ride because this is game-changing."

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'Ghost heart': Built from the scaffolding of a pig and the patient's cells, this cardiac breakthrough may soon be ready for transplant into humans -...

Cardiac Stem Cells Comments Off on ‘Ghost heart’: Built from the scaffolding of a pig and the patient’s cells, this cardiac breakthrough may soon be ready for transplant into humans -… | June 11th, 2022

Owing to Rising Demand for Less Invasive Treatments Among Heart Patients, Fact.MR Study Opines the Global Bioabsorbable Stents Market Share is Estimated to Reach a Value of Nearly US$ 1 Billion by 2032 from US$ 372 Million in 2021

Growing incidences of physicians and healthcare professionals preferring bioabsorbable stents over conventional stents is believed to have rapidly surged the bioabsorbable stent market growth in the global market.

Fact.MR, a Market Research and Competitive Intelligence Provider - The global bioabsorbable stents market is predicted to witness a moderate growth rate of 9.6% during the forecast years 2022 to 2032. The net worth of the bioabsorbable stents market share is expected to be valued at around US$ 1 Billion by the year 2032, growing from a mere US$ 372 Million recorded in the year 2021.

The growing prevalence of cardiovascular disease is sighted to be the leading cause of heart-related mortality worldwide. Around 17.5 million people die each year as a result of cardiovascular disease as a consequence of changing lifestyles, dietary habits, and rising blood pressure difficulties. All these factors have boosted the demand for bioabsorbable stents in the global market.

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Cardiovascular illnesses were responsible for more than 32% of fatalities in 2015, and this number is anticipated to grow to 45 per cent by 2030. The number of people diagnosed with diabetes has increased. Obesity, which is the leading cause of type 2 diabetes in adults, has increased as a result of changes in trends, food patterns, and regular exercise. The proliferation of such correlated diseases is suggested to be the major driving factor for the sales of bioabsorbable stents across the globe.

However, due to an increase in the prevalence of coronary artery disease, increased knowledge of bioabsorbable stents, increased demand for minimally invasive surgery, and increased adoption of unhealthy lifestyles, Asia-Pacific is predicted to have the highest CAGR from 2021 to 2032.

What is the Bioabsorbabale Stents Market Outlook in Asia Pacific Region?

As per the global market study on bioabsorbable stents, Asia Pacific is predicted to develop at the quickest rate. The rising number of cardiac patients in the Asia Pacific countries with the highest population count is predicted to drive the demand for bioabsorbable stents in the regional market.

During the projected period, the China bioabsorbable stents market is predicted to lead at the fastest rate of 8.8% in this geographical region. The net worth of the market is estimated to be around US$ 28 Million in 2022 and is projected to reach a total valuation of US$ 71.6 Million in the year 2032.

Other than that, bioabsorbable stents market opportunities in Japan and South Korea are also quite promising for the forecasted years, with an estimated growth rate of 8.1% and 7.3%, respectively. This new market research report on bioabsorbable stents also sheds light on the growth prospects in Indian Market as well.

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Recent Developments in the Market

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Point of Care Diagnostics Market - Shipments of point of care test (POCT) kits are projected to surge at a CAGR of around 7% from 2021 to 2028, as per this new analysis. In 2020, the global point of care diagnostics market stood at US$ 34.1 Bn, and is anticipated to surge to a valuation of US$ 66 Bn by the end of 2028.

Spectrometry Market - The global spectrometry market is projected to increase from a valuation of US$ 7.1 Bn in 2020 to US$ 13.8 Bn by 2028, expanding at a CAGR of 6.4% during the forecast period, Demand for mass spectrometry is set to increase faster at a CAGR of 7.4% over the forecast period 2021-2028.

Coronary Stents Market- Worldwide sales of coronary stents were valued at around US$ 10.1 Bn in 2020. The global coronary stents market is projected to register 12.9% CAGR and reach a valuation of US$ 25.7 Bn by the end of 2028.

Osteoporosis Therapeutics Market- The global osteoporosis therapeutics market stands at a valuation of US$ 12.7 Bn currently, and is predicted to reach US$ 14.2 Bn by the end of 2026. Consumption of osteoporosis therapeutic drugs is anticipated to increase at a CAGR of 2.9% from 2022 to 2026.

CNS Therapeutics Market- The CNS therapeutics market stands at a valuation of US$ 116.7 Bn in 2022, and is expected to reach US$ 142.1 Bn by the end of 2026. CNS drug sales are projected to rise at a steady CAGR of 4.9% from 2022 to 2026.

Induced Pluripotent Stem Cell (iPSC) Market- The global induced pluripotent stem cell (iPSC) market stands at a valuation of US$ 1.8 Bn in 2022, and is projected to climb to US$ 2.3 Bn by the end of 2026. Over the 2022 to 2026 period, worldwide demand for induced pluripotent stem cells is anticipated to rise rapidly at a CAGR of 6.6%.

Doxorubicin Market- Demand for doxorubicin is anticipated to increase steadily at a CAGR of 5.3% from 2022 to 2026. At present, the global doxorubicin market stands at US$ 1.1 Billion, and are projected to reach a valuation of US$ 1.3 Billion by the end of 2026.

Heart Attack Diagnostics Market- The heart attack diagnostics market is predicted to grow at a moderate CAGR of 7.1% during the forecast period of 2022 to 2032. The global heart attack diagnostics market is estimated to reach a value of nearly US$ 22.2 Billion by 2032 by growing from US$ 10.4 Billion in 2021.

Smart Implants Market- The global smart implants market is estimated at US$ 3.9 billion in 2022, and is forecast to surpass a market value of US$ 22.2 billion by 2032. Smart implants are expected to contribute significantly to the global implants market, with demand surging at a CAGR of 19% from 2022 to 2032.

Facial Implants Market- The global facial implant market was valued at US$ 2.7 Billion in 2022, and is expected to rise at a 7.7% value CAGR, likely to reach US$ 5.6 Billion by the end of the 2022-2032 forecast period.

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Bioabsorbable Stents Market to Grow at a Fine CAGR of 9.6% through 2032: Improvements in Healthcare Infrastructure and Growing Geriatric Population to...

Cardiac Stem Cells Comments Off on Bioabsorbable Stents Market to Grow at a Fine CAGR of 9.6% through 2032: Improvements in Healthcare Infrastructure and Growing Geriatric Population to… | June 11th, 2022

According to reports, currently, 64.34 million people suffer from heart failure worldwide[1]. Furthermore, the number of patients with end-organ heart failure is rising, leading to an all-time high in the number of people waiting for an organ transplant[2]. Several strategies have been devised to increase this strained supply of heart for transplantation, including expanding donor criteria[3], use of advanced perfusion machines such as organ care systems (OCS) to improve viability[4], use of normothermic regional perfusion (NRP) in donor from cardiac death (DCD) hearts, and xenotransplantation. Recently, the focus has shifted to new procedures using regenerative cells, angiogenesis factors, biological matrices, biocompatible synthetic polymers, and online registry systems that utilize bioimplants. These advanced technologies are collectively referred to as tissue engineering[5-8]. Ultimately, the goal is to grow a heart de novo. In addition to the unlimited organ supply, the new organ would be antigenically identical to the recipient as the recipients cells would be used, eliminating the need for immunosuppressive agents.

Even though bioengineering a fully functioning heart is in its infancy, huge strides have been made in achieving this goal. Scientists have been able to bioengineer models of the heart, lungs, pancreas, liver, and kidney. An important strategy for supporting the recipients cells and creating an autologous tissue/organ is to create a mechanical, geometrical, and biological environment that closely mimics the native organs properties. The breakthrough in growing an artificial heart was the invention of the decellularization of extracellular matrix (ECM), which maintains the native vascular network[9]. Numerous tissues and organs have been engineered using decellularization, including livers [10], lungs[11], kidneys[12], corneas[13], bladders[14], vasculature[15], articular cartilage[16], intestines[17], and hearts[18]. There has been some success in engineering a heart in the lab. Although technological innovations and biological model systems have resulted in great progress, constructing such complicated tissue structures effortlessly remains a challenge. This review aims to outline the techniques involved in bioengineering a heart in the lab and the challenges involved in developing it into a viable organ for transplantation (Figure 1).

The human heart comprises various cells, each specialized to perform a specific task. A human heart contains roughly 2-3 billion cardiomyocytes, making up only about one-third of its total cells [19]. Additionally, other cells include endothelial cells, fibroblasts, and specialized conducting cells like Purkinje fibers. On top of that, structural scaffolds support the functions of cells arranged into structures, such as vessels, muscles, and nerves. These scaffolds mainly consist of polysaccharides and proteoglycans embedded in complex sugars and chemokines matrix, allowing the heart to coordinate its mechanical and electrical functions [20,21]. Sprawled around this is a collection of protein fibers such as collagen and elastin, which confers mechanical strength to the heart and allow for the constant loading and unloading forces[22,23]. Thus, it is necessary to construct a scaffold around which the specialized cells can grow and maintain vitality through blood perfusion to recreate a functioning heart in a laboratory [24] (Figure 2).

Extracellular matrix (ECM) and cells in an organ display a dynamic reciprocity, whereby the ECM constantly adapts to the demands of the cells[25], and selecting the appropriate scaffold is the key component for growing a viable organ in the lab. Researchers have also studied various synthetic scaffolds as potential surrogates for the ECM, but none can replicate its intricacy or structure compared to native ECM. It is possible to vascularize synthetic materials such as polylactic acid (PLLA) and polylactic glycolic acid (PLGA) and to produce them consistently[26,27]. The significant advantage of synthetic ECM is its production scalability as it does not require to be harvested from living tissue, but these do not match the native myocardiums tensile strength. Hydrogels have also been studied extensively and even accepted by the Food and Drug Administration for drug delivery and adjunct for cell therapy. Hydrogels consist of a cross-linked hydrophilic polymer matrix with over 30% water content [28]. However, they have poor cell retention [29] or poor tensile strength [30]; hence, they are not feasible as a primary scaffold for constructing an organ. Decellularizing the whole heart and leaving the ECM serves as a potential solution to this problem with the particular advantage of having a balanced composition of all the proteins present physiologically [31].

The Badylak laboratory developed the first technique for decellularizing tissue[32]. This process involved the removal of the cell, leaving only the ECM, which retained its composition, architecture, and mechanical properties. There are several methods for removing cells from the ECM. These methods include physical methods (e.g., freeze/thaw cycles), enzymatic degradation (e.g., trypsin), and removal by using chemicals (e.g., sodium dodecyl sulfate)[33]. Ott et al. noted that decellularization could be achieved with different detergent solutions. Comparative studies on decellularization methods have mixed results regarding the superiority of different techniques [34-37]. Based on the results, the sodium dodecyl sulfate (SDS) solution was found to be the best [18]. However, a few studies have suggested that SDS treatment causes degradation of the ECM with a reduction in elastin, collagen, and glycosaminoglycans (GAG) content [34]. The decellularization process utilizes 1% SDS perfused through the coronary circulation, followed by washing it with de-ionized water and subsequently 1% Triton-X-100 (Sigma). Finally, the organ remnant is washed with phosphate-buffered saline (PBS) wash buffer, antibiotic, and protease, leaving a decellularized ECM[38,39]. Using this technique, they decellularized the heart, reseeded it with neonatal cardiac cells, and grew the first beating rodent heart in the lab [18]. Decellularized tissue provides a dynamic environment for the orientation and coupling of cells and facilitates the exchange of nutrients and oxygen throughout the depth of the tissue. Moreover, this process efficiently removes both allogeneic and xenogeneic antigens, possibly preventing the need for immunosuppressants [33], which is especially important as one of the causes of heart failure in transplanted hearts is myocardial fibrosis from chronic rejection [40]. This process can be potentially avoided by using a decellularized heart to generate an ECM scaffold which can then be repopulated using the recipients cells.

Researchers have used animal heart ECM and human heart ECM scaffolds to provide this decellularized ECM scaffold. The porcine heart has often been deemed suitable for its similarity with the human heart [41]. As decellularization removes most of the cells, much of the antigen load is removed. However, the porcine heart ECM contains -1,3-galactose epitope (-gal), which can stimulate an immune response [42,43]. One way to circumvent this is to use pigs lacking -gal epitope, but this technique needs further research. Another possible problem with using a porcine heart is the possible risk of horizontal transmission of porcine viruses like the porcine endogenous retrovirus, cytomegalovirus, HSB, circovirus, etc. [44,45]. Although a few tests can detect the presence of these viruses, they have poor sensitivity, and hence further work has to be done [46].

A cadaveric heart that is unfit for transplant can also be used to harvest an ECM scaffold [47]. The only drawback to this is that it may not always be possible to achieve the desired level of tissue engineering fidelity with these matrices because they may be damaged or diseased. Moreover, there is an assumption that they are superior for the growth and differentiation of human cells, but there is no robust evaluation to support this assumption. The method for decellularization of the cadaveric human heart is similar to that of other animals, utilizing 1% SDS and 1% Triton X-100, with the only difference being a longer perfusion time for these chemicals [48,49].

These cells are highly specialized and terminally differentiated, and hence, they do not proliferate normally. Therefore, to repopulate a human-sized scaffold, autologous human cardioblasts must be isolated or expanded in large quantities. Hence, for the recellularization of ECM, a method of inducing progenitor cells had to be devised. Thus, the discovery of methods to reprogram or induce adult cells into pluripotent stem cells was a significant milestone in stem cell biology and tissue bioengineering[50-52].

Once we have the cells for repopulation of ECM, recellularization is required to achieve a functional organ product for implantation. For recellularization to be achieved, choosing appropriate cell sources, seeding cells optimally, and cultivating them using organ-specific cultures are needed [24]. Cells from fetuses and adults, embryonic stem cells (ESCs), mesenchymal stem cells (MSCs), and induced pluripotent stem cells (iPSCs) have all been used[24]. Obtained with ease and ethically, stem cells from bone marrow stroma or adipose tissue (MSC) have shown promise as the ideal cells for recellularization [53]. In addition, human somatic cells can be reprogrammed to produce iPSCs, and they exhibit properties similar to ESCs [54].

A potential solution to the problem of getting a large number of human cells for tissue engineering or other regenerative medicine approaches is the ability to produce iPSCs from readily available autologous cells such as fibroblasts or blood cells[55,56]. The only drawback to using iPSCs is the possibility of teratoma formation due to its pluripotent nature [48,57]. However, the potential solution to this problem is to allow controlled differentiation toward a cardiac lineage before implantation into the ECM [58]. Although previously any attempts to produce iPSCs would result in karyotype instability [59], recent advances have been made with iPSCs maintaining chromosomal integrity [60]. These advances have ushered astep forward in the pursuit of creating viable organs in the lab.

Cell seeding techniques depend on the type of organ being engineered, and, for the heart, it usually involves seeding by perfusion through the vascular tree [24]. This step is called re-endothelization and is usually the first step to recellularization. A dynamic communication between endothelial cells and cardiomyocyte populations occurs via direct cell interactions and the secretion of various factors[61,62]. It is evident from multiple reports that seeding endothelial cell populations and cardiomyocyte populations simultaneously provides functional benefits that aid in maintaining the recellularization process [63]. Interestingly, endothelial cells have also demonstrated the ability to differentiate into cardiomyocytes in other cardiomyocyte cells [64], which may aid in more efficient recellularization. Moreover, besides the advantage, the recellularization of both the vascular tree and the heart parenchyma must be uniform to prevent two key issues in the heart, namely, thrombogenesis[65] and arrhythmogenesis[66].

Improved cell concentration and diffusion over the scaffold can be achieved by optimizing the mechanical environment, scaffold coating, and cell perfusion systems by using multiple perfusion routes simultaneously, which for the heart involves both direct intramyocardial injections and perfusion of the vascular tree [67]. However, the potential problem with intramyocardial injections is that even though the injection site shows dense cellularity, the cells are generally poorly distributed throughout the scaffold [58]. Moreover, sequential injections of cardiac cells will likely be required to rebuild the chamber parenchyma, which may compromise matrix integrity [48]. Nevertheless, given that cardiac cells include fibroblasts, in which ECM is produced and secreted, there is a possibility that endogenous matrix repair may occur after cell seeding to help resolve this issue [62].

While sourcing cells for recellularization using stem cells is a work in progress, multiple studies have explored ways to develop mature cardiomyocytes derived from iPSCs that are more physiologically similar to native cardiomyocytes [68,69]. One of the most recent cardiac constructs was engineered using PSC-derived cardiac cells in a ratio of equal cardiomyocyte and noncardiomyocyte cells, cultured in serum-free media [70]. Cardiomyocytes cultivated in this method were elongated, had organized sarcomeres and distinguished bands, and exhibited increased contractility [70]. It is encouraging to see these results that stem cells can be used to produce cardiomyocytes similar to native mature cells, reinforcing the notion that stem cells can be a cardiac cell source.

After enough cells have been seeded onto an organ scaffold, cell culture is required. A bioreactor is required for perfusion and provides a nutrient-rich environment that encourages organ-specific cell growth [24]. Bioreactors should allow nutrient-rich oxygen to be pumped with adjustable rates of flow and pressure and monitor and control the pH and temperature of the media. Moreover, mechanical stimulation is also an essential component for engineering organs of the musculoskeletal and cardiovascular systems [71]. A wide range of mechanical properties is employed in the design of bioreactors, including substrate stiffness and dynamic changes in stiffness throughout culture, pulsatile flow, and providing stretch to enhance cell maturation, alignment, and generation of force in engineered constructs [72]. Presently, there are several types of bioreactors available, with Radnoti [73] and BIOSTAT B-DCU II [74], to name a few. In addition, there has been an increase in bioreactor designs incorporating real-time monitoring to assess the status of engineered tissues. These designs may incorporate biochemical probes to assess transmural pressure changes or sampling ports to test cells viability and biochemical composition after recellularization [75,76]. The incorporation of sampling methods within bioreactor designs will keep constructs sterile, allowing for modifications in stimuli to be made while maintaining a closed system, and providing researchers with valuable feedback on cell responses throughout bioengineering. Further research is being conducted to make bioreactors that can be used to maintain the perfect milieu for growing these bioengineered tissues and organs.

For an organ to be viable for transplant, three things must be ensured: sterility of the process, structural integrity, and, lastly, patency for surgical anastomosis. Biological tissues are sterilized by gamma radiations or peracetic acid at low concentrations before the ECM is repopulated with cells[77]. Once the cells are added, antibacterial, antifungals, and other antibiotic drugs can be utilized. It is re-evaluated for integrity before the ECM is recellularized and only gets the green light for cell seeding if structural integrity is maintained. Interestingly, with the aid of endoscopy, decellularized constructs can be easily manipulated and visualized for macro and microstructure defects at the level of chambers, papillary muscle, and valves[47]. One of the most important aspects of evaluating the integrity of ECM is to check for intact coronary vasculature, which can be done by micro-optical coherence tomography [48].

Heart constructs engineered in the lab have been demonstrated to undergo cyclical muscular contraction but also have been shown to respond to drugs and exhibit electrical activity. However, electrocardiography analysis of the bioengineered hearts has shown irregular wave morphology due to loss of coupling between cardiomyocytes [78]. Therefore, it will be crucial to develop continuous monitoring of cardiac electrophysiology, function, and even vascular patency if these artificial constructs can be transplanted into patients.

Over the past decade, research in regenerative medicine has enabled us to understand better the challenges associated with developing a bioartificial heart. The first challenge was creating a biocompatible scaffold which has already been resolved with the development of various decellularization techniques, making it possible to generate an anatomically accurate and vascularized heart scaffold. With the advent of newer techniques for iPSC generation of stable karyotype, cell generation is also potentially resolved. Presently, research has to be aimed to address the challenges in reseeding the ECM scaffold. A potential solution might be the advancement in 3D-printed matrixes with embedded cells. However, decellularized ECM remains the gold standard for now as 3D-printed matrixes cannot replicate the complexity and structural integrity of the natural component of ECM.

Another potential problem is the creation of a bioreactor that can efficiently maintain the environment required for the growth of cardiac and other differentiated cells around the decellularized ECM scaffold. Constructing organs is no easy feat and involves much technical expertise. Hence, many resources are required in every step of artificially reproducing tissues and organs. Thus, even if bioengineering a heart is a possibility in the near future, it may not be financially feasible to use them for transplantation until the cost of making such constructs is lowered. Additionally, we do not know the long-term viability of such constructs. These constructs use chemicals to decellularize ECM as well as induce the conversion of adult cells into pluripotent cells. Some questions arise on how the complex network of cells and ECM would interact over the long run. The heart is a complex organ that requires a highly specialized conduction system to ensure efficient, coordinated, and purposeful contraction of the heart chambers. Any deviance may lead to fatal arrhythmia or thrombus formation. We are yet to reproduce a perfect conduction system in the lab, let alone test its long-term functionality. Furthermore, the use of induced pluripotent cells also raises the prospect of long-term tumorigenesis and malignancy. Despite rapid advances in bioengineering and artificial hearts, research and clinical trials must be conducted to determine the long-term feasibility of using these organs.

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DUBLIN--(BUSINESS WIRE)--The "Heart Failure - Pipeline Insight" clinical trials has been added to ResearchAndMarkets.com's offering.

This "Heart Failure - Pipeline Insight, 2022" report provides comprehensive insights about 90+ companies and 90+ pipeline drugs in Heart Failure pipeline landscape. It covers the pipeline drug profiles, including clinical and nonclinical stage products. It also covers the therapeutics assessment by product type, stage, route of administration, and molecule type. It further highlights the inactive pipeline products in this space.

"Heart Failure - Pipeline Insight, 2022" report outlays comprehensive insights of present scenario and growth prospects across the indication. A detailed picture of the Heart Failure pipeline landscape is provided which includes the disease overview and Heart Failure treatment guidelines.

The assessment part of the report embraces, in depth Heart Failure commercial assessment and clinical assessment of the pipeline products under development. In the report, detailed description of the drug is given which includes mechanism of action of the drug, clinical studies, NDA approvals (if any), and product development activities comprising the technology, collaborations, licensing, mergers and acquisition, funding, designations and other product related details.

Report Highlights

Heart Failure Emerging Drugs

Tirzepatide: Eli Lilly and Company

Tirzepatide is a once-weekly dual glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) receptor agonist that integrates the actions of both incretins into a single novel molecule. GIP is a hormone that may complement the effects of GLP-1. In preclinical models, GIP has been shown to decrease food intake and increase energy expenditure therefore resulting in weight reductions, and when combined with a GLP-1 receptor agonist, may result in greater effects on glucose and body weight. Tirzepatide is in phase 3 development for chronic weight management and heart failure with preserved ejection fraction (HFpEF). It is also being studied as a potential treatment for non-alcoholic steatohepatitis (NASH). Both the FDA and EMA have accepted Eli Lilly's marketing approval applications for its type 2 diabetes treatment, tirzepatide.

Finerenone (BAY94-8862): Bayer

Finerenone (BAY 94-8862) is an investigational novel, non-steroidal, selective mineralocorticoid receptor antagonist (MRA) that has been shown to block the harmful effects of the overactivated mineralocorticoid receptor (MR) system. MR overactivation is a major driver of heart and kidney damage. Current steroidal MRAs on the market have proven to be effective in reducing cardiovascular mortality in patients suffering from heart failure with reduced ejection fraction (HFrEF). However, they are often underutilized due to the incidence of hyperkalemia, renal dysfunction, and anti-androgenic/ progestogenic side effects.

CardiAMP Cell Therapy: BioCardia

CardiAMP Cell Therapy uses a patient's own (autologous) bone marrow cells delivered to the heart in a minimally invasive, catheter-based procedure to potentially stimulate the body's natural healing response. The CardiAMP Cell Therapy Heart Failure Trial is the first multicenter clinical trial of an autologous cell therapy to prospectively screen for cell therapeutic potency in order to improve patient outcomes. CardiAMP Cell Therapy incorporates three proprietary elements not previously utilized in investigational cardiac cell therapy, which the company believes improves the probability of success of the treatment: a pre-procedural diagnostic for patient selection, a high target dosage of cells, and a proprietary delivery system that has been shown to be safer than other intramyocardial delivery systems and more successful for enhancing cell retention.

Rexlemestrocel-L (Revascor): Mesoblast

Revascor consists of 150 million mesenchymal precursor cells (MPCs) administered by direct injection into the heart muscle in patients suffering from CHF and progressive loss of heart function. MPCs release a range of factors when triggered by specific receptor-ligand interactions within damaged tissue. Based on preclinical data, it is believed that these factors induce functional cardiac recovery by simultaneous activation of multiple pathways, including induction of endogenous vascular network formation, reduction in harmful inflammation, reduction in cardiac scarring and fibrosis, and regeneration of heart muscle through activation of tissue precursors.

BMS-986231: Bristol-Myers Squibb

Cimlanod (development codes CXL-1427 and BMS-986231) is an experimental drug for the treatment of acute decompensated heart failure. HNO gas (nitroxyl) is a chemical sibling of nitric oxide. Although nitric oxide and HNO appear to be closely related chemically, the physiological effects and biologic mechanisms of HNO and nitric oxide action are distinct. The biologic effects of HNO are mediated by direct post-translational modification of thiol residues in target proteins, including SERCA2a, phospholamban, the ryanodine receptor, and myofilament proteins in cardiomyocytes. In vitro, HNO increases the efficiency of calcium cycling and improves myofilament calcium sensitivity, which enhances myocardial contraction and relaxation. HNO also mediates peripheral vasodilation through endothelial soluble guanylate cyclase. HNO does not induce tachyphylaxis in peripheral vessels, unlike nitric oxide.

Elamipretide: Stealth BioTherapeutics

Elamipretide (MTP-131, Bendavia) is a novel tetra-peptide that targets mitochondrial dysfunction in energydepleted myocytes. Elamipretide crosses the outer membrane of the mitochondria and associates itself with cardiolipin, which is a phospholipid expressed only in the inner membrane of mitochondria. Cardiolipin has an integral role in mitochondrial stability and organization of respiratory complexes into super complexes for oxidative phosphorylation.Thus, elamipretide helps to enhance ATP synthesis in multiple organs of the body. Elamipretide has been shown to improve left ventricular ejection fraction (LVEF), LV end diastolic pressure, cardiac hypertrophy, myocardial fibrosis, and myocardial ATP synthesis in both animal models and humans.

FA relaxin: Bristol Myers Squibb

BMS-986259 is a next-generation version of Relaxin that is enabled with our technology and currently in Phase 1 clinical trials for ADHF. Relaxin, a peptide hormone, has been reported to reduce fibrosis in the multiple organs and to exert cardioprotective effects in preclinical studies. However, the therapeutic potential of Relaxin has been partially limited by its short half-life in humans. BMS-986259 has exhibited a prolonged half-life and therefore has the potential to enhance clinical benefit as a novel therapeutic for ADHF.

Key Players

Key Products

For more information about this clinical trials report visit https://www.researchandmarkets.com/r/soc45u

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Global Heart Failure Pipeline Market Research Report 2022: Comprehensive Insights About 90+ Companies and 90+ Pipeline Drugs - ResearchAndMarkets.com...

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Its a symbol of love and courage. It flutters with excitement and panic. It knows when to rest and when to quicken. But, most importantly, the heart is an extraordinary machine. These doors inside your heart [the valves] have to flap open and closed 100,000 times a day, says cardiologist James Wong. If you did that to your front door it would be gone in the afternoon.

Yet, as with all complex machinery, over time the heart can develop issues. One of the more insidious problems lies in its plumbing the coronary arteries which, when blocked, cause a heart attack.

One in every 25 deaths in Australia in 2020 was due to a heart attack. Thats the equivalent of 18 deaths a day, or one every 80 minutes. Sometimes, heart attacks are sudden and brutal. Other times, people dont realise they are having one. And they are often different for women and men.

So, how do you know if you are having a heart attack? What does a massive heart attack mean? Can you test for signs? And to what extent can you prevent them?

Credit:Artwork Matt Davidson

The heart is a pump made of muscle with its own electrical circuits and plumbing. Its job is to bring oxygen and nutrients to all our organs in just the right amount. It normally beats up to 100 times a minute more when you exercise. With each beat, it squeezes to circulate blood from the lungs to the rest of body then back again. Valves keep blood flowing in the right direction, pieces of thin, strong tissue like parachute material. Its amazing how resilient they are to withstand pressure without tearing, says Wong, an associate professor of medicine, who is director of the Royal Melbourne Hospitals echocardiography laboratory.

Its the best pump that Professor Garry Jennings knows of and the most hardy. Not many pumps work for 90 years, 100,000 times a day, says Jennings, the Heart Foundations chief medical adviser.

Its a lot of responsibility for an organ the size of a fist, but it has its own electrical system to help.

Tiny electrical impulses trigger each heartbeat, beginning in the sinus node at the top of the heart before travelling, like a Mexican wave, through the hearts four chambers two atria and two ventricles with the atria contracting a fraction of a second before the ventricles to push the blood. Wong likens the sinus node to the guy that beats the drum, which the rest of the heart follows, thereby controlling the heart rate.

Researchers have found that every time the heart beats, the brain pulses in sync ever so slightly.

An electrocardiogram, or ECG, produces the pulsing graph you see on screens at hospitals (and much beloved by makers of TV dramas). It detects the hearts contractions by reading its electrical activity via electrodes on the skin.

The heart contracts automatically, but the brains autonomic nervous system regulates the strength and pace of the contractions. The brain and heart depend on each other: the brain supports the hearts pumping, and the heart keeps the brain oxygenated. In fact, researchers have found that every time the heart beats, the brain pulses in sync ever so slightly.

But to do its job, the heart relies on having a rich blood supply, which is where its plumbing comes in: the coronary arteries are the blood vessels that wrap around the heart to nourish it with oxygenated blood. A heart attack occurs when that supply is impeded, cutting off nourishment and preventing the heart from keeping up with the demands of the body. The heart has to work pretty hard, and if you cut off the blood supply to a part of the muscle then it runs into trouble, says Jennings.

A heart attack is a medical event where blood flow in the coronary arteries becomes restricted, resulting in irreversible damage to the heart muscle. Because theres no blood flow being delivered to that part of the heart muscle, that part dies, Wong says.

The extent of the damage will vary but the consequences can be devastating, leading to a life sentence of chronic heart failure, or death.

What tends to determine a heart attacks severity is the location of the artery blockage and the time taken to clear it, as these two factors will dictate how much irreversible scarring is left behind.

You might hear that someone died of a massive heart attack. Picture the coronary arteries as being made up of three major freeways then side streets, avenues and laneways. Wong explains: If the blockage happened very much downstream and one of the side streets is blocked off, were not talking about a big volume of heart [thats low on supply]. Compare that to the start of the freeway being blocked then everything downstream is going to get wiped out because the narrowing happened to be at the wrong spot.

Blocked at the start of the freeway, the heart simply cant pump the blood out to the brain and other organs, and that can result in life-threatening cardiac shock. Wong says there is a particularly bad zone for a blockage, which is the left main stem where blood vessels lead into the heart. If it blocks off, probably two-thirds of the heart will go. That is not sustainable at all.

Its estimated that more than half of people killed by a heart attack die suddenly. In other cases, a blockage can harm the hearts electrical system causing cardiac arrhythmia, which can be fatal too: the hearts rhythm goes berserk and cant pump. The heart doesnt have time to fill then it cant empty properly. So its just fluttering instead of a regular beat in and out, Jennings says.

This can then lead to cardiac arrest, which is not the same as a heart attack, although heart attack is a common cause of cardiac arrest. You might think of a heart attack as more of a plumbing-related issue caused by a blockage while cardiac arrest is due to a malfunctioning of the hearts electrical system, prompting the heart to beat erratically thats where defibrillators come in, as an arrest is treated with electric shock.

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A heart attack is usually a result of coronary heart disease (also called ischaemic heart disease or coronary artery disease), an umbrella term for a range of conditions that can affect the heart when blood flow in the coronary arteries is compromised.

For some people, a heart attack is the first time a person realises they have the disease. Its Australias biggest killer overall; the leading cause of death in men, and, in women, it is the second-leading cause after dementia. Heart attacks are responsible for two-fifths of all coronary heart disease deaths.

Another important distinction: coronary heart disease is just one form of heart disease. Heart disease and cardiovascular disease are the same thing and are broad terms that include any disease of the heart or blood vessels, such as stroke and congenital heart conditions.

Angina, meanwhile, is a short-lived chest pain caused by blood flow issues its a sign of coronary heart disease but less intense than heart attack pain.

Most of us probably have an image in our heads of someone clutching their chest and collapsing. Wong says the textbooks dont always reflect real life but theyre the best place to start. People often get chest pains across the front of the chest, which radiate to their jaw or down their left arm. Its also associated with some breathlessness, sweatiness or nausea, he says.

Its not always like that, though. Women, for example, are less likely to have chest pains, more likely to have breathlessness, excessive sweating, dizziness or neck and back pain. One day in 2020, disability support worker Kath Moorby felt discomfort in her right shoulder and hand followed by tingling in her arms and fingers. Then she felt hot, clammy and sweaty. There was no chest pain, just a heaviness.

It was a surreal moment. Really? Im 44 and Im having a heart attack?

Paramedics eventually determined she was having a heart attack. It was a surreal moment, she recalls. Really? Im 44 and Im having a heart attack?

Moorby had two stents implanted. She says the effect was instant: the pressure in her upper-body reduced and her blood could flow freely again. They said I had a 20 per cent chance of surviving had I not made it to hospital when I did, she recalls.

Other people experience tightness rather than crushing pain.

People usually become cold, white and clammy, Jennings says. But symptoms can be variable.

Andrew van Vloten, a 53-year-old Victorian park ranger, had his first heart attack in 2014. With a family history of heart disease, he says, looking back, there had been signs for months that something was off: he felt occasional chest and jaw pain, especially when exercising, as well as shortness of breath. One day at work, the chest pains returned and wouldnt subside. It was getting quite intense, the pressure right on the centre of my chest I then started to get pins and needles in my fingers and toes. It was full-on, van Vloten says.

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He had a stent put in that day.

To avoid a repeat, he set about exercising more and ate less saturated fat, red meat and processed food. Six months down the track, I felt as fit as Id been in 10 years.

Its why he was so shocked when he had a second heart attack in 2020. This time he had no symptoms in the lead-up other than feeling a bit unwell. Then, as he was loading up timber into a ute, he was hit by nausea, breathlessness and chest pains. It just came on really quickly and intensely, he says. Everything started coming back to me.

It can be easy to mix up heart attack symptoms with heartburn, oesophageal spasms or angina. If the pain lasts more than 10 minutes, its worth seeking urgent medical attention. Its a heart attack when an artery blocks off and nothing a patient does makes it better, Jennings says.

Sometimes a heart attack can happen when the heart is under more pressure, such as during exercise or even following a big fright.Other times, theres no particular exertion. To complicate matters, one-sixth of people experience silent heart attacks no symptoms. This is more likely in people who have diabetes because their nerve endings can be blunted.

Sometimes we do ECGs on people for insurance purposes, and we find that theyve had an old heart attack somewhere along the way, Wong says. Its like if you damaged any part of you, you would scar, with scar tissue replacing the damaged tissue. The same thing happens in the heart.

Credit:Artwork Getty/Marija Ercegovac

They might seem to come out of the blue but a heart attack often reflects a process that has been going on throughout a persons life. Atherosclerosis is the narrowing and hardening of arteries. It starts in adolescence, if not before, brought on by a build-up of plaque (made of cholesterol and other substances) on the inner wall of the arteries. Once it gets underneath that inner lining of the vessel wall, its really hard to get out again, Wong says, so its almost like a one-way street.

By the time the guy whos been doing absolutely nothing, sitting all day, comes to you with chest pain, thats really late.

You wont be aware of much of the gradual narrowing because the body manages fine until it reaches a particular point. Its only once a coronary artery narrows by between 60 and 70 per cent that blood flow falls off noticeably and someone might begin to tire more easily or feel bursts of chest discomfort. That partly explains why some people feel great one week and dont feel good the next, Wong says.

This is also when coronary heart disease is in full swing. The artery wall becomes more unstable, so a blob of plaque can crack off and lead to clotting. This is the most common way a blockage happens before a heart attack but there are others. Sometimes, heart attacks occur in people without significantly clogged arteries, Wong says. There might be a spasm of the muscle lining in the artery that causes it to clamp down or, in rare cases (about 2 per cent of heart attacks) mainly in women, there can be a tear in the inner artery wall that peels off and blocks circulation (this is called spontaneous coronary artery dissection, or SCAD). Or plaque might simply be unstable, slough off and clog an artery more common in smokers.

Credit:Artwork Stephen Kiprillis

If someones exercise capacity is consistently worsening, it can be a sign their arteries are narrowing dangerously. It means when the heart is being asked to do more work, its not getting enough blood flow to it, Wong says. Maybe you used to be fine walking five kilometres, three the next month, then two; or walking room to room becomes too much. It will be unrelenting, its not something that would come and go away, Wong says. People need to be honest with themselves by the time the guy whos been doing absolutely nothing, sitting all day, comes to you with chest pain, thats really late. The artery is likely to be quite narrowed.

There are various tests you can do. As a first step, Wong advises his patients to try an online calculator such as cvdcalculator.com, where you punch in your data (for example, age, smoking status, cholesterol levels) to get an understanding of your risk and how making small lifestyle changes can make a big difference.

You dont have to have symptoms of heart disease to get a heart health check. Any patient over 30 is eligible.

A basic heart health check, usually done by a GP, can determine risk levels and help work out whether you are harbouring artery disease. You dont have to have symptoms of heart disease to get a heart health check. Any patient over 30 is eligible. Its covered by Medicare once in a 12-month period and is recommended for adults aged 45 and over, or Aboriginal and Torres Strait Islander people aged 30 and over.

A patient might have further tests if its appropriate, such as a calcium-score CT scan (more calcium deposits in the coronary arteries means theres a higher chance theyre narrowed) or an ECG or a cardiac stress test, which examines how the heart responds to exercise. These tests can cost a few hundred dollars, which Medicare generally covers only if someone has heart disease symptoms.

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To check to what extent someones arteries have narrowed, a coronary angiogram involves injecting dye into the hearts blood vessels, which is picked up using an X-ray machine.

Depending on the patient, they might be prescribed medication to treat cholesterol, blood pressure or clotting. Or a doctor might recommend inserting a stent or doing coronary artery bypass surgery to redirect blood flow by grafting a healthy blood vessel.

Its difficult not to be alarmed by the stories of fit, healthy people who collapse suddenly with a heart attack. Wong says these are rare events often caused by inherited, underlying heart disease. But anyone who has concerns can talk to their doctor about tests that will help them ascertain their hearts health, and what level of physical activity is safe for them.

Twice as many men are admitted to hospital with a heart attack compared to women, although the disparity in deaths is slimmer: in 2020, 2800 women and 3700 Australian men. This is, in large part, because of differences between how these events present in the two sexes studies having long shown that many women have their symptoms dismissed or misdiagnosed.

The average age of a first heart attack is 72 for women about 10 years older than men.

The average age of a first heart attack is 72 for women about 10 years older than men and theyre more likely to have a spontaneous artery tear, a blockage in a small coronary blood vessel or a mini heart attack where a smaller artery doesnt open up properly, despite no significant narrowing. The biology that causes heart attacks can be a bit more varied in women than men, Jennings says.

Women with a history of pre-eclampsia or gestational diabetes during pregnancy or endometriosis also have a higher risk of coronary heart disease.

There are some inequalities in who suffers most from heart attacks. The rate of hospitalisations and deaths is about 1.5 times higher for people in remote or lower socioeconomic areas, the Australian Institute of Health and Welfare reports. For Indigenous Australians, the rate is double that of non-Indigenous Australians.

People with diabetes are roughly four times more likely to have a heart attack. And mental health is important for the heart: depression can increase your risk of developing coronary heart disease just as much as smoking and high blood pressure.

Phone triple zero. While you wait for an ambulance, it helps to focus on breathing steadily to try to calm yourself. With any heart attack, Wong says the key is to have as short a door-to-needle time as possible. Normally, paramedics alert a hospital of a heart attack patient before arrival.

Sometimes theyll be given clot-dissolving medication, or a catheter tube is threaded up the arm or leg and a tiny balloon widens the narrowed coronary artery to leave behind a wire mesh, called a stent, to prop it open. Every minute counts in doing that, Jennings says, because the longer you wait, the more the heart muscle cells will be dying.

The part of the heart not affected by the blockage will keep working to contract, but it will be strained and the damage can spread. There is a risk of chronic heart failure, where the hearts pump mechanism is weakened long-term. They could be fine sitting or lying down but when they start walking up a hill, they cant do it. They have a limit and their lifestyle has to be adjusted to what the heart allows them to do, Wong explains. In severe heart failure cases, an artificial pacemaker or organ transplant may be needed.

Weve seen some horrendous things that could have been dealt with a lot sooner.

Treatment involves looking after the other arteries because you cant afford to lose any more heart muscle with another heart attack.If we get them from their home to hospital within two to three hours then we have a very high chance of salvaging their heart muscle and keeping them alive. If its five to six hours after the onset of the heart attack, even if you unblock the artery, the amount thats salvaged is much less, says Wong.

There have been too many preventable heart attack deaths from patients who stayed away from hospital during the pandemic, Wong says. Weve seen some horrendous things that could have been dealt with a lot sooner, he says. Having ambulances ramped outside emergency rooms is a particular concern in heart attack cases.

When treatment is swift, you can go on to lead a normal life, with medication and lifestyle adjustments to help keep your arteries open. Still, its estimated that about 20 per cent of heart attack patients will be hospitalised with a second one within five years, a reality that Wong says can make people feel very anxious.

Its why cardiac rehabilitation is so important as it involves structured physical activity and education on lifestyle and medicines, Jennings says, urging people to speak to their doctor about enrolling in a program or use the Heart Foundations directory to find one.

The heart does age and wear out eventually, Wong says. Sometimes I have to say to patients, Its more a case of youve had too many birthdays. That said, a heart attack is eminently preventable, Jennings says, particularly under the age of 80. The goal is to slow the rate at which the coronary arteries are narrowing and stiffening.

First, its good to understand what we can control. We cant change our age nor our genetics, both of which are unavoidable factors in our risk of heart disease. Some people can do all the wrong things [for their health] and never have a heart problem. Other people barely infringe and suffer from heart disease, says Jennings.

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Some people have a family history of heart disease. Wong starts to treat such patients about five years before their close relative who had heart trouble started having issues. Some people might have naturally high cholesterol (called familial hypercholesterolemia). Here, heart complications tend to occur in someones 20s.

Health issues such as high cholesterol or blood pressure have effective medications. But whatever your genetic background, youll still be better off with a better lifestyle, so never give up, Jennings says. Poor nutrition, low physical activity, drinking alcohol, smoking and being overweight: these are all major risk factors that can be improved. A 2019 study of more than 26,000 people aged over 18 found that a healthy lifestyle was linked to a 44 per cent lower risk of coronary heart disease.

This might sound a bit airy-fairy, but I say thank you to my heart every day. I am in absolute awe of my heart.

Sometimes people become scared of putting pressure on their heart with exercise but Jennings urges people to ditch the fear. Theres nothing better you can do for your heart than being physically active, he says. Sensible exercise, where people build up a program and get fit, is one of the healthiest things.

The Mediterranean diet remains the gold standard for a healthy heart, he says, and instead of focusing on food components, such as fat and cholesterol, there is increasing emphasis on healthy food combinations so, lots of fruit and vegetables, olive oil, fish and chicken because people eat food, not polyunsaturated fat .

Kath Moorby had many risk factors, from family history to years of weight struggles. Before her heart attack she had lost 100 kilograms but her diet remained unhealthy, and she was smoking 50 cigarettes a day. What you do in your younger years comes back to bite you on the bum, Moorby says. Today, she eats better, walks, doesnt drink and no longer smokes.

While coronary heart disease kills more Australians than any cancer (lung cancer is the fourth-leading cause of death in men and women), Jennings observes that cancer tends to be more feared in society, not least because people fade away in front of us, whereas with a heart attack [often] theyre just gone [suddenly].

He says there is a degree of unfair blame that is heaped on heart disease patients too. Its not necessarily their fault if theyre overweight or have undetected risk factors. We just need to help them a bit more, he says.

Andrew van Vloten, who had two heart attacks, urges people to learn about their bodies and their limits and take any heart disease risk factors seriously by visiting a doctor. Today, hes a proud 10-kilometre race finisher, and he connects with his heart through meditation. This might sound a bit airy-fairy, but I say thank you to my heart every day, van Vloten says. I am in absolute awe of my heart, the function it does and what its capable of doing.

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Whats a heart attack? How can you tell if youre on the edge of one? - Sydney Morning Herald

Cardiac Stem Cells Comments Off on Whats a heart attack? How can you tell if youre on the edge of one? – Sydney Morning Herald | May 29th, 2022