Regenerative medicine: Current therapies and future directions

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    Regenerative medicine: Current therapiesand future directionsAngelo S. Maoa,b and David J. Mooneya,b,1aJohn A. Paulson School of Engineering and Applied Sciences, Harvard University, Cambridge, MA 02138; and bWyss Institute for BiologicallyInspired 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 ontransplantations. 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 ofregenerative medicine therapies, including those designed for wound healing and orthopedics applications, have received Food and DrugAdministration (FDA) approval and are now commercially available. These therapies and other regenerative medicine approaches currentlybeing studied in preclinical and clinical settings will be covered in this review. Specifically, developments in fabricating sophisticated grafts andtissue mimics and technologies for integrating grafts with host vasculature will be discussed. Enhancing the intrinsic regenerative capacity ofthe host by altering its environment, whether with cell injections or immune modulation, will be addressed, as well as methods for exploitingrecently 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 toheal or replace tissues and organs damagedby age, disease, or trauma, as well as to nor-malize congenital defects. Promising preclin-ical and clinical data to date support thepossibility for treating both chronic diseasesand acute insults, and for regenerative med-icine to abet maladies occurring across a widearray of organ systems and contexts, includ-ing dermal wounds, cardiovascular diseasesand traumas, treatments for certain types ofcancer, and more (13). The current therapyof transplantation of intact organs and tis-sues to treat organ and tissue failures andloss suffers from limited donor supply andoften severe immune complications, butthese obstacles may potentially be bypassedthrough the use of regenerative medicinestrategies (4).The field of regenerative medicine encom-

    passes numerous strategies, including the useof materials and de novo generated cells, aswell as various combinations thereof, to takethe place of missing tissue, effectively replac-ing it both structurally and functionally, or tocontribute to tissue healing (5). The bodysinnate healing response may also be lever-aged to promote regeneration, although adulthumans possess limited regenerative capacityin comparison with lower vertebrates (6).This review will first discuss regenerativemedicine therapies that have reached themarket. Preclinical and early clinical workto alter the physiological environment ofthe patient by the introduction of materials,living cells, or growth factors either to replace

    lost tissue or to enhance the bodys innatehealing and repair mechanisms will then bereviewed. Strategies for improving the struc-tural sophistication of implantable grafts andeffectively using recently developed cell sourceswill also be discussed. Finally, potential futuredirections in the field will be proposed. Dueto the considerable overlap in how researchersuse the terms regenerative medicine and tis-sue engineering, we group these activities to-gether in this review under the heading ofregenerative medicine.

    Therapies in the MarketSince tissue engineering and regenerativemedicine emerged as an industry about twodecades ago, a number of therapies have re-ceived Food and Drug Administration (FDA)clearance or approval and are commerciallyavailable (Table 1). The delivery of thera-peutic cells that directly contribute to thestructure and function of new tissues is aprinciple paradigm of regenerative medicineto date (7, 8). The cells used in these thera-pies are either autologous or allogeneic andare typically differentiated cells that stillmaintain proliferative capacity. For example,Carticel, the first FDA-approved biologicproduct in the orthopedic field, uses autolo-gous chondrocytes for the treatment of focalarticular cartilage defects. Here, autologouschondrocytes are harvested from articularcartilage, expanded ex vivo, and implanted atthe site of injury, resulting in recovery com-parable with that observed using micro-fracture and mosaicplasty techniques (9).Other examples include laViv, which involves

    the injection of autologous fibroblasts toimprove the appearance of nasolabial foldwrinkles; Celution, a medical device that ex-tracts cells from adipose tissue derived fromliposuction; Epicel, autologous keratinocytesfor severe burn wounds; and the harvestof cord blood to obtain hematopoietic pro-genitor and stem cells. Autologous cells re-quire harvest of a patients tissue, typicallycreating a new wound site, and their use of-ten necessitates a delay before treatment asthe cells are culture-expanded. Allogeneic cellsources with low antigenicity [for example,human foreskin fibroblasts used in the fab-rication of wound-healing grafts (GINTUIT,Apligraf) (10)] allow off-the-shelf tissues tobe mass produced, while also diminishing therisk of an adverse immune reaction.Materials are often an important compo-

    nent of current regenerative medicine strate-gies because the material can mimic the nativeextracellular matrix (ECM) of tissues and di-rect cell behavior, contribute to the structureand function of new tissue, and locally presentgrowth factors (11). For example, 3D polymerscaffolds are used to promote expansion ofchondrocytes in cartilage repair [e.g., matrix-induced autologous chondrocyte implantation

    Author contributions: A.S.M. and D.J.M. wrote the paper.

    The authors declare no conflict of interest.

    This article is a PNAS Direct Submission.

    This article is part of the special series of PNAS 100th Anniversaryarticles to commemorate exceptional research published in PNASover the last century.

    1To whom correspondence should be addressed. Email:

    1445214459 | PNAS | November 24, 2015 | vol. 112 | no. 47

  • (MACI)] and provide a scaffold for fibroblastsin the treatment of venous ulcers (Derma-graft) (12). Decellularized donor tissues are alsoused to promote wound healing (Dermapure,a variety of proprietary bone allografts)(13) or as tissue substitutes (CryoLife andTorontos heart valve substitutes andcardiac patches) (14). A material alone cansometimes provide cues for regeneration andgraft or implant integration, as in the case ofbioglass-based grafts that permit fusion withbone (15). Incorporation of growth factorsthat promote healing or regeneration intobiomaterials can provide a local and sus-tained presentation of these factors, and thisapproach has been exploited to promotewound healing by delivery of platelet de-rived growth factor (PDGF) (Regranex)and bone formation via delivery of bonemorphogenic proteins 2 and 7 (Infuse,Strykers OP-1) (16). However, complicationscan arise with these strategies (Infuse,Regranex black box warning) (17, 18), likelydue to the poor control over factor releasekinetics with the currently used materials.The efficacies of regenerative medicine

    products that have been cleared or approvedby the FDA to date vary but are generallybetter or at least comparable with preexistingproducts (9). They provide benefit in termsof healing and regeneration but are unableto fully resolve injuries or diseases (1921).Introducing new products to the market ismade difficult by the large time and mone-tary investments required to earn FDA ap-proval in this field. For drugs and biologics,the progression from concept to market in-volves numerous phases of clinical testing,can require more than a dozen years of de-velopment and testing, and entails an averagecost ranging from $802 million to $2.6 billionper drug (22, 23). In contrast, medical devices,a broad category that includes noncellularproducts, such as acellular matrices, generallyreach the market after only 37 years of

    development and may undergo an expeditedprocess if they are demonstrated to be similarto preexisting devices (24). As such, acellularproducts may be preferable from a regulatoryand development perspective, compared withcell-based products, due to the less arduousapproval process.

    Therapies at the Preclinical Stage and inClinical TestingA broad range of strategies at both the pre-clinical and clinical stages of investigation arecurrently being explored. The subsequent sub-sections will overview these different strategies,which have been broken up into three broadcategories: (i) recapitulating organ and tissuestructure via scaffold fabrication, 3D bio-printing, and self assembly; (ii) integratinggrafts with the host via vascularization andinnervation; and (iii) altering the host envi-ronment to induce therapeutic responses,particularly through cell infusion and mod-ulating the immune system. Finally, methodsfor exploiting recently identified and devel-oped cell sources for regenerative medicinewill be mentioned.

    Recapitulating Tissue and Organ Struc-ture. Because tissue and organ architectureis deeply connected with function, the abilityto recreate structure is typically be