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Regenerative Medicine: Current Therapies and Future Directions Angelo S

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Regenerative Medicine: Current Therapies and Future Directions Angelo S SPECIAL FEATURE: PERSPECTIVE Regenerative medicine: Current therapies and future directions Angelo S. Maoa,b and David J. Mooneya,b,1 aJohn A. Paulson School of Engineering and Applied Sciences, Harvard University, Cambridge, MA 02138; and bWyss Institute for Biologically Inspired Engineering at Harvard University, Cambridge, MA 02138 Edited by Mark E. Davis, California Institute of Technology, Pasadena, CA, and approved September 4, 2015 (received for review June 12, 2015) Organ and tissue loss through disease and injury motivate the development of therapies that can regenerate tissues and decrease reliance on transplantations. Regenerative medicine, an interdisciplinary field that applies engineering and life science principles to promote regeneration, can potentially restore diseased and injured tissues and whole organs. Since the inception of the field several decades ago, a number of regenerative medicine therapies, including those designed for wound healing and orthopedics applications, have received Food and Drug Administration (FDA) approval and are now commercially available. These therapies and other regenerative medicine approaches currently being studied in preclinical and clinical settings will be covered in this review. Specifically, developments in fabricating sophisticated grafts and tissue mimics and technologies for integrating grafts with host vasculature will be discussed. Enhancing the intrinsic regenerative capacity of the host by altering its environment, whether with cell injections or immune modulation, will be addressed, as well as methods for exploiting recently developed cell sources. Finally, we propose directions for current and future regenerative medicine therapies. regenerative medicine | tissue engineering | biomaterials | review Regenerative medicine has the potential to lost tissue or to enhance the body’s innate the injection of autologous fibroblasts to heal or replace tissues and organs damaged healing and repair mechanisms will then be improve the appearance of nasolabial fold by age, disease, or trauma, as well as to nor- reviewed. Strategies for improving the struc- wrinkles; Celution, a medical device that ex- malize congenital defects. Promising preclin- tural sophistication of implantable grafts and tracts cells from adipose tissue derived from ical and clinical data to date support the effectively using recently developed cell sources liposuction; Epicel, autologous keratinocytes possibility for treating both chronic diseases will also be discussed. Finally, potential future for severe burn wounds; and the harvest and acute insults, and for regenerative med- directions in the field will be proposed. Due of cord blood to obtain hematopoietic pro- icine to abet maladies occurring across a wide to the considerable overlap in how researchers genitor and stem cells. Autologous cells re- array of organ systems and contexts, includ- use the terms regenerative medicine and tis- quire harvest of a patient’stissue,typically ing dermal wounds, cardiovascular diseases sue engineering, we group these activities to- creating a new wound site, and their use of- and traumas, treatments for certain types of gether in this review under the heading of ten necessitates a delay before treatment as cancer, and more (1–3). The current therapy regenerative medicine. the cells are culture-expanded. Allogeneic cell of transplantation of intact organs and tis- Therapies in the Market sources with low antigenicity [for example, sues to treat organ and tissue failures and human foreskin fibroblasts used in the fab- Since tissue engineering and regenerative loss suffers from limited donor supply and rication of wound-healing grafts (GINTUIT, medicine emerged as an industry about two Apligraf) (10)] allow off-the-shelf tissues to often severe immune complications, but decades ago, a number of therapies have re- be mass produced, while also diminishing the these obstacles may potentially be bypassed ceived Food and Drug Administration (FDA) risk of an adverse immune reaction. through the use of regenerative medicine clearance or approval and are commercially Materials are often an important compo- strategies (4). available(Table1).Thedeliveryofthera- nent of current regenerative medicine strate- The field of regenerative medicine encom- peutic cells that directly contribute to the passes numerous strategies, including the use structure and function of new tissues is a gies because the material can mimic the native of materials and de novo generated cells, as principle paradigm of regenerative medicine extracellular matrix (ECM) of tissues and di- well as various combinations thereof, to take to date (7, 8). The cells used in these thera- rect cell behavior, contribute to the structure the place of missing tissue, effectively replac- pies are either autologous or allogeneic and and function of new tissue, and locally present ing it both structurally and functionally, or to are typically differentiated cells that still growth factors (11). For example, 3D polymer ’ contribute to tissue healing (5). The body s maintain proliferative capacity. For example, scaffolds are used to promote expansion of innate healing response may also be lever- Carticel, the first FDA-approved biologic chondrocytes in cartilage repair [e.g., matrix- aged to promote regeneration, although adult product in the orthopedic field, uses autolo- induced autologous chondrocyte implantation humans possess limited regenerative capacity gous chondrocytes for the treatment of focal in comparison with lower vertebrates (6). articular cartilage defects. Here, autologous Author contributions: A.S.M. and D.J.M. wrote the paper. This review will first discuss regenerative chondrocytes are harvested from articular The authors declare no conflict of interest. medicine therapies that have reached the cartilage, expanded ex vivo, and implanted at This article is a PNAS Direct Submission. market. Preclinical and early clinical work the site of injury, resulting in recovery com- This article is part of the special series of PNAS 100th Anniversary articles to commemorate exceptional research published in PNAS to alter the physiological environment of parable with that observed using micro- over the last century. the patient by the introduction of materials, fracture and mosaicplasty techniques (9). 1To whom correspondence should be addressed. Email: mooneyd@ living cells, or growth factors either to replace OtherexamplesincludelaViv,whichinvolves seas.harvard.edu. 14452–14459 | PNAS | November 24, 2015 | vol. 112 | no. 47 www.pnas.org/cgi/doi/10.1073/pnas.1508520112 Downloaded by guest on September 30, 2021 Table 1. Regenerative medicine FDA-approved products PERSPECTIVE SPECIAL FEATURE: Category Name Biological agent Approved use Biologics laViv Autologous fibroblasts Improving nasolabial fold appearance Carticel Autologous chondrocytes Cartilage defects from acute or repetitive trauma Apligraf, GINTUIT Allogeneic cultured keratinocytes and Topical mucogingival conditions, leg and diabetic fibroblasts in bovine collagen foot ulcers Cord blood Hematopoietic stem and progenitor cells Hematopoietic and immunological reconstitution after myeloablative treatment Cell-based medical devices Dermagraft Allogenic fibroblasts Diabetic foot ulcer Celution Cell extraction Transfer of autologous adipose stem cells Biopharmaceuticals GEM 125 PDGF-BB, tricalcium phosphate Periodontal defects Regranex PDGF-BB Lower extremity diabetic ulcers Infuse, Infuse bone graft, BMP-2 Tibia fracture and nonunion, and lower spine fusion Inductos Osteogenic protein-1 BMP-7 Tibia nonunion (MACI)] and provide a scaffold for fibroblasts development and may undergo an expedited without the recellularization step, have also in the treatment of venous ulcers (Derma- process if they are demonstrated to be similar reached the market as medical devices, as graft) (12). Decellularized donor tissues are also to preexisting devices (24). As such, acellular noted above, and have been used to repair used to promote wound healing (Dermapure, products may be preferable from a regulatory large muscle defects in a human patient (32). a variety of proprietary bone allografts) and development perspective, compared with A variation on this approach involves the (13) or as tissue substitutes (CryoLife and cell-based products, due to the less arduous engineering of blood vessels in vitro and their Toronto’s heart valve substitutes and approval process. subsequent decellularization before place- cardiac patches) (14). A material alone can ment in patients requiring kidney di- sometimes provide cues for regeneration and Therapies at the Preclinical Stage and in alysis (33). Despite these successes, a number graft or implant integration, as in the case of Clinical Testing of challenges remain. Mechanical properties bioglass-based grafts that permit fusion with A broad range of strategies at both the pre- of tissues and organs may be affected by the bone (15). Incorporation of growth factors clinical and clinical stages of investigation are decellularization process, the process may that promote healing or regeneration into currently being explored. The subsequent sub- remove various types and amounts of ECM- biomaterials can provide a local and sus- sections will overview these different strategies, associated signaling molecules, and the pro- tained presentation of these factors, and this which have been broken up into three broad cessed tissue may degrade over time after approach has been exploited to promote
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