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Cell therapy worldwide: an incipient revolution

The regenerative medicine field is large, diverse and active worldwide. A variety of different organizational and product models have been successful, and pioneering entrepreneurs have shown both what can work and, critically, what does not. Evolving regulations, novel funding mechanisms combined with new technological breakthroughs are keeping the field in a state of flux. The field struggles to cope with the lack of infrastructure and investment, it nevertheless has evolved from its roots in human stem cell therapy and tissue and organ transplants to a field composed of a variety of products from multiple cell sources with approval for use in numerous countries. Currently, tens of thousands of patients have been treated with some kind of cell therapy. Keywords:  composites • cosmeceuticals • induced pluripotent stem cells • medical tourism • mesenchymal stem cells • neural stem cells • regenerative medicine • therapy • tissue • transplant

Stem cell biology and the overarching field of regenerative medicine is a relatively young discipline. Apart from the primarily autologous treatment of sibling and HLAmatched marrow transplants, which require minimal manipulation [1] , there was little additional activity. The discovery that cord blood could be used as an alternative to bone marrow led to a modest expansion of the field, which remained primarily autologous, with hospitals and clinicians leading the expansion [2] . There were a few allogeneic cell product efforts based on scientists’ ability to grow fibroblasts and develop simple 3D structures. Several companies pioneered cartilage, skin and valve and other vascular graft use [3,4] . The discovery of mesenchymal stem cells [5,6] and the use of other marrow-derived cells and marrow stem cell derivatives for cancer therapy, both of which were autologous modalities and required cell processing, led to a veritable explosion of attempts to grow such cells and use them in a variety of ways to treat numerous diseases [7] (Figure 1) .

10.2217/RME.14.80 © 2015 Future Medicine Ltd

Mahendra Rao*,1, Chris Mason2 & Susan Solomon1,3 New York Stem Cell Foundation, 3969 Broadway 4th floor, NYC, NY 10032, USA 2 Department of Biochemical Engineering, University College London, Roberts Building, Torrington Place, London, WC1E 7JE, UK 3 New York Stem Cell Foundation, 1995 Broadway Suite 600, NYC, NY 10023, USA *Author for correspondence: mrao@ nyscf.org 1

The discovery of human embryonic stem cells by Thomson and colleagues [8] , the development of somatic cell nuclear transfer (SCNT) [9] , followed by the discovery of induced pluripotency by Yamanaka and his colleagues [10] provided a source of cells for the manufacture of a multitude of cellular products. Potential applications of cellbased therapy further expanded by building on the Nobel Prize winning work of Dr Mario Capecchi [11,12] , and implementing new methods of engineering pluripotent cells [13,14] . Patents and regulations governing the delivery of cell-based therapies and the enormous expectations that people have for this novel type of therapy have shaped the stem cell field equally if not more than technological and scientific breakthroughs [15–17] . Similarly, regulatory authorities have strongly influenced the regenerative medicine field by imposing differing requirements country by country [18–22] . These regulations have led to different foci of activity in different countries and, by extension, different players implementing these technologies. The

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Medical tourism Unregulated

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Cosmeceuticals

ADSC Legal in a country but regulated in another Not considered a medical product

Medical practice

Devices

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Retina Synthetic glucose sensor Cornea composite Skin and so on HSC and derivatives Cultured

Allogenic/ autologous

Selected Engineered Combination

Cord blood and ancillary tissue MSC and MSC-like NSC and derivatives All other cells

Composite/tissue/ organoids

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Skin full thickness Valves and vessels Ureter, bladder and urethra Trachea and oesophagus Cardiac sheets/RPE sheets Pancreatic islets, liver organoids and so on

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Marrow Cartilage T cells NK cells Cord blood HSC Endothelial cells • • • • • • • • • •

NSC Oligos Astrocytes Neurons OEG Schwann cells Pancreatic islet Cardiomyocytes Hepatocytes Skeletal muscle and so on

Figure 1. An overview of the regulated and unregulated subfields that comprise the field of regenerative medicine is shown. ADSC: Adipose derived stem cell; HSC: Hematopoietic stem cell; MSC: Mesenchymal stem cell; NK: Natural killer; NSC: Neural stem cell; OEG: Olfactory ensheathing glia; RPE: Retinal pigment epithelium.

sections below outline how these factors influence the regenerative medicine industry and implementation of products and uses in different countries. Unregulated regenerative medicine: the cosmeceutical industry & medical tourism Regulatory requirements for introducing cosmeceuticals are much simpler than introducing drugs and, often, produce higher reimbursement or profit margins. Disregarding all other factors, at the very least the time to market is much shorter. This has persuaded several stem cell companies to consider expanding into the cosmeceutical market, where they can take advantage of the hype associated with stem cells and make claims about the value of their products without breaking the law. Many of the companies currently involved in this cosmeceuticals market have argued that this part of the industry is necessary for survival, providing profits and enabling survival as the standard avenues of raising money have been closed to them. Mesenchymal companies sell conditioned media that can be formulated into creams, lotions or ointments for use in

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a variety of cosmeceutical products. Other companies have begun examining the use of similar cell-based products for reducing scars, enhancing hair growth or improving wound healing. It is difficult to gauge the utility of such over-the-counter products, but anecdotal evidence seems to suggest that they appear to be satisfying some need within the market [23,24] . Encouraged by this success, companies and physicians have investigated extending these kinds of unregulated services and products. In addition, hospital-based products have been considered including products related to plastic surgery, and bone and cartilage-associated repair. The working assumption was that cells harvested from an individual could be transplanted into another, similar to skin grafts or organ transplant, would be regulated as a surgical procedure. Early results were encouraging, leading to an outbreak of activity among physicians and surgeons offering a variety of services, and the growth of an entire ancillary industry in providing bedside tissue processing devices. Indeed companies such as Cytori developed instruments for automated fat tissue processing

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Cell therapy worldwide: an incipient revolution 

and several other companies developed automated processes for marrow and cord blood processing [25] . With approval in the cosmeceutical and plastic surgery market, companies and individuals began to look at additional uses for this type of minimally processed cell-based therapy. Adipose-derived stem cells, autologous mesenchymal stem cells and immune modulators such as T cells, natural killer cells and other blood derivatives fit this criteria [26,27] . Although the cells could not be processed at the bedside, the processing was relatively straightforward and not too different from the familiar processes hospitals used to process blood and bone marrow for use in patients. This processing required a GLP processing site (akin to a bone marrow HSC processing site), a trained staff and a process for billing and third party reimbursement – things many hospitals already had. Processes offered included using CD34+ cells from marrow for nonhematopoietic use, adipose-derived stem cells or autologous mesenchymal stem cells (MSCs) for treatment of nonhealing ulcers, critical limb ischemia and congestive cardiac failure. Similarly, immunotherapy for cancer became popular in Japan and China where T cells, NK cells and dendritic cells were harvested from a patient, expanded using a standard protocol and re-infused back into the patient as a possible salvage or last option therapy based on a protocol pioneered by Rosenberg and colleagues [28] . Three types of cells were readily harvested from an individual and could be obtained in sufficient numbers directly from the individual or by short-term culture: MSC-like cells from marrow, fat, placenta skin, cord, etc., bone marrow aspirates and CD34+ cells and fibroblasts. These cells appeared to have multiple uses and appeared safe, and in a few short years had been infused, injected or transplanted in hundreds if not thousands of patients worldwide for a variety of uses. Importantly, these therapies were novel and could serve to distinguish one group of physicians from another, leading to physcians’ attempting more radical treatments and less experimentally verified therapies. Further, none of these treatments were considered experimental and, as such, controlled clinical trials or long-term followup was nonexistent. Clinics in many countries decided that this was safe and a practice of medicine and began offering additional cell-based therapy that was based on unproven assumptions. The US FDA tacitly acknowledged that this was not regulated but argued successfully in a series of court cases that if cells were manufactured then this was regulated. As a result since 2007 such activity is largely nonexistent in the USA and in Europe, many clinics have been closed [29–33] . The FDA clarified and defined what was a regulated product and was practice of medicine. This definition largely classified most of the pro-

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cedures described above as products regulated by the FDA  [34,35] . Other countries have followed suit with similar, though not identical, regulations. Chinese authorities, for example, defined the majority of cell therapy as experimental and requiring approval. This has led to a virtual freeze in cell-based activity until more clarity emerges as to what therapies are approved and unapproved [36] . Overall, the change in regulations has left this segment of the regenerative medicine industry in a state of flux worldwide. The cosmeceutical industry and the practice of cell-based medicine continues to grow; however, recent court rulings in the USA, publicized closure of clinics in Germany and Switzerland and the recent ban of unproven cell-based therapy in mainland China [37] have had a chilling effect on this rapid expansion. Hospitals have begun to reevaluate what services they can offer and some groups have begun the process of obtaining regulatory approval. Other groups have shifted operations to countries where the rules are lax and have asked patients to fly to these countries to obtain services. International efforts have emerged to harmonize rules on unproven therapies, which may ultimately provide additional checks and balances in the global system. Cord blood banking The regulations imposed allowed the use of bone marrow transplants, including the use of cord blood transplants, therefore enabling cord blood banks to continue to grow [38,39] . Cord blood banks number in the hundreds worldwide and the most prevalent model, by far, is the private cord blood bank model where cord units are stored for personal or family use rather than donated to a general pool. Private banks have seen this as a viable commercial model and in the absence of public banks have aggressively marketed the idea that cord blood derived stem cells offer a sort of insurance for their children and should be banked for future use. These private banks charge a fee for processing the sample and its subsequent storage, offsetting their marketing efforts and setting up costs in such a way as to allow them to profit. This business model has been attractive to investors and is one area of regenerative medicine where large companies have invested. Several groups, however, have raised ethics issues related to fairness and equality of access to healthcare, and have suggested that individuals donate to public cord blood banks instead of private banks. Indeed several public banks have been established, mostly in the developed world, and they provide an important alternative. This proliferation of public and private banks has translated into a rapidly developing medical field with over 15,000 cord blood transplants performed world-

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Review  Rao, Mason & Solomon wide through 2009. In the USA, more than half of all stem cell transplants in children from unrelated donors use cord blood [40] . The uptake from private cord blood banks is far more limited and perhaps less than a thousand transplants (estimate) have been utilized. Public banks have found it difficult to raise revenue in a manner similar to the private banks, and offset their costs by charging a fee to provide cord units. The price of such cord units is high but the banks’ ability to raise prices is constrained by alternate sources of CD34+ cells. This has meant that storing units for public use requires philanthropy, government support or developing additional commercial uses of cord-derived cells. These differences in structure and funding between public and private cord blood banks has led to a certain tension as the public banks provide most of the cords for use, while private banks make most of the money. Equally important, locations where there has been no public funding for maintaining public banks largely do not have any public banks, leaving the education and encouragement of donors largely in the hands of private banks. Many of the largest cord blood banks are now in Asia led by banks in China, Hong Kong and Taiwan – countries that lack public/government support of public banking. However, in recent years even the private banks have begun to suffer. There has been a huge increase in the number of banks and with competition, prices have been cut. Smaller banks have skimped on quality and as the overall economies have suffered in recent years, the number of people willing to store cords has declined. As a result, the rate of growth of cord blood banks has slowed and there is evidence of consolidation in the industry.figur This slow growth has led to companies exploring alternate methods of generating revenue within their

overall expertise in collection, processing and storage of tissues. Some companies have begun offering the opportunity to store cords as a source of MSC-like cells, others process and store MSCs, and still others have begun looking at other placental derivatives. Public cord blood banks in the USA have seen a change in regulations with the introduction of a licensure requirement. Several of the banks have now obtained the requisite licensure [35] , this may signal a further tightening of regulations by the FDA. Additional regulatory requirements will no doubt raise costs and, with public banks functioning at a deficit, it is likely that there will be pressure to develop additional sources of revenue. Indeed, some ambitious cord blood companies, including the public cord blood banks, have noted results iPSC can be manufactured from small amounts of cord blood and that this may be a way to deliver on the promise of personalized medicine [41] . When cells are HLA typed, as they are in public banks, it is also possible to consider a hybrid model akin to a bone marrow registry can be developed with licensed public cord blood banks providing clinically compliant iPSC or iPSC-derived products. While there has been a decline in demand for the core services of private cord blood banks, and support for public cord blood banks continues to be limited, technological breakthroughs and established infrastructure offer these banks an opportunity to remain relevant and even thrive in this rapidly evolving field. Regulated cell therapy & product approvals Regulated cell therapy development akin to developing a small molecule drug over a period of 5–10 years albeit with some differences [42,43] , by contrast, has been limited both in the developing world and in developed countries. The largest number of approved products are

Box 1. A list of the current cell-based products that are approved in the USA is provided.  FDA cell therapy-related approved products Cord blood banks (5) • HEMACORD (hematopoietic progenitor cells, cord blood) – NYCBB • Clinimmune Labs – 1855 • Duke University School of Medicine 1870 • LifeSouth Community Blood Centers, Inc. 1647 • SSM Cardinal Glennon Children’s Medical Center 1873

1. 2. 3. 4. 5. 6. 7.

Autologous cultured chondrocytes – Genzyme Autologous cellular immunotherapy – sipuleucel-T Dendreon Corportation Appligraf cell based device – Organogenesis Dermagraft cell based device – Advanced Biohealing Gintuit – skin type product – organogenesis Laviv (Azficel-T) – Fibrocell Marrow Collection Kit 510(k) device – Fenwal, Inc

Fewer products have been approved in other countries, for a list see [72]. 

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Cell therapy worldwide: an incipient revolution 

related to adult cells which require limited processing including fibroblasts, allogeneic mesenchymal stem cells and derivatives of hematopoietic stem cells including dendritic cells, T cells and NK cells (Box 1). These join previously approved cartilage related and skin products. While the numbers are very small and approvals are country specific, it is important to note that the number of cell-based products is larger than the number of approved gene therapy products. With the recent excitement around engineered cell-based therapy for hematological disorders, it is very likely that a wave of such products will be developed in the near future [44,45] . Another active but niche field is the combination product strategy meaning a scaffold or device combined with an autologous cell. This strategy combines the expertise of device manufacturers with the relatively easier path to regulatory approval enjoyed by products categorized as devices, as these combination products are. The best examples of this strategy in the regenerative medicine industry are seen in the orthopedic and skin substitute fields [46,47,48] . The rapid pace at which new uses of cells were being evaluated suffered a setback when new rules and guidelines were established and clinics that provided such services were forced to stop. Under these guidelines all ‘manufactured’ cells would have to be evaluated through a formal regulatory process and would not be classified as devices or as practice of medicine. Many countries including India, China and the EU rapidly adopted guidelines approved in the USA, with small variations, and draft guidelines to achieve a similar oversight are in preparation in Taiwan, Korea and Singapore and other countries. Unfortunately, this caused some unintended consequences. The players who initiated these studies lack the expertise and the infrastructure to convert their processes to an FDA approved, cGMP-compliant manufacturing process, meaning new players need to enter the market to supply such services and the investment required to obtain the necessary approvals. The pharmaceutical industry has been reluctant to enter the cell therapy based field [42,43] thus the single most important source of expertise in dealing with FDA and regulations is not an active player. Other traditional sources of investment such as angel investors, venture funds and initial public offering markets have been similarly limited as well [42] leaving support mainly to universities, hospitals and the government. In Asia, the governments have been less generous that those in the West and as such, hospitals and small biotechnology companies have attempted to enter the market, facing major financial challenges. Cell-based therapy requires a long time period to reach the market and the pricing power is far smaller in Asia, therefore

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venture capitalists have not been able to model investment returns. As such, Asian and other biotechnology companies have required different models of financing. Hospitals and private investors have filled this gap, seeing cell-based therapies as a logical extension of the services they already provide. In addition, many small Asian cell therapy companies have tried and tap the market with a reverse merger strategy or generate additional revenue by selling nonregulated cosmeceutical products (see above). The Korean market is the most active and the Korean FDA has taken a lead in product approvals. This market development is different from that seen in the Western world where a more conventional approach has been possible with the government funding early stages of research and translation, and venture and pharma companies providing ancillary services such as device manufacture. Companies in the West have been more willing to work with more difficult manufacturing processes and indeed most of the ESC-related trials are being funded in the west. The largest segment of the regulated market: MSC-based products It is unsurprising that MSCs based cell therapy is a large segment of the regenerative stem cell market. MSCs and MSC-like cells can be harvested with ease from bone marrow, wharton jelly, placental and likely could be harvested from most tissues. Obtaining and growing sufficient numbers of cells for treatment is comparatively straightforward requiring few complex steps  [43] . In addition, MSCs can integrate with existing tissues to form bone, cartilage and connective tissue elements and provide support to many different tissues and organs [44,45] . In addition, bone marrow-derived mesenchymal cells, and likely other MSC-like cells, can enhance the engraftment, survival and expansion of hematopoietic stem cells. MSC products derived from bone marrow or placenta are already approved for some clinical indications [46–50] . More recently, research has shown strong immunomodulatory activity in MSCs and cell products may be able to both suppress and or enhance immune response as required for various cancer therapies. This immunomodulatory activity has been targeted for the first MSC-based products and other are actively exploring the utility of MSCs in treating kidney, liver and CNS disorders. Clinical trials using MSCs are the largest fraction of clinical trials currently undertaken in the stem cell field. There are three major drivers for excitement surrounding MSCs. The Department of Defense in the USA, which has funded several high risk-high reward type of activities, the possible immune modulatory effect of MSCs, and the possibility that MSCs can be derived from iPSC and may be engineered using

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Review  Rao, Mason & Solomon newer gene editing technologies. Recently, novel uses of MSCs have been considered including using MSCs to make scaffolds for organs and MSCs for treatment in the nervous system and in the eye [51,52] . HSC & neural stem cell subfields remain active Bone marrow based stem cell transplants constitute a large segment of the regenerative medicine market and indeed have provided the infrastructure that the field has built on. The process of collection, storage, shipping, thawing, selection and delivery has been optimized as has the idea of HLA matching and immune suppression regimes. An important distinction between this subfield and other parts of the regenerative medicine field has been is that this is not industry led but rather primarily a hospital and physician led activity. However, this is changing as the use of HSC and other blood and marrow derivatives have expanded beyond marrow replacement (see references below). Active areas of research include expanding HSC in culture [53] , combining the cells with other products and sorting the cells to optimize engraftment. All areas would expand the current use of landscape. The potential of these cells for additional uses such as in treatment for autoimmune disorders or via lentivirus, adenovirus or retrovirus engineering technologies has been evaluated, as has their potential for transdifferentiation. Researchers have begun evaluating blood and bone marrow for other stem cell populations and differentiated expanded cells for therapy. These include but are not limited to possible hemangioblasts, endothelial cells, macrophages, T cells and NK cells. The well-established marrow transplant infrastructure and expertise allow many of these new avenues of research. Similarly, this research remains in the realm of investigator-initiated studies with few active companies within the field [53,54] . Other companies have identified anuclear cells, such as red blood cells and platelets, as possible needed derivatives that could be made in bulk using immortalizing strategies to augment the natural enormous expansion of stem cells. Companies such as Megakaryon, for example, have begun experimenting with such technology to make platelets [55] . The neural stem cells (NSCs) and neural derivative field, in contrast, is smaller and primarily an allogeneic therapy field based on companies that own proprietary cell manufacturing strategies or composition of matter patents on specific cell types. These are small companies that focus on a specific cell type for a specific indication. There is no consensus in the filed on which cell type to use, which indication will be most helped by cell therapy or which route of administration will be best [56–58] .

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Choices of cells to focus on include neural derivatives like neural stem cells. The best examples of such an effort are Stem Cell, Inc. and Neural Stem Biopharmaceuticals. Others have argued that perhaps an immortalized cell population will be better and Reneuron has successfully used this strategy to treat patients [59] . Other companies and groups have argued that astrocytes may be the better choice as these cells provide trophic support and, in any case, neurons cannot make functional connections over the long distances required in an adult brain [56] . Yet other groups have argued that treating demyelinating disorder will require using oligodendrocytes, and yet others have suggested that gene engineering and treatment of orphan and rare disorders such as lysosomal storage disease may be more important than neural disorders. Likewise, there has been controversy over whether the brain is an immune privileged site and will therefore require immune suppression  [60] , and whether cells given exogenously will cross the blood–brain barrier. The indications considered are numerous albeit with limited success and currently, there is no approved product for any indication available. Of note is that MSC-based companies have begun exploring the use of MSCs and MSC-like cells for the treatment of neurological disorders [52] giving promising early reports based on case reports provided, with several Phase I and Phase II trials underway. The result are somewhat surprising, as MSCs do not normally exist in the brain and, when transplanted, do not survive for long. Experts have argued that MSCs likely act in the brain by modulating the immune system and thereby abrogating inflammation, which is an important component of cell death in a damaged brain. MSC folks have argued that unlike other cells, NSCs migrate extensively and may cross the blood–brain barrier or migrate along olfactory nerves to reach the brain. More recently, investigators have suggested using microglia or macrophages to treat CNS damage, but this remains exploratory at best. Overall, the neural field appears somewhat experimental and early stage with companies sharing little in common either in terms of cell type, indication or manufacturing process. Nevertheless, it remains active as the number of CNS disorders for which there is no cure or no approved therapy remains large. The rest of the regenerative medicine market includes several other cell types Although MSCs, HSCs, NSCs, cord blood and their derivatives constitute by far the largest segment of the field, investigators have considered the use of several other cell products. The most established of these alternative efforts is the autologous cell model, pioneered by Genzyme, using cartilage cells for knee joint repair. Sev-

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Cell therapy worldwide: an incipient revolution 

eral other companies have approval for competing cell products, making this field an active and evolving niche segment of the overall market [61] . Genzyme recently divested this portfolio to Aastrom at a very low valuation, providing some indirect evidence that this may not be a very large market at the price that one can manufacture the cells. Fibrocell uses autologous fibroblasts to aid in wrinkle and antiscar therapy. With the availability of ESCs and iPSCs, both of which can differentiate into many different cell types, it is entirely possible that in the future these somatic cell products may be derived from these stem cell populations, increasing the number and variety of cell products. This represents a small section of the market, however, this segment of the market is likely to grow. It is also important to note that this somatic cell therapy has by far the largest number of approved products and probably the largest set of manufacturing expertise within the industry. The next phase of regenerative medicine: combination products, devices & 3D structures The device industry, represented by manufacturers of implantable devices, has seen and acted on a need for combination products [44,45] . Cellular products already in use or under investigation include skin, valves, bladders, blood vessels, hollow organs such as trachea, ureter and other simple 3D biological structures. Additional effort has been made to develop synthetic. This subfield represents an important area of activity in the field of regenerative medicine. The bioengineering expertise needed to develop such products is found worldwide and the development of 3D printing and novel scaffolds and the resurrection of decelluarization and recellularization techniques have led to increased activity. This field lies in a gray zone, and it is not yet clear how it will be regulated, though it is likely the regulations will differ among countries unless efforts at harmonization of regulations (that are currently in their infancy) succeed. Induced pluripotent stem cells may be a new subfield of regenerative medicine The field of embryonic stem cells underwent a paradigm shift when Yamanka and colleagues showed that virtually every adult cell in the human body can be modified by a technically simple process to become a pluripotent stem cell [62] . While embryonic stem cells were hailed as a dramatic advance in their own right and led to significant advances in our understanding of developmental biology and early stages of cell differentiation, they were hard to reduce to a commercial product. There were several reasons including the high cost of the process of deriving an ESC line, the ethical issues

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related to the destruction of a fertilized egg in the process of ESC generation and the international discord on whether ESC cells can be patented. The differing rules worldwide along with the religious issues raised, the restriction on the use of federal funding in the USA and the outright ban on this type of research in many countries slowed the use of these cells. The discovery by Yamanaka seemed to resolve most if not all of the issues seen with ESC. There was little ethical debate on the use of induced pluripotent stem cell (iPSC), the cost of making them was significantly lower, and the data suggested that the cells derived by this method were as good as ESC derived by more traditional methods [63] . Perhaps learning a lesson from the patent debacle with ESC, the patent offices clearly agreed that the iPSC process was patentable and the companies that owned the early patents agreed to a standardized patent policy. This allowed many companies to enter the field and rapidly accelerate the field [64] . Three major models of iPSC-based cell therapy are proposed: a personalized iPSC model akin to the private cord blood banks, a hybrid HLA matched panel model akin to the bone marrow and organ donor registries and an allogeneic model with immunesuppression akin to MSC-like therapies. Companies have been formed to try and advance such therapies and, in particular, the Japanese government highlighted iPSC-based therapy as an important focus for allocation of resources and other countries have also begun allocating resources toward this subfield of regenerative medicine. Another approach that several stem cell companies have taken is to use iPSC as a cell source for screening assays to discover new therapies, to effect a cure in a dish [65,67] and then use those small molecules to treat patients. A third approach to accelerate patient treatment has been to develop new human cell based toxicology tools with a variety of groups showing that iPSC-derived cells are better predictors of toxicity than animal cells or cell lines. It is indeed an exciting time for proponents of iPSC cell based therapy and, apart from such direct effects on the field, iPSC may fundamentally alter screening for new drugs [65] . SCNT may represent another new subfield The field of human cloning was tainted by fraud. Most infamously, Woo Suk Hwang of Seoul National University in South Korea used hundreds of human eggs to report two successes, in 2004 and 2005. Both turned out to be fabricated [68] . SCNT has also been overshadowed by the competing technology of iPSC, where it appeared that any adult cell could be reprogrammed to the pluripotent stage using technology and procedures developed by Shinya Yamanaka and colleagues, as discussed above.

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Review  Rao, Mason & Solomon The SCNT field, however, has seen some astonishing breakthroughs in recent years [69] . Two led by Shoukrat Mitalipov [70] and Dieter Egli [71] have reported the successful generation of ESC lines of a normal karyotype from SCNT embryos. Improvements in the process have reduced the risk of associated epigenetic defects which initially reduced the probability of carrying an SCNT-derived embryo to term. This success with human eggs appears similar to the success in other species, and the reported increase in the overall efficiency of the SCNT process suggests that it may now be feasible to consider treating humans. Two uses discussed have been related to mitochondrial disease where ooplasm from a healthy donor is used to correct a mitochondrial disorder or ESC lines are made from fertilized egg and the nucleus transferred to a healthy egg. Future perspective The discovery of pluripotent stem cells that can be manufactured in a cost-effective manner raises the potential of truly personalized medicine. It is likely the field will accelerate again as IPSC cells are merely a source for otherwise difficult to obtain cells and can readily be used as an alternative where adult cells were

difficult to obtain. Likewise since gene engineering can be performed with high efficiency in these cells several avenues of treatment that were not open to somatic cells are now possible. We expect to see many novel applications of cell-based therapy in the future. These will build on the efforts of the earlier trailblazers [72] . It is perhaps important to note that the first patient treated with iPSC-derived product [73] was a mere 7 years from the first report of the discovery of iPSC. Conclusion The regenerative medicine field comprises of many subfields that are focused on repair and replacement of damaged tissues or organs using cells isolated from a variety of sources that may or may not be engineered or combined with scaffolds and synthetic materials. Thus, the field is diverse encompassing everything from cell-derived products that are not regulated, to somatic cell products and products derived from stem cells. These products are being used in innovative ways that, in some cases, represent incremental change from existing activity or a small extension of expertise; examples of this are seen in the blood banking and marrow transplant industries. While other changes are completely novel uses of new types of cells

Executive summary Unregulated regenerative medicine: the cosmeceutical industry & medical tourism • The unregulated field comprises cosmeceuticals experimental stem cell therapy, unregulated medical tourism and outright fraud.   • Since 2009, the EU and the US FDA have clarified what constitutes the practice of medicine and what does not limiting excesses.   • In other countries, medical tourism has flourished and clinics offering dubious products and services have proliferated.

Cord blood banking • The cord blood industry is facing a crisis.   • The public banks do not have enough support.   • The revenue model for the private banks is under pressure.   • The banks are exploring alternate strategies to remain relevant.

Regulated cell therapy & product approvals • The unregulated market has grown rapidly.   • The regulated market has been slower to develop. New players, new models and increased risk given the uncertainty of regulations.   • In western countries, companies have had access to government funding and Asian companies have had less. As a result less complex products are being developed in Asia.

The largest segment of the regulated market: mesenchymal stem cell-based products • The regenerative medicine field has begun to expand.   • Progress has been steady as is to be expected.   • Novel findings such as mesenchymal stem cells may be immune modulatory has led to the exploration of novel uses of these cells.   • The ability to decellularize and recellularize tissue has led to the ability to make complex structures as has 3D printing.

Induced pluripotent stem cells may be a new subfield of regenerative medicine • Induced pluripotent stem cell represent a game changer.   • They are potentially immortal and offer the hope of personalized medicine.   • Induced pluripotent stem cell are a unique source of otherwise difficult to obtain cells.

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including neural stem cells, mesenchymal stem cells and, more recently, induced pluripotent stem cells. Perhaps the most radical change has been the newest results on somatic cell nuclear transfer, which offers an opportunity to treat mitochondrial diseases, and the development of technology to make 3D biological and engineered composites. Acknowledgements The authors apologize to all their colleagues whose important work could not be directly cited.

Disclaimer The New York Stem cell foundation did not commission this article and the opinions expressed in this article reflect the consensus opinion of the authors.

Financial & competing interests disclosure S Solomon is the cofounder of the New York Stem cell foundation. M Rao is the founder of Q therapeutics and serves as a consultant on several company boards and as a consultant to several companies involved in developing cell-based therapies. The work was supported by NYSCF and represents the views of the authors and does not reflect on the policy or the opinion of the organization. M Rao was not paid a fee to write this article. The work was supported by NIHCRM, UCL, NYSCF. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. No writing assistance was utilized in the production of this manuscript. transplantation of reporter human induced pluripotent stem cells generated by AAVS1 transcription activator-like effector nucleases. Stem Cells Transl. Med. 3(7), 821–835 (2014).

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Review on cord blood banks.

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