StemCell Therapy

Chennai eye hospital ties up with Iceland firm to adopt mathematical algorithm to predict diabetic retinopathy  The Hindu

More:
Chennai eye hospital ties up with Iceland firm to adopt mathematical algorithm to predict diabetic retinopathy - The Hindu

Abstract

Organ and tissue loss through disease and injury motivate the development of therapies that can regenerate tissues and decrease reliance on transplantations. Regenerative medicine, an interdisciplinary field that applies engineering and life science principles to promote regeneration, can potentially restore diseased and injured tissues and whole organs. Since the inception of the field several decades ago, a number of regenerative medicine therapies, including those designed for wound healing and orthopedics applications, have received Food and Drug Administration (FDA) approval and are now commercially available. These therapies and other regenerative medicine approaches currently being studied in preclinical and clinical settings will be covered in this review. Specifically, developments in fabricating sophisticated grafts and tissue mimics and technologies for integrating grafts with host vasculature will be discussed. Enhancing the intrinsic regenerative capacity of the host by altering its environment, whether with cell injections or immune modulation, will be addressed, as well as methods for exploiting recently developed cell sources. Finally, we propose directions for current and future regenerative medicine therapies.

Keywords: regenerative medicine, tissue engineering, biomaterials, review

Regenerative medicine has the potential to heal or replace tissues and organs damaged by age, disease, or trauma, as well as to normalize congenital defects. Promising preclinical and clinical data to date support the possibility for treating both chronic diseases and acute insults, and for regenerative medicine to abet maladies occurring across a wide array of organ systems and contexts, including dermal wounds, cardiovascular diseases and traumas, treatments for certain types of cancer, and more (13). The current therapy of transplantation of intact organs and tissues to treat organ and tissue failures and loss suffers from limited donor supply and often severe immune complications, but these obstacles may potentially be bypassed through the use of regenerative medicine strategies (4).

The field of regenerative medicine encompasses numerous strategies, including the use of materials and de novo generated cells, as well as various combinations thereof, to take the place of missing tissue, effectively replacing it both structurally and functionally, or to contribute to tissue healing (5). The body's innate healing response may also be leveraged to promote regeneration, although adult humans possess limited regenerative capacity in comparison with lower vertebrates (6). This review will first discuss regenerative medicine therapies that have reached the market. Preclinical and early clinical work to alter the physiological environment of the patient by the introduction of materials, living cells, or growth factors either to replace lost tissue or to enhance the body's innate healing and repair mechanisms will then be reviewed. Strategies for improving the structural sophistication of implantable grafts and effectively using recently developed cell sources will also be discussed. Finally, potential future directions in the field will be proposed. Due to the considerable overlap in how researchers use the terms regenerative medicine and tissue engineering, we group these activities together in this review under the heading of regenerative medicine.

Since tissue engineering and regenerative medicine emerged as an industry about two decades ago, a number of therapies have received Food and Drug Administration (FDA) clearance or approval and are commercially available (). The delivery of therapeutic cells that directly contribute to the structure and function of new tissues is a principle paradigm of regenerative medicine to date (7, 8). The cells used in these therapies are either autologous or allogeneic and are typically differentiated cells that still maintain proliferative capacity. For example, Carticel, the first FDA-approved biologic product in the orthopedic field, uses autologous chondrocytes for the treatment of focal articular cartilage defects. Here, autologous chondrocytes are harvested from articular cartilage, expanded ex vivo, and implanted at the site of injury, resulting in recovery comparable with that observed using microfracture and mosaicplasty techniques (9). Other examples include laViv, which involves the injection of autologous fibroblasts to improve the appearance of nasolabial fold wrinkles; Celution, a medical device that extracts cells from adipose tissue derived from liposuction; Epicel, autologous keratinocytes for severe burn wounds; and the harvest of cord blood to obtain hematopoietic progenitor and stem cells. Autologous cells require harvest of a patient's tissue, typically creating a new wound site, and their use often necessitates a delay before treatment as the cells are culture-expanded. Allogeneic cell sources with low antigenicity [for example, human foreskin fibroblasts used in the fabrication of wound-healing grafts (GINTUIT, Apligraf) (10)] allow off-the-shelf tissues to be mass produced, while also diminishing the risk of an adverse immune reaction.

Regenerative medicine FDA-approved products

Materials are often an important component of current regenerative medicine strategies because the material can mimic the native extracellular matrix (ECM) of tissues and direct cell behavior, contribute to the structure and function of new tissue, and locally present growth factors (11). For example, 3D polymer scaffolds are used to promote expansion of chondrocytes in cartilage repair [e.g., matrix-induced autologous chondrocyte implantation (MACI)] and provide a scaffold for fibroblasts in the treatment of venous ulcers (Dermagraft) (12). Decellularized donor tissues are also used to promote wound healing (Dermapure, a variety of proprietary bone allografts) (13) or as tissue substitutes (CryoLife and Toronto's heart valve substitutes and cardiac patches) (14). A material alone can sometimes provide cues for regeneration and graft or implant integration, as in the case of bioglass-based grafts that permit fusion with bone (15). Incorporation of growth factors that promote healing or regeneration into biomaterials can provide a local and sustained presentation of these factors, and this approach has been exploited to promote wound healing by delivery of platelet derived growth factor (PDGF) (Regranex) and bone formation via delivery of bone morphogenic proteins 2 and 7 (Infuse, Stryker's OP-1) (16). However, complications can arise with these strategies (Infuse, Regranex black box warning) (17, 18), likely due to the poor control over factor release kinetics with the currently used materials.

The efficacies of regenerative medicine products that have been cleared or approved by the FDA to date vary but are generally better or at least comparable with preexisting products (9). They provide benefit in terms of healing and regeneration but are unable to fully resolve injuries or diseases (1921). Introducing new products to the market is made difficult by the large time and monetary investments required to earn FDA approval in this field. For drugs and biologics, the progression from concept to market involves numerous phases of clinical testing, can require more than a dozen years of development and testing, and entails an average cost ranging from $802 million to $2.6 billion per drug (22, 23). In contrast, medical devices, a broad category that includes noncellular products, such as acellular matrices, generally reach the market after only 37 years of development and may undergo an expedited process if they are demonstrated to be similar to preexisting devices (24). As such, acellular products may be preferable from a regulatory and development perspective, compared with cell-based products, due to the less arduous approval process.

A broad range of strategies at both the preclinical and clinical stages of investigation are currently being explored. The subsequent subsections will overview these different strategies, which have been broken up into three broad categories: (i) recapitulating organ and tissue structure via scaffold fabrication, 3D bioprinting, and self assembly; (ii) integrating grafts with the host via vascularization and innervation; and (iii) altering the host environment to induce therapeutic responses, particularly through cell infusion and modulating the immune system. Finally, methods for exploiting recently identified and developed cell sources for regenerative medicine will be mentioned.

Because tissue and organ architecture is deeply connected with function, the ability to recreate structure is typically believed to be essential for successful recapitulation of healthy tissue (25). One strategy to capture organ structure and material composition in engineered tissues is to decellularize organs and to recellularize before transplantation. Decellularization removes immunogenic cells and molecules, while theoretically retaining structure as well as the mechanical properties and material composition of the native extracellular matrix (26, 27). This approach has been executed in conjunction with bioreactors and used in animal models of disease with lungs, kidneys, liver, pancreas, and heart (25, 2831). Decellularized tissues, without the recellularization step, have also reached the market as medical devices, as noted above, and have been used to repair large muscle defects in a human patient (32). A variation on this approach involves the engineering of blood vessels in vitro and their subsequent decellularization before placement in patients requiring kidney dialysis (33). Despite these successes, a number of challenges remain. Mechanical properties of tissues and organs may be affected by the decellularization process, the process may remove various types and amounts of ECM-associated signaling molecules, and the processed tissue may degrade over time after transplantation without commensurate replacement by host cells (34, 35). The detergents and procedures used to strip cells and other immunogenic components from donor organs and techniques to recellularize stripped tissue before implantation are actively being optimized.

Synthetic scaffolds may also be fabricated that possess at least some aspects of the material properties and structure of target tissue (36). Scaffolds have been fabricated from naturally derived materials, such as purified extracellular matrix components or algae-derived alginate, or from synthetic polymers, such as poly(lactide-coglycolide) and poly(ethylene glycol); hydrogels are composed largely of water and are often used to form scaffolds due to their compositional similarity to tissue (37, 38). These polymers can be engineered to be biodegradable, enabling gradual replacement of the scaffold by the cells seeded in the graft as well as by host cells (39). For example, this approach was used to fabricate tissue-engineered vascular grafts (TEVGs), which have entered clinical trials, for treating congenital heart defects in both pediatric and adult patients (40) (). It was found using animal models that the seeded cells in TEVGs did not contribute structurally to the graft once in the host, but rather orchestrated the inflammatory response that aided in host vascular cells populating the graft to form the new blood vessel (41, 42). Biodegradable vascular grafts seeded with cells, cultured so that the cells produced extracellular matrix and subsequently decellularized, are undergoing clinical trials in the context of end-stage renal failure (Humacyte) (33). Scaffolds that encompass a wide spectrum of mechanical properties have been engineered both to provide bulk mechanical support to the forming tissue and to provide instructive cues to adherent cells (11). For example, soft fibrincollagen hydrogels have been explored as lymph node mimics (43) whereas more rapidly degrading alginate hydrogels improved regeneration of critical defects in bone (44). In some cases, the polymer's mechanical properties alone are believed to produce a therapeutic effect. For example, injection of alginate hydrogels to the left ventricle reduced the progression of heart failure in models of dilated cardiomyopathy (45) and is currently undergoing clinical trials (Algisyl). Combining materials with different properties can enhance scaffold performance, as was the case of composite polyglycolide and collagen scaffolds that were seeded with cells and served as bladder replacements for human patients (46). In another example, an electrospun nanofiber mesh combined with peptide-modified alginate hydrogel and loaded with bone morphogenic protein 2 improved bone formation in critically sized defects (47). Medical imaging technologies such as computed tomography (CT) and magnetic resonance imaging (MRI) can be used to create 3D images of replacement tissues, sometimes based on the patient's own body (48, 49) (). These 3D images can then be used as molds to fabricate scaffolds that are tailored specifically for the patient. For example, CT images of a patient were used for fabricating polyurethane and polyethylene-based synthetic trachea, which were then seeded with cells (50). Small building blocks, often consisting of cells embedded in a small volume of hydrogel, can also be assembled into tissue-like structures with defined architectures and cell patterning using a variety of recently developed techniques (51, 52) ().

Regenerative medicine strategies that recapitulate tissue and organ structure. (A) Scanning electron microscopy image of a TEVG cross-section. Reproduced with permission from ref. 41. (B) Engineered bladder consisting of a polyglycolide and collagen composite scaffold, fabricated based on CT image of patient and seeded with cells. Reproduced with permission from ref. 46. (C) CT image of bone regeneration in critically sized defects without (Left) and with (Right) nanofiber mesh and alginate scaffold loaded with growth factor. Reproduced with permission from ref. 47. (D) Small hydrogel building blocks are assembled into tissue-like structures with microrobots. Reproduced from ref. 52, with permission from Nature Communications. (E) Blueprint for 3D bioprinting of a heart valve using microextrusion printing, with different colors representing different cell types. (F) Printed product. Reproduced with permission from ref. 59. (G) Intestinal crypt stem cells seeded with supporting Paneth cells self-assemble into organoids in culture. Reproduced from ref. 67, with permission from Nature.

Although cell placement within scaffolds is generally poor controlled, 3D bioprinting can create structures that combine high resolution control over material and cell placement within engineered constructs (53). Two of the most commonly used bioprinting strategies are inkjet and microextrusion (54). Inkjet bioprinting uses pressure pulses, created by brief electrical heating or acoustic waves, to create droplets of ink that contains cells at the nozzle (55, 56). Microextrusion bioprinting dispenses a continuous stream of ink onto a stage (57). Both are being actively used to fabricate a wide range of tissues. For example, inkjet bioprinting has been used to engineer cartilage by alternating layer-by-layer depositions of electrospun polycaprolactone fibers and chondrocytes suspended in a fibrincollagen matrix. Cells deposited this way were found to produce collagen II and glycosaminoglycans after implantation (58). Microextrusion printing has been used to fabricate aortic valve replacements using cells embedded in an alginate/gelatin hydrogel mixture. Two cell types, smooth muscle cells and interstitial cells, were printed into two separate regions, comprising the valve root and leaflets, respectively (59) (). Microextrusion printing of inks with different gelation temperatures has been used to print complex 3D tubular networks, which were then seeded with endothelial cells to mimic vasculature (60). Several 3D bioprinting machines are commercially available and offer different capabilities and bioprinting strategies (54). Although extremely promising, bioprinting strategies often suffer trade-offs in terms of feature resolution, cell viability, and printing resolution, and developing bioprinting technologies that excel in all three aspects is an important area of research in this field (54).

In some situations, it may be possible to engineer new tissues with scaffold-free approaches. Cell sheet technology relies on the retrieval of a confluent sheet of cells from a temperature-responsive substrate, which allows cellcell adhesion and signaling molecules, as well as ECM molecules deposited by the cells themselves, to remain intact (61, 62). Successive sheets can be layered to produce thicker constructs (63). This approach has been explored in a variety of contexts, including corneal reconstruction (64). Autologous oral mucosal cells have been grown into sheets, harvested, and implanted, resulting in reepithelialization of human corneas (64). Autonomous cellular self-assembly may also be used to create tissues and be used to complement bioprinting. For example, vascular cells aggregated into multicellular spheroids were printed in layer-by-layer fashion, using microextrusion, alongside agarose rods; hollow and branching structures that resembled a vascular network resulted after physical removal of the agarose once the cells formed a continuous structure (65). Given the appropriate cues and initial cell composition, even complex structures may form autonomously (66). For example, intestinal crypt-like structures can be grown from a single crypt base columnar stem cell in 3D culture in conjunction with augmented Wnt signaling (67) (). Understanding the biological processes that drive and direct self-assembly will aid in fully taking advantage of this approach. The ability to induce autonomous self-assembly of the modular components of organs, such as intestinal crypts, kidney nephrons, and lung alveoli, could be especially powerful for the construction of organs with complex structures.

To contribute functionally and structurally to the body, implanted grafts need to be properly integrated with the body. For cell-based implants, integration with host vasculature is of primary importance for graft success () (68). Most cells in the body are located within 100 m from the nearest capillary, the distance within which nutrient exchange and oxygen diffusion from the bloodstream can effectively occur (68). To vascularize engineered tissues, the body's own angiogenic response may be exploited via the presentation of angiogenic growth factors (69). A variety of growth factors have been implicated in angiogenesis, including vascular endothelial growth factor (VEGF), angiopoietin (Ang), platelet-derived growth factor (PDGF), and basic fibroblast growth factor (bFGF) (70, 71). However, application of growth factors may not be effectual without proper delivery modality, due to their short half-life in vivo and the potential toxicity and systemic effects of bolus delivery (45). Sustained release of VEGF, bFGF, Ang, and PDGF leads to robust angiogenic responses and can rescue ischemic limbs from necrosis (45, 72, 73). Providing a sequence of angiogenic factors that first initiate and then promote maturation of newly formed vessels can yield more functional networks (74) (), and mimicking development via delivery of both promoters and inhibitors of angiogenesis from distinct spatial locations can create tightly defined angiogenic zones (75).

Strategies for vascularizing and innervating tissue-engineered graft. (A) Tissue-engineered graft may be vascularized before implantation: for example, by self-assembly of seeded endothelial cells or by host blood vessels in a process mediated by growth factor release. Compared with bolus injection of VEGF and PDGF (B), sustained release of the same growth factors from a polymeric scaffold (C) led to a higher density of vessels and formation of larger and thicker vessels. Reproduced from ref. 74, with permission from Nature Biotechnology. (D) Scaffold vascularized by being implanted in the omentum before implantation at the injury site. Reproduced with permission from ref. 83. (E) Biodegradable microfluidic device surgically connected to vasculature. Reproduced with permission from ref. 85. Compared with blank scaffold (F), scaffolds delivering VEGF (G) increase innervation of injured skeletal muscle. Reproduced from ref. 97, with permission from Molecular Therapy.

Another approach to promote graft vascularization at the target site is to prevascularize the graft or target site before implantation. Endothelial cells and their progenitors can self-organize into vascular networks when transplanted on an appropriate scaffold (7679). Combining endothelial cells with tissue-specific cells on a scaffold before transplantation can yield tissues that are both better vascularized and possess tissue-specific function (80). It is also possible to create a vascular pedicle for an engineered tissue that facilitates subsequent transplantation; this approach has been demonstrated in the context of both bone and cardiac patches by first placing a scaffold around a large host vessel or on richly vascularized tissue, and then moving the engineered tissue to its final anatomic location once it becomes vascularized at the original site (8183) (). This strategy was successfully used to vascularize an entire mandible replacement, which was later engrafted in a human patient (84). Microfluidic and micropatterning techniques are currently being explored to engineer vascular networks that can be anastomosed to the femoral artery (85, 86) (). The site for cell delivery may also be prevascularized to enhance cell survival and function, as in a recent report demonstrating that placement of a catheter device allowed the site to become vascularized due to the host foreign body response to the material; this device significantly improved the efficacy of pancreatic cells subsequently injected into the device (87).

Innervation by the host will also be required for proper function and full integration of many tissues (88, 89), and is particularly important in tissues where motor control, as in skeletal tissue, or sensation, as in the epidermis, provides a key function (90, 91). Innervation of engineered tissues may be induced by growth factors, as has been shown in the induction of nerve growth from mouse embryonic dorsal root ganglia to epithelial tissue in an in vitro model (92). Hydrogels patterned with channels that are subsequently loaded with appropriate extracellular matrices and growth factors can guide nerve growth upon implantation, and this approach has been used to support nerve regeneration after injury (93, 94). Angiogenesis and nerve growth are known to share certain signaling pathways (95), and this connection has been exploited via the controlled delivery of VEGF using biomaterials to promote axon regrowth in regenerating skeletal muscle (96, 97) ().

Administration of cells can induce therapeutic responses by indirect means, such as secretion of growth factors and interaction with host cells, without significant incorporation of the cells into the host or having the transplanted cells form a bulk tissue (98). For example, infusion of human umbilical cord blood cells can aid in stroke recovery due to enhanced angiogenesis (99), which in turn may have induced neuroblast migration to the site of injury. Similarly, transplanted macrophages can promote liver repair by activating hepatic progenitor cells (100). Transplanted cells can also normalize the injured or diseased environment, by altering the ECM, and improve tissue regeneration via this mechanism. For example, some types of epidermolysis bullosa (EB), a rare genetic skin blistering disorder, are associated with a failure of type VII collagen deposition in the basement membrane. Allogeneic injected fibroblasts were found to deposit type VII collagen deposition, thereby temporarily correcting disease morphology (101). A prototypical example of transplanted cells inducing a regenerative effect is the administration of mesenchymal stem cells (MSCs), which are being widely explored both preclinically and clinically to improve cardiac regeneration after infarction, and to treat graft-versus-host disease, multiple sclerosis, and brain trauma (2, 102) (). Positive effects of MSC therapy are observed, despite the MSCs being concentrated with some methods of application in the lungs and poor MSC engraftment in the diseased tissue (103). This finding suggests that a systemic paracrine modality is sufficient to produce a therapeutic response in some situations. In other situations, cellcell contact may be required. For example, MSCs can inhibit T-cell proliferation and dampen inflammation, and this effect is believed to at least partially depend on direct contact of the transplanted MSCs with host immune cells (104). Cells are often infused, typically intravenously, in current clinical trials, but cells administered in this manner often experience rapid clearance, which may explain their limited efficacy (105). Immunocloaking strategies, such as with hydrogel encapsulation of both cell suspensions and small cell clusters and hydrogel cloaking of whole organs, can lead to increased cell residency time and delayed allograft rejection (106, 107) (). Coating infused cells with targeting antibodies and peptides, sometimes in conjunction with lipidation strategies, known as cell painting, has been shown to improve residency time at target tissue site (108). Infused cells can also be modified genetically to express a targeting ligand to control their biodistribution (109).

Illustrations of regenerative medicine therapies that modulate host environment. (A) Injected cells, such as MSCs, can release cytokines and interact with host cells to induce a regenerative response. (B) Polyethylene glycol hydrogel (green) conformally coating pancreatic islets (blue) can support islets after injection. (Scale bar: 200 m.) Reproduced with permission from ref. 107.

Although the goal of regenerative medicine has long been to avoid rejection of the new tissue by the host immune system, it is becoming increasingly clear that the immune system also plays a major role in regulating regeneration, both impairing and contributing to the healing process and engraftment (110, 111). At the extreme end of immune reactions is immune rejection, which is a serious obstacle to the integration of grafts created with allogeneic cells. Immune engineering approaches have shown promise in inducing allograft tolerance: for example, by engineering the responses of immune cells such as dendritic cells and regulatory T cells (112, 113). Changing the properties of implanted scaffolds can also reduce the inflammation that accompanies implantation of a foreign object. For example, decreasing scaffold hydrophobicity and the availability of adhesion ligands can reduce inflammatory responses, and scaffolds with aligned fibrous topography experience less fibrous encapsulation upon implantation (114). Adaptive immune cells may actively inhibit even endogenous regeneration, as shown when depletion of CD8 T cells improved bone fracture healing in a preclinical model (115). Engineering the local immune response may thus allow active promotion of regeneration. For example, the release of cytokines to polarize macrophages to M2 phenotypes, which are considered to be antiinflammatory and proregeneration, was found to increase Schwann cell infiltration and axonal growth in a nerve gap model (116).

Most regenerative medicine strategies rely on an ample cell source, but identifying and obtaining sufficient numbers of therapeutic cells is often a challenge. Stem, progenitor, and differentiated cells derived from both adult and embryonic tissues are widely being explored in regenerative medicine although adult tissue-derived cells are the dominant cell type used clinically to date due to both their ready availability and perceived safety (8). All FDA-approved regenerative medicine therapies to date and the vast majority of strategies explored in the clinic use adult tissue-derived cells. There is great interest in obtaining greater numbers of stem cells from adult tissues and in identifying stem cell populations suitable for therapeutic use in tissues historically thought not to harbor stem cells (117). Basic studies aiming to understand the processes that control stem cell renewal are being leveraged for both purposes, with the prototypical example being studies with hematopoietic stem cells (HSCs) (3). For example, exposure of HSCs in vitro to cytokines that are present in the HSC niche leads to significant HSC expansion, but this increase in number is accompanied by a loss of repopulation potential (118, 119). Coculture of HSCs with cells implicated in the HSC niche and in microenvironments engineered to mimic native bone marrow may improve maintenance of HSC stemness during expansion, enhancing stem cell numbers for transplantation. For example, direct contact of HSCs with MSCs grown in a 3D environment induces greater CD34+ expansion than with MSCs grown on 2D substrate (120). Another example is that culture of skeletal muscle stem cells on substrates with mechanical properties similar to normal muscle leads to greater stem cell expansion (121) and can even rescue impaired proliferative ability in stem cells from aged animals (122).

Embryonic stem (ES) cells and induced pluripotent stem (iPS) cells represent potentially infinite sources of cells for regeneration and are moving toward clinical use (123, 124). ES cells are derived from blastocyst-stage embryos and have been shown to be pluripotent, giving rise to tissues from all three germ layers (125). Several phase I clinical trials using ES cells have been completed, without reports of safety concerns (Geron, Advanced Cell Technology, Viacyte). iPS cells are formed from differentiated somatic cells exposed to a suitable set of transcription factors that induce pluripotency (126). iPS cells are an attractive cell source because they can be generated from a patient's own cells, thus potentially circumventing the ethical issues of ES and rejection of the transplanted cells (127, 128). Although iPS cells are typically created by first dedifferentiating adult cells to an ES-like state, strategies that induce reprogramming without entering a pluripotent stage have attracted attention due to their quicker action and anticipation of a reduced risk for tumor formation (129). Direct reprogramming in vivo by retroviral injection has been reported to result in greater efficiency of conversion, compared with ex vivo manipulation, and allows in vitro culture and transplantation to be bypassed (130). Strategies developed for controlled release of morphogens that direct regeneration could potentially be adapted for controlling delivery of new genetic information to target cells in vivo, to improve direct reprogramming. Cells resulting from both direct reprogramming and iPS cell differentiation methods have been explored for generating cells relevant to a variety of tissues, including cardiomyocytes, vascular and hematopoietic cells, hepatocytes, pancreatic cells, and neural cells (131). Because ES and iPS cells can form tumors, a tight level of control over the fate of each cell is crucial for their safe application. High-throughput screens of iPS cells can determine the optimal dosages of developmental factors to achieve lineage specification and minimize persistence of pluripotent cells (132). High-throughput screens have also been useful for discovering synthetic materials for iPS culture, which would allow culture in defined, xenogen-free conditions (133). In addition, the same principles used to engineer cellular grafts from differentiated cells are being leveraged to create appropriate microenvironments for reprogramming. For example, culture on polyacrylamide gel substrates with elastic moduli similar to the heart was found to enable longer term survival of iPS-derived cardiomyocytes, compared with other moduli (134). In another study, culture of iPS cell-derived cardiac tissue in hydrogels with aligned fibers, and in the presence of electrical stimulation, enhanced expression of genes associated with cardiac maturation (135).

To date, regenerative medicine has led to new, FDA-approved therapies being used to treat a number of pathologies. Considerable research has enabled the fabrication of sophisticated grafts that exploit properties of scaffolding materials and cell manipulation technologies for controlling cell behavior and repairing tissue. These scaffolds can be molded to fit the patient's anatomy and be fabricated with substantial control over spatial positioning of cells. Strategies are being developed to improve graft integration with the host vasculature and nervous system, particularly through controlled release of growth factors and vascular cell seeding, and the body's healing response can be elicited and augmented in a variety of ways, including immune system modulation. New cell sources for transplantation that address the limited cell supply that hampered many past efforts are also being developed.

A number of issues will be important for the advancement of regenerative medicine as a field. First, stem cells, whether isolated from adult tissue or induced, will often require tight control over their behavior to increase their safety profile and efficacy after transplantation. The creation of microenvironments, often modeled on various stem cell niches that provide specific cues, including morphogens and physical properties, or have the capacity to genetically manipulate target cells, will likely be key to promoting optimal regenerative responses from therapeutic cells. Second, the creation of large engineered replacement tissues will require technologies that enable fully vascularized grafts to be anastomosed with host vessels at the time of transplant, allowing for graft survival. Thirdly, creating a proregeneration environment within the patient may dramatically improve outcomes of regenerative medicine strategies in general. An improved understanding of the immune system's role in regeneration may aid this goal, as would technologies that promote a desirable immune response. A better understanding of how age, disease state, and the microbiome of the patient affect regeneration will likely also be important for advancing the field in many situations (136138). Finally, 3D human tissue culture models of disease may allow testing of regenerative medicine approaches in human biology, as contrasted to the animal models currently used in preclinical studies. Increased accuracy of disease models may improve the efficacy of regenerative medicine strategies and enhance the translation to the clinic of promising approaches (139).

Visit link:
Regenerative medicine: Current therapies and future directions

For many centuries, we have looked to medicine to heal us when we are sick or injured. Major breakthroughs, like vaccines and antibiotics, have improved quality of life, and, in some cases, led to the effective eradication of infectious diseases.

While modern medicine has certainly changed the human experience for the better, we remain at the mercy of disease. There are no vaccines for malaria or HIV, for example. And chronic diseases, like heart disease, Alzheimers, diabetes, and osteoporosis, although treatable, are relentless causes of suffering. There are no silver bullet for these conditions. Often the best we can do is manage the symptoms.

One key to changing that may be regenerative medicine, a field of research with its sights set on the root causes of diseases, including many being studied now at the Institute for Stem Cell and Regenerative Medicine (ISCRM).

As a discipline, regenerative medicine combines principles of biology and engineering to develop therapies for diseases characterized by cell depletion, lost tissue, or damaged organs. The broad aim of regenerative medicine is to engineer, regenerate, or replace tissue using natural growth and repair mechanisms, such as stem cells. Organoids, 3D organ printing, and tissue engineering are examples of biopowered technologies used in regenerative medicine.

Many common chronic diseases begin with harmful cell depletion. For example, Alzheimers disease is associated with a loss of brain cells, heart disease is often marked by a loss of healthy heart muscle, and type 1 diabetes occurs when cells in the pancreas fail to produce insulin. In the case of cancer, the problem is that cells grow too quickly. (Click here to read more about diseases being researched at ISCRM.)

For scientists, regenerative medicine is a way to fix the root causes of disease by harnessing the bodys natural capacity to repair itself in other words, to regenerate lost cells and tissue and restore normal functioning. At the Institute for Stem Cell and Regenerative Medicine, researchers are studying how to jump start the growth of cells in the brain, heart, pancreas, liver, kidney, eyes, ears, and muscles.

Ultimately, the goal of regenerative medicine is to improve the daily wellbeing of patients with debilitating chronic diseases by developing a new generation of therapies that go beyond treating symptoms.

Stem cells are powerful tools of discovery used by researchers hoping to understand how regenerative medicine could be used to treat patients. Right now, ISCRM researchers are using stem cells to study how heart diseases develop, testing stem cell-based therapies that could regenerate damaged or lost heart tissue, and even launching heart tissue into space to study the effects of microgravity on cardiovascular health. Many ISCRM scientists use stem cells to create 3D organ models, known as organoids, that allow them to study diseases and test regenerative treatments without involving animals or human subjects.

Heart RegenerationResearchers in multiple ISCRM labs are pursuing novel approaches that can potentially cure rather than manage heart disease. In 2018, a study led by ISCRM Director Dr. Charles Murry demonstrated that stem cell-derived cardiomyocytes have the potential to regenerate heart tissue in large non-human primates, a major step toward human clinical trials. In another investigation, ISCRM faculty members Jen Davis, PhD and Farid Moussavi-Harami, MD are developing new tools to help cardiologists design personalized treatments for certain heart diseases.

DiabetesISCRM researchers are studying the mechanisms that regulate the development and function of beta cells in the pancreas that produce insulin a key to future treatments for any type of diabetes. Vincenzo Cirulli MD, PhD, is screening for biological factors that could promote the growth of beta cells necessary for insulin production. Dr. Cirullis ISCRM colleague Laura Crisa MD, PhD is using a disease-in-a-dish model to study how islet cells falter and whether they can be regenerated, and eventually transplanted, into patients.

Vision DisordersResearchers at the Institute for Stem Cell and Regenerative Medicine (ISCRM) are using stem cell-derived retinal organoids to study how diseases of the retina form and how they can be treated. Organoids closely approximate human tissue without many of the ethical questions and supply limitations that complicate the use of fetal tissue. Read more about recent efforts to validate stem cell-derived organoids as disease models here.

In an approach could someday be used to help repair the retinas in patients who have lost vision due to macular degeneration, glaucoma and diabetes, the Reh Lab has successfully induced non-neuronal cells to become retinal neurons. In an October 2021 study published in the journal Cell Reports, Reh and his team using proteins (known as transcription factors) that regulate the activity of genes to induce glial cells in the retina to produce neurons. The effort demonstrates that gene therapy could someday be used in clinics to help repair damaged retinas and restore vision.

Link:
What Is Regenerative Medicine? | Goals and Applications | ISCRM

June 3, 2021

The US Food and Drug Administration (FDA) regulates regenerative medicine products. There continues to be broad marketing of unapproved products considered regenerative medicine therapies that are intended for the treatment or cure of a wide range of diseases or medical conditions. These products require FDA licensure/approval to be marketed to consumers. Before approval, these products require FDA oversight in a clinical trial. These unapproved products whether recovered from your own body or another persons body, include stem cells, stromal vascular fraction (fat-derived cells), umbilical cord blood and/or cord blood stem cells1, amniotic fluid, Whartons jelly, ortho-biologics, and exosomes. FDA has received reports of blindness, tumor formation, infections, and more, detailed below, due to the use of these unapproved products.

If you are being offered any of these products outside of a clinical trial for which FDA has oversight, please contact FDA at ocod@fda.hhs.gov. Additionally, contact FDA if you are considering treatment with any of these products and have questions, or if you have been treated with these products and wish to report any adverse effects or file a complaint. We take these reports seriously and want to hear from you.

If you were hurt or had a bad side effect following treatment with a regenerative medicine product, or a similar product, we also encourage you to report it to the FDAs MedWatch Adverse Event Reporting program. Additional information for patients on reporting adverse events for these products can be found here.

Please know that if you are being charged for these products or offered these products outside of a clinical trial, you are likely being deceived and offered a product illegally. Likewise, FDA is aware that patients and consumers are being referred to clinicaltrials.gov, or are told that a product is registered with FDA, as a way to suggest that the products being offered are in compliance with FDA laws and regulations. This is often false. The inclusion of a product in the clinicaltrials.gov database or the fact that a firm has registered with FDA and listed its product does not mean the product is legally marketed. If you are considering receiving one of these products, please contact FDA at ocod@fda.hhs.gov.

This web posting reemphasizes the warning to consumers in FDAs July 2020 Consumer Alert:

FDA has repeatedly notified manufacturers, clinics, and health care practitioners of the need for Investigational New Drug applications (INDs) to legally administer these products and to ensure safety measures are in place prior to administration.

These regenerative medicine products have risks but are often illegally marketed by clinics as being safe and effective for the treatment of a wide range of diseases or conditions, even though they havent been adequately studied under an IND to demonstrate the claims of safety and effectiveness. Safety concerns with any product that is illegally marketed as a regenerative medicine therapy include the following:

Helpful Links

FDA Voices

Warnings and Safety Notifications

FDA Warning Letters

FDA/CBER Untitled Letters

FDA letter to clinics and health care providers offering stem cell or related products to treat a variety of diseases or conditions

Questions and Answers Regarding the End of the Compliance and Enforcement Policy for Certain Human Cells, Tissues, or Cellular or Tissue-based Products (HCT/Ps)

1Currently, the only stem cell products that are FDA-approved for use in the United States consist of blood-forming stem cells (also known as hematopoietic progenitor cells) that are derived from umbilical cord blood. These products are approved for use in patients with disorders that affect the production of blood (i.e., the hematopoietic system) but they are not approved for other uses.

07/09/2021

Continued here:
Important Patient and Consumer Information About Regenerative Medicine ...

Regenerative medicine can be a boon for those with Drug-Resistant Tuberculosis  Hindustan Times

Read more:
Regenerative medicine can be a boon for those with Drug-Resistant Tuberculosis - Hindustan Times

Stem Cells May Help In Treatment of Tuberculosis, But Challenges Remain: Study  News18

See the article here:
Stem Cells May Help In Treatment of Tuberculosis, But Challenges Remain: Study - News18

Live Cell Encapsulation Market To Reach USD 313.3 Million at a CAGR of 4% in 2032  EIN News

Continued here:
Live Cell Encapsulation Market To Reach USD 313.3 Million at a CAGR of 4% in 2032 - EIN News

FORT LAUDERDALE, Fla. , April 13, 2023 (GLOBE NEWSWIRE) -- Motus GI Holdings, Inc. (NASDAQ: MOTS) ("Motus GI" or the "Company"), a medical technology company focused on improving endoscopic outcomes and experiences, today announced executive changes and restructuring as part of its strategy to reduce operating costs while supporting key value creation drivers, including ongoing R&D efforts to bring Pure-Vu Upper GI, and an enhanced Lower GI platform to market, while continuing to support existing customer base and target pipeline opportunities in contracted health systems. As part of the executive changes, Mr. Moran has elected to step down as Chief Executive Officer (CEO) of the Company to pursue other business opportunities. Mr. Moran will remain on the Board and has been appointed Chairman of the Board, succeeding David Hochman, who will remain an independent director, effective immediately. Mark Pomeranz, the Company’s current President, Chief Operating Officer, and director and former CEO of the Company, has been appointed as the Company’s CEO, effective immediately. Mr. Moran will work closely with Mr. Pomeranz to support a smooth transition and maintain key relationships with Motus GI’s stakeholders.

Continue reading here:
Motus GI Announces Executive Leadership Restructuring and Additional Cost Saving Initiatives to Support Near-Term Milestones

REDWOOD CITY, Calif., April 13, 2023 (GLOBE NEWSWIRE) -- Revolution Medicines, Inc. (Nasdaq: RVMD), a clinical-stage oncology company developing targeted therapies for RAS-addicted cancers, today announced that Mark A. Goldsmith, M.D., Ph.D., the company’s chief executive officer and chairman, will be the featured speaker in a fireside chat at the 22nd Annual Needham Healthcare Conference. The conference will take place April 17-20, 2023.

Go here to see the original:
Revolution Medicines to Participate in 22nd Annual Needham Healthcare Conference

Lille (France); Cambridge (Massachusetts, United States); Zurich (Switzerland); April 13, 2023 - GENFIT (Nasdaq and Euronext: GNFT), a late-stage biopharmaceutical company dedicated to improving the lives of patients with severe chronic liver diseases characterized by high unmet medical needs, today announced annual financial results for the year ended December 31, 2022. A summary of the consolidated financial statements is included further below.

Excerpt from:
GENFIT Reports Full-Year 2022 Financial Results and Provides Corporate Update

WINNIPEG, Manitoba, April 13, 2023 (GLOBE NEWSWIRE) -- Kane Biotech Inc. (TSX- V:KNE; OTCQB:KNBIF) (the “Company” or “Kane Biotech”), a biotechnology company engaged in the research, development and commercialization of technologies and products that prevent and remove microbial biofilms, will announce its fourth quarter and full year 2022 financial results after market close on Thursday, April 20, 2023.

See the article here:
Kane Biotech to Release Fourth Quarter and Full Year 2022 Financial Results on April 20, 2023 – Conference Call to Follow

REDWOOD CITY, Calif., April 13, 2023 (GLOBE NEWSWIRE) -- Biomea Fusion, Inc. (“Biomea”)(Nasdaq: BMEA), a clinical-stage biopharmaceutical company dedicated to discovering and developing novel covalent small molecules to treat and improve the lives of patients with genetically defined cancers and metabolic diseases, today announced the upcoming presentation of two preclinical abstracts at the American Association for Cancer Research (AACR) Annual Meeting in Orlando, Florida from April 14-19, 2023.

Read the rest here:
Biomea Fusion To Present Two Preclinical Posters at the 114th AACR Annual Meeting

PHILADELPHIA, April 13, 2023 (GLOBE NEWSWIRE) -- Cabaletta Bio, Inc. (Nasdaq: CABA), a clinical-stage biotechnology company focused on developing and launching the first curative targeted cell therapies for patients with autoimmune diseases, today announced that Steven Nichtberger, M.D., Chief Executive Officer, will present a company presentation at the 22nd Annual Needham Virtual Healthcare Conference on Thursday, April 20, 2023 at 9:30 a.m. ET.

More here:
Cabaletta Bio to Present at the 22nd Annual Needham Virtual Healthcare Conference

MORRISVILLE, N.C., April 13, 2023 (GLOBE NEWSWIRE) -- Syneos Health® (Nasdaq:SYNH), a leading fully integrated biopharmaceutical solutions organization, will release its first quarter 2023 financial results on Wednesday, May 10th, 2023, prior to its earnings call at 8:00 a.m. ET.

Continued here:
Syneos Health Schedules First Quarter 2023 Earnings Call for Wednesday, May 10th, 2023

SAN DIEGO, April 13, 2023 (GLOBE NEWSWIRE) -- Oncternal Therapeutics, Inc. (Nasdaq: ONCT), a clinical-stage biopharmaceutical company focused on the development of novel oncology therapies, today announced that two key industry opinion leaders and management will participate in Oppenheimer & Co.’s Virtual Fireside Chat: Discussion of ROR1 CAR-T Cell Therapy in Hematological Malignancies and Solid Tumors on Tuesday, April 18, 2023 at 1:30 p.m. EDT.

View original post here:
Oncternal Therapeutics Participating in Oppenheimer & Co.’s Virtual Fireside Chat: Discussion of ROR1 CAR T Cell Therapy in Hematological...

SAN DIEGO, April 13, 2023 (GLOBE NEWSWIRE) -- Travere Therapeutics, Inc. (NASDAQ: TVTX) today announced that on April 10, 2023, the Compensation Committee of its Board of Directors granted inducement equity grants to five new employees, consisting of inducement restricted stock units, or RSUs, covering an aggregate of 30,000 shares of its common stock. These inducement RSUs are subject to the terms of Travere’s 2018 Equity Incentive Plan (“2018 Plan”) but were granted outside of the 2018 Plan and were granted as inducements material to the new employees entering into employment with Travere in accordance with Nasdaq Listing Rule 5635(c)(4).

Read this article:
Travere Therapeutics Reports Inducement Grants Under Nasdaq Listing Rule 5635(c)(4)

Alvotech (NASDAQ: ALVO), a global biotech company specializing in the development and manufacture of biosimilar medicines for patients worldwide, announced today that the U.S. Food and Drug Administration (FDA) has issued a complete response letter (CRL) for Alvotech’s Biologics License Application (BLA) for AVT02, a high-concentration biosimilar candidate for Humira® (adalimumab). The CRL noted that certain deficiencies, which were conveyed following the FDA’s reinspection of the company’s Reykjavik facility that concluded on March 17, 2023, must be satisfactorily resolved before the application can be approved.  No other deficiencies in the application were noted by the FDA.  Alvotech provided the FDA comprehensive responses to the inspection observations on April 3, 2023, and is awaiting communication from the agency assessing those responses.

View post:
Alvotech Provides Regulatory Update on AVT02 Biologics License Application

Vivoryon Therapeutics N.V. to Report Full Year 2022 Financial Results and Operational Progress on April 19, 2023

Original post:
Vivoryon Therapeutics N.V. to Report Full Year 2022 Financial Results and Operational Progress on April 19, 2023

View original post here:
Additional Future Royalty Revenue Stream for Nicox from 2024 following New Drug Application Submission for ZERVIATE in China

Oslo, 14 April 2023: In connection with the Annual General Meeting of Ultimovacs ASA to be held on 20 April 2023, Jónas Einarsson, Chair of the Board of Directors, has so far received proxy based voting rights without voting instructions for 11,364,278 shares, representing 33.04% of the total voting rights in the company.

See the original post:
Ultimovacs ASA – Disclosure of voting rights of Annual General Meeting