StemCell Therapy

Have you ever wondered if theres a way to heal tissues, regenerate damaged organs, or even reverse the aging process? The answer might lie in a groundbreaking field known as regenerative medicine. In recent years, this area of science has attracted increasing attention due to its potential to revolutionize the way we treat diseases and injuries. Regenerative medicine is no longer a futuristic concept but is fast becoming an integral part of medical treatments, offering hope to millions of people worldwide.

From repairing damaged tissues to potentially regrowing entire organs, the possibilities are truly limitless. With advancements in stem cell therapy, gene editing, and tissue engineering, were witnessing the dawn of a new era in healthcare. But what exactly is regenerative medicine, and how does it work? In this article, well explore its key components, benefits, challenges, and future prospects.

Regenerative medicine is a branch of medical science that focuses on repairing, replacing, or regenerating damaged tissues and organs. The goal is to restore normal function by stimulating the bodys natural healing processes or using advanced techniques to regenerate tissues that are beyond repair. Unlike traditional medicine, which primarily treats symptoms, regenerative medicine aims to address the root causes of diseases and injuries, leading to more effective and long-lasting outcomes.

This field encompasses various methods, including stem cell therapy, gene therapy, tissue engineering, and bioprinting. By harnessing the bodys ability to heal itself, regenerative medicine has the potential to revolutionize the way we approach everything from chronic diseases to trauma recovery.

Regenerative medicine includes several cutting-edge technologies that contribute to tissue repair and regeneration. Lets dive into the core components:

Stem cells are undifferentiated cells with the ability to develop into various specialized cell types. These cells hold immense potential in regenerative medicine because they can regenerate damaged tissues or replace dysfunctional cells. Stem cell therapy can be used to treat a variety of conditions, including heart disease, neurodegenerative disorders, and joint injuries.

There are different types of stem cells used in therapy:

Gene therapy involves altering the genes inside a patients cells to treat or prevent disease. In regenerative medicine, gene therapy is used to correct defective genes responsible for diseases or enhance the regenerative abilities of specific tissues. This approach has shown promise in treating genetic disorders, such as cystic fibrosis, muscular dystrophy, and hemophilia, as well as in promoting tissue regeneration following injury.

Tissue engineering combines biology, engineering, and materials science to create functional tissues or organs that can be implanted into the body. By using scaffolds, growth factors, and cells, scientists can grow new tissues in the lab that mimic the structure and function of natural tissues. This technology holds significant potential for creating replacement tissues for organs such as the heart, liver, or kidneys.

Bioprinting is the use of 3D printing technology to create tissues and organs layer by layer using bioinks made from living cells. The goal is to create fully functional biological tissues that can be used for transplantation or as models for drug testing. While still in its early stages, bioprinting is a rapidly advancing field with immense potential for creating personalized treatments and reducing the dependency on donor organs.

Regenerative medicine works by leveraging the bodys innate ability to heal itself, amplifying and guiding those processes to repair damaged tissues or organs. Heres a simplified breakdown of how these technologies function:

Regenerative medicine has wide-ranging applications across various fields of medicine. Below are some key areas where these therapies are already being used or show great promise:

One of the most common applications of regenerative medicine is in treating musculoskeletal injuries, such as torn ligaments, cartilage damage, and fractures. Stem cell injections and platelet-rich plasma (PRP) therapy are used to promote tissue healing, reduce inflammation, and enhance recovery time. These treatments are often used to avoid invasive surgeries and provide longer-lasting results.

Regenerative therapies are being explored to treat heart conditions such as heart attacks and heart failure. Stem cells can be used to regenerate damaged heart tissue, promote blood vessel growth, and improve heart function. Clinical trials are ongoing to determine the best methods for using regenerative medicine in cardiovascular care.

Stem cells are also being studied for their potential to treat neurodegenerative diseases like Parkinsons disease, Alzheimers, and spinal cord injuries. The idea is to replace damaged neurons and promote regeneration in the brain and spinal cord, which could help restore lost functions and alleviate symptoms.

Perhaps one of the most exciting aspects of regenerative medicine is the potential to regenerate entire organs. Using stem cells, tissue engineering, and bioprinting, scientists hope to one day create fully functional organs like kidneys, livers, and hearts that could be used in transplants. This would help address the critical shortage of donor organs and provide life-saving treatments to those on organ transplant waiting lists.

Regenerative medicine is also making strides in aesthetic treatments. Platelet-rich plasma (PRP) therapy and stem cell injections are being used to rejuvenate skin, reduce wrinkles, and stimulate hair growth. These treatments are less invasive than traditional cosmetic procedures and promote the bodys natural healing processes for more natural-looking results.

The potential benefits of regenerative medicine are vast and transformative. Some of the key advantages include:

Despite its vast potential, regenerative medicine faces several challenges:

The future of regenerative medicine holds immense promise. As technologies such as stem cell therapy, tissue engineering, and gene editing continue to advance, we can expect even more breakthroughs that could lead to cures for previously untreatable diseases. The ability to grow replacement organs, repair heart tissue, or reverse neurological damage could revolutionize healthcare as we know it.

Regenerative medicine is changing the landscape of modern medicine. With its potential to heal the body from within, it promises to provide solutions to some of the most challenging health issues of our time. While we are still in the early stages of fully understanding and harnessing these technologies, the future of regenerative medicine looks incredibly bright. It offers hope for those suffering from debilitating conditions, bringing us closer to a world where healing is not just a possibility, but a reality.

References:

Follow this link:
Regenerative Medicine: The Future of Healthcare

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 (Table 1). 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) (Fig. 1 A and B). 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) (Fig. 1C). 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) (Fig. 1D).

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) (Fig. 1 E and F). 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) (Fig. 1G). 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 (Fig. 2A) (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) (Fig. 2 B and C), 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) (Fig. 2D). 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) (Fig. 2E). 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) (Fig. 2 F and G).

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) (Fig. 3A). 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) (Fig. 3B). 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).

See the rest here:
Regenerative medicine: Current therapies and future ...

Space Doctors and Stem Cell Production in Microgravity  Cedars-Sinai

See the original post:
Space Doctors and Stem Cell Production in Microgravity - Cedars-Sinai

Tracking Tissue Development to Inspire Regenerative Therapies  the-scientist.com

Follow this link:
Tracking Tissue Development to Inspire Regenerative Therapies - the-scientist.com

Study aims to stop Alzheimers with stem cell infusions  Drug Target Review

Read this article:
Study aims to stop Alzheimers with stem cell infusions - Drug Target Review

RheeGen's Topical Stem Cell Therapy Pioneers Future of Regenerative Medicine  Yahoo Finance

Continued here:
RheeGen's Topical Stem Cell Therapy Pioneers Future of Regenerative Medicine - Yahoo Finance

Lab-grown meat: you may find it icky, but it could drive forward medical research  ET HealthWorld

See the original post here:
Lab-grown meat: you may find it icky, but it could drive forward medical research - ET HealthWorld

Abstract

Significant progress has been made in regenerative medicine for skin repair and rejuvenation. This review examines core technologies including stem cell therapy, bioengineered skin substitutes, platelet-rich plasma (PRP), exosome-based therapies, and gene editing techniques like CRISPR. These methods hold promise for treating a range of conditions, from chronic wounds and burns to age-related skin changes and genetic disorders. Challenges remain in optimizing these therapies for broader accessibility and ensuring long-term safety and efficacy.

Keywords: skin regeneration, rejuvenation, regenerative medicine, stem cells, bioengineered skin substitutes, wound healing, chronic wounds, burns

This review systematically analyzed articles published in English from 2015 to 2024 focusing on regenerative medicine approaches for skin regeneration and rejuvenation. Searches were conducted using PubMed, Scopus, and Web of Science databases. Keywords included combinations of skin regeneration, skin rejuvenation, regenerative medicine, and specific treatment modalities (e.g., stem cell therapy, platelet-rich plasma, exosomes). Studies were included if they presented original research or comprehensive reviews related to the specified topic. Exclusion criteria included studies not published in English, those focusing solely on animal models without human relevance, and those not meeting minimum methodological quality standards such as lack of adequate controls, small sample sizes.

Regenerative medicine is a developing field focused on the repair, rejuvenation, replacement, or regeneration of tissues and organs to reestablish normal function (Mao and Mooney, 2015; Sampogna et al., 2015; Jafarzadeh et al., 2024). In the context of skin, regenerative medicine offers innovative approaches to healing (Shimizu et al., 2022; Mahajan et al., 2024) and rejuvenating the skin (Jo et al., 2021; Taub, 2024), the bodys largest organ and serves as the first line of defense.

The skin is a complex, multi-layered organ composed of the epidermis (outer layer), dermis (middle layer), and hypodermis (subcutaneous tissue). It possesses several critical functions such as a) barrier protection against pathogens, ultraviolet radiation (UV), and physical injury; b) temperature regulation, maintaining body temperature through sweat production and blood vessel dilation or constriction, c) sensory perception, since it contains nerve endings and d) immune defense, where host immune cells protect against infections and participate in wound healing (Yousef et al., 2024).

Skin can be damaged by several factors, including injury, diseases, aging, and environmental stressors (Parrado et al., 2019; Arabpour et al., 2024). Traditional treatments often focus on managing symptoms rather than focusing on the underlying damage. On the other hand, regenerative medicine for skin focuses on repairing or replacement of damaged skin tissue, restoring the skin normal function and appearance by promoting the regeneration of the tissue (Fadilah et al., 2022). Innovative techniques, including stem cell therapy, tissue engineering, and growth factors, have been developed to address conditions such as chronic wounds, burns, scars, chronic ulcers, and aged skin (Shimizu et al., 2022). These approaches aim to accelerate healing, minimize scarring, and restore skin integrity (Fadilah et al., 2022).

Specifically, chronic wounds, such as diabetic foot ulcers (DFU), venous leg (VLU) or pressure ulcers, can be difficult to treat and often fail to heal with conventional methods (Frykberg and Banks, 2015; OuYang et al., 2023). Regenerative approaches such as stem cell therapy and bioengineered skin can promote faster and effective healing in DFU (Chiu et al., 2023). Platelet-rich plasma (PRP), which is rich in growth factors, can be used to enhance healing and regeneration in chronic skin conditions where skin healing is impaired (Xu et al., 2020).

Also, severe burns can result in significant tissue loss and scarring. Traditional burn treatments often involve skin grafts, which can be painful and leave significant scarring (Chogan et al., 2023). On the other hand, regenerative medicine, requires advanced therapies like bioengineered skin grafts, stem cell treatments, exosome therapy, topical application of growth factors, such as Epidermal Growth Factor (EGF) and Platelet Derived Growth Factor (PDGF) directly to burn wounds, to promote faster and more effective healing (Chogan et al., 2023), reducing scarring, and improving functionality, elasticity, and sensitivity, as well as aesthetic outcomes. Additionally, advanced dressings and scaffolds are being proposed such as hydrogel dressings, which provide a moist environment that promotes healing and reduces pain. They can also be infused with growth factors, stem cells, or other regenerative agents to further enhance wound healing (Surowiecka et al., 2022). As far as burned skin, fractional CO2 laser therapy can be applied to remodel scar tissue and improve the texture and elasticity of the skin. This therapy can also be combined with stem cells or growth factors, as treatments to enhance skin regeneration (Roohaninasab et al., 2023). In case of burns, many regenerative treatments, such as stem cell therapy can also be tailored to the individual patient, reducing the risk of immune rejection and improving outcomes (Lukomskyj et al., 2022).

Chronic skin conditions like psoriasis, eczema, and vitiligo often present significant challenges in terms of management and treatment. Regenerative medicine offers new perspectives by targeting the underlying causes of these diseases and promoting long-term regeneration of skin (Paganelli et al., 2020; Daltro et al., 2020; Park et al., 2019; Bellei et al., 2022). It has been shown, for example, that mesenchymal stem cells (MSCs) can reduce the hyperproliferation of skin cells and modulate the immune response, potentially leading to remission of symptoms in autoimmune-related skin conditions like psoriasis and eczema (Shin et al., 2017; Daltro et al., 2020; Diotallevi et al., 2022). Also, exosomes can be topically applied or injected into affected areas to improve skin health and reduce the symptoms of chronic skin conditions (Wang et al., 2019; Farabi et al., 2024). In vitiligo, exosomes may help restore pigmentation by stimulating melanogenesis and melanocyte-stimulating factors (Wong et al., 2020). Gene therapy is another modality that offers a promising approach to correcting the genetic mutations underlying chronic skin diseases. In conditions like epidermolysis bullosa, a severe blistering disorder, gene therapy can be used to restore functional genes in skin cells, potentially improving skin integrity and improving skin integrity and reducing blister formation (Bischof et al., 2024). In addition, CRISPR/Cas9, a gene-editing technology has the potential to correct mutations at the DNA level, a potential solution for certain genetic skin diseases (Abdelnour et al., 2021).

Finally, skin aging, a complex interplay of internal and external factors, can now be targeted with regenerative medicine (He et al., 2023). Since skin health is considered one of the main factors associated with welfare and the perception of health in humans, numerous anti-aging strategies have been developed and proposed (Ganceviciene et al., 2012). In the context of regenerative medicine and skin rejuvenation, anti-aging therapies focus on reversing or slowing down the signs of skin aging, which includes wrinkles, loss of elasticity, pigmentation, and thinning. The aim is to repair damaged skin, promote and/or stimulate collagen production, and restore young skin features (Wong et al., 2020; Ribaudo and Gianoncelli, 2023).

Given stem cells remarkable potential to differentiate into various cell types, they can be used to rejuvenate tissues and organs, enhancing their regenerative capacity (Jin et al., 2023). Mesenchymal stem cells (MSCs) are not only capable of differentiating into skin cells but also are able to release growth factors and cytokines that enhance collagen synthesis and skin tissue regeneration. In this way, stem cell-based treatments are being explored for reducing wrinkles, improving skin elasticity, and treating scars (Jo et al., 2021). Also, adipose-derived stem cells (ADSCs) can be harvested from fat tissue and used in skin rejuvenation procedures, specifically ADSCs injected into areas of the face to restore volume and improve skin texture (Surowiecka and Struyna, 2022). Exosomes from stem cells have been shown to be particularly effective in promoting healing after procedures like laser therapy or microneedling, as they can accelerate skin regeneration (Prasai et al., 2022). In skin care, topical growth factors such as EGF and transforming growth factor-beta (TGF-) or injected formulations can stimulate collagen synthesis, accelerate wound healing, and reduce the appearance of fine lines (He et al., 2023). In the same line, studies suggest that PRP can improve fine lines, wrinkles, and overall skin texture by promoting cellular repair and enhancing skin regeneration (Phoebe et al., 2024). Lately, gene editing tools such as CRISPR are being explored to repair age-related genetic damage (Yu et al., 2022) as well as some therapies targeting genes associated with aging, like telomerase activation, have been proposed to extend the lifespan of cells (Tenchov et al., 2024). Finally, advances in 3D bioprinting and tissue scaffolds are enabling the development of engineered skin substitutes for cosmetic applications (Pleguezuelos-Beltrn et al., 2024). These skin substitutes can provide a platform for delivering stem cells or growth factors to damaged skin, promoting regeneration and rejuvenation.

Skin regenerative medicine generally encompasses two key approaches: cell-based and cell-free therapies. These include stem cell therapy, platelet-rich plasma (PRP), growth factors, cytokines, wound dressings, gene therapy, and tissue engineering, encompassing the use of biomaterials, skin grafts, bioengineered skin substitutes, and 3D bioprinting.

Stem cells are undifferentiated cells with the ability to self-replicate, self-renewal, homing and plasticity potential. They can differentiate into various cell types, such as nerve cells, cardiomyocytes, liver cells and skin cells (Jin et al., 2023). They possess anti-inflammatory properties, promote epithelial cell proliferation, inhibit wound scarring, maintain homeostasis, repair tissue injuries, and accelerate healing (Jin et al., 2023; Khandpur et al., 2021; Zhang and Huang, 2023). Stem cells also secrete bioactive molecules, including growth factors, cytokines, chemokines and exosomes, which are responsible for the paracrine effects of these cells in bone tissue and nervous system regeneration, as well as in wound healing and endothelial cells (Tran et al., 2023; Wu et al., 2024).

There are different sources for using stem cells in regenerative medicine classified according to their differentiation potential (Khandpur et al., 2021), including embryonic stem cells (ESCs), umbilical cord mesenchymal stem cells (UCMSCs), induced pluripotent stem cells (iPSCs), MSCs, ADSCs and bone marrow mesenchymal stem cells (BMMSC) (Jin et al., 2023; Semsarzadeh and Khetarpal, 2022; Tran et al., 2023).

MSCs are originated from the mesoderm and ectoderm, and can differentiate into various cell types, such as osteocytes, chondrocytes, adipocytes, neurons and endothelial cells (Ma et al., 2023; Tran et al., 2023). Additionally, MSCs can be found in bone marrow, adipose tissue, synovial tissue, muscle, lung, liver, and umbilical cord blood (Khandpur et al., 2021; Huynh et al., 2022; Jin et al., 2023). MSCs play a pivotal role in wound healing and exhibit additional functions including immunomodulation, anti-inflammatory and anti-apoptotic effects, and pro-angiogenic activity (Khandpur et al., 2021; Wu et al., 2024).

Currently, there are several therapies using MSCs for the treatment of graft-versus-host disease, bone defects, ischemic heart failure, burns, autoimmune-related skin conditions, and diabetic foot (Jin et al., 2023; Wu et al., 2024; Farabi et al., 2024). Since MSCs can differentiate into skin cells such as keratinocytes, fibroblasts, and endothelial cells, they can be used to enhance the healing process. This is not only due to their cell differentiation capabilities but also because of their crosstalk with macrophages, which play a role in the wound repair process (Wu et al., 2024).

MSCs can be applied to burn injuries by inhibiting cellular inflammation through the release of anti-inflammatory cytokines. Additionally, MSCs exert paracrine effects that polarize macrophages from an inflammatory phenotype (M1) to a wound-healing phenotype (M2), promoting tissue repair and clearance (Ma et al., 2023; Wu et al., 2024; Zhang and Huang, 2023). Moreover, they stimulate the formation of new blood vessels, which results in increased blood perfusion and the delivery of nutrients to affected areas, thereby accelerating the healing process (Jin et al., 2023; Semsarzadeh and Khetarpal, 2022). On top of that, MSCs improve the wound structure by secreting proteins that make up the extracellular matrix (ECM), such as collagen, elastin and fibronectin, enhancing the reconstruction of the dermis (Mazini et al., 2020; Tran et al., 2023; Wu et al., 2024).

Beyond that, bone marrow-derived MSCs can be used for scars reduction, anti-aging, and systemic sclerosis (Tran et al., 2023). Conget et al. (2010) conducted a study in which they used these cells to treat two patients with severe generalized recessive dystrophic epidermolysis bullosa (EB). After 12 weeks of intradermal treatment, the ulcers healed completely, however this effect only lasted 4months.

Another type of stem cells are the iPSCs. They are capable of differentiating into more cell types compared to MSCs, and they have the ability for unlimited self-renewal (Zhang and Huang, 2023). Studies show that these cells promote angiogenesis, perfusion, collagen deposition, and accelerate the natural healing process in murine models (Clayton et al., 2018; Farabi et al., 2024).

Besides MSCs and IPSCs, ADSCs are another promising cell type for regenerative therapy. ADSCs have shown potential applications in dermatology and aesthetics, including scar reduction, anti-aging, wrinkle reduction, and hair loss treatment (Khandpur et al., 2021; Suh et al., 2019; Tran et al., 2023). Anderi et al. (2018) injected ADSCs, derived from liposuction, into 20 patients with alopecia areata, and after 6months of follow-up, they observed a statistically significant difference in hair growth rates among all treated patients. Indeed, Zhang et al. (2014) evaluated the antioxidant effects of ADSCs in a mouse model and found that, after 28 days of injection, ADSCs reversed the aging phenotype, increased dermal thickness and collagen content, and enhanced skin vascular density. In addition, Chen et al. (2020) showed that ADSCs were effective in improving the appearance of the skin, particularly in reducing wrinkles in UV-damaged skin. These results highlight the paracrine effects of ADSCs in promoting skin rejuvenation.

Interestingly, Li et al. (2016) used the conditioned medium from ADSCs (ADSC-CM) to evaluate its effect on hypertrophic scars ex vivo, injecting them into rats. Through Western blotting, they analyzed key proteins involved in healing, such as collagen I, collagen III, and -SMA (alpha-smooth muscle actin). The results showed that the use of ADSC-CM reduced collagen deposition in hypertrophic scar tissues and improved fibrosis in these tissues.

Not only ADSC-CM, but also conditioned medium from MSCs (MSC-CM) have been investigated to be used on regenerative medicine because it contains anti-apoptotic, anti-inflammatory and anti-aging substances. Because of that, there are pre-clinical studies using MSC-CM to show whether it influence on lung progenitor cell development or its paracrine effect influences tissue regeneration (Smolinsk et al., 2023).

Yet another ADSCs derivative, nano-fat, obtained through a multi-step process involving mechanical digestion and filtration of fat tissue, has demonstrated several benefits, including reduced scar size, improved skin color, and enhanced overall skin quality (Suh et al., 2019; Hajimortezayi et al., 2024).

In addition, UCMSCs can also be used in regenerative medicine, having advantages over other types of stem cells because they are abundant, easy to collect, cause no harm to donors, have low immunogenicity, and high differentiation capacity (Jin et al., 2023; Li et al., 2024). They can be used for the treatment of cardiovascular diseases, liver diseases, degenerative muscle diseases, and autoimmune diseases (Wu et al., 2024). They can also be used for treating burns and psoriasis vulgaris (Tran et al., 2023) and for treating chronic wounds, facial and body rejuvenation, even combination therapies with other biomaterials (Li et al., 2024).

The Stromal Vascular Fraction (SVF) is isolated from adipose tissue and contains various cell types, such as MSCs, endothelial cells, stromal cells, and immune cells (Surowiecka and Struyna, 2022). For example, in a pilot study, SVF was used for the treatment of alopecia, where a significant increase in hair growth in patients was observed (Semsarzadeh and Khetarpal, 2022).

While various stem cell types exist, extensive preclinical and clinical research suggests that mesenchymal stem cells (MSCs) and MSC-based products offer the most promising balance of safety and efficacy, with a low risk of tumor formation and minimal immune rejection (Hoang et al., 2022; Farabi et al., 2024). Despite their widespread use, MSCs have limitations, such as a decline in viability and activity with age (Wu et al., 2024).

PRP was first used in 1954 to improve wound healing in dentistry (Kingsley, 1954). Since its inception, the application of PRP has grown significantly, becoming a valuable tool in tissue repair and regeneration across various medical fields. (Cecerska-Hery et al., 2022). The treatment is based on injections of the patients own platelets highly concentrated in plasma and separated from other blood components by centrifugation cycles (Samadi et al., 2019; Pixley et al., 2023).

The peripheral blood contains at least five times fewer platelets than PRP. This increased platelet concentration in PRP enhances its potential for wound healing (Davies and Miron, 2024). Platelets are involved in a wide range of growth factors, proteins, cytokines and other biological agents that have effects in processes like cellular migration, proliferation, differentiation, angiogenesis, tissue regeneration and collagen synthesis (Pincelli et al., 2024). The variety of molecules derived from PRP enables efficient wound healing, as the healing process involves multiple molecules and complex pathways (Samadi et al., 2019; Davies and Miron, 2024).

Platelet-derived molecules could be secreted by -granules, dense granules and lysosomes. Platelet derived growth factor (PDGF), insulin-like growth factor 1 (IGF-1), EGF, TGF-, fibroblast growth factor (FGF) and vascular endothelial growth factor (VEGF) are secreted from -granules, in addition to adhesive proteins, coagulation factors, angiogenic regulators, cytokines and exosomes. They are the more abundant secretory granules and are responsible for releasing the greatest number of molecules with a direct effect on wound healing (Cecerska-Hery et al., 2022; Pincelli et al., 2024). On the other hand, dense granules contribute to platelet activation and subsequent release of -granules constituents, in which it has been shown that PRP lysosomes functions participate in antimicrobial activity and the degradation of extracellular matrices (Everts et al., 2024).

The composition of PRP can vary depending on the preparation. It can be categorized as pure (P-PRP), leukocyte-poor (LP-PRP), leukocyte-rich (LR-PRP) or platelet-rich fibrin (PRF), considering the centrifugation time, speed and the presence or absence of non-autologous anticoagulants (Karimi and Rockwall, 2019; Everts et al., 2024). PRF specifically has gained prominence in regenerative medicine in recent years due to its benefits, such as the release of platelet-related therapeutic granules over a longer period and at a slower rate than PRP (Narayanaswamy et al., 2023). In this way, PRF also offers a valuable adjunct to both surgical and non-surgical interventions, demonstrating great potential for enhancing treatment outcomes.

PRP treatment offers several advantages, including low cost, ease of preparation, versatility, and safety. However, further research is necessary to standardize preparation procedures and establish regulations regarding the composition of PRP injectables. Additionally, the efficacy of PRP and its various categories remains uncertain in relation to specific diseases and clinical conditions (Everts et al., 2020; Cecerska-Hery et al., 2022; Pincelli et al., 2024).

Micro-vesicles, currently known as exosomes, were first identified in 1983. Initially, exosomes were considered just a cell waste, however, later research revealed that exosomes play important roles in cell communication and signal transduction. As an alternative for cell-based therapies, exosomes emerged as potential tools for treating skins conditions, such as improving wound healing and even skin rejuvenation. Since exosomes are small vesicles secreted by different cells, there are many possibilities for their isolation and use as an effective carrier for bioactive compounds or genetic material. Exosomes not only transport and protect molecules from degradation, but also exhibit biocompatibility, reducing the risk of immune reactions and tumorigenesis. In this way, clinical application of exosomes is a promising avenue for free-cell therapies (Hajialiasgary Najafabadi et al., 2024; Pea and Martin, 2024; Quan, 2023; Sonbhadra and Pandey, 2023; Zhou et al., 2023).

Exosomes are extracellular vesicles, approximately 30200nm in size, which can be obtained from cell culture and that function as membrane-bound carriers of biomolecules and metabolites, reflecting their cellular origin. These vesicles, spherical in solution, exhibit a lipid bilayer structure, which decreases the risks of immune responses and provides protection of their cargo from degradation. Furthermore, exosomes pose a low risk of uncontrolled cell proliferation and differentiation, minimizing concerns related to tumorigenicity. Their ability to carry and deliver bioactive substances to cells makes exosome-based therapies a promising possibility for therapeutic applications like various skin conditions, including psoriasis, atopic dermatitis and vitiligo, as well as for promoting skin regeneration, such as in diabetic wound healing, hypertrophic scarring and keloid formation, and even for addressing skin aging (Gurung et al., 2021; Hajialiasgary Najafabadi et al., 2024; Yu et al., 2024).

Exosomes are ubiquitous in various body fluids, including serum, saliva, milk, cerebrospinal fluid, urine and semen. Among these, stem cell-derived exosomes have been extensively investigated for their potential role in mediating the biological effects of paracrine factors, particularly in wound healing (Zhou et al., 2023).

Tissue repair is a complex process involving initial clot formation, followed by inflammatory cell signaling, cell proliferation and remodeling. These phases overlap, each with its own purpose and time before the next starts. Mesenchymal stem cells exosomes (MSC-exos) derived from different tissues, like ADSC, hold a promise for cutaneous repair due to their ability to stimulate fibroblast activity. In the dermis, fibroblasts play a pivotal role in wound healing through collagen synthesis, making MSC-exos, which enhance fibroblast function, valuable contributors to the healing microenvironment and the promotion of wound repair. ADSC-derived exosomes demonstrate significant potential for treating diabetic wounds due to their ability to induce collagen I and III production in the early stages of healing, which can help prevent scar and keloid formation (Song et al., 2023; Zhou et al., 2023; Pea and Martin, 2024).

Data from an ECM loaded with ADSC-exosomes indicate that this combination is also a possible therapeutic approach for both normal and pathological wound healing. The results demonstrated that ECM-loaded exosomes promoted increased cell growth, cell migration, collagen deposition, and decreased inflammation in vivo (Song et al., 2023).

Moreover, given their role in wound healing, stem cell-derived exosomes could potentially be used to treat skin photoaging, a condition marked by uneven pigmentation and wrinkles (Hajialiasgary Najafabadi et al., 2024).

Park et al. (2023) demonstrated that exosomes derived from human foreskin fibroblasts (BJ-5ta Exo) can mitigate oxidative stress by upregulating the expression of antioxidant genes CAT, SOD-1, SOD-2, and GPX. Additionally, BJ-5ta Exo promoted a decrease in programmed cell death and cell cycle arrest.

In addition, it was suggested that exosomes obtained from 3D culture of human dermal fibroblasts (HDFs) may be able to promote collagen synthesis and reduce skin inflammation. Data also revealed that 3D-HDF-exos, through tumor necrosis factor alpha (TNF-) downregulation and TGF- upregulation, promoted a procollagen type I increase while reducing matrix metalloproteinase-1 (MMP-1) expression. Given the age-related decline in HDF collagen production and repair, coupled with increased MMP-mediated ECM degradation, these findings suggest that exosomes may possess anti-aging properties (Xiong et al., 2021).

Given the abundance of exosomes in bovine milk, recent studies have explored the potential of milk-derived exosomes (MK-exo) as novel anti-aging compounds. These investigations have revealed that MK-exo can stimulate the expression of filaggrin and CD44 in keratinocytes, as well as hyaluronidase levels in fibroblasts. Furthermore, MK-exo protected collagen biosynthesis from UV-induced damage. Notably, these exosomes also stimulated increased cell migration rates in fibroblasts (Lu et al., 2024).

However, while exosomes demonstrate significant promise as therapeutic agents, several challenges must be addressed for their clinical application. These include standardizing isolation and analysis, ensuring safety and purity, and preserving exosome activity during preparation and storage (Lu et al., 2024; Rezaie et al., 2022).

Despite above stated challenges, exosomes, being versatile carriers of biomolecules, offer promise for clinical applications. Their biocompatibility, low risk of immune responses and tumorigenicity make them attractive candidates for treating diseases. In the context of skin, their potential to influence collagen synthesis and inflammation suggests their value for wound healing and skin rejuvenation. Future research should focus on exploring these possibilities and ensuring the safety of exosomes for medical use.

Dermal fillers, also known as facial fillers, are soft, gel-like substances injected beneath the skin. Over time, the loss of soft tissue volume, fat redistribution, reduced skin elasticity, and thickness contribute to the formation of wrinkles and folds characteristic of aging. In this context, injectable fillers are an option for treating wrinkles, scars, folds, and areas under the skin lacking volume (Callan et al., 2013; Maio, 2018; Colon et al., 2023; Faris, 2024).

The principle behind the use of these products is based on strengthening the ECM in the dermal layer. They are made of various low-crosslinking polymeric ingredients with different effects on the skin (Yi et al., 2024). Among the most used ingredients are hyaluronic acid, poly-L-lactic acid, polymethylmethacrylate, and calcium hydroxyapatite (CaHA) (Colon et al., 2023).

Hyaluronic acid is the most commonly used dermal filler, naturally found in the skin, being safe and effective for use (Yi et al., 2024). Poly-L-lactic acid is synthetic, acting as a collagen stimulator, recommended for softening lines and treating wrinkles (Ao et al., 2024). Similarly, according to the American Board of Cosmetic Surgery (2022), polymethylmethacrylate comprises synthetic microspheres that remain under the skin indefinitely, providing continuous support and containing collagen in their composition. In addition, CaHA is a natural substance found in bones that helps stimulate the skins natural collagen production and is recommended for treating deeper lines.

Focusing on hyaluronic acid fillers due to their widespread use, it is the most abundant glycosaminoglycan found in the human dermis, contributing to tissue hydration and volume, as well as providing structural support (Ballin et al., 2015; Wongprasert et al., 2022). A recent study by Chen et al. (2023) demonstrated the anti-aging ability of hyaluronic acid fillers by inhibiting the expression of MMP-1, promoting collagen accumulation, and increasing the expression of dermo-epidermal junction proteins.

One of the most significant advantages of hyaluronic acid fillers is that they can be easily removed by injecting hyaluronidase (Wongprasert et al., 2022). However, some limitations persist in their use, which can sometimes extend to other types of fillers, such as the duration of the compounds, discomfort caused by the injections, and the ability to achieve precise delivery of the fillers to the intended location and skin layer (Colon et al., 2023).

Growth factors are polypeptides or proteins that regulate physiological processes in and between cells. They are naturally found in the skin, secreted by various cell types in this tissue. Many growth factors are involved in wound healing, both acute and chronic, and are some of the most important signalers during this process (Pamela, 2018; Yamakawa and Hayashida, 2019; Vaidyanathan, 2021). Furthermore, the processes of aging and wound healing naturally stimulate the release of growth factors, which affect critical biochemical repair pathways in the dermal matrix and have inspired the use of these factors to improve skin appearance (Kremer and Burkemper, 2024).

Some of the growth factors used in skin treatment are EGF, FGF, hepatocyte growth factor (HGF), and IGF-1, which can be used in combination (Vaidyanathan, 2021; Yamakawa and Hayashida, 2019). They can come from various sources, including human and non-human cell cultures and recombinant sources (Quinlan et al., 2023).

Treatments involving the use of different growth factors have been reported to improve wrinkles, skin texture, photo-damage, and the overall appearance of facial skin (Quinlan et al., 2023). In addition to cosmetic use, human EGF (hEGF) is also applied in regenerative medicine for the treatment of alopecia, dermatitis following chemotherapy, burns, diabetic foot ulcers, and post-surgical ulcers (Kong and Hong, 2013; Kim et al., 2017; Esquirol-Caussa and Herrero-Vila, 2019; Jeon et al., 2019; Kahraman et al., 2019; Lou, 2021; Vaidyanathan, 2021).

The use of EGF for aesthetic purposes also shows broad applications, presenting a regenerative effect in the aging skin process by promoting the migration of aged fibroblasts and increasing the synthesis of hyaluronic acid and collagen in this tissue (Kim et al., 2015; Miller-Kobisher et al., 2021; Vaidyanathan, 2021). Growth factors can also be combined with other treatments for apparent skin rejuvenation, such as lasers, microneedling, radiofrequency, or chemical peels, to amplify results or improve side effects from these treatments (Quinlan et al., 2023). However, in recent years, the development of cell-penetrating peptides associated with growth factors has improved the topical application of these factors, increasing their ability to penetrate the skin and epithelial cells (Chen et al., 2017; Choi et al., 2018; Jeon et al., 2019, Lee et al., 2020, Xie et al., 2020.

Aiming to correct genetic defects and thereby prevent or cure genetic disorders, gene therapy has been applied to skin regenerative medicine. All types of skin diseases are candidates for gene therapy, from inflammatory diseases to skin cancers and genodermatoses (Ain et al., 2021), as well as more aesthetic aspects like skin regeneration and scar and keloid treatment (Hosseinkhani et al., 2023; Luo et al., 2023).

Gene therapy technologies include the use of messenger RNA, silencing RNA, antisense oligonucleotides (AON), plasmid DNA, minicircle DNA, mini-string DNA, and CRISPR/Cas9 technology (Wan et al., 2021; Guri-Lamce et al., 2024; Tenchov et al., 2024), which must have specific action on the desired area of the skin, representing one of the current challenges in this type of therapy.

Currently, there are three main methods of delivering gene therapies to the skin: viral delivery, nanoparticles and physical methods. In this perspective, viral delivery is the most used and effective method (Picano-Castro et al., 2020), though it presents challenges such as limitations in efficacy due to pre-existing immunity, the inability to redose, and genome integration capacity, which increases the risk of unwanted insertional mutagenesis. Additionally, there are size limitations for the genetic cargo (Anzalone et al., 2019; Ain et al., 2021). Lipid-based nanoparticles, a more recent and promising method (Guri-Lamce et al., 2024); polymeric nanoparticles, capable of associating with negatively charged genetic cargoes and forming spherical complexes, but which still present high toxicity related to particle size (Blakney et al., 2020); and physical methods, such as electroporation, ultrasound application, or microneedles (Wan et al., 2021), which have limitations for clinical application, such as limited cargo capacity and challenges with whole-body administration (Ain et al., 2021).

Other substances can be incorporated into skin care products, playing an active role in tissue regeneration or inflammation by improving ECM synthesis or inhibiting its degradation, neutralizing free reactive species, or reducing proinflammatory factors (Makpol et al., 2013; Wang H. et al., 2021; Torres et al., 2023). Among these substances, zinc-based compounds stand out. This metal has been shown to reduce inflammation and the risk of infections, being involved in cell proliferation and migration and collagen synthesis, thus promoting epithelialization (Lin et al., 2017; Chen et al., 2022; Pino et al., 2023). Other substances primarily act as moisturizers, provided by ingredients that increase the synthesis of structural skin lipids, directly restoring the skin barrier, such as vitamin A, or hygroscopic substances like dexpanthenol, which bind to and retain water in the stratum corneum (Liu, 2022). Other substances are lipids, oils, and fatty acids, known as emollients, such as petrolatum derivatives, which also promote hydration by directly replacing missing fatty acids in the tissue (Elias, 2022; Torres et al., 2023).

Smart dressings were developed to enhance wound care management based on the injury type and patient conditions (Raju et al., 2022). Multifunctional wound dressings promote wound healing by encapsulating bioactive substances, sustaining the release of medicines by stimuli-responsive technology (Raju et al., 2022). Biopolymers such as alginate, chitosan, polyvinyl alcohol (PVA), and collagen are increasingly used to create innovative wound dressings due to their cost-effectiveness and eco-friendliness. Among these, alginate dressings are the most popular because they promote skin regeneration, accelerate wound closure, minimize scarring, absorb exudates effectively, and are biocompatible. Alginates gelling properties and stability in warm environments make it ideal for various applications, including hydrogels, nanofibers, dermal patches, films, and foams (Nqoro et al., 2022).

Other than that, hydrocolloids are effective in wound care because they can absorb significant amounts of wound fluid and are impermeable to water vapor, creating a moist healing environment. They also block oxygen, which speeds up epithelialization and collagen synthesis while lowering the pH to reduce bacterial growth (Nguyen et al., 2023). Nonetheless, new smart hydrogel wound dressings with embedded sensors have been rapidly developed to monitor wound conditions. Notable examples include flexible pH-sensing alginate-based hydrogel fibers for skin wounds and PVA/xyloglucan (PVA/XG) hydrogel membranes that absorb exudate and release biological factors (Tamayol et al., 2016; Ajovalasit et al., 2018; Tavakoli and Klar, 2020).

Although high-end wound dressings have been developed in recent years, the products face several limitations, including a complicated production process, inadequate quality assurance for biological materials and questions about the effectiveness of their components for widespread use. In addition to that, more trials and experiments are needed to assess the true effectiveness of these advanced dressings in wound healing (Nguyen et al., 2023).

Tissue engineering has become a multidisciplinary research field that involves the use of techniques to replicate biological prototypes, such as skin, to study the regeneration of physiological tissue on repairing or replacement of damaged skin (Berthiaume et al., 2011; Deepa and Bhatt, 2024; Wei et al., 2024). Indeed, it is possible to introduce biomaterials and hydrogels, which can be used as scaffolds to facilitate wound healing, combined with the knowledge of cell culture, for the improvement of techniques such as the use of nanomaterials and 3D bioprinting (Kondej et al., 2024; Wei et al., 2024; Loukelis et al., 2024; Bian et al., 2024).

Studies in the last 20years have involved the use of different skin cell cultures (mainly keratinocytes), umbilical cord mesenchymal stem cells differentiated to keratinocytes, or co-culture of skin cells with other cell types, including immune cells and dermal fibroblasts, in a two-dimensional (2D) monolayer (Abaci et al., 2017; Santos et al., 2023), to study the signaling pathways of skin diseases such as psoriasis or melanoma, wound healing, also to test the efficacy of safety treatments (Karras and Kunz, 2024). However, 2D models do not often represent a sufficient level of complexity to assess the various cell-cell and cell-extracellular matrix interactions, as well as oxygen and nutrient gradients (Loke et al., 2021; Santos et al., 2023).

On the other hand, it is possible to better understand most complex skin diseases in the three-dimensional (3D) microenvironment by involving additional cell lineages, such as immune cells or skin appendages as innervation type, to generate more effective in vitro skin models, using spheroids or skin constructs, for example, to improve skin replacement therapy (Abaci et al., 2017; Karras and Kunz, 2024; Loke et al., 2021).

The in vivo model can be better mimicked in spheroid cultures compared to 2D models, representing a more complex tissue architecture, with increased cell-cell contacts and heterogeneous cell growth. In addition, spheroids have been used for semi-high-throughput drug screening, as well as being used in co-culture models to evaluate different tissue responses under paracrine stimulation (Raghavan et al., 2016; Loke et al., 2021; Karras and Kunz, 2024).

The application of spheroid cultures in skin models can be generated from cell aggregates of fibroblast or keratinocyte lineages, for example, under non-adherent conditions, by so-called spinner culture, hanging drop, magnetic levitation or gel incorporation (Abaci et al., 2017; Klicks et al., 2019; Schfer et al., 2021; Ohguro et al., 2024). To improve the formation of the spheroids, it is important to choose an ECM based on biomaterials, such as hydrogels or collagens, for the architecture of the dermal matrix (Enyedi et al., 2023; Santos et al., 2023).

Some methods for evaluating the different cell configurations in spheroids still remain limited, but the main ones based on microscopy, such as phase contrast microscopy, are used to analyze the size and shape of spheroids. Other methods, such as cell surface staining and flow cytometry, are used to analyze the presence of specific molecules. Cryosectioning, after fixation in formalin and embedding in paraffin, is used for a deeper view of the sectioned spheroid (Filipiak-Duliban et al., 2022; Habanjar et al., 2021; Karras and Kunz, 2024).

Due to the cell aggregate structure, spheroid nuclei are exposed to low oxygen conditions, as well as limited access to nutrients and metabolites, which can lead to an increase in apoptotic cells (Karras and Kunz, 2024; Loke et al., 2021). On the other hand, the cells on the periphery are proliferative, due to the availability of oxygen and nutrients. Interestingly, the middle layer contains quiescent and senescent cells, and as a result, this spheroid configuration becomes a suitable model for testing pathophysiological conditions (Karras and Kunz, 2024; Loke et al., 2021; Ohguro et al., 2023).

Another model of organotypic cultures are the so-called raft cultures, also known as skin reconstructs. Cells are established in a manner as to allow the stratified epithelium and the dermal component of the skin, to be reconstituted in a tissue culture environment. Keratinocytes, for example, are seeded in a dermal equivalent containing fibroblast and, when raised to the air-liquid interface, reproduce the process of stratification and terminal differentiation of keratinocyte (Klicks et al., 2019; Santos et al., 2023). Histological analysis of these skin reconstructs shows the similarity and tissue organization to human skin, with a cornified epidermal-equivalent appearing on top of a dermal, containing human fibroblasts (Klicks et al., 2019; Loke et al., 2021; Santos et al., 2023).

This skin reconstruct is a useful system for testing pharmacological dynamics, efficacy tests, analysis of absorption by different forms of administration, or for preclinical screening of drugs and cosmetics (Torre et al., 2020; Portugal-Cohen et al., 2023; Suthar et al., 2024). This model takes less time to obtain results and is less expensive than performing experiments using animals (Abaci et al., 2017; Karras and Kunz, 2024). Therefore, it has been emphasized in recent years that organotypic cultures for skin reconstructions can also be obtained using the bioprinting technique, in order to construct highly reproducible dermal equivalents, with architecture similar to the in vivo (Cubo et al., 2016; Fernandes et al., 2022; Bian et al., 2024), to be widely used in regenerative medicine or in strategies for testing immunotherapy (Ao et al., 2022; Santos et al., 2023).

Tissue bioengineering has been expanding as a new strategy by employing advanced techniques of bioprinting, biopolymer engineering, stem cell research and nanomedicine (Augustine, 2018; Pasierb et al., 2022; Wei et al., 2024). Bioprinting has attracted attention as a promising technique, in which the technology aims to generate, precisely, a controlled and organized complex with similar architectures of native tissues (Loukelis et al., 2024; Bian et al., 2024). Bioprinting has been used to generate tissues and transplants, including skin and its multilayers, tracheal splints, cardiac tissue and cartilaginous textures (Kaur et al., 2019; Miguel et al., 2019; Bian et al., 2024).

In fact, bioprinting technique has the potential to revolutionize contemporary regenerative medicine, considering that by taking advantage of tissue regeneration techniques. Using approaches that facilitates the production of skin and consequently its use in cases of wound closure, it is also possible within this model to mimic characteristic inflammatory profiles, in order to study drug-related toxicity or investigate the pathological mechanism of some skin diseases, including psoriasis and atopic dermatitis (Randall et al., 2018; Lorthois et al., 2019; Derr et al., 2019; Liu et al., 2020; Deepa and Bhatt, 2024).

The simultaneous incorporation of different cells into the bioprint, including fibroblasts and melanocytes in dermal equivalents, makes it possible to study the impact of UV radiation (Pasierb et al., 2022). Compared to machining prototypes, bioprinting makes skin production cheaper and faster, as the prototype can be finished in hours, allowing the process to be efficient, even with design modifications in production. The manufacturing process can also reduce material costs, as it uses only the amount of material needed for the prototype itself, minimizing or eliminating waste (Wang H. et al., 2021; Wang Z. et al., 2021).

Other advantages of using the bioprinting technique include: 1) customization of the skin to be used. Depending on the shape and depth of the wound surface, imaging technology using computer digitization can quickly print the skin graft compatible with the wound. Indeed, this technique confers the characteristics of punctuality, high flow and high repeatability (Weng et al., 2021). 2) the use of bioinks, which can be deposited flexibly and precisely with different biological agents, including living cells, nucleic acids, growth factors, among others, is usually required to help build skin structures (Zhu et al., 2016; Wei et al., 2024; Loukelis et al., 2024). According to the different printing materials, three different techniques of bioprinting can be mentioned, such as: droplet-based bioprinting (DBB), laser-assisted bioprinting (LAB) and extrusion-based bioprinting (EBB) (Gudapati et al., 2016; Weng et al., 2021; Kang et al., 2022).

DBB technique includes the drop-by-drop mode. In this model, drops of biomaterial on a substrate are deposited when necessary. DBB-based bioprinters are suitable for deposition and patterning of materials, due to their high precision and minimal biomaterial waste. In addition, DBB mainly uses piezoelectric, thermal or electrostatic forces to generate droplets, which can precisely deposit the biomaterial to make a spatially heterogeneous tissue structure (Gudapati et al., 2016; Matai et al., 2020; Kang et al., 2022). Its non-contact printing mode is more suitable for biological printing directly onto a wound, for example,. Some studies have used the DBB technique to print human keratinocytes and fibroblasts directly onto dermal wounds on the backs of mice. Compared to the control group without any biological dressing, the skin grafts in the experimental group promoted wound healing (Gudapati et al., 2016; Matai et al., 2020; Wang Z. et al., 2021). On the other hand, DBB has some limitations. Its inkjet injector is small, measuring up to 150m, which can be easily blocked by biomaterials. Only low-viscosity hydrogels or other low-concentration biological agents can be used (Wang H. et al., 2021).

LAB technique consists of the emission of laser light, that is focused on the metal film on the back of the silicate glass and heated locally, so that the bioink deposited on the equipment evaporates and is sprayed onto the substrate in the form of liquid drops (Matai et al., 2020; Wang Z. et al., 2021). The LAB technique mainly uses a nanosecond laser with ultraviolet wavelengths as an energy source, and its printing resolution can reach the picogram level, performing bioprinting without direct contact with the substrate and can print cells with high resolution. (Zhang et al., 2023). However, LAB does not have a suitable rapid gelling mechanism yet, which limits its ability to produce high-performance prints (Wang H. et al., 2021; Zhang et al., 2023).

EBB technique makes controllable impressions using fluid distribution systems and automated machines. Under the control of a computer, the biomaterial passes through a catheter, using pneumatic, piston or screw approaches (Zhang et al., 2023). Hydrogels better perform in bioprinting by pneumatic extrusion, because it is kept in this material the profile of printed filaments, after extrusion. The screw-driven structure can bioprint biomaterial at high viscosity, which is conducive to producing a more stable bioprinted tissue (Zieliski et al., 2023). In addition, extrusion bioprinting can print a porous grid structure, promote the circulation of nutrients and metabolites, which allows better control over porosity, shape and distribution of cells in the printed prototype (Pasierb et al., 2022; Zhang et al., 2023). Compared to DBB and LAB models, the advantages of EBB include faster bioprinting speed, more usable bioink types (including cell clusters, high-viscosity hydrogels, microcarriers and cell matrix components) (Pasierb et al., 2022; Zhang et al., 2023), more versatility and suitability for manufacturing prosthetic implants for tissue bioengineering. However, the limitation of this technique is that it has a lower resolution of at least 100m (Zhang et al., 2023; Zieliski et al., 2023).

In general, different approaches in bioprinting techniques are used, in order to allow specialists to acquire more precision and high resolution in the regeneration of the skin and its appendages, including hair follicles, sebaceous and sweat glands. The same approaches might be used on selecting between the different biomaterials, which make the skin cell lineages remain highly viable and metabolically active, to keep the accuracy in replicating the tissue layers and to not compromise functionality (Weng et al., 2021).

Biomaterials can be of natural, synthetic, or a combination of both origins and are of great interest in tissue engineering due to their properties of biocompatibility, biodegradability, promoting cell adhesion and migration in scaffolds, potential resemblance the extracellular matrix, and presenting controllable properties and architecture (Chaudhari et al., 2016; Liu et al., 2023).

Natural biomaterials are primarily derived from proteins, such as collagen and spider silk, for example, (Liu et al., 2023), but can also originate from carbohydrates, such as alginate (Farshidfar et al., 2023).

Firstly, collagen is a protein that contains triple helices capable of forming strong and stable fibers through cross-linking. This stability can be used to form scaffolds that resemble the ECM of living tissues (Chattopadhyay and Raines, 2014; Amirrah et al., 2022; Zhu et al., 2022). Thus, in regenerative medicine, collagen as a biomaterial can be used as a wound dressing, promoting healing, or as a supplement for the skin, improving aspects such as elasticity and hydration (Ghomi et al., 2021).

Spider silk, as a natural biomaterial, is explored for its biocompatibility and low density. Because it is difficult to cultivate directly from arachnids, this protein has been produced recombinantly for the construction of scaffolds for cell culture. Using these supports, the regeneration of bone, cartilage, muscle, nerve, and epidermal tissues, especially in burn patients, has been studied. (Salehi et al., 2020).

It is important to highlight that some materials have limited properties, such as alginate, which has low stability due to its chemical properties, and polydopamine, which has low hydrogel-forming capacity. However, they can be used in combination with other materials, such as hydroxyapatite, chitosan, gelatin, and collagen, to achieve results and applications in tissue engineering. Thus, in combination, they can be used for bone tissue repair, corneal reconstruction, wound healing and covering, and even in drug delivery systems (Farshidfar et al., 2023; Yazdi et al., 2022).

Another way to apply the biomaterials, in general, is using as hydrogels, which provide a moist environment with the ability to retain proteins, growth factors, and nutrients within the gel structure and release these molecules into the medium (Berthiaume et al., 2011; Lei et al., 2022). Due to technological advancements in tissue engineering, it has become possible to work on an increasingly smaller scale of these gels, creating nanogels which can reach smaller and more internal wounds than hydrogels, ensuring drug release in the region, facilitating wound healing and tissue regeneration (Grimaudo et al., 2019; Brianna et al., 2024). In addition to hydrogels, there are also nanomaterials, which can be made of a single chemical element, such as silver or gold, that possess antimicrobial characteristics, can stimulate cell growth and can be delivered in systems along with nanogels (Bellu et al., 2021). The field of nanostructures in regenerative medicine and tissue engineering is still a novelty and shows extreme promise with ongoing research advancements.

As mentioned previously, the field of regenerative medicine for skin regeneration and rejuvenation, while promising, faces several significant limitations as described:

1. High costs and limited accessibility:many regenerative therapies, especially those involving stem cells or bioengineered tissues, are expensive and require specialized equipment and expertise, limiting their accessibility to many patients.

2. Variability in treatment outcomes: the effectiveness of regenerative therapies can vary significantly depending on factors like disease severity, individual genetic background, and overall health. This makes it challenging to predict outcomes and standardize treatment protocols.

3. Long development times and regulatory hurdles: developing and gaining regulatory approval for new regenerative therapies is time-consuming and costly, which slows down the introduction of promising treatments to the market.

4. Technical challenges in production and application: producing sufficient quantities of high-quality regenerative materials (stem cells, bioengineered tissues, exosomes) consistently and reliably for clinical applications remains a significant technological hurdle. The delivery and distribution of these materials in the body can also be complex and may not always be effective.

5. Uncertain long-term efficacy and safety: while many therapies show promise in short-term studies, the long-term efficacy and safety of regenerative treatments are often not fully established. Potential risks such as tumorigenicity or immune responses need further investigation.

6. Ethical considerations: the use of stem cells and gene editing technologies raises ethical concerns, including issues related to stem cell sources (embryonic vs. adult), the potential for off-target effects in gene editing, and the ethical considerations surrounding the use of human tissue and data. Animal testing used in preclinical research may also raise ethical questions.

7. Standardization and quality control: there is a lack of standardization in the preparation and quality control of several regenerative materials and treatments (e.g., PRP, exosomes). This affects the reproducibility and reliability of treatment outcomes.

8. Complex biological systems: the skin is a complex organ with multiple interacting cell types and signaling pathways. Fully understanding these complexities is crucial for developing truly effective regenerative therapies. Current therapies often target only a subset of these mechanisms, limiting their overall impact.

9. Limited understanding of underlying mechanisms: while many regenerative therapies show promise, a complete understanding of their precise mechanisms of action is often lacking. This limits the ability to further improve and refine treatments.

Table 1 summarizes various techniques and approaches used in skin regeneration and treatment, categorized into in vitro and in vivo methods, as well as clinical applications. For each technique, it details specific findings, strengths, and limitations or challenges encountered. The in vitro methods include organotypic cultures (2D and 3D), spheroids, skin reconstructs, cell cultures, exosome studies, and ADSC injections. In vivo techniques cover PRP injections, growth factor application, exosome application, bioprinting, animal models, stem cell and gene therapy. Finally, clinical applications include PRP therapy, growth factor therapy, and dermal fillers. The table provides a comprehensive overview of the current state of skin regeneration research and its therapeutic potential, highlighting both the advantages and drawbacks of different methodologies.

In vitro, in vivo and clinical approaches to skin repair: strengths, limitations, and specific findings.

Table 2 was designed in order to compare various techniques used in skin regeneration, categorized into cell-based and cell-free methods, providing a concise overview of advantages and disadvantages. The cell-based methods include cell therapy, platelet-rich plasma, and growth factors and cytokines, while the cell-free methods encompass exosomes, wound dressings, and gene therapy. Additionally, there is a section for bioengineered skin including biomaterials and nanodevices.

Comparison of cell-based and cell-free approaches for skin regeneration.

Basically, cell-based therapies rely on the biological activity of living cells (e.g., growth factors, immunomodulation), while cell-free methods utilize components derived from cells or synthetic materials to stimulate tissue repair. In general, cell-based therapies offer potential for multifaceted benefits, nevertheless they are often more complex and costly to produce than cell-free options. Also, it is possible to assume that while some cell-based therapies (like PRP) have gained clinical traction, others are still in earlier stages of development. Similarly, the table indicates cell-free options like dermal fillers are established clinically whereas gene therapy, for example, remains limited due to distinct factors such as cost, scalability, and ethical issues. In addition, the comparison sheds light on the potential safety concerns associated with each technique. While cell-based methods carry risks such as immune rejection, cell-free methods have limitations regarding long-term stability and potential off-target effects (e.g., gene therapy). This is vital for evaluating the risk-benefit profile of each approach. By highlighting the limitations of current technologies, the comparison stimulates innovation and the development of new techniques. For instance, challenges in exosome isolation and standardization may boost research into improved purification and delivery methods.

In summary, comparing cell-based and cell-free methods provides a framework for assessing the strengths and weaknesses of different regenerative approaches, contributing to decisions about research direction, clinical translation, and resource allocation within the field of skin regeneration. Addressing these limitations requires continued research, development of standardized protocols, improved manufacturing processes, robust clinical trials, and careful ethical consideration of the technologies making them more effective, affordable, and accessible.

Since the cave age, man has been healing his wounds, treating burns and preventing bleeding. Nowadays, the importance of aesthetics and the growth of the geriatric population is propelling the demand for skin regeneration and rejuvenation products and services. In this context, the interest in maintaining a skin with youthful appearance, the demand for treatment of disorders/disease and superficial or full-thickness skin injuries, has led to the development of regenerative medicine-based approaches, with the aim of repair, replace, regenerate, and rejuvenate (the four Rs) the skin. In recent years we have seen rapid growth in the field of regenerative medicine-based approaches for skin.

View original post here:
Advances in regenerative medicine-based approaches for skin ...

This case study was developed as one of a set of three studies, focusing on somewhat mature but rapidly evolving technologies. These case studies are intended to draw out lessons for the development of a cross-sectoral governance framework for emerging technologies in health and medicine. The focus of the case studies is the governance ecosystem in the United States, though where appropriate, the international landscape is included to provide context. Each of these case studies:

Each case study begins with two short vignettes designed to highlight and make concrete a subset of the ethical issues raised by the case (seeBox 1andBox 2). These vignettes are not intended to be comprehensive but rather to provide a sense of the kinds of ethical issues being raised today by the technology in question.

The cases are structured by a set of guiding questions, outlined subsequently. These questions are followed by the historical context for the case to allow for clearer understanding of the trajectory and impact of the technology over time and the current status (status quo) of the technology. The bulk of the case consists of a cross-sectoral analysis organized according to the following sectors: academia, health care/nonprofit, government, private sector, and volunteer/consumer. Of note, no system of dividing up the world will be perfectthere will inevitably be overlap and imperfect fits. For example, government could be broken into many categories, including international, national, tribal, sovereign, regional, state, city, civilian, or military. The sectoral analysis is further organized into the following domains: science and technology, governance and enforcement, affordability and reimbursement, private companies, and social and ethical considerations. Following the cross-sectoral analysis is a broad, nonsectoral list of additional questions regarding the ethical and societal implications raised by the technology.

The next section of the case is designed to broaden the lens beyond the history and current status of the technology at the center of the case. The Beyond section highlights additional technologies in the broad area the focal technology occupies (e.g., neurotechnology), as well as facilitating technologies that can expand the capacity or reach of the focal technology. The Visioning section is designed to stretch the imagination to envision the future development of the technology (and society), highlighting potential hopes and fears for one possible evolutionary trajectory that a governance framework should take into account.

Finally, lessons learned from the case are identifiedincluding both the core case and the visioning exercise. These lessons will be used, along with the cases themselves, to help inform the development of a cross-sectoral governance framework, intended to be shaped and guided by a set of overarching principles. This governance framework will be created by a committee of the National Academies of Sciences, Engineering, and Medicine (https://www.nationalacademies.org/our-work/creating-a-framework-for-emerging-science-technology-and-innovation-in-health-and-medicine).

Regenerative medicine as a field is quite broad but is generally understood to focus on the regeneration, repair, and replacement of cells, tissues, and organs to restore function (Mason and Dunnill, 2008). The aspect of regenerative medicine on which this case study focuses relates to the ability to treator curegenetic hematologic disease safely and effectively, and the significant trade-offs that come with these novel therapies.

The story of this therapy begins in the history of bone marrow transplants. The medicinal value of bone marrow has long been recognized and was first discussed in the 1890s as a potential treatment (administered orally) of diseases believed to be characterized by defective hemogenesis (Quine, 1896).

While allogeneic bone marrow transplant (in which stem cells from a donor are collected and transplanted into the recipient) may be the most broadly known form of hematopoietic stem and progenitor cell (HSPC) transplant, a range of other cell types are also used. HSPCs used in transplant can be either allogeneic (i.e., from a donor) or autologous (i.e., from the person who will also receive the transplant). The cells used in transplant research and clinical care can come from bone marrow, peripheral blood stem cells (PBSCs), umbilical cord blood, and pluripotent stem cell-derived cells.

A major challenge throughout the history of HSPC transplantation has been the dire risks associated with these transplants, including the morbidity and mortality caused by immunological reactions between the transplanted cells and the tissues of the recipient. In particular, graft-versus-host disease (GVHD) is a serious response in which the transplanted stem cells view the recipients tissues as foreign and mount an immune response, attacking the recipients body. If an autologous transplant is not possible given the nature of the disease to be treated, an immunologically well-matched healthy donor for allogeneic transplant is critical. For genetic hematologic disease, a new approach that would not only treat but cure the condition is now being tested: genetic modification of the patients own HSPCs to correct or compensate for the defect, followed by transplantation of the corrected autologous cells.

This challenge of matching transplantable cells to patients has driven evolution within the field of regenerative medicine, including logistical fixes in the form of HSPC registries and banks to technological approaches including the use of pluripotent stem cell-derived cell sources and genome editing (e.g., clustered regularly interspaced short palindromic repeats [CRISPR]).

This challenge of immunological matching has also driven significant ethical challenges, even beyond the substantial risks of HSPC transplantation itself. In contrast to many novel technologies, where finances are a primary barrier to access, in the case of regenerative medicine, there is the additional barrier of biology. People who are not of European descent have a lower probability of finding well-matched donors than do people of European descent. Furthermore, genetic hematologic diseases like sickle cell disease (SCD) and thalassemia, for which HSPC transplant is the only established cure (and a fraught one, at that), have struggled to garner the financial and grant support needed to move research forward. This challenge persists despite SCD being three times more prevalent in the United States than cystic fibrosis, which has historically benefited from generous public and private funding (Farooq et al., 2020; Wailoo and Pemberton, 2006). All of this stands on a background of long-understood barriers even to standard of care (e.g., adequate pain management) for individuals with SCD in particular (Haywood et al., 2009). Together, these facts raise concerns related to equity and access at multiple stages of research, development, and clinical care.

Finally, advances in this science have also attracted the attention of those who are willing to take advantage of patients under the guise of cutting-edge therapy, creating a robust market of direct-to-consumer (DTC) cell-based services and interventions that at best waste time and money and at worst cause serious harm or death (Bauer et al., 2018).

The following guiding questions were used to frame and develop this case study.

Additional guiding questions to consider include the following:

HSPC transplant was initially only attempted in terminally ill patients (Thomas, 1999). The first recorded bone marrow transfusion was given to a 19-year-old woman with aplastic anemia in 1939 (Osgood et al., 1939). This was long before the Nuremburg Code, the Declaration of Helsinki, or the Belmont Report and anything like current understandings of informed consent (NCPHSBBR, 1979; Rickham, 1964; International Military Tribunal, 1949). There was also little understanding of the factors associated with graft failureno attempts at bone marrow transfusions succeeded, and all patients died. Despite this early experience, the consequences of World War II, particularly the need to improve radiation and burn injury treatment, propelled this work forward (de la Morena and Gatti, 2010).

As human transplant work continued, experiments in mice and dogs in the 1950s and 1960s showed that after lethal radiation, these animals would recover if given autologous bone marrow. However, if given allogeneic marrow, the animal would reject the graft and die or accept the graft but then die from wasting syndrome, which later came to be understood as GVHD (Mannick et al., 1960; Billingham and Brent, 1959; Barnes et al., 1956; Rekers et al., 1950). It became clear that close immunologic matching between donor and recipient and management of GVHD in the recipient would be vital to the success of allogeneic bone marrow transplants (de la Morena and Gatti, 2010).

A 1970 accounting of the reported experience with HSPC transplants to date described approximately 200 allogeneic stem cell graft attempts (six involving fetal tissue) in subjects aged less than 1 to over 80 years, most of which had taken place between 1959 and 1962 (Bortin, 1970). (Of note, there were likely scores of unreported cases; in fact, the author ended the article with a call for reporting of all HSPC transplant attempts to the newly established American College of Surgeons-National Institutes of Health Organ Transplant Registry.) Of the reported cases (which often included the subjects initials), only 11 individuals were unequivocal allogeneic chimeras, and of those, only five were still alive at the time their case was reported. Many of the reported subjects died of opportunistic infections or GVHD, the noting of which often did not capture the true human toll of these deaths. For many years, even success (i.e., engraftment of the transplanted marrow) ended in death due to these other causes (Math et al., 1965; Thomas et al., 1959). As Donnall Thomas, a pioneer and leader in the field who won the Nobel Prize for discoveries concerning organ and cell transplantation in the treatment of human disease in 1990, reflected years later, the experience with allogeneic transplants had been so dismal that questions were raised about whether or not such studies should be continued (Thomas, 2005; Nobel Prize, 1990). In fact, the dismal experience with HSPC transplant eventually led most investigators to discontinue this work in humans, the focus returning for a time to animal studies (Little and Storb, 2002).

However, the discovery of human leukocyte antigen (HLA) in 1958 by Jean Dausset, which helps the immune system differentiate between what is self and what is foreign, and subsequent advances in the understanding of HLA matching and immunosuppression during the 1960s and 1970s led to a resumption of human clinical trials (Nobel Prize, 1980). In 1971, the first successful use of HSPC transplant to treat leukemia was reported (Granot and Storb, 2020). The following decades saw additional developments in HSPC transplant, improving the safety of the intervention, thus enabling its consideration for treatment of a broader array of blood diseases, including the hemoglobinopathies (Granot and Storb, 2020; Apperley, 1993).

The first use of HSPC transplant to cure thalassemia was in 1981, in a 16-month-old child, with an HLA-identical sibling donorthis patient was alive and thalassemia-free more than 20 years later (Bhatia and Walters, 2008; Thomas et al., 1982). Thalassemia major (the most serious form of the disease) requires chronic blood transfusion and chelation for life, a process which leads to gradual iron buildup and related organ damage, including heart failure, which is a common cause of death. Life expectancy for treated patients has increased substantially and varies by thalassemia type and treatment compliance, but patients can now live into their 40s and beyond (Pinto et al., 2019).

The first cure of SCD via HSPC transplant was incidental. An 8-year-old girl with acute myeloid leukemia (AML) was successfully treated for her leukemia with a bone marrow transplant, curing her SCD in the process (Johnson et al., 1984). By this time, life expectancy for an individual with SCD had improved substantially, reaching the mid-20s due to advances in understanding and treatment of the disease (particularly the use of antibiotics to manage the frequent infections that plagued those with the disease) (Wailoo, 2017; Prabhakar et al., 2010). The first five patients, all children, in whom HSPC transplants were used intentionally to treat SCD were reported in 1988 (Vermylen et al., 1988). As Vermylen and colleagues reported, In all cases there was complete cessation of vaso-occlusive episodes and haemolysis (Vermylen et al., 1988).

Around this same time, there were also advancements in the sources of transplantable hematopoietic cells, expanding beyond bone marrow to include peripheral blood stem cells and umbilical cord blood (Gluckman et al., 1989; Kessinger et al., 1988). Cord blood was particularly appealing for a number of reasons, including that it is less immunogenic than the other cell sources, reducing the risk of GVHD.

The development of cord blood transplant has a very different origin story to that of bone marrow, beginning with a hypothesis and the founding of a company (Ballen et al., 2013). The company, Biocyte Corporation (later PharmaStem Therapeutics), funded the early work and held two short-lived patents over the isolation, preservation, and culture of umbilical cord blood (Shyntum and Kalkreuter, 2009). The longevity of the science has thankfully surpassed that of the company that launched it. The first cord bloodbased HSPC transplant was conducted with the approval of the relevant institutional review boards (IRBs) and the French National Ethics Committee, to treat a 5-year-old boy with Fanconi anemia using cells from the birth of an unaffected, HLA-matched sister (Ballen et al., 2013; Gluckman et al., 1989). The success of the early cases (the 5-year-old boy was still alive and well 25 years later) led to the use of unrelated cord blood transplant and expansion of use beyond malignant disease (Ballen et al., 2013; Kurtzberg et al., 1996). Benefits of cord blood include noninvasive collection, ability to cryopreserve characterized tissue for ready use, reduced likelihood of transmitting infections, and lower immunogenicity relative to bone marrow, enabling imperfect HLA matching and expanding access, in particular for people not of European descent (Barker et al., 2010; Gluckman et al., 1997). Cord blood HSPC transplant was first used primarily in children, because it was thought that the relatively low number of cells in a cord blood unit would limit its use in adults, but over time, as techniques and supportive care have improved, so has success of cord blood transplant in adults (Eapen et al., 2010; Ballen et al., 2007). Today, cord blood is widely used for HSPC transplants in both children and adults, with outcomes as good as or better than with bone marrow. Despite these advancements, however, allogeneic HSPC transplant continued to depend on the availability of HLA-matched donors.

Unfortunately, only about 35 percent of patients have HLA-matched siblings, so patients have needed to look beyond their immediate family for matched donors. This need led to the creation of HLA-typed donor registries, starting with the founding of the Europdonor registry in the Netherlands in 1970 and the International Blood and Marrow Transplant Registry at the Medical College of Wisconsin in 1972 (McCann and Gale, 2018). In 1986, the National Marrow Donor Program (NMDP), which operates the Be the Match registry, was founded by the U.S. Navy. Other registries in the United States and Europe followed, and by 1988, there were eight active registries around the world with more than 150,000 donors (van Rood and Oudshoorn, 2008). The Bone Marrow Donors Worldwide network, which connected these registries, was formed in 1988 to facilitate the identification of potential donors, and in 2017 its activities were taken over by the World Marrow Donor Association (WMDA) (Oudshoorn et al., 1994). Today, the combined registry includes more than 37,600,000 donors and more than 800,000 cord blood units from 54 different countries (seeFigure 1) (WMDA, 2021; Petersdorf, 2010).

However, even with tremendous global collaboration to identify and make available donor information, access is not equal. The NMDP estimates suggest that while approximately 90 percent of people of European descent will identify a well-matched unrelated marrow donor, the same will be true for only about 70 percent of people of Asian or Hispanic descent and 60 percent of those of African descent (Pidala et al., 2013). Causes for this disparity include higher HLA diversity among these populations compared to those of European descent and smaller numbers of racial and ethnic minority volunteers in donor registries and ultimately available for transplant (Sacchi et al., 2008; Kollman et al., 2004).

Alongside the public registries, trading on the success of cord blood HSPC transplants and playing on the fears of new parents, a thriving market of private cord blood banks has developed (Murdoch et al., 2020). These for-profit private banks market their servicescollecting and storing cord blood for potential future personal useas insurance policies for the health of ones newborn, without much data to support the claim. While donation of cord blood to a public bank is free to the donor, costs associated with private banking include a collection fee (US$1,350$2,300) and annual storage fees ($100$175/year), which are unlikely to be covered by health insurance (Shearer et al., 2017). At the same time, public banks are held to transparent, rigorous storage and quality standards that do not apply to private banks, leading to lower overall quality of cord blood in private banks (Shearer et al., 2017; Sun et al., 2010; Committee on Obstetric Practice, 2008). Finally, cord blood stored in public banks is 30 times more likely to be accessed for clinical use than samples stored in private banks, and there is broad professional consensus, and associated professional guidance, that public banking is preferable to private banking (Shearer et al., 2017; Ballen et al., 2015). Despite these differences, in 2017, there were about 800,000 cord blood units in public banks, compared with more than 5 million in private banks (Kurtzberg, 2017).

While adult stem cell sources (bone marrow, peripheral blood, and cord blood) have dominated research and clinical care for many decades, in the late 1990s and mid-2000s, new tools were added in the form of several pluripotent stem cell types, including embryonic stem cells, embryonic germ cells, nuclear transfer (NT)-derived stem cells, and most recently, induced pluripotent stem cells (iPSCs) (Tachibana et al., 2013; Yu et al., 2007; Takahashi and Yamanaka, 2006; Shamblott et al., 1998; Thomson et al., 1998). In contrast to the previous cell sources, which are restricted to repopulating blood cell types, these new pluripotent stem cells can turn into any of the approximately 220 cell types in the human body and have a correspondingly diverse array of potential applications. For the purposes of this case, the authors focus on the use of these cells in hematologic disease, but understanding some of the history of the development and use of these cells is helpful for the broader goals of the case. Importantly, these new cell types emerged in a very different regulatory and societal environment than the environment in which bone marrow transplants were first being developed.

The first derivations of human embryonic stem cells (ESCs) and embryonic germ cells (EGCs) were published in 1998 (Shamblott et al., 1998; Thomson et al., 1998). Both of these seminal papers concluded with discussion of the potential for the use of these cells in transplantation-based treatments and cures and emphasized the need to address the challenge of immune rejection, either through the development of cell banks, akin to the registries described previously, or through the genetic modification of the cells to create universal donor cells or to match the particular cellular therapy to the particular patient.

Unlike bone marrow or cord blood, however, the source of these cells was human embryos and fetal tissue, and at the time of these publications, there was already a notable history of governance of these tissues (Matthews and Yang, 2019; Green, 1995; NIH, 1994). In addition, the Dickey-Wicker Amendment had been in place for 3 years, prohibiting the use of federal funds to create human embryos for research or to conduct research in which human embryos are destroyed, discarded, or knowingly subjected to risk of injury or death (104th Congress, 1995). Within weeks of the papers publication, a legal opinion was issued from the Department of Health and Human Services (HHS) interpreting Dickey-Wicker with regard to the new research (Rabb, 1995). Though federal dollars could not be used to create ESCs or EGCs, it was determined that federal dollars could be used to conduct research with pluripotent stem cells thus derived. This interpretation was supported later that year by a report of the National Bioethics Advisory Commission (NBCA, 1999). This did not, however, settle the issue.

A year later, President George W. Bush was elected following a campaign in which he made clear his opposition to this research (Cimons, 2001). In August 2001, in his first address to the nation, President Bush announced that federal funding would be permitted for research using the approximately 60 ESC lines already in existence at the time of his announcement, but not for research with newly derived lines (CNN, 2001). The president seemed to be attempting to walk a fine line between allowing promising research to move forward and not causing the federal government (and taxpayers) to be complicit in the destruction of human embryos. Ultimately, many of these 60 approved Bush lines proved impossible to access or difficult to work with. Furthermore, the accounting required in institutions and laboratories working with both Bush lines and newer lines was daunting (Murugan, 2009).

As ethical and policy debates raged, states began passing their own legislation governing human ESC research, beginning with California, and creating over time a patchwork of state-level policy that ranged from providing government funding for ESC research, as in California, to classifying the work as a felony, such as in Arizona (CIRM.ca.gov, n.d.; Justia US Law, 2020). In 2005, Congress passed its own bill that would permit federal funding of research with an expanded number of human ESC lines, but the bill was subsequently vetoed by President Bush (109th Congress, 2005). The same year, the National Research Council and the Institute of Medicine published its tremendously influential report titled Guidelines for Human Embryonic Stem Cell Research (IOM and NRC, 2005). These guidelines led to highly effective self-regulation in the field, as the Guidelines were adopted across the United States at institutions conducting human ESC research (Robertson, 2010). The Guidelines recommended the creation of a new institutional oversight committee to review ESC research, similar to IRBs, among other recommendations. The Guidelines remained the primary source of governance for ESC research through the end of the Bush administration.

An additional scientific innovation during this time was the announcement of the creation of iPSCs in 2006 (Nobel Prize, 2012; Takahashi and Yamanaka, 2006). iPSCs are derived from somatic tissue, not embryonic or fetal tissue, through the introduction of a small set of transcription factors that effectively reset the mature cell back to a pluripotent state. This concept had actually been introduced as an alternative to ESCs by President Bushs bioethics commission, though it had been met with skepticism, and Shinya Yamanakas announcement at the 2006 International Society for Stem Cell Research (ISSCR) annual meeting stunned the assembled scientists (Scudellari, 2016; The Presidents Council on Bioethics, 2005). This scientific end-run around the destruction of human embryos led to a flood of new researchers, as scientists now needed only somatic cells, rather than highly regulated embryonic or fetal tissue, to participate in this new wave of regenerative medicine research.

By the end of President Bushs second term, in addition to the National Academies Guidelines, guidelines were also issued from the ISSCR and a number of other academic groups (ISSCR, n.d.; The Hinxton Group, 2006). Internationally, as in the United States, a patchwork of policy responses had emerged, ranging from very restrictive to permissive to supportive, leading both domestically and internationally to a degree of brain drain as some scientists relocated to jurisdictions that permitted this research (Verginer and Riccaboni, 2021; Levine, 2012).

When President Barack Obama took office in 2009, he issued an Executive Order reversing former president Bushs prior actions (White House, 2009). Rather than establishing the final rules himself, he permitted funding of ESC research to the extent permitted by law (a nod to the Dickey-Wicker Amendment) and charged the National Institutes of Health (NIH) with developing guidelines for such funding. The NIH guidelines, which largely followed the Guidelines, were finalized in July 2009 and were promptly tied up in a years-long battle in the courts until the Supreme Court declined to hear the final appeal in 2013, leaving the NIH guidelines intact (NIH, 2013, 2009).

The final piece of the regenerative medicine puzzle is the need to overcome immune rejection of transplanted cells. As noted in the initial HPSC papers, potential ways to overcome immune rejection (in the absence of iPSCs) included both banking of a large number of diverse cell lines and genetic modification of the cells intended for transplant, although at the time the technology to do so did not exist (Faden et al., 2003). Gene therapy of this sort had been contemplated for years, and gene transfer trials had begun in the 1990s using the tools scientists had at the time (IOM, 2014). Governance structures grew up around these trials, including the transition of the Recombinant DNA Advisory Committee (RAC) from reviewing NIH-funded research involving recombinant DNA (rDNA) to reviewing gene transfer protocols (IOM, 2014). Of note, though the RAC served as a model internationally for the governance of rDNA research, its mandate was repeatedly questioned and its work critiqued, even as its role evolved (IOM, 2014). As the pace and volume of gene transfer research picked up, the pace of review slowed. Responding not only to the resulting critiques but also the accumulated experience and data, the RAC relaxed restrictions and expedited reviews where possible, ultimately pivoting again to a focus on novel protocols, and leaving more straightforward protocols to the U.S. Food and Drug Administration (FDA) to approve or deny (IOM, 2014). But the original vision of genetically tailored cellular therapy articulated in the 1998 papers did not become possible until almost 15 years later.

In 2012, the publication of the paper that introduced clustered regularly interspaced short palindromic repeats-CRISPR associated protein 9 (CRISPR-Cas9) launched a new era of genetic modification (Jinek et al., 2012). This new tool dramatically improved upon prior gene editing tools with respect to technical ease, speed, and cost, putting the kind of editing imagined in the 1998 papers within reach.

Today, median health care costs for HSPC (including the procedure and 3 months of follow-up) in the United States are approximately $140,000$290,000, depending on the type of procedure (Broder et al., 2017). While 200-day nonremission mortality has decreased substantially since 2000, it remains high (11%) (McDonald et al., 2020). The risks of transplant remain a significant barrier to access, in particular for those with nonmalignant disease, such as SCD. Beyond this, and as noted previously, there are significant ethnic and racial disparities in access to HSPC transplant, largely due to the relatively lower probability of identifying a well-matched HSPC donor (Barker et al., 2019). A recent study demonstrated that while White patients of European descent have a 75 percent chance of finding a well-matched (8/8 HLA-matched) donor, for White Americans of Middle Eastern or North African descent, the probability is 46 percent (Gragert et al., 2014). For Hispanic, Asian, Pacific Islander, and Native American individuals, the probability of such a match ranges from 27 to 52 percent, and for Black Americans, the probability is 1619 percent (Gragert et al., 2014). Contributing to these disparities for racial and ethnic minority groups are higher HLA diversity, smaller numbers of racial and ethnic minority volunteers in donor registries, and the higher rates at which matched minority volunteers become unavailable for donation (e.g., due to inability to reach the volunteer or medical deferral due to diabetes, asthma, infectious disease, or other identified condition) (Sacchi et al., 2008; Kollman et al., 2004). Giving preference to 8/8 HLA-matched pairs therefore benefits White patients and disadvantages patients of color, but removing this preference might result in higher rates of graft failure. Attempts to balance these competing considerations raise ethical questions about justice and beneficence.

Another ethical question in HSPC transplantation revolves around compensation or incentives for donation. Increasing the number and availability of HSCP donors would improve the probability of identifying an appropriate unrelated match for patients in need of a transplant, but the 1984 National Organ Transplant Act (NOTA) banned the sale of bone marrow and organs, making the provision of financial incentives to donate illegal (98th Congress, 1983). Nonetheless, debates over the ethics of providing incentives to encourage the donation of bone marrow and HSCs persist among bioethicists and health economists. In an effort to reduce disincentives to donate, the federal government offers up to 1 work week of leave for federal employees who donate bone marrow, and most states have followed suit for state employees (Lacetera et al., 2014). Some states also offer tax deductions for nonmedical donation-related costs, and there is some evidence that these types of legislation do lead to modest increases in donation rates (Lacetera et al., 2014).

Although removing disincentives to donation is generally considered ethically acceptable, there is more debate about whether offering financial incentives for donation equates to a morally problematic commodification of the human body. In 2011, the 9th Circuit held in Flynn v. Holder that compensation for the collection of PBSCs does not violate NOTAs ban on compensation (Cohen, 2012). In response, a coalition of cell therapy organizations published a statement arguing that this decision would mean that donors would no longer be motivated by altruism, and that people seeking to sell PBSCs might withhold important health information (Be the Match, 2012). After a regulatory back-and-forth over the status of PBSCs, HHS withdrew a proposed rule that would have effectively reversed Flynn v. Holder, so the current state of the law allows compensation for PBSCs (Todd, 2017).

Although Linus Pauling declared sickle cell disease (SCD) to be the first molecular disease (i.e., the first disease understood at the molecular level) in 1949, and it has long been considered an ideal target for gene therapy given that it is predominantly caused by a single mutation in the HBB gene and its phenotypic consequences are in a circulating cell type, developing a cure has not been as straightforward as hoped (Pauling et al., 1949). Though the presentation of SCD can vary significantly, clinical effects include anemia, painful vaso-occlusive crises, acute chest syndrome, splenic sequestration, stroke, chronic pulmonary and renal dysfunction, growth retardation, and premature death (OMIM, n.d.a.).

Standard treatment for SCD consists primarily of preventative and supportive care, including prophylactic penicillin, opioids for severe chronic pain, hydroxyurea, and transfusion therapy (Yawn et al., 2014). Such care has dramatically increased the life expectancy of those living with SCD (median survival in the United States is in the mid- to late 40s) (Wailoo, 2017; Ballas et al., 2016; Prabhakar et al., 2010). At the same time, this care costs more than $35,000 annually, and many patients have difficulty accessing such high-quality care, particularly adequate pain management (Bergman and Diamond, 2013; Haywood, 2013; Haywood et al., 2009; Kauf et al., 2009; Smith et al., 2006). Until recently, the only evidence-based cure for SCD and beta-thalassemia major was allogeneic hematopoietic cell transplantation (HCT), which comes with significant costs and risks (Bhatia and Walters, 2008).

Despite the fact that SCD is one of the most common genetic diseases worldwide and it was the first genetic disease to be molecularly defined, it has received relatively little research funding over the years, an observation that has been a frequent subject of critique (Farooq et al., 2020; Demirci et al., 2019; Benjamin, 2011; Smith et al., 2006; Scott, 1970). In contrast to better-funded diseases, such as cystic fibrosis and Duchenne muscular dystrophy, which are more common in White individuals of European descent, in the United States, SCD predominantly affects non-Hispanic Black and Hispanic populations, including 1 in 365 Black individuals and 1 in 16,300 Hispanic individuals (OMIM, n.d.b., n.d.c.; CDC, 2022). This disparity in research funding despite disease prevalence is part of the larger story of the impacts of structural racism in the United States and on its medical system (The New York Times, 2019; IOM, 2003; HHS and AHRQ, 2003).

Furthermore, as noted previously, those of African and Hispanic ancestry are less likely to be able to identify a suitable match in the existing registries. Due to this difficulty, the improvements in treatment not focused on an HSPC transplant, and the risks of such a transplant, relatively few patients with SCD are treated with HSPC transplant (Yawn et al., 2014; Benjamin, 2011). Gene therapy delivered in the context of an autologous HSPC transplant offers the possibility not only of a safer cure but also broader access by eliminating the need to identify a matched donor.

Recently, the promise of regenerative medicine and gene therapy for genetic hematologic disease appears to be coming to fruition (Ledford, 2020; Stein, 2020; Kolata, 2019). While a number of approaches are currently in various stages of preclinical and clinical research, two promising clinical trials involve the induction of fetal hemoglobin (rather than direct correction of the disease-causing mutation in the HBB gene) (Demirci et al., 2019). Fetal hemoglobin is the predominant globin type in the second and third trimester fetus and for the first few months of life, at which point production shifts from fetal to adult hemoglobin. It has long been recognized that SCD does not present until after this shift occurs (Watson et al., 1948). Furthermore, some patients with the causative SCD mutation are nonetheless asymptomatic, due to also having inherited hereditary persistence of fetal hemoglobin mutations (Stamatoyannopoulos et al., 1975). These findings and others suggested that inducing fetal hemoglobin, even in the presence of a faulty HBB gene, could mitigate the disease.

The first trial uses a viral vector to introduce into autologous bone marrow a short hairpin RNA (shRNA) that inhibits the action of the BCL11A gene. BCL11A is an inhibitor of fetal hemoglobin, so when BCL11A is inhibited, fetal hemoglobin can be produced (Esrick et al., 2021). The second trialthe first published study to use CRISPR to treat a genetic diseaseincludes both patients with SCD and with transfusion-dependent -thalassemia (Frangoul et al., 2021). In this trial, CRISPR-Cas9 is used to target the BCL11A gene to affect the same de-repression of fetal hemoglobin as in the first trial. Both trials, which have collectively enrolled more than 15 patients, have reduced or eliminated the clinical manifestation of disease in all patients thus far, though it remains to be seen how long-lasting this effect will be. However, the first trial was recently suspended after participants in the first trial and a related trial developed acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS) (Liu, 2021); an investigation is under way regarding the cause of the AML and MDS. Marketing of a treatment for transfusion-dependent -thalassemia currently approved and available in the European Union (EU) was also suspended, as that treatment is manufactured using the same vector (BB305 lentiviral vector) used in the current trials, and it is possible that the vector is the source of the serious adverse events in the research participants.

Further challenges remain, including technical challenges, such as the possibility that gene editing tools, as they are derived from bacterial systems, will provoke an immune response; and concerns about financial access, given the anticipated cost of such curative therapies (ICER, 2021; Kim et al., 2018). In addition, despite the technical ease of the technology and designing new nucleic acid targets, intellectual property protecting CRISPR has, to date, narrowed the number of developers actively pursuing CRISPR-based clinical trials (Sherkow, 2017). At the same time, this new technology might also solve a number of ethical issues around HSPC transplants, including by expanding biological access to HSPC transplant and mitigating the concerns raised by the creation of savior siblings for HLA-matched cord blood transplantation for older siblings (Kahn and Mastroianni, 2004).

A long-standing challenge in the field of regenerative medicine is the DTC marketing of unproven cell-based interventions. Since at least the 2000s, unscrupulous scientists and health professionals in the United States and internationally have been offering stem cell therapy at significant cost, often to vulnerable individuals, and without a legitimate scientific or medical basis (Knoepfler and Turner, 2018; Murdoch et al., 2018; Regenberg et al., 2009; Enserink, 2006). From 2009 to 2016, the number of such clinics in the United States doubled annually (Knoepfler and Turner, 2018). While the clinics look legitimate, their claims are fantastical, promising to treat or cure everything from knee pain to Parkinsons disease. Such clinics are often vague about the cell sources involved in the interventions offered, but sometimes they claim to use bone marrow, cord blood, embryonic stem cells, and iPSCs, as well as other types of autologous adult stem cells (e.g., adipose, olfactory) and a range of other cell types, cell sources, and cell mixtures (Murdoch et al., 2018). While such interventions launch from legitimate science and scientific potential, the claims exceed and diverge from what is proven. The interventions are at best very expensive placebos and at worst could cause serious harm or death (Bauer et al., 2018).

Over time, attempts have been made to rein in these clinics by the FDA, the Federal Trade Commission (FTC), the ISSCR, individual customers and their lawyers, and others, but these attempts have faced a number of challenges (Pearce, 2020). The ISSCR, the primary professional society for those engaged in regenerative medicine, has struggled for years against such clinics. Early on, they attempted to establish a mechanism to publicly vet these clinics, though the effort was abandoned in part due to push back from the clinics lawyers (Taylor et al., 2010; personal communication from ISSCR Leadership, n.d.). In part because the majority of US-based clinics offer autologous interventions (removing and then reintroducing the patients own cells), the FDA struggled to clarify the line between medical practice and their regulatory authority. The FDA began issuing occasional warning letters to these clinics starting in 2011, though the letters were issued infrequently (Knoepfler and Turner, 2018). Under this relatively weak enforcement, the market expanded dramatically, and pressure increased on the FDA to take meaningful action (Knoepfler, 2018; Turner and Knoepfler, 2016).

In late 2017, the FDA took several significant steps to curtail these clinics, including using U.S. marshals to seize product from a California clinic, bringing a lawsuit against a Florida clinic, and publishing largely celebrated finalized guidance outlining a risk-based approach to the regulation of regenerative medicine products (FDA, 2019; Pew Research Center, 2019). The following year, the FTC took independent action against clinics making false claims about their interventions, and Google banned advertising for unproven or experimental medical techniques such as most stem cell therapy, cellular (non-stem) therapy, and gene therapy (Biddings, 2019; Fair, 2018). In 2019, the FDA won their case against US Stem Cells in Florida, significantly strengthening their ability to regulate these clinics (Wan and McGinley, 2019). Following the establishment of clear regulatory authority over at least a subset of clinics, FDA has begun to step up its enforcement (Knoepfler, 2020; Wan and McGinley, 2019; FDA, 2018). Increased action is anticipated following the end of the 3-year grace period established in the 2017 guidance, though there is some concern about the capacity of the agency to make significant headway against the more than 600 clinics now in operationa worry bolstered by a 2019 study suggesting that despite increased enforcement, the unproven stem cell market seems to have shifted rather than contracted (Knoepfler, 2019; Pew Research Center, 2019). What seems clear is that it will take a collective and multipronged approach to ensure that the cell-based interventions to which patients have access are safe and effective (Lomax et al., 2020; Pew Research Center, 2019; Master et al., 2017; Zarzeczny et al., 2014).

The cross-sectoral analysis is structured according to sectors (seeFigure 2) and domains (science and technology, governance and enforcement, end-user affordability and insurance reimbursement [affordability and reimbursement], private companies, and social and ethical considerations). The sectors described subsequently are intended to be sufficiently broad to encompass a number of individuals, groups, and institutions that have an interest or role in regenerative medicine. Health care is the primary nonprofit actor of interest, and so in this structure, health care has replaced nonprofit, though other nonprofit actors may have a role in this and other emerging technologies, and, of course, not all health care institutions are nonprofits.

Today, many regenerative medicine technologies are researched, developed, and promoted by a scientific-industrial complex largely driven by market-oriented goals. The development of various components of regenerative medicine may be altered by differing intellectual property regimes. This larger ecosystem is also embedded in a broad geopolitical context, in which the political and the economic are deeply intertwined, shaping national and regional investment and regulation. The political economy of emerging technologies involves and affects not only global markets and regulatory systems across different levels of government but also nonstate actors and international governance bodies. Individuals and societies subsequently adopt emerging technologies, adjusting their own values, attitudes, and norms as necessary, even as these technologies begin to shape the environments where they are deployed or adopted. Furthermore, individual and collective interests may change as the hype cycle of an emerging technology evolves (Gartner, 2022). Stakeholders in this process may include scientific and technological researchers, business firms and industry associations, government officials, civil society groups, worker safety groups, privacy advocates, and environmental protection groups, as well as economic and social justicefocused stakeholders (Marchant et al., 2014).

This intricate ecosystem of stakeholders and interests may be further complicated by the simultaneous introduction of other technologies and platforms with different constellations of ethical issues, modes of governance, and political economy contexts. In the following sections, this ecosystem is disaggregated and organized for ease of presentation. It is important to keep in mind that there are entanglements and feedback loops between and among the different sectors, such that pulling on a single thread in one sector often affects multiple areas and actors across the broader ecosystem.

For the purposes of this case study, the primary actors within the academic sector are academic and clinical researchers and the professional societies that represent them.

Science and technology:This case involves a tremendous amount of research and development that has taken place in and grown out of academia, including preclinical and clinical HSPC transplant research; human ESC, EGC, and iPSC research; and genome editing.

Governance and enforcement:Current work at research institutions is governed by IRBs and REBs, stem cell research oversight committees, and institutional animal care and use committees, among other bodies. In addition, research funding bodies, academic publication standards, and scientific and professional societies (i.e., self-regulation) also have a role to playin particular, the ISSCR and its role in the governance of pluripotent stem cell research and in addressing clinics offering unproven cell-based therapies. The National Academies of Sciences, Engineering, and Medicine played a critical role in the governance of ESC research, particularly from 2005 until 2010.

Affordability and reimbursement:While not strictly a matter of patient affordability, it is important to reiterate, as noted previously, that funding available for academic research has disproportionately benefited those with diseases such as cystic fibrosis and Duchenne muscular dystrophy, which are more common in White individuals of European descent, compared to SCD, which in the United States is more prevalent among non-Hispanic Black and Hispanic populations (Farooq et al., 2020; Demirci et al., 2019; Benjamin, 2011; Smith et al., 2006; Scott, 1970).

Private companies:Academicindustry research partnerships, including industry-funded clinical trials, are involved in this space; for example, the CRISPR-based clinical trial was funded by two biotechnology companies (Frangoul et al., 2021). Such partnerships are often predicated on exclusive intellectual property licenses to surrogate licensors (Contreras and Sherkow, 2017).

Social and ethical considerations:Extensive bioethics literature exists on the ethical, legal, and societal issues raised by human subjects research, first-in-human clinical trials, stem cell research, clinics offering unproven cell-based interventions, genome editing, health disparities, and structural racism. Much has also been written on the role of intellectual property and data and materials sharing in the context of human tissue research and genome editing.

Given the focus of CESTI on health and medicine, for the purpose of this case study, the primary actors within the nonprofit sector are those involved in health care, including hematopoietic stem and progenitor cell registries, health insurance companies, and medical profession associations.

Science and technology:HSPC transplants have been clinically available for decades, but research and improvement in this space continue.

Governance and enforcement:Today, the WMDA serves as the accrediting body for registries and promulgates regulations and standards to which the registries adhere on issues like the organization of a registry, the recruitment of volunteer donors, and the collection and transportation of HPCs (WMDA, 2022; Hurley et al., 2010). These standards represent the minimum guidelines for registries, which demonstrate their commitment to comply with WMDA Standards through the WMDA accreditation process (Hurley et al., 2010). Other groups involved in the governance of aspects of HSPC transplant are included inTable 1.

It is important to note that the nonprofit label in this context is somewhat fraught. Many (perhaps most) health care organizations are very much in the business of making money. One of these is the NMDP, which operates Be the Match, and which has diversified its portfolio over time, including the launch in 2016 of Be the Match BioTherapies, which partners with dozens of cell and gene therapy companies, supplying cells and services to advance the development of life-saving cell and gene therapies (Be the Match, 2021a,b).

The FDA generally has authority to regulate bone marrow transplantation through its oversight of bone marrow itself as a human cellular tissue product (HCT/P) and, therefore, a biologic (U.S. Code 262, n.d.). Typically, biologic products are required to submit to the FDAs premarket review process, including the filing of an investigative new drug application and clinical trials. With that said, the FDA has exempted certain types of bone marrow transplantation procedures from such review: namely, bone marrow products that are used in a same-day surgical procedure and those that are only minimally manipulated (FDA, 2020). Importantly, while the FDAs minimally manipulated exception broadly applies to autologous therapy, including the sort of therapy private cord blood banks are intended to plan for, it only applies to allogenic therapy if derived from a first-degree or second-degree blood relative; allogenic therapy using cells from more distant relatives requires the FDAs premarket review (FDA, 2020).

Cord blood matching and donor priority is controlled by the NMDP and regulated by the FDA (CFR, 2012). However, because cord blood therapy is almost always allogenic and usually from anonymized donors unrelated to the patient, cord blood HSPC transplant generally does not fulfill the FDAs minimal manipulation exemptions for HCT/P (FDA, 2020). As such, a total of eight public cord blood banks have applied for, and received, approval from the FDA for their cord blood products (FDA, 2022). Generally, public banks are held to transparent, rigorous storage and quality standards that do not apply to private banks, leading to lower overall quality of cord blood in private banks (Shearer et al., 2017; Sun et al., 2010; Committee on Obstetric Practice, 2008).

The American Academy of Pediatrics has taken a position on private versus public cord blood banks and supports public banking, as do the American Medical Association and the American Congress of Obstetricians and Gynecologists (AMA, n.d.; ACOG, 2019; Shearer et al., 2017).

Affordability and reimbursement:Both public and private insurers in the United States tend to distinguish autologous from allogenic bone marrow therapies, covering autologous transplantation for some indications and allogenic transplantation for others (CMS, 2016).

Leaving aside the broader issues of health insurance and health care affordability in the United States, annual and lifelong care costs for genetic hematologic diseases like SCD and thalassemia are considerablethe yearly cost of standard of care for a patient with SCD is more than $35,000 (Kauf et al., 2009). Novel therapiesboth pharmacologic and those based on HSPC transplantsare anticipated to be extraordinarily expensive, if proven safe and effective. For example, the drugs Oxbryta and Adakveo, approved in 2019 for treating SCD, are estimated to cost $84,000 and $88,000 per year, respectively (ICER, 2021; Sagonowsky, 2020). CART-T cell therapy, which as another novel, genetically modified cell-based therapy may be a reasonable bellwether for the cost of the SCD therapies described previously, costs at least $373,000 for a single infusion before hospital and other associated costs (Beasley, 2019). Many patients suffering from these diseases are from historically marginalized and underserved populations that tend to have lower levels of income. In addition, as therapies become more bespoke, scaling will increasingly become a challenge, from both a regulatory and delivery perspective. However, these delivery challenges may also open new business opportunities.

While donation of cord blood to a public bank is free to the donor, costs associated with private banking include a collection fee ($1,350$2,300) and annual storage fees ($100$175 a year), which are unlikely to be covered by health insurance (Shearer et al., 2017).

Private companies:Many private companies advertise private cord blood banking to new parents as a form of biological insurance; however, the costs of collection and storage are not generally covered by medical insurance (private companies offering unproven cell-based interventions are included under the private sector rather than health care).

Go here to see the original:
Regenerative Medicine: Case Study for Understanding and Anticipating ...

Top 3 Grants in Regenerative Medicine: February 2025  RegMedNet

Read the original:
Top 3 Grants in Regenerative Medicine: February 2025 - RegMedNet

Editorial: Tissue Engineering and Regenerative Medicine: Advances, Controversies, and Future Directions by Frontiers in Bioengineering and Biotechnology  Frontiers

More here:
Editorial: Tissue Engineering and Regenerative Medicine: Advances, Controversies, and Future Directions by Frontiers in Bioengineering and...

Malaysia To Host 7th World Conference On Exercise And Regenerative Medicine  BERNAMA

Read the original here:
Malaysia To Host 7th World Conference On Exercise And Regenerative Medicine - BERNAMA

Advancing Regenerative Medicine: A Comprehensive Outlook on the Global Cell Therapy Market  openPR

View original post here:
Advancing Regenerative Medicine: A Comprehensive Outlook on the Global Cell Therapy Market - openPR

Worlds First 3D-Printed Penis Implant Successfully Restores Function in Pigs and Rabbits  The Daily Galaxy --Great Discoveries Channel

The rest is here:
Worlds First 3D-Printed Penis Implant Successfully Restores Function in Pigs and Rabbits - The Daily Galaxy --Great Discoveries Channel

AskBio Receives FDA Regenerative Medicine Advanced Therapy designation for Parkinsons disease investigational gene therapy  Bayer

Continued here:
AskBio Receives FDA Regenerative Medicine Advanced Therapy designation for Parkinsons disease investigational gene therapy - Bayer

The link you followed may be broken, or the page may have been moved.

To find the right page:

Once you find what you're looking for, please update your links or bookmarks.

You also may report the broken linkto the UNMC webmaster. Please include in your email the URL of the page where you clicked on the broken link. We need that URL in order to fix the broken link.

See the original post here:
What is Regenerative Medicine? | Regenerative Medicine | University of ...

The quest for a communication device that tells cells to regenerate the body  Big Think

Read the rest here:
The quest for a communication device that tells cells to regenerate the body - Big Think

Transforming the future of regenerative medicine  Reuters

Read the rest here:
Transforming the future of regenerative medicine - Reuters

Breakthrough Alzheimer's Treatment Gets Official WHO Recognition - Major Milestone for Rare Disease Therapy  StockTitan

Link:
Breakthrough Alzheimer's Treatment Gets Official WHO Recognition - Major Milestone for Rare Disease Therapy - StockTitan

Regenerative Medicine Pioneer with 35-Year Track Record Takes Scientific Helm at ZEO ScientifiX  StockTitan

View post:
Regenerative Medicine Pioneer with 35-Year Track Record Takes Scientific Helm at ZEO ScientifiX - StockTitan