Transforming healthcare through regenerative medicine
© The Author(s). 2016
Received: 8 July 2016
Accepted: 5 August 2016
Published: 10 August 2016
Regenerative medicine therapies, underpinned by the core principles of rejuvenation, regeneration and replacement, are shifting the paradigm in healthcare from symptomatic treatment in the 20th century to curative treatment in the 21st century. By addressing the reasons behind the rapid expansion of regenerative medicine research and presenting an overview of current clinical trials, we explore the potential of regenerative medicine to reshape modern healthcare.
The current dilemmas for modern day healthcare, such as an aging population and the increasing prevalence of chronic diseases, require solutions that limit organ dysfunction and tissue degeneration and which potentially offer replacement. This was first addressed through transplantation, a field that advanced rapidly in the 1950s through a combination of surgical innovations and fundamental scientific breakthroughs in immunosuppression . In contrast to the allogenic replacement of transplantation, regenerative medicine seeks to apply stem cell research with developmental biology principles to regenerate cells, tissues and organs de novo .
Regenerative medicine has been recognized worldwide as a developing research field that offers the potential to revolutionize patient care in the 21st century . The prospect of addressing massive healthcare markets, such as cardiovascular disease, neurological conditions or chronic metabolic diseases (e.g. end-stage renal disease or diabetes), means that there has been sustained scientific, public and commercial interest despite early setbacks and slow progress.
Expansion and potential impact of regenerative medicine
Demand for regenerative medicine products has been driven by an increase in degenerative and chronic diseases which place cost pressures on healthcare providers, combined with advances in new technologies such as nanotechnology, bioengineering and stem cell therapy . Long-term cell, tissue and organ replacement will not only provide an alternative to transplantation , but will also provide therapeutic options for degenerative conditions (e.g. neurodegenerative conditions (Parkinson’s), stroke and heart failure), which are currently only managed through palliation [12, 13].
According to the World Regenerative Medicines Market forecast for 2013–2020 , the global regenerative medicines market for small molecules and biologics, gene therapy and cell therapy is expected to reach $67.5 billion by 2020, which is an increase of $51.1 billion from 2013, thus reflecting its commercial potential. Governments across Europe and the US, as well as their medical research councils, have identified tissue engineering and regenerative medicine at the top of their research priorities . Removal of previous restrictions in embryonic stem cell research in 2009 by the Obama organization is predicted to contribute to further considerable growth within the field as well as improved potential for clinical translation .
Clinical trials in regenerative medicine
Applications of regenerative medicine therapies in different medical specialties
Clinical Trial Phase
Clinical Trial Study
Pubmed Clinical Trial database
Fetal porcine cells
Transplantation of embryonic dopamine neurons
Fink 2001; Freed 2001
Paraplegia, Spinal cord injuries
MSCs transplanted directly into injured spinal cord.
Bone marrow nucleated cells injected intrathecally and intravenously coupled with MSC infusion by lumbar puncture
Park 2012; Jarocha 2015
IV infusion of MSCs
Haemopoietic stem cell transplants
Ischaemic cardiomyopathy, heart failure
Transendocardial injection of MSC derived from BM or adipose tissue
Intracoronary injection of cardiac stem cells IV infusion of MSC
Heldman 2014; Hare 2014; Chugh 2012; Perin 2014
Idiopathic pulmonary fibrosis
IV infusion of placental- Chambers derived MSC
Chronic lung disease
IV infusion of HLA-matched allogeneic MSCs derived from BM/umbilical cord
Intra-articular injection of autologous or allogeneic MSC
I, II, III
Orozco 2013; Jo 2014
Allogeneic bone marrow derived MSC
Haemopoietic stem cell transplant plus MSC infusion
Horwitz 2002; Horwitz 2002
MSC combined with/without calcium sulphate
Allogenic bone graft containing stem cells
G-CSF-mobilised Haemopoietic stem cells with collagen scaffold for non-union fracture healing
Kuoroda 2014; Jones 2015; Bajada 2007
Hematopoietic stem cell transplant (HSCT); Graft versus Host Disease (GvHD)
Prochymal (MSC) for severe refractory acute GvHD
MSC infused with or following hematopoietic stem cell transplant
I, II, III
Prasad 2011; Ringden 2006; Perez-Simon 2011
ESC-derived retinal pigment epithelium
Liver cirrhosis; Decompensated liver disease
MSC injected into peripheral or portal vein
Autologous bone marrow mononuclear cells infused IV for liver cirrhosis
UC-MSC IV in fusion in decompensated liver disease
Kharaziha 2009; terai 2006; Zhang 2012
Autologous hematopoietic)stem cell transplantation for refractory Crohn’s
I, II, III
Diabetes (type I & 2)
Stem cell educator therapy with cord blood derived stem cells for insulin resistant type II diabetes
Hematopoietic stem cell transplantation for new onset type I diabetes
Zhao 2013, D’Addio 2014
Kidney transplant rejection
MSC based therapy to prevent rejection in living-related kidney transplants
Overview of testing of regenerative medicine products to validate sterility, stability and potency
Direct inoculation test in aerobic and anaerobic media
Animal testing to investigate interactions between native tissue and product
Flow cytometry and immunohistochemical analysis
Purity and viability of cell population
Fluorescent/superparamagnetic iron oxide cell labeling prior to animal implantation
Cell-based therapies work either via stimulation of endogenous repair through extracellular factors or differentiation and functional replacement of endogenous cell types ; they include stem cell implantation or infusion to treat hematopoietic diseases, cardiac conditions and Parkinson’s disease. Most of the pioneering work has been performed using haematopoietic stem cells due to the early bone marrow transplant work, making them the most well-studied stem cell type . In particular, adult mesenchymal stem cells have gained interest as they avoid the ethical concerns of using embryonic stem cells, can be rapidly expanded in vitro and avoid immunogenicity. Studies have shown contradictory results on the efficacy of the transplanted cells, with patient variability with regards to response (Table 1); further work is needed to elucidate cell identity and health to ensure patient safety (Table 2).
The tissue engineering strand of regenerative medicine incorporates cells with biodegradable scaffolds to engineer replacement tissues like dermis or cartilage  and whole organs such as trachea and bladder [21, 22]. Limitations of synthetic polymer scaffolds, such as infection, extrusion and degradation product toxicity, have encouraged interest in decellularised matrices as well biologics for use as scaffolds as one of the more effective ways of replicating native tissue anisotropy [21, 22]. Decellularised matrices provide durability, enhanced integration and biocompatibility whilst avoiding allosensitization . This may explain why many of the significant breakthroughs and first-in-man studies have utilized this technique combined with autologous cell-seeding with some success [21–23], and even showed promise in vitro for more complex structures such as pulmonary and aortic valves as well as whole organs such as heart and liver [24, 25]. However, despite early interest and investment in tissue engineering research, with annual R&D spending estimated at US$580 million, initial clinically applicable product release has been slow but steady .
Controversies in the field
The regenerative medicine field has been shrouded in controversy. Significant potential gains have led to several high profile allegations of research misconduct [27, 28]. There is also a growing stem cell tourism industry based on unproven treatments that aims to capitalize on stem cell hype [29, 30]. Desperate patients would rather approach private clinics offering experimental stem cell treatments, with unproven safety and efficacy profiles, than wait for outcomes of clinical trials . Media coverage and direct advertising of stem cell therapies as well as the political, ethical and religious controversies surrounding human embryonic stem cells, can contribute not only to increased public awareness but also inflated expectations of regenerative medicine products, and there continues to be a significant gap between the perceived and realistic benefits . A concerted effort from the scientific community as well as robust outcome data from clinical trials will be needed to temper unrealistic claims [16, 17].
Medical breakthroughs often require the convergence of multiple scientific advances for which interdisciplinary collaboration is fundamental. Similar to transplant medicine, regenerative medicine requires the convergence of a number of scientific disciplines, including stem cell biology, developmental and molecular biology, engineering and biomaterials. Despite media hype, scientific overclaim and unrealistic expectations, which have been previously witnessed for a number of healthcare technologies, regenerative medicine continues to make steady progress reflected by the increasing number of clinical trials [16, 17]. Significant potential has been demonstrated in the cell therapy field to treat haematological, neurological and rheumatological conditions. The tissue engineering field, although holding great promise, still has some way to develop before the excitement surrounding novel biofabrication strategies, such as 3D bioprinting, is translated to patient care. The fast moving and versatile field of regenerative medicine is at the cutting edge of translational research and could shift the paradigm in healthcare from symptomatic to curative treatment. BMC Medicine is very interested in breakthroughs in regenerative medicine/stem cell therapy and submission of such relevant articles is encouraged.
Mr. Steve Atherton RMIP MIMI, Medical Illustrator, ABMU Health Board for Fig. 1.
ZMJ, AA and WF undertook a literature review, collated data and wrote the final manuscript. ISW conceived the manuscript, contributed content and provided a critical overview. All authors read and approved the final manuscript.
Ms Zita M. Jessop is a Medical Research Council (MRC) Clinical Research Training Fellow in the Reconstructive Surgery & Regenerative Medicine Research Group, at Swansea University Medical School and a Clinical Lecturer on the Welsh Clinical Academic Track Fellowship Scheme.
Dr Ayesha Al-Sabah is a Postdoctoral Scientist in the Reconstructive Surgery & Regenerative Medicine Research Group, at Swansea University Medical School.
Dr Wendy R. Francis is a Postdoctoral Scientist at the Centre for NanoHealth at Swansea University.
Professor Iain S Whitaker is the Chair of Plastic & Reconstructive Surgery and Director of the Reconstructive Surgery & Regenerative Medicine (ReconRegen) Research Group at Swansea University Medical School and Honorary Consultant Plastic Surgeon at The Welsh Centre for Burns & Plastic Surgery.
There are no sources of financial or other support, or any financial or professional relationships that might pose a competing interest for any of the authors.
Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
- Calne R. The history and development of organ transplantation: biology and rejection. Baillieres Clin Gastroenterol. 1994;8:389–97.View ArticlePubMedGoogle Scholar
- Haseltine W. Regenerative medicine 2003: an overview. J Regener Med. 2003;4:15–8.Google Scholar
- Landecker H. Culturing Life. Cambridge, MA: Harvard University Press; 2009.Google Scholar
- Stevens LC. The development of transplantable teratocarcinomas from intratesticular grafts of pre- and postimplantation mouse embryos. Developmen Biol. 1970;21:364–82.View ArticleGoogle Scholar
- Evans MJ, Kaufman MH. Establishment in culture of pluripotential cells from mouse embryos. Nature. 1981;292:154–6.View ArticlePubMedGoogle Scholar
- Thomson JA, Itskovitz-Eldor J, Shapiro SS, Waknitz MA, Swiergiel JJ, Marshall VS, Jones JM. Embryonic stem cell lines derived from human blastocysts. Science. 1998;282:1145–7.View ArticlePubMedGoogle Scholar
- Takahashi K, Yamanaka S. Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell. 2006;126:663–76.View ArticlePubMedGoogle Scholar
- Sunderland ME. Studying Development: The Value of Diversity, Theory, and Synthesis. PhD Thesis. Tempe, AZ: Arizona State University; 2008.Google Scholar
- O’Dowd A. Peers call for UK to harness “enormous” potential of regenerative medicine. BMJ. 2013;347:f4248.View ArticlePubMedGoogle Scholar
- Mason C, Dunnill P. The strong financial case for regenerative medicine and the regen industry. Regen Med. 2008;3(3):351–63.View ArticlePubMedGoogle Scholar
- Orlando G, Wood KJ, Stratta RJ, Yoo JJ, Atala A, Soker S. Regenerative medicine and organ transplantation: past, present, and future. Transplantation. 2011;91(12):1310–7.View ArticlePubMedGoogle Scholar
- Tsukamoto A, Abbot SE, Kadyk LC, DeWitt ND, Schaffer DV, Wertheim JA, Whittlesey KJ, Werner MJ. Challenging regeneration to transform medicine. Stem Cells Transl Med. 2006;5(1):1–7.View ArticleGoogle Scholar
- Nelson TJ, Behfar A, Terzic A. Strategies for therapeutic repair: the “R3” regenerative medicine paradigm. Clin Transl Sci. 2008;1:168–71.View ArticlePubMedPubMed CentralGoogle Scholar
- World Regenerative Medicines Market - Opportunities and Forecasts, 2013–2020. Allied Market Research Report. 2014. https://www.alliedmarketresearch.com/regenerative-medicines-market. Accessed 6 July 2016.
- Remarks of President Barack Obama. The White House. 2009. https://www.whitehouse.gov/the-press-office/remarks-president-prepared-delivery-signing-stem-cell-executive-order-and-scientifi. Accessed 6 July 2016.
- Trounson A. New perspectives in human stem cell therapeutic research. BMC Med. 2009;7:29.View ArticlePubMedPubMed CentralGoogle Scholar
- Trounson A, Thakar RG, Lomax G, Gibbons D. Clinical trials for stem cell therapies. BMC Med. 2011;9:52.View ArticlePubMedPubMed CentralGoogle Scholar
- Lee MH, Arcidiacono JA, Bilek AM, Wille JJ, Hamill CA, Wonnacott KM, Wells MA, Oh SS. Considerations for tissue-engineered and regenerative medicine product development prior to clinical trials in the United States. Tissue Eng Part B Rev. 2010;16(1):41–54.View ArticlePubMedGoogle Scholar
- Ford CE, Hamerton JL, Barnes DW, Loutit JF. Cytological identification of radiation-chimaeras. Nature. 1956;177:452–4.View ArticlePubMedGoogle Scholar
- Cao Y, Vacanti JP, Paige KT, Upton J, Vacanti CA. Transplantation of chondrocytes utilizing a polymer-cell construct to produce tissue-engineered cartilage in the shape of a human ear. Plast Reconstr Surg. 1997;100:297–304.View ArticlePubMedGoogle Scholar
- Macchiarini P, Jungebluth P, Go T, Asnaghi MA, Rees LE, Cogan TA, Dodson A, Martorell J, Bellini S, Parnigotto PP, Dickinson SC, Hollander AP, Mantero S, Conconi MT, Birchall MA. Clinical transplantation of a tissue-engineered airway. Lancet. 2008;372:2023–30.View ArticlePubMedGoogle Scholar
- Atala A, Bauer SB, Soker S, Yoo JJ, Retic AB. Tissue-engineered autologous bladders for patients needing cystoplasty. Lancet. 2006;367:1241–6.View ArticlePubMedGoogle Scholar
- Gonfiotti A, Jaus MO, Barale D, Baiguera S, Comin C, Lavorini F, Fontana G, Sibila O, Rombolà G, Jungebluth P, Macchiarini P. The first tissue-engineered airway transplantation: 5-year follow-up results. Lancet. 2014;383(9913):238–44.View ArticlePubMedGoogle Scholar
- Ott HC, Matthiesen TS, Goh SK, Black LD, Kren SM, Netoff TI. Perfusion-decellularized matrix: using nature’s platform to engineer a bioartificial heart. Nat Med. 2008;14(2):213–21.View ArticlePubMedGoogle Scholar
- Soto-Gutierrez A, Zhang L, Medberry C, Fukumitsu K, Faulk D, Jiang H. A whole-organ regenerative medicine approach for liver replacement. Tissue Eng Part C Methods. 2011;17(6):677–86.View ArticlePubMedPubMed CentralGoogle Scholar
- Kemp P. History of regenerative medicine: looking backwards to move forwards. Regen Med. 2006;1(5):653–69.View ArticlePubMedGoogle Scholar
- Cyranoski D. Acid bath offers easy path to stem cells. Nature News. 2014. http://www.nature.com/news/acid-bath-offers-easy-path-to-stem-cells-1.14600. Accessed 6 July 2016
- Vogel G. Regenerative medicine. Report finds misconduct by surgeon. Science. 2015;348(6238):954–5.View ArticlePubMedGoogle Scholar
- Alta CR. On the road (to a cure?) — Stem-cell tourism and lessons for gene editing. N Engl J Med. 2016;374:901–3.View ArticleGoogle Scholar
- Matthews KR, Iltis AS. Unproven stem cell-based interventions and achieving a compromise policy among the multiple stakeholders. BMC Med Ethics. 2015;16:75.View ArticlePubMedPubMed CentralGoogle Scholar
- Bubela T, Li MD, Hafez M, Bieber M, Atkins H. Is belief larger than fact: expectations, optimism and reality for translational stem cell research. BMC Med. 2012;10:133.View ArticlePubMedPubMed CentralGoogle Scholar
- Galbraith DN. Regulatory and microbiological safety issues surrounding cell and tissue-engineering products. Biotechnol Appl Biochem. 2004;40:35–9.View ArticlePubMedGoogle Scholar
- Carpenter MK, Frey-Vasconcells J, Rao MS. Developing safe therapies from human pluripotent stem cells. Nat Biotechnol. 2009;27:606–13.View ArticlePubMedGoogle Scholar
- Chacko BK, Kramer PA, Ravi S, Benavides GA, Mitchell T, Dranka BP, Ferrick D, Singal AK, Ballinger SW, Bailey SM, Hardy RW, Zhang J, Zhi D, Darley-Usmar VM. The Bioenergetic Health Index: a new concept in mitochondrial translational research. Clin Sci (Lond). 2014;127:367–73.View ArticleGoogle Scholar
- Progatzky F, Dallman MJ. Lo Celso. From seeing to believing: labelling strategies for in vivo cell-tracking experiments. Interface. Focus. 2013;3(3):20130001.Google Scholar
- Christensen JL, Weissman IL. Flk-2 is a marker in hematopoietic stem cell differentiation: A simple method to isolate long-term stem cells. Proc Natl Acad Sci. 2001;98:14541–6.View ArticlePubMedPubMed CentralGoogle Scholar
- Ram-Liebig G, Bednarz J, Stuerzebecher B, Fahlenkamp D, Barbagli G, Romano G, Balsmeyer U, Spiegeler ME, Liebig S, Knispel H. Regulatory challenges for autologous tissue engineered products on their way from bench to bedside in Europe. Adv Drug Deliv Rev. 2015;82-83:181–91.View ArticlePubMedGoogle Scholar