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.

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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

Dr. Sara Vasconcelos in the laboratory at Toronto General Hospital on May 11.Christopher Katsarov/The Globe and Mail

When Sara Vasconcelos talks about her work, it sounds as if shes in the restoration business. But instead of repairing damaged buildings, the researcher at Torontos University Health Network wants to fix damaged hearts by using stem cells to rebuild cardiovascular tissue.

Now, Dr. Vasconcelos is one step closer to achieving that goal with a $3-million grant from the Stem Cell Network, a Canadian research funding organization. Her effort is one of 32 projects across the country that rose to the top in a competition for in the largest outlay of federal funding for regenerative medicine in 20 years.

On Thursday, the Ottawa-based network announced a total of $19.5-million in awards, which together with matching funds from various partners, will translate into $42-million for research and clinical trials over the next three years. The funding will enable the work of more than 400 scientists, clinicians and trainees, the organization said.

Its a big step, said Dr. Vasconcelos, who said she will use her award to build on preliminary findings obtained using rats. She will next work with pig hearts, which offer a much closer analogue to the human organ.

While doing so, she also hopes to overcome a barrier that has stood in the path of those who are trying to repair hearts using cardiomyocytes heart tissue cells that are grown from embryonic stem cells. The problem is that the replacement cells wither away if they are not nourished and kept alive by blood vessels.

As part of her project Dr. Vasconcelos aims to use a technique in which small sections of microscopic blood vessels are harvested from human fat and implanted along with the heart cells.

The microvessels that are like Lego pieces, she said. You can put a whole bunch of them in with the stem cell-derived cardiomyocytes and they will connect to each other and connect to the host vessels that carry blood.

With her grant secured, Dr. Vasconcelos said she is assembling the team that will test the method on pig hearts later this year. Ultimately, her goal is to develop the technique into a therapy that can restore cardiac function in human patients following a heart attack, she said.

Among the other projects to win funding are some that are already heading for clinical studies. That includes a large study led by Guy Sauvageau, a hematologist at Maisonneuve-Rosemont Hospital in Montreal, that involves developing engineered blood stem cells to treat leukemia.

Working with a group of clinical sites in the U.S., Dr. Sauvageau and his team have already had success at treating patients with leukemia who relapse. The new project will involve introducing genetical engineered stem cells into people who are better able to withstand cancer treatment and facilitate recovery.

Between 10,000 and 20,000 patients a year would benefit from this kind of therapy, Dr. Sauvageau said.

In the future, he added, the study could open the door to teaching the body to continually produce and replenish its own cancer-killing immune cells rather than having those cells created externally and infused in a form of treatment know as CAR T-cell therapy.

As part of another of the funded projects, David Thompson at the Vancouver Coastal Health Research Institute will conduct clinical trials for one of the worlds first genetically engineered cell replacement therapies for type 1 diabetes.

Dr. Sara Vasconcelos points to an image of vascular tissue in the laboratory at Toronto General Hospital where they engineer cell and tissue regeneration.Christopher Katsarov/The Globe and Mail

The diversity of the projects highlights the increasing prominence of stem cells in multiple domains of health research, an area where Canada has a long track record of success ever since University of Toronto researchers James Till and Ernest McCullough established the existence of stem cells cells which can differentiate into more specialized types in bone marrow in 1961.

Tania Bubela, dean of health sciences at Simon Fraser University in Burnaby, B.C., said the kind of funding the Stem Cell Network provides helps bridge a crucial gap between fundamental laboratory research and proven therapies for patients.

What weve realized over time is that where you get public sector investments to close the funding gap is exactly in that translational space from preclinical into early stage clinical trials, Dr. Bubela said. Once you have that proof that things are going to work and that they can be taken up by the health system, thats when venture capital starts to get interested.

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Heart, cancer and diabetes projects among winners of funding boost for stem cell therapies - The Globe and Mail

Cardiac Stem Cells Comments Off on Heart, cancer and diabetes projects among winners of funding boost for stem cell therapies – The Globe and Mail | May 13th, 2022

Lab animalshave been an essential part of life-altering and lifesaving scientific research and discovery. But a growing number of scientists are calling for an end to their use, and pushing for new methods that can better replicate human biology instead.

Among them is biomedical researcher Dr. Charu Chandrasekera. She'sthe founder and executive director of the Canadian Centre for Alternatives to Animal Methods at the University of Windsor. Here is part of her conversation with Quirks & Quarks host Bob McDonald.

Animal testing historically has been considered a regrettable necessity in the quest to save human lives. Why do you think this is not the case?

Animals have played an integral role in science over the past century or more, to the point where we have made them the gold standard for human biology. And therein lies the problem.

Over 90 per centof drugs tested to be safe and effective in animals, fail in human clinical trials. And even the ones that make it through, they can still be withdrawn or receiveblack box warnings due to unpredicted side effects in humans. And it's not just the drugs that fail, but the drugs that we missed,like the drugs that never made it to human clinical trials because they had some irrelevant side effects in animals. They could very well been safe in humans.So we've likely missed out on many life saving, history altering medications.

Why would a drug work in an animal but not in a human?

Well, there's a very simple answer to that. We humans, we are not 70-kilogram versionsof mice, rats, guinea pigs, rabbits, cats, dogs, sheep or monkeys. We're human. We're separated by hundreds of millions of years of evolution from some of these laboratory animal species.

And it's not only just the species' differences, but there are also so many issues with the way we conduct this research. We have to induce disease by either doing surgical modifications, giving them a high-fat diet. So dietary modifications, genetic modifications, take out a gene, put in a gene, or chemically destroy their pancreas, for example, to create diabetic models. So when you're doing these experimental modifications in these animals, you're really not recreating the human disease. You are creating a version of a human disease.

What motivated you to go from doing animal research in your lab to trying to end the practice altogether?

It was the scientific failures combined with the ethical standards that I was not happy with. So I worked with animal models of heart failure. And while I was doing all these studies, my dad actually had a heart attack and he required quadruple bypass surgery. And while I was with him at the Halifax Heart Centre, I thought to myself, is the research that I'm doing going to truly help humans like my father and everybody else in this ward?

A few weeks later, when I came back to the lab, I ran into this veteran cardiovascular researcher, and he had worked on receptors similar to the ones that I was working on. And I just looked at him and I said, "Do you think these receptors were activated in my dad's heart during his heart attack?" And his response was, "How the hell would I know? We've never looked at this in the human heart."And for me, that day, it was a profound realization. It was almost like an epiphany. What am I doing this for?

Those are the reasons why we should end animal research. Let's explore some of the solutions. What are some of the alternative methods to animals in research that are being developed?

Recreating human biology in a petri dish is no easy feat. There's no single magical method that can replace all animal testing tomorrow morning. It's really all about context of use, fit for purpose. What is the biological question you're trying to answer, and in what context, and how best can we address that?

So we can use human cells and tissues from cadavers and surgical remains. We can take a diseased heart removed during transplant surgery and bring it back to life in the lab, make it beat again, infused with drugs to study cardiac physiology and cardiac toxicity. We can take just a single human cell and obtain hundreds of data points on human DNA and RNA through multiomics studies. We can engineer human tissue, create miniature organ models like organoids to recapitulated complex diseases using stem cell technologies. The field is just exploding.

Can you give me a list of some of the projects that you're working on at your centreright now?

We currently have liver, gut, kidney, lung and blood brain barrier models in development. And we have a number of projects that incorporate these tissues in different configurations to create disease in a dish, and toxicity on a chip. One of the first disease models we're creating is diabetes in a dish, and we're also doing Alzheimer's in a dish. We actually have a project designed specifically to reduce and replace toxicity testing in dogs. And we even have an eco-toxicology project where we're using fish lines to replace toxicity testing on live fish.

This is all based on evidence now. So for some of these methods that we have, we are already seeing that they are able to recapitulate these human responses. We can actually look at the data that we get from using these new technologies and compare them against existing data. But we are also seeing things like new data where we're going back and reevaluating these old drugs that failed in one system and then putting them through a human biology based system. And we're seeing that they are able to predict human biology better.

How hopeful are you that we can make this shift away from using animals in scientific research?

I'm actually very hopeful that we will be able to shift away from this animal-centred paradigm to one where human biology is the gold standard and humans are the quintessential animal model. There are scientific, innovative financial and legislative efforts happening around the world to make this happen.

The goal really is to reduce as much as possible at this point. And even if we needed to use animals, could they become the last resort that you are only using, you know, five rats, for example, for a procedure that required 400 rats before?So because of all of these efforts happening globally, I'm very hopeful.

Produced by Amanda Buckiewicz. This interview has been edited for length and clarity.

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Meet the Canadian researcher determined to take the animals out of lab testing - CBC.ca

Cardiac Stem Cells Comments Off on Meet the Canadian researcher determined to take the animals out of lab testing – CBC.ca | May 13th, 2022

Stem Cell Investig. 2019; 6: 19.

1Stem Cell Research Center, Tabriz University of Medical Sciences, Tabriz, Iran;

2Department of Clinical Sciences, Faculty of Veterinary Medicine, University of Tabriz, Tabriz, Iran;

2Department of Clinical Sciences, Faculty of Veterinary Medicine, University of Tabriz, Tabriz, Iran;

3Hematology and Oncology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran

1Stem Cell Research Center, Tabriz University of Medical Sciences, Tabriz, Iran;

2Department of Clinical Sciences, Faculty of Veterinary Medicine, University of Tabriz, Tabriz, Iran;

3Hematology and Oncology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran

Contributions: (I) Conception and design: E Fathi, R Farahzadi; (II) Administrative support: E Fathi, R Farahzadi; (III) Provision of study materials or patients: None; (IV) Collection and assembly of data: R Farahzadi, N Rajabzadeh; (V) Data analysis and interpretation: All authors; (VI) Manuscript writing: All authors; (VII) Final approval of manuscript: All authors.

#These authors contributed equally to this work.

Received 2018 Nov 11; Accepted 2019 Mar 17.

Recent developments in the stem cell biology provided new hopes in treatment of diseases and disorders that yet cannot be treated. Stem cells have the potential to differentiate into various cell types in the body during age. These provide new cells for the body as it grows, and replace specialized cells that are damaged. Since mesenchymal stem cells (MSCs) can be easily harvested from the adipose tissue and can also be cultured and expanded in vitro they have become a good target for tissue regeneration. These cells have been widespread used for cell transplantation in animals and also for clinical trials in humans. The purpose of this review is to provide a summary of our current knowledge regarding the important and types of isolated stem cells from different sources of animal models such as horse, pig, goat, dog, rabbit, cat, rat, mice etc. In this regard, due to the widespread use and lot of attention of MSCs, in this review, we will elaborate on use of MSCs in veterinary medicine as well as in regenerative medicine. Based on the studies in this field, MSCs found wide application in treatment of diseases, such as heart failure, wound healing, tooth regeneration etc.

Keywords: Mesenchymal stem cells (MSCs), animal model, cell-based therapy, regenerative medicine

Stem cells are one of the main cells of the human body that have ability to grow more than 200 types of body cells (1). Stem cells, as non-specialized cells, can be transformed into highly specialized cells in the body (2). In the other words, Stem cells are undifferentiated cells with self-renewal potential, differentiation into several types of cells and excessive proliferation (3). In the past, it was believed that stem cells can only differentiate into mature cells of the same organ. Today, there are many evidences to show that stem cells can differentiate into the other types of cell as well as ectoderm, mesoderm and endoderm. The numbers of stem cells are different in the tissues such as bone marrow, liver, heart, kidney, and etc. (3,4). Over the past 20 years, much attention has been paid to stem cell biology. Therefore, there was a profound increase in the understanding of its characteristics and the therapeutic potential for its application (5). Today, the utilization of these cells in experimental research and cell therapy represents in such disorders including hematological, skin regeneration and heart disease in both human and veterinary medicine (6).The history of stem cells dates back to the 1960s, when Friedenstein and colleagues isolated, cultured and differentiated to osteogenic cell lineage of bone marrow-derived cells from guinea pigs (7). This project created a new perspective on stem cell research. In the following, other researchers discovered that the bone marrow contains fibroblast-like cells with congenic potential in vitro, which were capable of forming colonies (CFU-F) (8). For over 60 years, transplantation of hematopoietic stem cells (HSCs) has been the major curative therapy for several genetic and hematological disorders (9). Almost in 1963, Till and McCulloch described a single progenitor cell type in the bone marrow which expand clonally and give rise to all lineages of hematopoietic cells. This research represented the first characterization of the HSCs (10). Also, the identification of mouse embryonic stem cells (ESCs) in 1981 revolutionized the study of developmental biology, and mice are now used extensively as one of the best option to study stem cell biology in mammals (11). Nevertheless, their application a model, have limitations in the regenerative medicine. But this model, relatively inexpensive and can be easily manipulated genetically (12). Failure to obtain a satisfactory result in the selection of many mouse models, to recapitulate particular human disease phenotypes, has forced researchers to investigate other animal species to be more probably predictive of humans (13). For this purpose, to study the genetic diseases, the pig has been currently determined as one the best option of a large animal model (14).

Stem cells, based on their differentiation ability, are classified into different cell types, including totipotent, pluripotent, multipotent, or unipotent. Also, another classification of these cells are based on the evolutionary stages, including embryonic, fetal, infant or umbilical cord blood and adult stem cells (15). shows an overview of stem cells classifications based on differentiation potency.

An overview of the stem cell classification. Totipotency: after fertilization, embryonic stem cells (ESCs) maintain the ability to form all three germ layers as well as extra-embryonic tissues or placental cells and are termed as totipotent. Pluripotency: these more specialized cells of the blastocyst stage maintain the ability to self-renew and differentiate into the three germ layers and down many lineages but do not form extra-embryonic tissues or placental cells. Multipotency: adult or somatic stem cells are undifferentiated cells found in postnatal tissues. These specialized cells are considered to be multipotent; with very limited ability to self-renew and are committed to lineage species.

Toti-potent cells have the potential for development to any type of cell found in the organism. In the other hand, the capacity of these cells to develop into the three primary germ cell layers of the embryo and into extra-embryonic tissues such as the placenta is remarkable (15).

The pluripotent stem cells are kind of stem cells with the potential for development to approximately all cell types. These cells contain ESCs and cells that are isolated from the mesoderm, endoderm and ectoderm germ layers that are organized in the beginning period of ESC differentiation (15).

The multipotent stem cells have less proliferative potential than the previous two groups and have ability to produce a variety of cells which limited to a germinal layer [such as mesenchymal stem cells (MSCs)] or just a specific cell line (such as HSCs). Adult stem cells are also often in this group. In the word, these cells have the ability to differentiate into a closely related family of cells (15).

Despite the increasing interest in totipotent and pluripotent stem cells, unipotent stem cells have not received the most attention in research. A unipotent stem cell is a cell that can create cells with only one lineage differentiation. Muscle stem cells are one of the example of this type of cell (15). The word uni is derivative from the Latin word unus meaning one. In adult tissues in comparison with other types of stem cells, these cells have the lowest differentiation potential. The unipotent stem cells could create one cell type, in the other word, these cells do not have the self-renewal property. Furthermore, despite their limited differentiation potential, these cells are still candidates for treatment of various diseases (16).

ESCs are self-renewing cells that derived from the inner cell mass of a blastocyst and give rise to all cells during human development. It is mentioned that these cells, including human embryonic cells, could be used as suitable, promising source for cell transplantation and regenerative medicine because of their unique ability to give rise to all somatic cell lineages (17). In the other words, ESCs, pluripotent cells that can differentiate to form the specialized of the various cell types of the body (18). Also, ESCs capture the imagination because they are immortal and have an almost unlimited developmental potential. Due to the ethical limitation on embryo sampling and culture, these cells are used less in research (19).

HSCs are multipotent cells that give rise to blood cells through the process of hematopoiesis (20). These cells reside in the bone marrow and replenish all adult hematopoietic lineages throughout the lifetime of the human and animal (21). Also, these cells can replenish missing or damaged components of the hematopoietic and immunologic system and can withstand freezing for many years (22).The mammalian hematopoietic system containing more than ten different mature cell types that HSCs are one of the most important members of this. The ability to self-renew and multi-potency is another specific feature of these cells (23).

Adult stem cells, as undifferentiated cells, are found in numerous tissues of the body after embryonic development. These cells multiple by cell division to regenerate damaged tissues (24). Recent studies have been shown that adult stem cells may have the ability to differentiate into cell types from various germ layers. For example, bone marrow stem cells which is derived from mesoderm, can differentiate into cell lineage derived mesoderm and endoderm such as into lung, liver, GI tract, skin, etc. (25). Another example of adult stem cells is neural stem cells (NSCs), which is derived from ectoderm and can be differentiate into another lineage such as mesoderm and endoderm (26). Therapeutic potential of adult stem cells in cell therapy and regenerative medicine has been proven (27).

For the first time in the late 1990s, CSCs were identified by John Dick in acute myeloid diseases. CSCs are cancerous cells that found within tumors or hematological cancers. Also, these cells have the characteristics of normal stem cells and can also give rise to all cell types found in a particular cancer sample (28). There is an increasing evidence supporting the CSCs hypothesis. Normal stem cells in an adult living creature are responsible for the repair and regeneration of damaged as well as aged tissues (29). Many investigations have reported that the capability of a tumor to propagate and proliferate relies on a small cellular subpopulation characterized by stem-like properties, named CSCs (30).

Embryonic connective tissue contains so-called mesenchymes, from which with very close interactions of endoderm and ectoderm all other connective and hematopoietic tissues originate, Whereas, MSCs do not differentiate into hematopoietic cell (31). In 1924, Alexander A. Maxi mow used comprehensive histological detection to identify a singular type of precursor cell within mesenchyme that develops into various types of blood cells (32). In general, MSCs are type of cells with potential of multi-lineage differentiation and self-renewal, which exist in many different kinds of tissues and organs such as adipose tissue, bone marrow, skin, peripheral blood, fallopian tube, cord blood, liver and lung et al. (4,5). Today, stem cells are used for different applications. In addition to using these cells in human therapy such as cell transplantation, cell engraftment etc. The use of stem cells in veterinary medicine has also been considered. The purpose of this review is to provide a summary of our current knowledge regarding the important and types of isolated stem cells from different sources of animal models such as horse, pig, goat, dog, rabbit, cat, rat, mice etc. In this regard, due to the widespread use and lot of attention of MSCs, in this review, we will elaborate on use of MSCs in veterinary medicine.

The isolation method, maintenance and culture condition of MSCs differs from the different tissues, these methods as well as characterization of MSCs described as (36). MSCs could be isolated from the various tissues such as adipose tissue, bone marrow, umbilical cord, amniotic fluid etc. (37).

Diagram for adipose tissue-derived mesenchymal stem cell isolation (3).

Diagram for bone marrow-derived MSCs isolation (33). MSC, mesenchymal stem cell.

Diagram for umbilical cord-derived MSCs isolation (34). MSC, mesenchymal stem cell.

Diagram for isolation of amniotic fluid stem cells (AFSCs) (35).

Diagram for MSCs characterization (35). MSC, mesenchymal stem cell.

The diversity of stem cell or MSCs sources and a wide aspect of potential applications of these cells cause to challenge for selecting an appropriate cell type for cell therapy (38). Various diseases in animals have been treated by cell-based therapy. However, there are immunity concerns regarding cell therapy using stem cells. Improving animal models and selecting suitable methods for engraftment and transplantation could help address these subjects, facilitating eventual use of stem cells in the clinic. Therefore, for this purpose, in this section of this review, we provide an overview of the current as well as previous studies for future development of animal models to facilitate the utilization of stem cells in regenerative medicine (14). Significant progress has been made in stem cells-based regenerative medicine, which enables researchers to treat those diseases which cannot be cured by conventional medicines. The unlimited self-renewal and multi-lineage differentiation potential to other types of cells causes stem cells to be frontier in regenerative medicine (24). More researches in regenerative medicine have been focused on human cells including embryonic as well as adult stem cells or maybe somatic cells. Today there are versions of embryo-derived stem cells that have been reprogrammed from adult cells under the title of pluripotent cells (39). Stem cell therapy has been developed in the last decade. Nevertheless, obstacles including unwanted side effects due to the migration of transplanted cells as well as poor cell survival have remained unresolved. In order to overcome these problems, cell therapy has been introduced using biocompatible and biodegradable biomaterials to reduce cell loss and long-term in vitro retention of stem cells.

Currently in clinical trials, these biomaterials are widely used in drug and cell-delivery systems, regenerative medicine and tissue engineering in which to prevent the long-term survival of foreign substances in the body the release of cells are controlled (40).

Today, the incidence and prevalence of heart failure in human societies is a major and increasing problem that unfortunately has a poor prognosis. For decades, MSCs have been used for cardiovascular regenerative therapy as one of the potential therapeutic agents (41). Dhein et al. [2006] found that autologous bone marrow-derived mesenchymal stem cells (BMSCs) transplantation improves cardiac function in non-ischemic cardiomyopathy in a rabbit model. In one study, Davies et al. [2010] reported that transplantation of cord blood stem cells in ovine model of heart failure, enhanced the function of heart through improvement of right ventricular mass, both systolic and diastolic right heart function (42). In another study, Nagaya et al. [2005] found that MSCs dilated cardiomyopathy (DCM), possibly by inducing angiogenesis and preventing cardial fibrosis. MSCs have a tremendous beneficial effect in cell transplantation including in differentiating cardiomyocytes, vascular endothelial cells, and providing anti-apoptotic as well angiogenic mediators (43). Roura et al. [2015] shown that umbilical cord blood mesenchymal stem cells (UCBMSCs) are envisioned as attractive therapeutic candidates against human disorders progressing with vascular deficit (44). Ammar et al., [2015] compared BMSCs with adipose tissue-derived MSCs (ADSCs). It was demonstrated that both BMSCs and ADSCs were equally effective in mitigating doxorubicin-induced cardiac dysfunction through decreasing collagen deposition and promoting angiogenesis (45).

There are many advantages of small animal models usage in cardiovascular research compared with large animal models. Small model of animals has a short life span, which allow the researchers to follow the natural history of the disease at an accelerated pace. Some advantages and disadvantages are listed in (46).

Despite of the small animal model, large animal models are suitable models for studies of human diseases. Some advantages and disadvantages of using large animal models in a study protocol planning was elaborated in (47).

Chronic wound is one of the most common problem and causes significant distress to patients (48). Among the types of tissues that stem cells derived it, dental tissuederived MSCs provide good sources of cytokines and growth factors that promote wound healing. The results of previous studies showed that stem cells derived deciduous teeth of the horse might be a novel approach for wound care and might be applied in clinical treatment of non-healing wounds (49). However, the treatment with stem cells derived deciduous teeth needs more research to understand the underlying mechanisms of effective growth factors which contribute to the wound healing processes (50). This preliminary investigation suggests that deciduous teeth-derived stem cells have the potential to promote wound healing in rabbit excisional wound models (49). In the another study, Lin et al. [2013] worked on the mouse animal model and showed that ADSCs present a potentially viable matrix for full-thickness defect wound healing (51).

Many studies have been done on dental reconstruction with MSCs. In one study, Khorsand et al. [2013] reported that dental pulp-derived stem cells (DPSCs) could promote periodontal regeneration in canine model. Also, it was shown that canine DPSCs were successfully isolated and had the rapid proliferation and multi-lineage differentiation capacity (52). Other application of dental-derived stem cells is shown in .

Diagram for application of dental stem cell in dentistry/regenerative medicine (53).

As noted above, stem cells have different therapeutic applications and self-renewal capability. These cells can also differentiate into the different cell types. There is now a great hope that stem cells can be used to treat diseases such as Alzheimer, Parkinson and other serious diseases. In stem cell-based therapy, ESCs are essentially targeted to differentiate into functional neural cells. Today, a specific category of stem cells called induced pluripotent stem (iPS) cells are being used and tested to generate functional dopamine neurons for treating Parkinson's disease of a rat animal model. In addition, NSC as well as MSCs are being used in neurodegenerative disorder therapies for Alzheimers disease, Parkinsons disease, and stroke (54). Previous studies have shown that BMSCs could reduce brain amyloid deposition and accelerate the activation of microglia in an acutely induced Alzheimers disease in mouse animal model. Lee et al. [2009] reported that BMSCs can increase the number of activated microglia, which effective therapeutic vehicle to reduce A deposits in AD patients (55). In confirmation of previous study, Liu et al. [2015] showed that transplantation of BMSCs in brain of mouse model of Alzheimers disease cause to decrease in amyloid beta deposition, increase in brain-derived neurotrophic factor (BDNF) levels and improvements in social recognition (56). In addition of BMSCs, NSCs have been proposed as tools for treating neurodegeneration disease because of their capability to create an appropriate cell types which transplanted. kerud et al. [2001] demonstrated that NSCs efficiently express high level of glial cell line-derived neurotrophic factor (GDNF) in vivo, suggesting a use of these cells in the treatment of neurodegenerative disorders, including Parkinsons disease (57). In the following, Venkataramana et al. [2010] transplanted BMSCs into the sub lateral ventricular zones of seven Parkinsons disease patients and reported encouraging results (58).

The human body is fortified with specialized cells named MSCs, which has the ability to self-renew and differentiate into various cell types including, adipocyte, osteocyte, chondrocyte, neurons etc. In addition to mentioned properties, these cells can be easily isolated, safely transplanted to injured sites and have the immune regulatory properties. Numerous in vitro and in vivo studies in animal models have successfully demonstrated the potential of MSCs for various diseases; however, the clinical outcomes are not very encouraging. Based on the studies in the field of stem cells, MSCs find wide application in treatment of diseases, such as heart failure, wound healing, tooth regeneration and etc. In addition, these cells are particularly important in the treatment of the sub-branch neurodegenerative diseases like Alzheimer and Parkinson.

The authors wish to thank staff of the Stem Cell Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.

Funding: The project described was supported by Grant Number IR.TBZMED.REC.1396.1218 from the Stem Cell Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Conflicts of Interest: The authors have no conflicts of interest to declare.

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Stem cell-based regenerative medicine - PMC

Cardiac Stem Cells Comments Off on Stem cell-based regenerative medicine – PMC | April 29th, 2022

The new report by Expert Market Research titled, Global Stem Cell Market Report and Forecast 2022-2027, gives an in-depth analysis of the globalstem cell market, assessing the market based on its segments like types, treatment types, applications and major regions. The report tracks the latest trends in the industry and studies their impact on the overall market. It also assesses the market dynamics, covering the key demand and price indicators, along with analysing the market based on the SWOT and Porters Five Forces models.

Request a free sample copy in PDF or view the report summary@https://www.expertmarketresearch.com/reports/stem-cell-market/requestsample

The key highlights of the report include:

Market Overview (2017-2027)

The stem cell business is growing due to an increase in activities to use stem cells in regenerative treatments due to their medicinal qualities. The increasing use of human-induced pluripotent stem cells (iPSCs) for the treatment of hereditary cardiac difficulties, neurological illnesses, and genetic diseases such as recessive dystrophic epidermolysis bullosa (RBED) is driving the market forward.

Furthermore, because human-induced pluripotent stem cells (iPSCs) may reverse immunosuppression, they serve as a major source of cells for auto logic stem cell therapy, boosting the industrys expansion. Furthermore, the rising incentives provided by major businesses to deliver breakthrough stem cell therapies, as well as the increased use of modern resources and techniques in research and development activities (R&D), are propelling the stem cell market forward.

Because of increased research and development (R&D) in the United States and Canada, North America accounts for a significant portion of the overall stem cell business. Furthermore, the increased frequency of non-communicable chronic diseases such as cancer and Parkinsons disease, among others, is boosting the use of stem cell therapy, boosting the industrys growth. Furthermore, the regions stronghealthcaresector is improving access to innovative cell therapy treatments, assisting the regional stem cell industrys expansion. Aside from that, due to the rising use of regenerative treatments, the Asia Pacific area is predicted to rise rapidly. Furthermore, rising clinical trials are assisting market expansion due to low labour costs and the availability of raw materials in the region, contributing considerably to overall industry growth.

Industry Definition and Major Segments

A stem cell is a type of cell that has the ability to develop into a variety of cells, including brain cells and muscle cells. It can also help to repairtissuesthat have been injured. Because stem cells have the potential to treat a variety of non-communicable and chronic diseases, including Alzheimers and diabetes, theyre being used in medical and biotechnological research to repair tissue damage caused by diseases.

Explore the full report with the table of contents@https://www.expertmarketresearch.com/reports/stem-cell-market

The major product types of stem cell are:

The market can be broadly categorised on the basis of its treatment types into:

Based on applications, the market is divided into:

The EMR report looks into the regional markets of stem cell-like:

Market Trends

The market is expected to rise due to increased research activity in regenerative medicine and biotechnology to personalise stem cell therapy. The usage of stem cells is predicted to increase as the need for treatment of common disorders, such as age-related macular degeneration (AMD), grows among the growing geriatric population. Due to multiple error bars during research operations, it becomes extremely difficult to characterise cell products because each cell has unique properties. As a result, the integration of cutting-edge technologies such as artificial intelligence (AI), blockchain, and machine learning is accelerating. Artificial intelligence (AI) is being used to analyse images quickly, forecast cell functions, and classify tissues in order to identify cell products, which is expected to boost the market growth.

With the rising frequency of cancer and cancer-related research initiatives, blockchain technology is increasingly being used to collect and assimilate data in order to improve access to clinical outcomes and the latest advances. Blockchain can also help with data storage for patients while improving the cost-effectiveness of cord-blood banking for advanced research and development (R&D) purposes. In addition, the use of machine learning techniques to analyse photos and infer the relationship between cellular features is boosting the market growth. The increased interest in understanding cellular processes and identifying critical processes using deep learning is expected to move the stem cell business forward.

Latest News on Global Stem Cell Market@https://www.expertmarketresearch.com/pressrelease/global-stem-cell-market

Key Market Players

The major players in the market are Pluristem Therapeutics Inc., Thermo Fisher Scientific Inc., Cellular Engineering Technologies, Merck KGaA, Becton, Dickinson and Company, and STEMCELL Technologies Inc The report covers the market shares, capacities, plant turnarounds, expansions, investments and mergers and acquisitions, among other latest developments of these market players.

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Expert Market Research is a leading business intelligence firm, providing custom and syndicated market reports along with consultancy services for our clients. We serve a wide client base ranging from Fortune 1000 companies to small and medium enterprises. Our reports cover over 100 industries across established and emerging markets researched by our skilled analysts who track the latest economic, demographic, trade and market data globally.

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Global Stem Cell Market To Be Driven By Increasing Activities To Use Stem Cells In Regenerative Medicines In The Forecast Period Of 2022-2027 ...

Cardiac Stem Cells Comments Off on Global Stem Cell Market To Be Driven By Increasing Activities To Use Stem Cells In Regenerative Medicines In The Forecast Period Of 2022-2027 … | April 29th, 2022

Newswise April 28, 2022 (BRONX, NY)CAR-T therapy, a form of immunotherapy that revs up T-cells to recognize and destroy cancer cells, has revolutionized the treatment of blood cancers, including certain leukemias, lymphomas, and most recently, multiple myeloma. However, Black and Hispanic people were largely absent from the major clinical trials that led to the U.S. Food and Drug Administration approval of CAR-T cell therapies.

In a study published today in Bone Marrow Transplantation (BMT), investigators at the National Cancer Institute-designated Montefiore Einstein Cancer Center (MECC) report that Black and Hispanic patients had outcomes and side effects following CAR-T treatment that were comparable to their white and Asian counterparts.

Representation in cancer clinical trials is vital to ensuring that treatments are safe and effective for everyone, said Mendel Goldfinger, M.D., co-corresponding author of the paper, a medical oncologist at Montefiore Health System, assistant professor of medicine at Albert Einstein College of Medicine, and member of the MECC Cancer Therapeutics Program. We couldnt have been happier to learn that our patients who identify as Black and Hispanic have the same benefits from CAR-T therapy as white patients. We can only begin to say that a cancer treatment is transformational when these therapies benefit everyone who comes to us for care.

People who identify as Black and Hispanic often have tumor biology, immune system biology, and side effects that are distinct from white people. However, very few minorities were enrolled in the major trials that led the FDA to approve CAR-T cell therapy.

Parity for Black and Hispanic PatientsThe new BMT study evaluated outcomes for 46 participants treated at Montefiore between 2015 and 2021. Seventeen of the participants were Hispanic, 9 were African American, 15 were white, and 5 were Asian.

Among Black and Hispanic patients, 58% achieved a complete response after treatment and 19% achieved a partial response. For white and Asian patients, 70% achieved a complete response and 20% had a partial response, indicating no statistical differences among racial and ethnic backgrounds. Results were similar with respect to major side effects experienced: Approximately 95% of participants in each group had mild to moderate cytokine release syndrome, a common side effect to immunotherapy in which people experience fever and other flu-like symptoms.

Diversifying Cancer Clinical TrialsOur findings demonstrate that we are able to effectively treat people from historically marginalized groups using CAR-T; our hope is that more people from a diverse range of racial and ethnic backgrounds will be included in clinical trials, said co-author Amit Verma, M.B.B.S., associate director of translational science at MECC, director of the division of hemato-oncology at Montefiore and Einstein, and professor of medicine and of developmental and molecular biology at Einstein. Ira Braunschweig, M.D., associate professor of medicine at Einstein and director of Stem Cell Transplantation and Cellular Therapy and clinical program director, Hematologic Malignancies at Montefiore, is also co-corresponding author on the study.

At Montefiore, approximately 80% of clinical trial participants are minorities, compared with the nationwide figure of only 8%.

As an academic medical center, it is not enough to make novel therapies like CAR-T available, said Susan Green-Lorenzen, R.N. M.S.N., system senior vice president of operations at Montefiore and study co-author. We need to be at the forefront of ensuring that these treatments are effective for the communities we serve this research reflects this commitment.

The study is titled Efficacy and safety of CAR-T cell therapy in minorities. In addition to Drs. Goldfinger, Verma, and Braunschweig and Ms. Green-Lorenzen, other Einstein and Montefiore authors are Astha Thakkar, M.D., Michelly Abreu, N.P., Kith Pradhan, Ph.D., R. Alejandro Sica, M.D., Aditi Shastri, M.D., Noah Kornblum, M.D., Nishi Shah, M.D., M.P.H., Ioannis Mantzaris, M.D., M.S., Kira Gritsman, M.D., Ph.D., Eric Feldman, M.D., and Richard Elkind, P.A.-C.

***

About Albert Einstein College of MedicineAlbert Einstein College of Medicineis one of the nations premier centers for research, medical education and clinical investigation. During the 2021-22 academic year, Einstein is home to 732M.D.students, 190Ph.D.students, 120 students in thecombined M.D./Ph.D. program, and approximately 250postdoctoral research fellows. The College of Medicine has more than 1,900 full-time faculty members located on the main campus and at itsclinical affiliates. In 2021, Einstein received more than $185 million in awards from the National Institutes of Health. This includes the funding of majorresearch centersat Einstein in cancer, aging, intellectual development disorders, diabetes, clinical and translational research, liver disease, and AIDS. Other areas where the College of Medicine is concentrating its efforts include developmental brain research, neuroscience, cardiac disease, and initiatives to reduce and eliminate ethnic and racial health disparities. Its partnership withMontefiore, the University Hospital and academic medical center for Einstein, advances clinical and translational research to accelerate the pace at which new discoveries become the treatments and therapies that benefit patients. For more information, please visiteinsteinmed.org, read ourblog, followus onTwitter, like us onFacebook,and view us onYouTube.

About Montefiore Health SystemMontefiore Health System is one of New Yorks premier academic health systems and is a recognized leader in providing exceptional quality and personalized, accountable caretoapproximately three million people in communities across the Bronx, Westchester and the Hudson Valley. It is comprised of 10hospitals, including the Childrens Hospital at Montefiore, Burke Rehabilitation Hospital and more than 200 outpatient ambulatory care sites. The advanced clinical and translational research at its medical school, Albert Einstein College of Medicine, directly informs patient care and improves outcomes. From the Montefiore-Einstein Centers of Excellence in cancer, cardiology and vascular care, pediatrics, and transplantation,toits preeminent school-based health program, Montefiore is a fully integrated healthcare delivery system providing coordinated, comprehensive caretopatients and their families. For more information, please visitwww.montefiore.org. Followus onTwitter and Instagram and LinkedIn, or view us onFacebookandYouTube.

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Montefiore Einstein Cancer Center Finds CAR-T Therapy Effective in Black and Hispanic Patients - Newswise

Cardiac Stem Cells Comments Off on Montefiore Einstein Cancer Center Finds CAR-T Therapy Effective in Black and Hispanic Patients – Newswise | April 29th, 2022

The change in the prevalence of HHD

At the global level, the prevalence of HHD increased by 137.91% from 7.82 million in 1990 to 19.60 million in 2019 (Fig.1A, Table S1). The prevalence rate went up year by year, while the ASPR was relatively stable (Fig. 1C). The ASPR was 233.77 (95% UI=170.52312.9) per 100,000 population in 2019, which increased slightly compared with that in 1990 with an EAPC of 0.17 (95% UI=0.150.18) (Fig. 1C, Tables S2 and S3). Compared with the ASPR trend of the female subjects (EAPC, 0.28, 95% UI=0.260.30), the trend of the male subjects was more stable during the study period (EAPC, 0.02, 95% UI=0.000.04, Table S3).

The global trend of hypertensive heart disease from 1990 to 2019. The number of prevalence (A), death (D), and DALY (G). The rate of prevalence (B), death (E), and DALY (H). Age-standardized rate of prevalence (C), death (F), and DALY (I). Dashed lines represent 95% uncertainty interval; DALY, disability adjusted life-year

HHD occurred mostly in people aged over 65 (Fig. S1A). We also found that the ASPR increased with age growth for both men and women in 1990 and 2019. The female prevalence rate was much higher than male in people aged over 80 during 2019, yet there was a similar prevalence rate for aged men and women in 1990 (Fig.2).

The gender-specific global prevalence, death, and DALY rate of hypertensive heart disease in 1990 and 2019. The vertical axis represents DALY, death, and prevalence rate (per 100,000 population). DALY, disability adjusted life-year

Among 25 GBD regions, top three regions with the highest prevalence cases were Asia, East Asia, and America. In addition, the three regions with the highest ASPR were East Asia (426.15, 95% UI=306.64574.76), Oceania (344.91, 95% UI=248.54477.87), and Southeast Asia (334.77, 95% UI=244.81451.58) (Table S4). At the national level, China carried the highest HHD prevalence, followed by the United States of America and India (Fig. S2A). The highest ASPR of HHD occurred in Cook Islands, Jordan, Kuwait and Seychelles (Fig. S2C).

A total of 1.16 (95% UI=0.861.28) million people were estimated to experience HHD associated deaths worldwide in 2019, which increased from 0.65 (95% UI=0.530.73) million death cases in 1990 (Table S1). The ASDR in females was 15.05 (95% UI=11.5117.09) per 100,000 population in 2019, which was moderately higher than that in males (14.95, 95% UI=10.3216.75) (Table S2). Although the number of HHD deaths grew up dramatically during 19902019, the trend of death rate was relatively stable and the global ASDR declined with a negative value of EAPC (0.74, 95% UI=-0.92--0.58) (Fig. 1D, E, and F, Table S3). Meanwhile, the male and female ASDR shared a similar trend (EAPC for men, 0.72, 95% UI=-0.95--0.50; EAPC for women, 0.79, 95% UI=-0.93--0.65).

For both men and women, age-specific distribution of death rate remained stable in 1990 and 2019 (Fig. 2). Like HHD prevalence, people aged over 65 were more likely to suffer HHD deaths (Fig. S1B).

At the regional level, Central Sub-Saharan Africa, Eastern Sub-Saharan Africa, North Africa and Middle East had the highest ASDR; Australasia, high-income Asia Pacific and Eastern Europe were the three regions with the lowest ASDR (Table S5). At the national level, China carried the highest HHD death burden, followed by India and the Untied States of America (Fig. S2D). Bulgaria, Afghanistan, and Central African Republic were the three countries with highest ASDR (Fig. S2F).

A total of 21.50 (95% UI=16.4023.90) million DALYs were estimated on a global scale in 2019, and 13.94 (95% UI=11.3115.65) DALYs in 1990 (Table S1). There was a consistent rise in DALY number (Fig. 1G). However, DALY rate declined between 1990 and 2005, then ascended during 20062019 (Fig. 1H). In addition, it shown a persistent decline for the age-standardized DALY rate over the 30years (Fig. 1I).

The age-standardized DALY rate in men was 277.86 (95% UI=199.58311.14) per 100,000 population in 2019, which was higher than that in women (256.81, 95% UI=205.22291.98) (Table S2). The DALY rate distribution for males and females in 2019 was similar to that in 1990 (Fig. 2). In 2019, the age-specific trends of DALY rate attributed to HHD were similar for both sexes.

On the observation of the regions scale, Central Sub-Saharan Africa, Eastern Sub-Saharan Africa, and Oceania were the three regions with the highest age-standardized DALY rates (Table S5). It revealed a considerable national disparity in the burden of HHD. DALY numbers varied more than 10-fold between countries (Fig.3A). China had the highest HHD DALY number, followed by India and Indonesia (Fig. 3D). After adjusting population, Bulgaria, Estonia, and Cook Islands were the three countries with the highest rate of DALYs (Fig. 3B and E). After adjusting for age and population, Afghanistan, Cook Islands, and Central African Republic had the highest age-standardized DALY rates (Fig. 3C and F).

Global map of the disease burden of hypertensive heart disease (A, DALY number; B, DALY rates; C, Age-standardized DALY rates) and the top 20 countries with disease burden (D, DALY number; E, DALY rates; F, Age-standardized DALY rates)

The drift of HHD-related ASPR, ASDR, and age-standardized DALYs rate among five SDI quintiles were presented in Fig.4. The ASPR of HHD was highest in the middle SDI region, and the lowest in the high SDI region between 1990 and 2019 (Fig. 4A). It was interesting to note that, as opposed to the regions with other SDI, the middle SDI region presented a descending trend of ASPR (EAPC, 0.24, 95% UI=-0.2--0.20) (Table S3). ASDR and age-standardized DALY rate decreased the fastest in the middle SDI region (EAPC, 1.58, 95% UI=-1.98--1.20 for ASDR; EAPC, 1.74, 95% UI=-2.11--1.41 for age-standardized DALY rate) (Table S3, Fig. 4B and C). In the middle SDI region, the trend of ASDR and age-standardized DALY rate presented undulating curves (Fig. 4B and C). Compared with a downward trend for females (EAPC, 0.28, 95% UI=-0.4--0.11), male age-standardized DALY rate showed an upward tendency in the high SDI region (EAPC, 0.34, 95% UI=0.110.57).

The age-standardized prevalence, death, and DALY rate for hypertensive heart disease by different SDI regions, 19902019. ASPR, age-standardized prevalence rate; ASDR, age-standardized death rate; DALY, disability adjusted life-year; SDI, socio-demographic index

ASPR, ASDR, and age-standardized DALY rate of HHD stratified by SDI were shown in Fig.5. ASPR of HHD rose before SDI value of 0.4 and then start to decrease (Fig. 5A). There was a negative and significant Pearsons correlation between HHD disease burden and SDI (r=0.74, 95% CI=-0.77--0.70, p<0.001, for age-standardized DALY rate; r=0.70, 95% CI=-0.74--0.66, p<0.001, for ASDR) (Fig. 5C). The univariate linear regression indicated that many socioeconomic variables (HDI, IHDI, SDI, HAQ, population with at least some secondary education, life expectancy, and physicians per 10,000 people) had a significantly negative correlation with age-standardized DALY rate (all p<0.001, Table1).

The trend in ASPR (A), ASDR (B), age-standardized DALY rate (C) of hypertensive heart disease in 21 regions based on SDI. Expected values are shown as the dark blue line. ASPR, age-standardized prevalence rate; ASDR, age-standardized death rate; DALY, disability adjusted life-year; SDI, socio-demographic index

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Global, regional, and national burden of hypertensive heart disease during 19902019: an analysis of the global burden of disease study 2019 - BMC...

Cardiac Stem Cells Comments Off on Global, regional, and national burden of hypertensive heart disease during 19902019: an analysis of the global burden of disease study 2019 – BMC… | April 29th, 2022

By Steve Gorman

(Reuters) The first all-private astronaut crew to fly aboard the International Space Station (ISS) headed for splashdown Monday off the coast of Florida, wrapping up a two-week mission that NASA has touted as a landmark in commercial spaceflight.

A SpaceX Crew Dragon capsule carrying the four-man team of Houston-based startup Axiom Space Inc began its return flight about 9 p.m. EDT Sunday (0100 Monday GMT) as it undocked from the space station orbiting about 250 miles (420 km) above Earth.

The Crew Dragon was expected to parachute into the Atlantic around 1 p.m. EDT on Monday (1700 GMT), capping a 16-hour ride home from orbit that had been postponed for several days because of unfavorable weather.

The multinational Axiom team was led by Spanish-born retired NASA astronaut Michael Lopez-Alegria, 63, the companys vice president for business development. His second-in-command was Larry Connor, 72, a technology entrepreneur and aerobatics aviator from Ohio designated the mission pilot.

Joining them as mission specialists were investor-philanthropist and former Israeli fighter pilot Eytan Stibbe, 64, and Canadian businessman and philanthropist Mark Pathy, 52.

Launched from NASAs Kennedy Space Center on April 8, they spent 15 days aboard the space station with the seven regular, government-paid ISS crew members: three American astronauts, a German astronaut and three Russian cosmonauts.

The ISS has hosted several wealthy space tourists from time to time over the years.

But the Axiom quartet was the first all-commercial team ever welcomed to the space station as working astronauts, bringing with them 25 science and biomedical experiments to conduct in orbit. The package included research on brain health, cardiac stem cells, cancer and aging, as well as a technology demonstration to produce optics using the surface tension of fluids in microgravity.

Axiom, NASA and SpaceX have hailed the mission as a milestone in the expansion of privately funded space-based commerce, constituting what industry insiders call the low-Earth orbit economy, or LEO economy for short.

It was the sixth human spaceflight for SpaceX in nearly two years, following four NASA astronaut missions to the ISS and the Inspiration 4 flight in September that sent an all-private crew into Earth orbit for the first time, though not to the space station.

SpaceX, the private rocket company founded by Tesla Inc electric carmaker CEO Elon Musk, has been hired to fly three more Axiom astronaut missions to ISS over the next two years. The price tag for such outings is high.

Axiom charges customers $50 million to $60 million per seat, according to Mo Islam, head of research for the investment firm Republic Capital, which holds stakes in both Axiom and SpaceX.

Axiom also was selected by NASA in 2020 to build a new commercial addition to the space station, which a U.S.-Russian-led consortium of 15 countries has operated for more than two decades. Plans call for the Axiom segment to eventually replace the ISS when the rest of the station is retired around 2030.

(Reporting by Steve Gorman in Los Angeles. Editing by Gerry Doyle)

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First all-private astronaut team aboard space station heads for splashdown - KFGO

Cardiac Stem Cells Comments Off on First all-private astronaut team aboard space station heads for splashdown – KFGO | April 29th, 2022

Inflammation represents one of the leading drivers of disease. Biotech company 180 Life Sciences is developing novel, anti-TNF therapies for treating distinct inflammatory diseases.

DocWire News spoke to James Woody, CEO of 180 Life Sciences, to learn more about the company, its mission, its treatment assets, and current clinical trials its involved in.

*Interview recorded in March 2022.

DocWire News:Can you give us some background on yourself, and the company, 180 Life Sciences?

James Woody:So by background, Im a pediatric immunologist, and in my prior life, I was Chief Scientific Officer of a company called Centocor, which was one of the very early biotech companies. And we were the first ones ever to make a anti-TNF antibody and to test it in patients, and we were able to show that it was remarkably effective in patients with rheumatoid arthritis, Crohns disease and psoriasis and ulcerative colitis. And that actually began the pretty much the whole antibody based biologics industry. We were the first ones to do this with a humanized antibody.

I went on from there to run a pharmaceutical company called Syntex, former Syntex that was after Roche bought it and did that for eight years, we invented a lot of small molecules. And then I went on to start a company in oncology, cancer stem cells. And from there I went over to the dark side and joined a venture capital group and helped start companies for about 10 years and some of them are really successful. Some of them are okay and some crashed and burned, but thats the nature of the business. And then more recently I helped start a couple companies on my own. And then I was approached by the founders of 180 LS to help them out and also to be CEO of their company, so thats how I came to be CEO of 180 Life Sciences.

180 Life Sciences is repurposing anti-TNF for unmet needs. What is anti-TNF?

So in your body, you have lots of protein circulating around in your blood. These tell the body cells what to do, and some of them are called cytokines and cytokines are the ones that kind of tell your immune system what to do. And theres quite a lot of these. And theres some of them that are very good. Theres some of them that are bad actors and one of them is called tumor necrosis factor. It was named that totally by accident because it seemed to eliminate tumors in mice, but thats never been able to be shown in humans, but the name has stuck with it. So tumor necrosis factor is the thing that causes some types of inflammation, if theres an overproduction. For example, in rheumatoid arthritis, its the tumor necrosis factor that drives the destruction of the joints of your fingers and knees and shoulders and everything, so its a destructive cytokine. And what we did is we made a specialized antibody against TNF that binds it up and blocks it and prevents it from causing the inflammation. And that was the basis of infliximab or Remicade that we discovered from Centocor.

What is Dupuytrens disease, how is it characterized?

Dupuytrens Contracture is kind of a chronic disease, but it affects quite a lot of people, maybe 16 or 20 million in the US, same in Europe. It starts out as a small nodule in your palm. And over time, maybe a couple of years, some faster, some slower, it begins to form cords underneath the palm of your hand, it pulls your fingers together and contracts them. Sometimes this is inherited in families and sometimes it just occurs. So what happens is that this nodule starts, and as I said, over time, the fingers become contracted. So theres no therapies for the early stage when the nodules just form, but thats the basis of what were doing, Ill talk about that in a minute.

Later on, after the fingers are already contracted and you have the disability, you cant button your clothes, you cant type with that hand. You cant do many of the things that you like to do with your hand. Theres several therapies that they try. One of them is injecting a collagenase thats partially effective, but they all, about half of those recur. You can try to disrupt these cords with a needle called needle aponeurectomy or alternatively, what happens is you end up going to surgery and they cut these cords out. Ironically, my wife had this and went through a whole year of steroid injections into her hand, finally had to have the surgery. So Im familiar with the process. But thats what happens, and I think people, as soon as the nodule forms, people these days, because they have Dr. Google, can immediately know whats going to happen in the long run, so the information out there is quite impressive.

180 Life Sciences recently completed a Phase 2 study for Dupuytrens. Tell us about the study protocol, the drug used and other updates on the study.

Our colleague in England, Dr. Jagdeep Nanchahal, was able to look at Dupuytrens Contracture and especially the nodules, and through a series of very elegant experiments, he was able to show that the nodule was driven by the TNF, the bad actor. And in this case, the inflammation caused the fibrosis that were talking about, that leads to the finger contracture. And so he was able to work out that if you inject anti-TNF into this nodule, you can impact the course of the disease.

And so he did a very large trial of about 150 patients in the UK and was able to inject anti-TNF into the nodules of their hands. And in that trial, which took over a year, there were three or four injections, but we were able to show that both the primary and secondary endpoints of the trial were met and the endpoints had to do with the size of the nodule, whether it was growing, whether it was shrinking, whether it was harder or whether it was softer or whether the fingers were contracting, all of that, but we met the primary endpoints and the full publication with all the details will be out, hopefully in the next couple of months.

You have another trial planned for Frozen Shoulder. What is Frozen Shoulder, and how will the trial aim to address it?

Yes, Frozen Shoulder is another kind of inflammatory condition where fibrosis forms in the shoulder. And it initially starts out as being extremely painful. And that goes on for several months and then eventually the pain subsides, but the shoulder becomes totally immobile. And eventually you have to have surgery to remove the fibrotic tissues. Interestingly enough, this occurs more common in patients with diabetes, but about half of those patients also have Dupuytrens. And so we think that the fibrosis in the Dupuytrens and the fibrosis in the shoulder is the same mechanism. And so Dr. Nanchahal will be injecting anti-TNF into the shoulder very early, as soon as the pain is evident, then hell try to inject anti-TNF and maybe relieve the pain and also the formation of the fibrosis, so that one can avoid the surgery, which is actually quite expensive. And also, theres quite a long course of physical therapy after the surgery, so its something youd like to avoid. And so were trying to treat patients both with Dupuytrens and Frozen Shoulder before the disability develops.

A third program, which is soon to be clinical, is anti-TNF for post-operative cognition delirium or POCD. Tell me about POCD, and the preliminary research that led the team to pursue this indication?

We know that now that theyre doing fairly aggressive surgery in older patients, either hip replacements or emergency hip corrections or CABG procedure, coronary artery bypass graft, or cardiac surgery, that a fair percentage of these people after the surgery, just have a foggy brain. And the fog goes on for some time and we call it postoperative cognitive dementia, as the technical term. And in some patients, maybe 15 or 20%, it doesnt go away. And they end up in nursing homes and they actually dont live very long after that. And so our colleagues in the UK, Dr. Nanchahal and Dr. Feldmann and his colleagues, have shown that during the surgery, any kind of aggressive surgery, that TNF is released from the tissue damage, and the TNF goes to the brain and opens it up and lets inflammatory cells get into the area of the brain thats where your cognitive areas are, and so that leads to the dementia.

And in the past, theyve thought this all had to do with the anesthesia, but we think its the TNF thats actually causing this dementia going forward. And so were actually going to do a trial in patients that are having their hip repaired that are older, and were going to administer one dose of anti-TNF just before the surgery starts with a view towards preventing the dementia going forward. So this will be a long trial, but if it works, itll be something that everybody who goes into major surgery would want to have. So its another exciting opportunity for 180 LS and our investigators.

180 Life Sciences recently announced licensing of a compound called HMGB1. Tell us more about HMGB1 and the companys plans for it.

The company is also working on other areas of fibrosis, not just Dupuytrens Contracture and Frozen Shoulder, but other areas like liver fibrosis, which occurs with NASH. And we are working on ways to prevent that as well, much like were working on Dupuytrens and Frozen Shoulder. The fibrosis in the liver is really hard to reverse, and there are no real agents that do that, but theres a lot of people trying different things. Now what the HMGB-1 does, it doesnt change the fibrosis, but once the fibrosis is stopped, it could help the liver cells to regenerate. So this is kind of a regenerative medicine. It makes the tissues regenerate, whether its heart or whether its liver or whether its lung or whatever. And so its going to be used after the fibrosis is stopped. And so thats kind of what were interested in. And were just getting that program off the ground and making the initial compounds to do our testing.

Any closing thoughts?

Well, Id like to talk about our team. The company was founded by Dr. Mark Feldmann, who was the one, he was the original person who figured out that TNF was causing the joint destruction and arthritis, and with he and I and others, that actually did the very first trials ever. And this was done in patients with wheelchairs, and they actually got up out of their wheelchairs and walked around. It was a phenomenal moment. We had no idea it would work that well. And some of them actually did a pirouette down some stairs. We have videos of this. So its kind of like The Awakening movie where they gave them the L-DOPA and they all woke up. Well, in this case, they got up out of their wheelchairs and theres no patients in wheelchairs with rheumatoid arthritis in the whole world because of that drug, and the ones that followed on.

The current Humira from AbbVie is the preferred one. But the whole idea and concept, we started back then. Other founders, Dr. Larry Steinman, he and Mark put 180 LS together. And he developed Tysabri, the very first drug to help MS patients. And it was another phenomenal discovery that he made. And hes also working on MS and other areas. But so we have the leaders in inflammation as the people who actually founded the company. So its a pleasure to work with them. Ive been acquainted with them off and on for the past, maybe 25 years, so working with them again is a real pleasure.

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James Woody, CEO of 180 Life Sciences: Developing New Therapies to Treat Inflammatory Diseases - DocWire News

Cardiac Stem Cells Comments Off on James Woody, CEO of 180 Life Sciences: Developing New Therapies to Treat Inflammatory Diseases – DocWire News | April 29th, 2022

SUNNYVALE, Calif., April 12, 2022 (GLOBE NEWSWIRE) -- BioCardia, Inc.[Nasdaq: BCDA], a developer of cellular and cell-derived therapeutics for the treatment of cardiovascular and pulmonary diseases, today announced that the U.S. Food and Drug Administration (FDA) has approved the Company's Investigational New Drug (IND) application for BCDA-04, a proprietary allogeneic mesenchymal cell (MSC) population that is Neurokinin-1 receptor positive (NK1R+). This allows BioCardia to initiate its First-in-Human Phase I/II trial in adult patients recovering from Acute Respiratory Distress Syndrome (ARDS) due to COVID-19, with trial initiation expected in the third quarter of 2022.

The first part of the clinical trial will evaluate increasing doses of the NK1R+ MSCs and the optimal dose will be taken to Phase II in a randomized study in adult patients recovering from ARDS due to COVID-19. "This investigational cell therapy is administered intravenously (IV) and follows a significant body of compelling clinical results by NIH investigators and peer companies," said Ian McNiece, Ph.D., BioCardias Chief Scientific Officer. "After IV delivery, the cells migrate to the lungs for local therapeutic benefit. We expect the anti-inflammatory nature of these mesenchymal stem cells to have a positive impact in ARDS because of the interaction of the Neurokinin-1 receptors with Substance P, a neuropeptide that has long been known to be a primary mediator of inflammation in the lungs. Our goal is to help recovering patients with ARDS due to COVID-19 recover faster and more fully, while avoiding longer term respiratory issues."

"In addition to our critically important autologous cell therapies being studied for ischemic heart failure and chronic myocardial ischemia with refractory angina, the FDA's acceptance of this IND for patients recovering from ARDS is an important milestone in the development of our allogeneic mesenchymal stem cell therapy platform and validation for its potential to provide therapeutic benefit beyond the cardiovascular system," said Peter Altman, Ph.D., Chief Executive Officer. "Our off the shelf MSC platform may have significant advantages over others in clinical development for multiple indications because the MSCs express the biologically important NK1 receptor which binds Substance P. Our in-house clinical cell manufacturing is also expected to be an important strategic asset that enables rapid and cost-effective development."

About ARDS

Acute respiratory distress syndrome (ARDS) occurs when fluid builds up in the tiny, elastic air sacs (alveoli) in the lungs. The fluid keeps the lungs from filling with enough air, which means less oxygen reaches the bloodstream. This deprives organs of the oxygen they need to function. ARDS typically occurs in people who are already critically ill or who have significant injuries. Severe shortness of breath the main symptom of ARDS usually develops within a few hours to a few days after the precipitating injury or infection. Many people who develop ARDS don't survive. The risk of death increases with age and severity of illness. Of the people who do survive ARDS, some recover completely while others experience lasting damage to their lungs1. Based on preliminary clinical reports on COVID-19, respiratory failure complicated by ARDs is the leading cause of death for COVID-19 patients.2 Despite multiple clinical studies, no pharmacological treatments have proven effective for ARDS.3, 4

About BioCardia

BioCardia, Inc., headquartered in Sunnyvale, California, is developing cellular and cell-derived therapeutics for the treatment of cardiovascular and pulmonary disease. CardiAMP autologous and NK1R+ allogeneic cell therapies are the Companys biotherapeutic platforms that enable four product candidates in clinical development. The CardiAMP Cell Therapy Heart Failure Trial investigational product has been granted Breakthrough designation by the FDA, has CMS reimbursement, and is supported financially by the Maryland Stem Cell Research Fund. The CardiAMP Chronic Myocardial Ischemia Trial also has CMS reimbursement. For more information visit:www.BioCardia.com.

FORWARD LOOKING STATEMENTS

This press release contains forward-looking statements that are subject to many risks and uncertainties. Forward-looking statements include, among other things, initiation of our BCDA-04 clinical trial, and the mechanism of action and ease of administration of our NK1R+ MSC therapy.

We may use terms such as believes, estimates, anticipates, expects, plans, intends, may, could, might, will, should, approximately or other words that convey the uncertainty of future events or outcomes to identify these forward-looking statements. Although we believe that we have a reasonable basis for each forward-looking statement contained herein, we caution you that forward-looking statements are not guarantees of future performance and that our actual results may differ materially from the forward-looking statements contained in this press release. As a result of these factors, we cannot assure you that the forward-looking statements in this press release will prove to be accurate. Additional factors that could materially affect actual results can be found in BioCardias Form 10-K filed with the Securities and Exchange Commission on March 29, 2022, under the caption titled Risk Factors. BioCardia expressly disclaims any intent or obligation to update these forward-looking statements, except as required by law.

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Media Contact:Anne Laluc, MarketingEmail:alaluc@BioCardia.comPhone: 650-226-0120

Investor Contact:David McClung, Chief Financial OfficerEmail:dmcclung@BioCardia.comPhone: 650-226-0120

(1)MayoClinic.Org

(2)Rajagopal K, Keller SP, Akkanti B, et al. Advanced pulmonary and cardiac support of COVID-19 patients, emerging recommendations from ASAIOa living working document. Circ Heart Fail. 2020 May;13(5).

(3)Thompson BT, Chambers RC, Liu KD (2017) Acute respiratory distress syndrome. N Engl J Med 377(19):19041905.

(4)3. Group RC, Horby P, Lim WS et al (2020) Dexamethasone in hospitalized patients with Covid-19preliminary report. N Engl J Med.

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BioCardia Announces FDA Approval of Its IND for NK1R+ Mesenchymal Stem Cells for the Treatment of Patients Recovering from Acute Respiratory Distress...

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