Prospects for translational regenerative medicine

Biotechnology Advances 30 (2012) 658–672

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Biotechnology Advances journal homepage: www.elsevier.com/locate/biotechadv

Research review paper

Prospects for translational regenerative medicine Fa-Ming Chen a, b, Yi-Min Zhao c,⁎, Yan Jin b, d, Songtao Shi e a

Department of Periodontology & Oral Medicine, School of Stomatology, Fourth Military Medical University, Xi'an 710032, Shaanxi, PR China Translational Research Team, School of Stomatology, Fourth Military Medical University, Xi'an 710032, Shaanxi, PR China c Department of Prosthodontics, School of Stomatology, Fourth Military Medical University, Xi'an 710032, Shaanxi, PR China d Research and Development Center for Tissue Engineering, Fourth Military Medical University, Xi'an 710032, Shaanxi, PR China e Center for Craniofacial Molecular Biology, Ostrow School of Dentistry, University of Southern California, Los Angeles, CA 90033, USA b

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Article history: Received 15 April 2011 Received in revised form 12 November 2011 Accepted 15 November 2011 Available online 27 November 2011 Keywords: Translational medicine Regenerative medicine Stem cell therapy Tissue engineering Regenerative dentistry Clinical translation

a b s t r a c t Translational medicine is an evolutional concept that encompasses the rapid translation of basic research for use in clinical disease diagnosis, prevention and treatment. It follows the idea “from bench to bedside and back”, and hence relies on cooperation between laboratory research and clinical care. In the past decade, translational medicine has received unprecedented attention from scientists and clinicians and its fundamental principles have penetrated throughout biomedicine, offering a sign post that guides modern medical research toward a patient-centered focus. Translational regenerative medicine is still in its infancy, and significant basic research investment has not yet achieved satisfactory clinical outcomes for patients. In particular, there are many challenges associated with the use of cell- and tissue-based products for clinical therapies. This review summarizes the transformation and global progress in translational medicine over the past decade. The current obstacles and opportunities in translational regenerative medicine are outlined in the context of stem cell therapy and tissue engineering for the safe and effective regeneration of functional tissue. This review highlights the requirement for multi-disciplinary and inter-disciplinary cooperation to ensure the development of the best possible regenerative therapies within the shortest timeframe possible for the greatest patient benefit. © 2011 Elsevier Inc. All rights reserved.

Contents 1. 2. 3. 4.

Introduction . . . . . . . . . . . . . . . . . . . . . . The concept of translational medicine . . . . . . . . . . Global progress in translational medicine . . . . . . . . Hot topics in translational regenerative medicine . . . . 4.1. Regenerative therapies: an overview . . . . . . . 4.2. Stem cell therapy . . . . . . . . . . . . . . . . 4.2.1. Clinical need for stem cell therapy . . . . 4.2.2. Translational research for stem cell therapy 4.2.3. Stem cell therapy in regenerative dentistry 4.2.4. Crucial barriers to progress . . . . . . . 4.3. Tissue engineering technology . . . . . . . . . . 4.3.1. Tissue engineering in reconstructive surgery 4.3.2. Challenges ahead: a bridgeable gap . . . 5. Difficulties and perspectives . . . . . . . . . . . . . . 6. Closing remarks . . . . . . . . . . . . . . . . . . . . Acknowledgments . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . .

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⁎ Correspondence to: Y.M. Zhao, Department of Prosthodontics, School of Stomatology, Fourth Military Medical University, Xi'an 710032, Shaanxi, PR China. Tel./fax: + 86 29 8477 6001. E-mail addresses: [email protected] (F.-M. Chen), [email protected] (Y.-M. Zhao), [email protected] (Y. Jin), [email protected] (S. Shi). 0734-9750/$ – see front matter © 2011 Elsevier Inc. All rights reserved. doi:10.1016/j.biotechadv.2011.11.005

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1. Introduction

Over recent years, there has been increasing interest in funding opportunities for initiatives that aim to bridge the ‘translational gap’ between

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basic and clinical research. As an emerging trend of medical practice and interventional epidemiology, translational medicine has now been established as a research platform in biomedical science. It acts as a bidirectional link between research and application to promote the rapid clinical translation and feedback of basic research results (Humes, 2005; Mankoff et al., 2004). Meanwhile, as an evolutional concept, translational medicine promotes cross-disciplinary integration and focuses medical research on the treatment or prevention of clinical diseases, where biomedical research has led to “patient-oriented” care (Petrou et al., 2009). Basic research and clinical research have developed rapidly since the start of the 21st century. In parallel, barriers and gaps have become increasingly significant between clinical and basic research—a common perception is that the new discoveries generally fail to be efficiently translated into clinical research and ultimately into clinical practice (Katz, 2008; Mao, 2009; Newnham and Page, 2010; Tesio, 2004). More scientific researchers and government departments have realized that the gap between research and application will be a stumbling block for the continued rapid development of the life sciences. Many important discoveries lay dormant, leading to an imbalance between investments in basic biomedical research and rewards from treating human disease (Fig. 1). With the progressive advancements in life sciences, basic research has now penetrated into all fields of clinical medicine, rendering the rapid translation of knowledge and results acquired in the laboratory into techniques and therapeutics for clinical diagnosis and treatment a possibility. For example, stem cells grown in the laboratory have been the source of many breakthroughs in the treatment of heart disease (Perin et al., 2004; Segers and Lee, 2008; Stamm et al., 2004), graft-versus-host disease (GVHD) (Jacobsohn et al., 2004) and systemic lupus erythematosus (SLE) (Sun et al., 2009) in human beings. In 1998, the U.S. Food and Drug Administration (FDA) approved tissue-engineered skin called TransCyte® for clinical use, and numerous patients have received this treatment thus far. Recent advances in biomedical research and biotechnologies have offered new promises for the development of advanced therapies for human diseases (Cuende and Izeta, 2010), which may greatly improve patients' expectance of cures, patients' quality of life and public health. However, a substantial amount of basic medical research has not yet been translated to the bedside for routine clinical use (Belardelli et al., 2011). In this context, translational medicine has received increased attention and hence, has been popularized in the scientific arena (Milne and Kaitin, 2009; Valdespino Gómez, 2010). As a platform for communication between basic medicine, drug discovery and clinical disciplines, the

Fig. 1. Schematic depiction of the imbalance between investments in basic biomedical research and rewards from treating human disease. Potential new regenerative therapies are reported so frequently that one might predict a complete regeneration of multiple human tissues/organs in the next few years. However, most of these exciting discoveries never go beyond the laboratory bench. Obviously, some basic biomedical research in regenerative medicine is valuable even if it is not translated into a therapy. However, too many important discoveries are not further developed, with little research effort directed toward their potential for clinical translation, resulting in unrealized dividends from our investments in basic biomedical research.

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importance of translational medicine in medical research and the health industry has significantly increased in recent years. Alongside recent positive developments in stem cell biology, regenerative medicine has enabled the development of new biotechnologies that exploit effective biological methods to promote self-repair and regeneration, such as the construction of new tissues to improve or restore the function of injured or destroyed tissues and organs (Gurtner et al., 2007). Although the challenges of introducing these therapies into widespread healthcare are still substantial, including significant biological, technical, clinical and regulatory hurdles, the potential benefits to patients would be profound (Chen and Jin, 2010; Chen et al., 2010a; Dutta and Dutta, 2010; Ruff and Fehlings, 2010; Vilquin and Rosset, 2006). Therefore, strengthening research on translational regenerative medicine may promote the application of new clinical therapeutic strategies and supply effective therapeutic measures for the treatment of severe tissue or organ deficits, and ultimately produce profound innovations that may drive the future of regenerative and engineering technology (Feuerstein and Ruffolo, 2007; Feuerstein et al., 2008; Shah et al., 2009). The primary purpose of this review is to inform the reader of the current state of knowledge on translational regenerative medicine. We provide a conceptual description of translational medicine and a general introduction to current developments, with a particular emphasis on the status of research in regenerative medicine and the urgent need to translate advanced therapies from bench to bedside. This review utilizes a traditional approach rather than a systematic approach to provide a broad overview of the global translational medicine trends. This review is not meant to be exhaustive but aims to outline how stem cells and tissue engineering can provide a breakthrough in future reconstructive surgery, highlighting the orthopedic surgeons and oral health researchers remaining at the forefront of the movement to bring together clinicians, research scientists and industry partners to accelerate the pace of the clinical translation of medical research. 2. The concept of translational medicine The pursuit of translational medicine was a priority of the scientific community at the beginning of the 21st century. Translational medicine encompasses the continuum of activities that extend from the conception of an idea to advanced preclinical and clinical testing and, ultimately, to the development of new therapeutics for patients (Mao, 2009; Newnham and Page, 2010). The concept of translational medicine has garnered wide attention and acceptance by the scientific community, but its precise definition has not been fully established thus far. With the increasing complexity and rigor of clinical research, the barrier between clinical and basic research is high, which limits the translation of new knowledge into clinical research and the subsequent feedback to basic research (Katz, 2008; Tesio, 2004). Translational medicine is increasingly important in the healthcare industry as it facilitates the movement of advanced therapies from a laboratory discovery to pre-clinical testing, early clinical trials, and late confirmatory studies that may lead to regulatory approval of therapeutics for use in patients (Belardelli et al., 2011; Schmidt, 2007). The goals of translational medicine are to break down the barriers between basic medicine, drug research and clinical medicine, to strengthen the integration between research and applications (Kreeger, 2003; Marincola, 2003; Moore, 2008). On the one hand, the knowledge and results obtained by basic scientists can be transformed into clinical applications to provide more advanced concepts, techniques, tools and methods related to disease diagnosis, treatment and prevention (Kreeger, 2003). On the other hand, clinical researchers communicate with basic science researchers to amend deficiencies in proposed therapeutics in a timely fashion, thereby promoting the development of basic research. These relationships are the foundation of the so-called dual-channel modulation and “Bench-2-Bedside (B2B)”

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model (“bench to bedside” as well as “bedside to bench”) (Moore, 2008). The modern meaning of translational research can be divided into two levels of translation. The first level corresponds to efficacy studies under controlled conditions with careful attention to internal validity (clinical research) and refers to the translation of findings “from bench to bedside”. The second level is the translation of results from clinical studies into everyday clinical practice and health-related decision-making (the theory to practice or the translation from the bench to community) (Kreeger, 2003; Ledford, 2008; Moore, 2008; Petrini, 2011; Zinner and Campbell, 2009). Meanwhile, new issues discovered by the observation and practice of clinical medicine can further stimulate new ideas for basic science research and can focus research specifically on solving clinically significant problems. Thus, translational medicine is a cyclical scientific system (Ledford, 2008; Marincola, 2003). The current goal of translational medicine is to build an effective “hub” between the researchers who are engaged in basic scientific discovery and the clinicians who understand the needs of patients. The focus of translational medicine is to use basic cellular and molecular biomedical research to efficiently and appropriately develop diagnostics, treatments and prevention options for clinical medicine (Ledford, 2008; Moore, 2008; Tesio, 2004; Zinner and Campbell, 2009). Typically, basic research focuses on knowledge exploration, discovery and innovation; clinical medicine focuses on disease diagnosis, treatment and prevention, whereas translational medicine focuses on disease diagnosis and treatment that serves as the starting point for research to promote the translation of scientific discoveries to medical practice and the return of feedback to basic research (Cao, 2009; Huang, 2010). Translational medicine advocates “patient-oriented research”, which means research must focus on questions driven by clinical findings. Basic researchers conduct in-depth studies and analyze problems, then rapidly translate their results to clinical applications and problem solving (Liu and Lv, 2008). This translation requires basic researchers and clinical scientists to work closely to achieve the objective of improving the overall healthcare. Therefore, the establishment of translational medicine as a hot discipline strives to break the previous work models of “individualism” or “limited cooperation”, instead emphasizing the integrated exploitation of our available research resources and promoting more open, multidisciplinary and multi-field research teams to contribute their respective advantages to a same research purpose (Jiang, 2010). Collectively, translational medical research includes conceptual scientific research, preclinical studies, clinical trials and implementation of research findings (Fig. 2) (Buter, 2008; Woolf, 2008). Translational medicine follows the principles of evidence-based medicine. It rests at the intersection of theory and practice, or basic research and clinical research, and it has been an inevitable ‘product’ of the life science and bioinformatics revolutionary era. Translational medicine spans many fields of biology, including studies of cellular biology,

Fig. 2. Four main aspects and their dynamic feedback in translational research in determining new therapeutics/techniques for clinical use. Because the safety and efficacy of the therapeutics may change during the translational process (from in vitro to in vivo, from animal to human), continual feedback will be needed to improve the design of therapeutics from the original bench-based development through preclinical studies and clinical trials.

molecular biology, structural biology, function, phenotypic biology, pathogenesis, physiology, pathology, environmental genetics, diagnostic markers, disease prevention and treatment, medical information systems, and multi-disciplinary, multi-level, multi-target, microscopic and macroscopic, static and dynamic systems. It may also involve the cross-integration of humanities and science. Translational medicine has revolutionized medicine by fostering the translation of cuttingedge basic biomedical research into efficient and tailored disease diagnosis, treatment and prevention. Translational medicine has also played a role in the reformation of medical education. Basic science must work in concert with clinical medicine in order to prosper. Likewise, basic medicine must produce clinical applications to have a promising future. The combination of basic and clinical research proposed by translational medicine is the direction of future medical education and provides guidelines for political reform of medical training (Mark and Kelch, 2001). The concept of translational medicine will promote the training of more medical personnel, to promote and ensure the healthy and stable development of biomedical research (Kuehn, 2006; Littman et al., 2007; Plebani, 2008; Schwartz-Bloom, 2005; Snape et al., 2008; Solway et al., 2009). In short, at the forefront of medicine development, translational medicine plays an increasingly important role in guiding and supporting the development of the field of medicine. It promotes basic laboratory research and makes it more effective and efficient, with a greater focus on patients. At the same time, it promotes the timely and effective use of basic research results in clinical study and medical decision-making (Plebani, 2008; Snape et al., 2008). In summary, translational medicine is a medical practice that integrates research from the basic sciences, social sciences and political sciences with the aim of optimizing patient care and preventive measures, which may extend beyond healthcare services. It focuses on using pre-clinical study findings to improve clinical practice through the course of predicting, preventing, diagnosing, and treating diseases. It also uses findings gleaned from clinical studies to sharpen and improve pre-clinical efforts to discover new medicines. As a multi-disciplinary field, translational medicine applies the principles of evidence-based medicine to promote knowledge integration and inter-disciplinary collaboration and to facilitate the translation and feedback of research outcomes from the basic sciences and clinical sciences, yielding a continuous, patient-oriented, circular scientific system to bridge basic scientific discoveries and physicians' care for their patients. This bridge can be described as a bidirectional translational channel between the laboratory and clinic (Sanchez-Serrano, 2006; Solway et al., 2009; Zerhouni, 2005). 3. Global progress in translational medicine Although the field of translational medicine has only been developed as a well-recognized biomedical guideline over the past decade, the concept has been associated with the development of life sciences, medical physiological research and education for a much longer period (Sanchez-Serrano, 2006; Zerhouni, 2005). In 1968, an editorial discussion in the New England Journal of Medicine first proposed the “bench–bedside interface” research model (Editorial, 1968). However, after a long period of time, due to the constraints of technological development and insufficient awareness of diseases, this model had not received substantial attention or in-depth investigation. In 1994, the use of the concept of “translational research” to prevent and control cancer was formally proposed. In that case, behavioral science played an integral, essential role by providing a pragmatic conceptual model for clinical practice and facilitating collaborative research between basic scientists and clinical researchers (Morrow and Bellg, 1994). Translational medicine was then gradually understood and accepted by the scientific community (Morrow and Bellg, 1994). Over the following 20 years, the role and power of translational medicine has become increasingly significant. The number of studies on translational medicine has continued to increase. In 2003,

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the National Institutes of Health (NIH) in the U.S. established a roadmap that formally defined the modern concept of translational medicine as a so-called two-way, open loop system (Zerhouni, 2003). In 2004, the NIH took a significant step toward addressing the need to accelerate translational research when it launched the NIH Roadmap—three major initiatives, among which ‘Re-Engineer the Clinical Research Enterprise’ specifically addresses the translational research initiative as a major priority in the selection of annual Pioneer Awards for researchers whose vision is judged to be particularly broad and creative (Hörig et al., 2005). In early May 2006, Scotland and one of the world's largest pharmaceutical companies, Wyeth Pharmaceuticals, launched the world's first Cooperative Research Centre for Translational Medicine, with a total investment of close to £50 million. The organizations involved in the project include four prestigious universities in Scotland (Aberdeen, Dundee, Edinburgh and Glasgow), Wyeth Pharmaceuticals, Scottish Enterprise and the National Health Service (NHS) in the associated Scottish areas (http://stmti.mvm.ed.ac.uk) The goals of this center are to diagnose and monitor human diseases, i.e., biological markers (such as newly discovered proteins or indicators). These biomarkers can be detected through blood sampling of patients or X-rays, and can be used in observation of the progress of treatments (e.g., for conditions such as cancer, depression and osteoporosis) and the patients' responses (Huang, 2010; Liu and Lv, 2008). The hope of such collaboration is that the new research will alleviate patients' suffering from different diseases in the near future. At the same time, the world-renowned pharmaceutical company AstraZeneca announced in Beijing, China that they would invest $100 million (USD) in China in the following three years to establish the AstraZeneca China Innovation Center and to develop the translational medical research of gene therapy (Jiang, 2010). Since 2006, the NIH has set up collaborative groups with more than twenty universities and organizations, and established a new discipline called Clinical and Translational Science. The NIH's aim is to promote and accelerate multi-disciplinary and inter-disciplinary cooperation, develop innovative research tools and technologies (such as tissue engineering, clinical translation of cancer prevention and treatment and stem cell treatment of human diseases) and catalyze new knowledge and new therapeutics. This series of collaborative works by the NIH marks the formal establishment of the concept of translational medicine. Thus far, 38 universities in the US have established numerous translational research centers, and this number will purportedly increase to 60 centers in 2012 (Buter, 2008; Ledford, 2008; Pearson, 2008). The NIH currently allocates approximately US$500 million each year to translational medicine research, and it is reported that the investment in medical translational research at this stage is £450 million in Britain and €6 billion in the European Union (www. genewatch.org; www.who.int/phi/en). In just a few years of rapid development, translational medicine research has been confirmed as a new starting point and focus for global medical research. It has received a large degree of attention and concern (Carpenter, 2007; Lenfant, 2003). On December 7, 2010, the Scientific Management Review Board (SMRB), a NIH advisory body, recommended the establishment of a center for translational medicine, making the translation of basic research to the clinic a top priority. The proposed National Center for Advancing Translational Sciences will combine several existing programs, with a budget of at least US $650 million and could be operational by October 2011 (Collins, 2010). Recently, large-scale international seminars focusing on translational medicine have taken place in almost every corner of the world to promote the development of this field. Many journals have started columns on translational medical research to provide an exchange platform for the growing research studies on translational medical research. In 2009, Science Translational Medicine and The American Journal of Translational Research were founded simultaneously, joining other international journals that were founded a few years ago, such as the

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Journal of Translational Medicine, Translational Research and Clinical and Translational Science, to constitute an information network for translational medicine. As a relatively new inter-disciplinary field, translational medicine remains in its infancy and accordingly is in need of further development (Collins, 2010; Lee et al., 2009; Moss, 2008; Pober et al., 2001). The use of translational medicine to promote progress in other areas and to navigate research and education requires additional experience, and attention from management, scientists and society is highly encouraged. Multi-disciplinary knowledge should be integrated to promote close communication between inter-disciplinary research groups for their mutual improvement, and finally to maximize the promotion of human health (Moss, 2008; Pober et al., 2001). 4. Hot topics in translational regenerative medicine Repair, restoration and replacement of tissue that is lost resulting from damage, congenital defects or chronic ailments is unique among clinical treatments because of the large numbers of patients involved, rendering regenerative medicine a key field for translational medical research (Belardelli et al., 2011; Ginty et al., 2011). Although organ transplantation and prosthetic restoration allows for partial recovery from a small number of tissue defects, factors such as limited sources of organs, immune rejection and poor physical function severely restrict their use for a wide range of clinical applications. Both autologous and allogeneic transplantation are inadequate (Khan et al., 2005). The growing number of cases and the limited organ sources indicate the increasing imbalance between supply and demand, and this phenomenon is particularly serious in developed countries. In addition, organ transplantation poses the challenging problems of rejection after organ transplantation and ethical issues of transplantation of another person's organs. In this regard, regenerative medicine, which refers to the process of regenerating living and functional tissues to repair or replace tissue or organ function, is an early adopter of the concept of translational medicine by integrating current limited resources and use of a multi-disciplinary strategy to translate medical research outcomes into improved healthcare in a timely manner (Ginty et al., 2011). Today, regenerative medicine stands at the forefront of the movement to bring together clinicians, research scientists and industry partners to speed the translation of medical advances from the laboratory to clinical services. This progress may reduce the burden on the world's healthcare systems and address the desperate need for replacement of tissues and organs. 4.1. Regenerative therapies: an overview Regeneration and repair are widespread phenomena in the human body even in the absence of a therapeutic intervention; however, the regenerative capacity varies among tissues, organs and patients (Place et al., 2009). In most instances, tissues are capable only of incomplete regeneration because healing may be restricted by the deficiency or inability of endogenous pools of stem/progenitor cells in elderly populations or by the intrinsically low regenerative potential of certain tissues (Chen et al., 2011a, 2011b). To this end, the function or structure of an organ will not be restored after tissue damage. Wounded tissue is most often replaced by scarring fibrous tissue (Place et al., 2009). If an existing organ or tissue dysfunction cannot be restored by endogenous mechanisms alone, the use of therapeutic interventions that facilitate tissue repair may be required, leading to the development of inductive and constructive biomaterials, the use of tissue grafts and the concept of guided tissue and bone regeneration (Beaman, et al., 2006; Chim and Gosain, 2009; Pou, 2003). Such regenerative procedures have been widely employed in clinics since the early 1980s and are regarded as the first generation of regenerative technologies. However, these techniques principally lead to the production of scarring fibrous tissue, which has material properties that are inferior to the original tissues, and hence, this process should

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be termed ‘repair’ and not ‘regeneration’. Indeed, the overall tissue functionality cannot be self-restored in many, if not all, cases with severe tissue insults. Following the introduction of a wide range of biomaterials (natural and synthetic) into regenerative medicine, various growth factors, enamel matrix derivative (EMD) and patient-derived preparations, such as platelet-rich plasma (PRP), have been selectively applied in reconstructive surgeries to augment regeneration (Trombelli and Farina, 2008). These factors appear to accelerate the recruitment of and repopulation by key tissue-forming cells once implanted into the tissue defect spaces and may encourage further progression of tissue regeneration. Some of these materials have already become commercially available or found their way into clinics (e.g., a number of recombinant human growth factors and Emdogain®). PRP techniques have been used in the clinic for nearly 30 years (Fig. 3), although outcomes vary considerably among the different studies (Bosch, et al., 2010; Cervelli et al., 2009; Martínez-Zapata et al., 2009; Plachokova et al., 2008). These applications may be categorized as the second generation of regeneration technologies. However, these medical products still demonstrate limited regeneration potential, particularly in cases with large-scale tissue deficits. Furthermore, the clinical use of growth factors is often hindered by delivery problems (Anitua et al., 2008; Chen et al., 2009, 2010b, 2011b; Lee et al., 2011). In parallel, the use of EMD and PRP in reconstructive surgery has been evaluated in various experimental and clinical models (e.g., periodontal tissue defects), yet the outcomes were frequently inconsistent or conflicting

between studies (Trombelli and Farina, 2008). Although countless clinical trials based on biological molecules have been performed, the clinical experience thus far has been disappointing, spurring further research at the bench (Anitua et al., 2008; Chen et al., 2010b, 2011b). The identification of both the essential growth factors that determine the fate of a specific tissue and the criteria by which to establish the dosing, regulation and optimization of both EMD/PRP technology and their composition; the development of tailored products for each pathological situation; and the establishment of a standard clinical application strategy are a few of the key steps that must be addressed to promote the clinical application of advanced EMD/PRP technology (Anitua et al., 2008; Chen et al., 2010b). Hence, the practice of translational regenerative research cannot neglect basic science (Moss, 2008). Together with the recent progress in regenerative techniques, cell transplantation has developed as a novel generation of regenerative technology (Ginty et al., 2011; Khan et al., 2005; Place et al., 2009) (Fig. 4). However, it would be more preemptive and advantageous if one could apply a material device to achieve in situ tissue regeneration without the use of exogenously manipulated cells (Guldberg, 2009). This basic concept of in vivo tissue engineering relies upon the existence of potentially useful cell populations in the body. These cells would need to be attracted to a desired anatomic site and would then have the potential to provide a new therapeutic option in certain ideal scenarios (Anitua et al., 2010; Chen et al., 2011a; Kim et al., 2010a, 2010b; Lee et al., 2010; Mao et al., 2010;

Fig. 3. Schematic illustration of the use of platelet-rich plasma (PRP) technology for the facilitation of tissue regeneration. Whole blood was collected and centrifuged according to a strict preparation procedure to generate plasma with a high concentration of platelets that remains in the bottom of the superior fraction (the plasma fraction). PRP is the plasma fraction that contains multiple endogenous cues and growth factors and could be clotted by the use of calcium chloride as a clot activator. PRP gels/scaffolds could be easily obtained by use of PRP alone or PRP combined with other biomaterials. When a PRP preparation is ready for use, it can be implanted into tissue defects, leading to tissue regeneration via cell recruitment from extracellular matrices (ECMs) and/or cell homing from peripheral blood vessels (modified from Chen et al., 2010b).

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Fig. 4. Schematic representation of three ex vivo cell-based approaches for tissue regeneration (the receptor may be the donor or a different person). The presumption for this schematic is that there is already an existing degree of organ or tissue dysfunction that cannot be restored by endogenous mechanisms alone. Cell therapy encompasses the harvesting of tissue biopsies from a patient, isolation of the cells, culture and expansion of the cell population, and collection and injection of the cells into the diseased site. Alternatively, the cells can be collected and seeded into a three-dimensional (3D) scaffold that contains either growth factors or vehicles pre-loaded with growth factors. The cell-seeded scaffold is either immediately implanted into tissue defects or used to generate tissue-like constructs in a bioreactor before transplantation. For a gene-enhanced approach, the cells are modified to produce endogenous growth factors to augment tissue regeneration.

Sun et al., 2011a; 2011b). The capture of exogenous stem cells for therapeutics is a process normally termed active stem cell homing (Chen et al., 2011a, 2011b; Mao et al., 2010). In general, “homing” is defined as cellular circulation throughout the body via the circulatory system until the cell is arrested by microvascular endothelial cells at a target organ, following a coordinated multistep process including adhesion to the endothelium, transendothelial migration, chemotaxis, matrix degradation and invasion, and in situ differentiation (Chavakis et al., 2008; Chen et al., 2011a; Laird et al., 2008; Sun et al., 2011b). This mode of stem cell trafficking is best understood for hematopoietic stem cells (HSCs), but this process may also apply to other stem cell types (Laird et al., 2008). Recently, the definition of cell homing has been broadly extended to include the active recruitment of neighboring or distant endogenous cells, including stem/progenitor cells, to a desired anatomic compartment for therapeutic applications (Kränkel et al., 2011; Mao et al., 2010; Martínez-Zapata et al., 2009; Sun et al., 2011b). The recruitment of stem cells from distant niches involves a mode that is similar to that of HSC homing and is dependent on blood flow, while neighboring stem cells can actively reach a target site via interstitial migration that requires stem cells to recognize and obey extravascular guidance cues (Chen et al., 2011a; 2011b; Sun et al., 2011b). Although the cellular and molecular mechanisms involved in stem cell homing remain largely unexplored, the participation of endogenous stem/progenitor cells in tissue repair and regeneration is incontrovertible and has garnered significant research interest in recent years (Kim et al., 2010a, 2010b; Kimura et al., 2010; Kumagai et al., 2008; Lee et al., 2010; Otsuru et al., 2007, 2008; Thieme et al., 2009). In addition, homing and engraftment of stem/progenitor cells is a prerequisite

for cell-based therapy, particularly in cases where exogenous cells are administrated systemically via injection (Chavakis et al., 2008). In terms of large-volume tissue regeneration, a common cellbased therapeutic strategy is to seed ex vivo cultured cells into a biomaterial device that defines the geometry of the replacement tissue and provides supports and cues that manipulate cell fate and regulate tissue regeneration (Chen et al., 2010a) (Fig. 4). Although the magnitude of regulatory and commercialization difficulty decreases from cell-based approaches to regenerative technologies that avoid using exogenous cultured cells (Belardelli et al., 2011; Schmidt, 2007), endogenous regenerative approaches may not provide a universal solution or be suitable for large-scale tissue defects. The use of biological approaches marks a new era of tissue regeneration (third generation) that is normally termed ‘true’ regenerative medicine. This term is often used interchangeably with tissue engineering. It encompasses a spectrum of innovative technologies and approaches ranging from the use of stem cells (Cuende and Izeta, 2010; Daley and Scadden, 2008; Parekkadan and Milwid, 2010), designed biomaterials (Lutolf et al., 2009) and signaling biomolecules (Discher et al., 2009), individually or in combination, that will enable the body to energetically repair, replace and regenerate damaged or diseased tissues and organs, and maximally restore body functions (Baylis and McLeod, 2007; Discher et al., 2009; Kiskinis and Eggan, 2010; Lutolf et al., 2009; Place et al., 2009). In terms of clinical use, ex vivo organogenesis for the creation of a complete tissue or organ replacement, irrespective of its great potential for treatment of severe damage or disease, represents the most costly and challenging task of translational medicine (Fig. 5).

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4.2. Stem cell therapy Stem cell-based therapy is emerging as a rapidly evolving field of research and therapeutics and holds great promise for future translational research and clinical applications in many fields. Resident pools of somatic stem cells are responsible for tissue maintenance and repair in many organs and the rapid advances in stem cell biology over the past two decades have fueled an ever-increasing effort to develop translational stem cell-based regenerative therapies (Moss, 2008). It has become increasingly clear that a lack of or decline in endogenous stem/progenitor cell populations to restore normal cellularity and physiological function is the common reason for the failure of most, if not all, tissues to endogenously regenerate following a tissue insult (Cuende and Izeta, 2010). Thus, stimulating and augmenting stem cells for tissue repair processes serves as an attractive and valuable route to combat a broad array of tissue deficits. This arena is well suited to translational medicine. Ultimately, the clinical use of stem cell therapy is to exploit cells as therapeutics either by transplanting them from an exogenous source or by activating endogenous stem cells pharmacologically in few well-selected cases (a cellfree or in vivo approach), where the plasticity and self-renewal capabilities of stem cells make them promising tools for the orchestration of tissue repair/regeneration (Daley and Scadden, 2008). 4.2.1. Clinical need for stem cell therapy Stem cell research and its application in cardiovascular disease, diabetes, neurological disorders, liver disease and other major diseases and a variety of tissue defects (such as bone, cartilage, nerve system, blood vessel and periodontal defects) provides a new approach for repair and regeneration (Daley and Scadden, 2008; Parekkadan and Milwid, 2010). The potential of stem cell therapy has caused it to be a focus of international attention in the field of life sciences and translational medical research (Cuende and Izeta, 2010; Daley and Scadden, 2008; Parekkadan and Milwid, 2010). The acceleration and application of clinical stem cell therapy technology has great social and economic benefits that will have a profound impact on human health. However, basic research in stem cells has not yet significantly affected patients, and there are many issues to consider when

Fig. 5. Schematic depiction of escalating the magnitude of regulatory and commercialization difficulty, where different regenerative therapies range from methods to enhance the body's endogenous regenerative capacity to combination technologies capable of ex vivo organogenesis for the creation of a complete tissue/organ replacement. Therefore, as illustrated, an increase in the degree of organ or tissue dysfunction is logically linked to a parallel increase in the complexity and number of therapeutic interventions (i.e., technologies) required for the repair or restoration of function. The magnitude of difficulty in clinical translation increases from biomaterials or biological cues alone, cues in biomaterials, release technology and advanced biomaterials to ex vivo cell manipulation and delivery; in addition, the use of tissue engineered replacements represents the most costly and challenging approach for regulatory approval and commercialization.

preparing a cell-based therapy for clinical use (Cuende and Izeta, 2010). Nevertheless, clinical trials of stem cells being developed around the world suggest that further study is necessary to address the serious discrepancy between basic research and clinical application in this area (Cuende and Izeta, 2010). Future clinical translation of stem cell therapy should focus on issues of the selection of appropriate cell sources, the establishment and evaluation of animal models of related diseases, cell transplantation and the determination of the optimal dosage, in vivo tracer techniques after transplantation, dose safety and efficacy testing, mechanisms of effective treatment, improvement of the efficiency of transplanted cells, complete clinical and pre-clinical studies of related products, establishment of key technologies for the prevention and treatment of immune rejection and the development of relevant clinical access criteria (Cuende and Izeta, 2010; Parekkadan and Milwid, 2010). These issues are reviewed in detail by another manuscript prepared for Cell Transplantation. Reconstruction of a tissue defect is a common surgical operation that remains a major challenge in the management of patients. The limited therapeutic interventions that can induce functional regeneration result in many people never fully recovering their function or quality of life, which affects the patient's social, financial and psychological well being (Shekkeris et al., 2011). It is increasingly evident that cell therapy provides one of the most important solutions to the unmet need for new treatments in clinics. The field of regenerative medicine has begun to provide new strategies by which engineered tissue can be tailored to a specific site of injury (Choi et al., 2010). This area of research has undergone a rapid translation into humans, with bone marrow-derived mesenchymal stem cells (BMMSCs) being the cell type with the most clinical data (Filho Cerruti et al., 2007; Gan et al., 2008; Kraus and Kirker-Head, 2006; Kuroda, et al., 2007; Mosna et al., 2010). The possible clinical applications of stem cells in the management of chronic critical limb ischemia, foot ulcers (Procházka et al., 2010), knee osteoarthritis (Davatchi et al., 2011) and heart disease (Martino et al., 2010; Wang et al., 2010; Wöhrle et al., 2010) are evident and exciting. Initial studies indicate an immense potential for cell-based strategies to enhance current tissue reconstructive therapies (Gómez-Barrena et al., 2011). As noted earlier in this review, the efficacy of such treatment options is not well understood. Appropriately conducted randomized clinical trials, with adequate patient numbers, are necessary to evaluate these therapies (Shekkeris et al., 2011). An improved understanding of stem cell biology and better control over stem-cell fate are also necessary. Of considerable interest is the fact that surgeons are in an ideal position to capitalize on emerging technologies and will be at the forefront of transitioning basic science research into the clinical reconstructive arena (Wong et al., 2010; Wright et al., 2011). Once stem cell therapies are properly mastered and perfected for reconstructive surgery, the benefits to both surgeons and patients will be immense. 4.2.2. Translational research for stem cell therapy Over 3000 adult stem cell therapies are currently in clinical studies in the global range of the world, covering a broad spectrum of therapeutic applications in spite of their potentially undetermined, unwanted and poorly controlled consequences (Cuende and Izeta, 2010; Daley and Scadden, 2008; Parekkadan and Milwid, 2010). Much research has focused on mesenchymal stem cells (MSCs) isolated from bone marrow in vitro and in vivo; however, bone marrow procurement causes considerable discomfort to the patient and yields a relatively small number of harvested cells (Griffin et al., 2011). Significantly, it is now well-recognized that MSCs can be isolated from many different adult tissues besides bone marrow, and they unexceptionally represent a rare heterogeneous subset of pluripotent stromal cells that exhibit the potential to give rise to cells of diverse lineages (Salem and Thiemermann, 2010). Recent data describing the identity, nature, origin, and in vivo function of each “MSC” subtype indicate that they may function as organizers and regulators of

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the regenerative microenvironment (Bianco, 2011). The nature of these cells, the suitable culture conditions for tissue regeneration, and their potential therapeutic applications have been extensively reviewed and include descriptions of possible caveats (Bianco, 2011; Gómez-Barrena et al., 2011; Griffin et al., 2011; Kagami et al., 2011; Salem and Thiemermann, 2010). The past decade has witnessed an explosion of preclinical data relating to the isolation, characterization, cryopreservation, differentiation and transplantation of freshly isolated stromal vascular fraction cells from adipose tissue in vitro and in animal models (Gimble et al., 2010). Recent studies have also emerged on the use of stem cells derived from adipose tissue in cell-mediated therapy for the degenerative diseases due to their potential to equally differentiate along multiple lineage pathways (Utsunomiya et al., 2011). Adipose tissue may serve as an abundant and easily accessible source of adult stem cells with a wide range of potential clinical implications. Today, a body of literature has provided evidence supporting clinical translational applications of adipose-derived cells in safety and efficacy trials (Kuhbier et al., 2010; Locke et al., 2011; Yarak and Okamoto, 2010). Besides adult stem cells, the pace of global research involving human induced pluripotent stem (iPS) cells is also very frantic, based on the enormous therapeutic potential of patient-specific pluripotent cells free of the ethical and political issues that have plagued human embryonic stem cell (ESC) research (Kiskinis and Eggan, 2010). ESCs have great potential for the treatment of a host of diseases, but their use is still limited by ethical issues related to the procurement, use and destruction of an “embryo” and scientific considerations, such as the maintenance of the ESC state, ESC differentiation and somatic cell reprogramming (Baylis and McLeod, 2007). Furthermore, cell manufacturers that plan to use human ESCs must be particularly stringent in their final purification steps, due to the unrestricted growth potential of these cells (Bajada et al., 2008). In comparison with ESCs, iPS cells are relatively easy to isolate from somatic cells and reprogramming can be accomplished by nonmutagenic technologies (Csete, 2010). These cells, like ESCs, are likely to have a major impact on regenerative medicine because they may self-renew and retain the potential to be differentiated into most, if not all, human cell types (Kiskinis and Eggan, 2010). For translation of these cell therapies, the major advantage of iPS cells is that they are autologous. For many reasons, perfect immunologic tolerance of iPS-based grafts should not be assumed (Csete, 2010; Zarzeczny et al., 2009). The numerous recent advances in stem cell biology, cell signaling and genome studies have revolutionized our understanding of the mechanisms underlying the genetics, biology and clinical behavior of stem cells, provoking great interest and suggesting high therapeutic promise for transplantation and regenerative medicine based on the possibility of stimulating ex vivo and in vivo cellular expansion (Daley and Scadden, 2008; Parekkadan and Milwid, 2010). Meanwhile, biomedical imaging has developed very quickly and a number of new tools are increasingly being used to monitor the fate of transplanted stem cells, including but not limited to their survival, trafficking, proliferation, differentiation and homing to targeted destinations (Banerjee, 2011). The elucidation of the molecular complexity of cellular products, the development of material systems to deliver these cells to the body and the promotion of their efficient engraftment and integration with the target tissue, in addition to several issues aforementioned in Section 4.2.1, remain to be addressed. Stem cell culture techniques and the laboratory conditions in many medical institutions have been able to meet the requirements of clinical applications. Translational medical research has the important tasks of developing in-depth and extensive clinical trials of stem cell treatments, with safety and efficacy in mind and to promote stem cells as a powerful tool for clinical treatment. Only with the “B2B” mode to provide feedback from clinical research can basic research unlock the true potential of a broad spectrum of stem cells. Of note, bone

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marrow-, umbilical cord-, adipose tissue-, skin- and amniotic fluidderived MSCs may be adequate alternatives for translational practice. In particular, bone marrow-derived stem cells have been used successfully in the clinic for bone, cartilage, spinal cord, cardiac and bladder regeneration (Bajada et al., 2008). MSCs as multipotent cells are capable of differentiating into mesodermal and non-mesodermal lineages (Salem and Thiemermann, 2010). However, further studies must be performed to elucidate the differentiation capacity of MSCs from different sources and to understand the involved pathways and processes (Hilfiker et al., 2011). To evaluate the available clinical evidence and recent progress in strategies that attempt to use autologous and heterologous MSCs in clinical practice, a recently published review compared various procedures for isolating and expanding a sufficient number of MSCs for use in a clinical setting (Griffin et al., 2011). At the same time, the possibilities and challenges of this technology have also been comprehensively reviewed elsewhere (Bianco, 2011; Gómez-Barrena et al., 2011; Griffin et al., 2011; Kagami et al., 2011; Salem and Thiemermann, 2010). The successful implantation of MSCs has been reported in a number of clinical studies for the treatment of large bone defects (Filho Cerruti et al., 2007; Gan et al., 2008; Kraus and Kirker-Head, 2006; Kuroda, et al., 2007; Mosna et al., 2010), GVHD (Jacobsohn et al., 2004), SLE (Sun et al., 2009), cardiovascular diseases (Perin et al., 2004; Segers and Lee, 2008; Stamm et al., 2004), hematological pathologies (Fouillard et al., 2007; Lazarus et al., 2005) and osteogenesis imperfecta (Horwitz et al., 2001), suggesting that MSC therapy is an effective, safe and durable method for aiding tissue repair and regeneration. Importantly, most of the initiated trials had a limited scope with respect to controls and outcome. With the implementation of a new regulatory framework for Advanced Therapeutic Medicinal Products (ATMPs, typically including three main types: gene therapy, somatic cell therapy and tissue engineered products) (Cuende and Izeta, 2010), the stage is set for stem cell therapy to pave the way for improved controlled and well-designed translational research and clinical trials. A coordinated effort of scientists and clinicians will provide new clinical breakthroughs in the translation of stem cell therapies for the treatment of a wide variety of diseases (Gómez-Barrena et al., 2011). 4.2.3. Stem cell therapy in regenerative dentistry The accelerated pace of progress in stem cell biology and tissue engineering in the recent decade and the accumulated body of knowledge in translational medicine has spurred interest in the potential clinical translation of stem cells in all branches of medicine, including craniofacial reconstruction and regenerative dentistry (Runyan and Taylor, 2010; Volponi et al., 2010). These developments have created exciting opportunities for tooth tissue engineering, including the biological regeneration of tooth/periodontal tissues in vivo and the generation of a complete tooth in vitro. These developments are based upon a better understanding of the biology of spatially and temporally organized and structured dental morphogenesis. The identification of stem cells from periodontal ligaments (Seo et al., 2004), dental pulp (Gronthos et al., 2000), exfoliated deciduous teeth (Miura et al., 2003), dental follicle (Morsczeck et al., 2005), apical papilla (Sonoyama et al., 2006,2008) and gingival tissue (Tang et al., 2011) and new insights into their in vitro and in vivo manipulation (Demarco et al., 2010; Fan et al., 2009; Gronthos et al., 2011; Iwata et al., 2009; Mrozik et al., 2010; Yang et al., 2009) have rendered the regeneration of functional dental tissues possible. Most immediate is the identification of epithelial and mesenchymal cell populations from dental or other tissue resources that can be maintained and expanded in culture or in a bioreactor to provide the large cell populations needed to reconstruct defective dental tissues (Huang et al., 2009). Dental stem cells have many advantages over other sources of MSCs, and outcomes to date suggest that teeth are a viable source of adult MSCs for a wide range of clinical applications (Casagrande et al., 2011; Huang et al., 2009). Ultimately, use of these

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dental stem cells in regenerative dentistry will not only depend on their ease of use and accessibility, but also on their efficiency and quality of repair in relation to cost (Catón et al., 2011; Chen and Jin, 2010; Inanç and Elçin, 2011; Sun et al., 2011a; Volponi et al., 2010). Cell-based therapy is more likely to be accepted and warranted by both the government and patients for currently incurable and lifethreatening diseases, such as diabetes (Bhansali et al., 2009), Parkinson's (Lindvall and Kokaia, 2009; Vidaltamayo et al., 2010), muscular dystrophy (Meng et al., 2011; Meregalli et al., 2010), Alzheimer's (Sugaya et al., 2007), neural (Sanberg et al., 2005) and cardiac diseases (Benetti et al., 2010; Sun et al., 2010; Wöhrle et al., 2010) and refractory systemic lupus erythematosus (Liang et al., 2010; Sun et al., 2009). Dental tissue regeneration by cell therapy, however, will not be economically viable or competitive with current root canal therapy or dental implants (Sun et al., 2011a). Keeping this limitation in mind, more work must be performed to make current stem cell therapy safer, simpler, more practical and economical. Due to their non-life-threatening nature, dental tissues were not considered as a major target for regenerative medicine research. Nevertheless, this very fact makes therapeutics that aim at regeneration of dental tissues ideal for the evaluation of new cell-based therapies considering that the patients are usually healthy. Possible therapeutic complications would be far less risky or life-threatening for such healthy patients compared to those with substantial co-morbidity. Furthermore, the accessibility of teeth implies that treatment would not require major surgery (Sun et al., 2011a; Volponi et al., 2010). However, safety issues cannot be ignored. Cancerous formations, migration of cells to unwanted areas, infections and unintended cell growths could all result as serious complications of this therapy (Rayment and Williams, 2010). Despite possible rejection problems, the use of allogeneic stem cells is much cheaper than the use of autologous cells, representing a research direction that is closer to clinical translation and use in the clinic (Volponi et al., 2010). The decision to incorporate allogeneic stem cellbased therapies into routine clinical dental practice requires careful analysis of the risks and benefits associated with this procedure (Fig. 6). Indeed, the translational use of autologous and allogeneic stem cells for patient therapy far exceeds the standard that is currently permitted in human medicine. To date, a number of studies have reported that stem cells, in conjunction with different physical matrices and/or growth factors, have the capacity to regenerate periodontal tissues in vivo (Huang et al., 2010; Liu et al., 2008; Sonoyama et al., 2006). A human feasible study showed that implantation of periodontal progenitor cells is an appropriate approach for periodontitis treatment (Feng et al., 2010). Notwithstanding these significant advances, there remain numerous biological, technical and clinical hurdles to be overcome; hence, the reader is pointed to several extensive reviews for more information (Lin et al., 2009; Rayment and Williams, 2010; Salem and Thiemermann, 2010). In the future, the collaborative endeavor of stem cell biologists and clinical scientists offers the potential to deliver the correct stem cells in the correct manner, with exposure to the correct signals for targeting to specific dental/periodontal injury sites, thereby representing a new and exciting field that has the potential to transform the practice of dentistry (Chapple, 2009). Dentistry has begun to explore the potential application of stem cells for the repair and regeneration of dental structures. This conceptual approach will have its place in the clinical practice of dentistry in the future. 4.2.4. Crucial barriers to progress Despite dramatic advances in stem cell biology and biomaterials science, translation of basic biomedical research into safe and effective clinical applications remains a slow, expensive and failure-prone endeavor. Considerable controversy regarding stem cell clinical therapy and significant biological, practical and clinical hurdles (partially aforementioned in Section 4.2.2) must be overcome prior to the broad application of stem cell therapies (Ahrlund-Richter et al., 2009; Hyun et al., 2008; Placzek et al., 2009). In particular, a thorough understanding of the underlying processes of tissue development, as well as the mechanisms of

Fig. 6. Cell-based therapies generally involve the harvesting of tissue biopsies from a patient, isolation and expansion of cells and implantation of the cells into the patient. Despite possible rejection problems, the use of allogeneic cells deposited in a cell bank that avoids ex vivo cell manipulation is much cheaper than the use of autologous cells. However, the decision to incorporate allogeneic stem cell-based therapies into routine clinical practice requires careful analysis of the risks and benefits associated with this procedure.

stem cell self-renewal and differentiation will be required due to the high complexity of stem cell therapy (Rayment and Williams, 2010). Refinement of current laboratory techniques to facilitate handling of stem cells and their translation to a clinical setting will be equally critical in advancing this field (Lin et al., 2009). Basic studies on ESCs, iPS cells, MSCs and other somatic stem cells should continue as part of a collective effort to expand our knowledge of cellular function and the disease process. This combined and solid knowledge base will underpin future treatment modalities and ultimately make stem cell-based therapies a realistic alternative for clinically therapeutic regeneration (Lin et al., 2009; Rayment and Williams, 2010). In terms of clinical trials and application, stem cell scientists aiming to impact patient care often lack the multi-disciplinary skills needed to overcome complex barriers and may feel deterred from pursuing clinical implementation (Cuende and Izeta, 2010). Scientists are dedicated to translating basic research findings into translational human studies at the earliest possible stage (Lenfant, 2003; Mankoff et al., 2004). Although there is a wide range of stem cell technologies, the maturity of different technologies is inconsistent. It is clear that very few investigators have had experience in developing manufacturing processes or sourcing material in cell therapy with the exception of the hematopoietic system and skin replacement therapies. Although a number of manufacturing industries are emerging to translate unique cellular therapy bioprocesses to robust, scaled manufacturing production for widespread use, there is limited understanding of how to fulfill requirements, such as regulatory and manufacturing guidelines. Hence, few technologies have achieved commercialization and successful clinical translation (Ratcliffe et al., 2011). Many human diseases are not accurately reflected in animal models. It is increasingly apparent that animal models often fail to capture all of the aspects relevant to the transition from lead validation to clinical development (Arnoczky et al., 2010; Derwin et al., 2010; McCarty et al., 2010; Muschler et al., 2010; Pellegrini et al., 2009; Simon and Aberman, 2010). Finally, safety concerns to consider in the translation of stem cell therapy include aberrant cellular development and tissue or vehicle contamination with infectious agents or foreign biological or non-biological substances used in laboratory processing of the stem cells (Rayment and Williams, 2010). These issues will need to be addressed at a translational research center. 4.3. Tissue engineering technology Not surprisingly, stem cells are inherently able to self-organize to form new tissues. They will spontaneously form complex structures under the appropriate conditions. Mounting evidence suggests that

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cell therapy alone unfortunately has not provided a universal regenerative solution (Daley and Scadden, 2008; Lutolf et al., 2009). A tissue with an intrinsically high regeneration potential or a tissue with a low degree of dysfunction easily allows for the formation of new tissue, whereas a tissue with a low regenerative capacity or substantial tissue dysfunction may require, in addition to stem cells, external stimulation or biomaterials to catalyze the repair (Lutolf et al., 2009) (Fig. 4). Moreover, a whole tissue is very difficult to replace with a single exogenous cell type because it is made of many cell types with an organizational framework that is crucial for its function. Importantly, stem cell fate is influenced by a number of factors and interactions that require robust control for safe and effective regeneration of a functional tissue (Discher et al., 2009; Place et al., 2009). For the formation of a large-scale tissue, a cell-instructive scaffold that provides cells with a local environment is used to regulate cell fates toward regeneration (Dutta and Dutta, 2009, 2010). Tissue engineering is a newly emerging biomedical technology and methodology that encompasses a multi-disciplinary approach geared toward augmenting functional regeneration or the development of biological substitutes designed to restore and maintain normal function in diseased or damaged tissues (Belardelli et al., 2011). The basic idea of tissue engineering is to obtain a small amount of the corresponding tissue or organ from the patient, disperse it into single cells, and culture the cells to achieve a suitable expansion of the population. The cells are inoculated into the proper vehicle and holder, either directly or after in vitro culture. The tissue construct is then transplanted to the site of the defective tissue or the corresponding organ (Fig. 4) (Griffith and Naughton, 2002). Due to the lack of organs available for transplantation, tissue-engineering methods have been used to construct artificial tissues and organs for transplantation. In perspective, in the future, tissue engineering may provide laboratory-made tissues with greater functional and biomechanical stability, even after transplantation. 4.3.1. Tissue engineering in reconstructive surgery In the last two decades, much activity in basic and translational research has taken place in the field of tissue engineering. Progress made in cell and stem cell biology, biomaterial sciences and engineering strategies have enabled researchers to develop cutting-edge technology that has led to the creation of nonmodular tissue constructs, such as skin, bladders, vessels and upper airways (Atala et al., 2006; Dieckmann et al., 2010; Levenberg et al., 2005; Orlando et al., 2011; Shevchenko et al., 2010; Zimmermann et al., 2006). These advances are now opening new avenues for surgical practice and have shown the potential of “bench-to-bedside” translational research in specific clinical settings. However, translating the progress in tissue engineering into new therapies has met with limited success; the route from idea to therapeutic has many hurdles that are similar to those met by translational stem cell research. The fragmentation of this process is evident at all levels and across geographic boundaries. Orthopedic surgery is in an exciting transitional period as modern surgical inventions, implants and scientific developments are providing new therapeutic options (Moran et al., 2010). In terms of bone repair, grafts are traditionally an important part of an orthopedic surgeon's armament. However, the treatment of delayed union, malunion, nonunion and large bone defects presents a challenge for orthopedic surgeons in veterinary and human fields despite the well-established bonegrafting techniques available today (Nandi et al., 2010). Although efforts have been made to develop osteoconductive, osteoinductive and osteogenic bone-replacement systems, clinical imperatives for new bone to replace or restore the function of traumatized bone or bone lost as a consequence of age or disease has led to the need for therapies or procedures to generate bone for skeletal applications (Tare et al., 2010). A convergence of technologies based on biology and engineering has afforded opportunities previously not available with conventional

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surgical reconstructive techniques. As advances in basic science and technology improve our understanding of the pathology and repair of musculoskeletal tissue, traditional operations may be replaced by newer, less invasive yet more effective procedures that are more appropriately targeted at the underlying pathophysiology (Moran et al., 2010). In this regard, tissue engineering in clinical use and at the translational research stage promises to deliver specific replacement tissues or custom-tailored constructs with the potential to regenerate tissue in the host without significant donor site morbidity, suggesting the prospect of effective alternative therapies for orthopedic applications, such as non-union fractures, healing of critical sized segmental defects and regeneration of articular cartilage in degenerative joint diseases (Moran et al., 2010; Tare et al., 2010). These biological techniques may provide better structure, aesthetics and function than the currently available options (Costello et al., 2010). However, if we consider the currently proposed tissue engineering strategies for routine reconstructive surgery in the clinic, it is soon realized that much more translational research is required and that evidence-based practice will remain a basic requirement of care. Although competition is the driving force for basic research, cooperation, coordination and infrastructures are essential for translational research, especially in the field of tissue engineering, where the regulatory framework is still under development. Moreover, public health issues and industrial interests need to be addressed in a comprehensive manner (Belardelli et al., 2011). 4.3.2. Challenges ahead: a bridgeable gap As noted previously in this review, despite recent advances in tissue engineering, a gap from the bench to the bedside remains. At a basic level, the use of engineered bone for the reconstruction of small to moderate sized bone defects is technically feasible; however, the reconstruction of large defects remains a daunting challenge (Johnson et al., 2011). The essential steps towards optimized clinical application of tissue-engineered bone are dependent upon recent advances in the area of neovascularization of the engineered construct (Davidson et al., 2011). The incorporation of more personalized medicine approaches, including the use of biomarkers to identify the proper patients and the responders to treatment, will contribute to progress in this field (Gómez-Barrena et al., 2011). As mentioned for stem cell therapy, there is a lack of effective and standardized animal models to assess the predictive value of preclinical models, to determine the relative clinical efficacy, to effectively mimic the wound-healing environment and mass transport conditions in the most challenging clinical settings, to detect cell trafficking events and to discern cell fates during the processes of tissue modeling, remodeling and regeneration (Arnoczky et al., 2010; Derwin et al., 2010; McCarty et al., 2010; Muschler et al., 2010; Pellegrini et al., 2009; Simon and Aberman, 2010). Although a number of translational models are available for translational research, the general consensus is that there is a substantial need for improved and standardized animal models and that large animal models are a critical preclinical step of translating research from bench to bedside (Sah and Ratcliffe, 2010). These gaps may ultimately be bridged by a closer collaboration between basic scientists and reconstructive surgeons. There remain ongoing needs for continued innovation and refinement in both animal model systems and engineering techniques for translational research (Orlando et al., 2011). Many tissue-engineering technologies are now available for research purposes. Some of these technologies have been tested in humans, although the clinical experience so far has been relatively disappointing compared to the disproportionally broad financial resources leveraged for tissue engineering research (Fig. 1). In the future, orthopedic surgeons will remain at the forefront of translational regenerative medicine with the development of novel therapeutic interventions as well as their preclinical and clinical application. The development of bench research into an improved array of orthopedic

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treatments in an effective yet safe manner will require the development of a subgroup of specialists with extended training (Moran et al., 2010; Rayment and Williams, 2010). International regulations regarding the introduction of new biological treatments and ATMPs will place an additional burden on this translational process. Orthopedic surgeons need to be trained not only in science and surgery but also in the regulatory environment so that they may obtain the skills required to translate scientific discovery into effective and properly assessed clinical practice (Moran et al., 2010; Muschler et al., 2010; Nandi et al., 2010; Shekkeris et al., 2011; Tare et al., 2010). Due to a lack of suitable investment and business models and to the constantly evolving regulatory framework, the successful commercialization of biological therapeutics continuously provides a unique challenge for the timely translation of scientific discoveries into safe and clinically efficacious therapies. From a regulatory perspective, these advanced treatments must not only be safe and effective, they must also be made by high-quality manufacturing processes that allow for on-time delivery of viable products (Moran et al., 2010). Although there is still a long way to go, tissue-engineering technology has undoubtedly brought enormous changes to regenerative medicine that will make a great contribution in this area. Using translational medicine strategies as a guide to enhance the translation of research results in tissue engineering research has a broad application potential for research and development and commercialization (Rayment and Williams, 2010). 5. Difficulties and perspectives The excessive cost of commercialization and difficulties in regulatory approval of stem cell therapy and tissue engineering have delayed clinical translation of these therapeutics from bench to bedside (Bianco, 2011; Cuende and Izeta, 2010; Daley and Scadden, 2008; Evans et al., 2007; Mosna et al., 2010; Parekkadan and Milwid, 2010; Rayment and Williams, 2010; Salem and Thiemermann, 2010). Clearly, health policy initiatives that are intended to foster the translation of basic science into clinical and public health advances must consider the unique bioethical issues raised by the increased focus on translational research (Petrini, 2010; 2011). At a basic level, the use of human materials that are obtained from surgical diagnosis for translational research is not formally approved. In addition, during the current period of transition from investigation to practice, consumers should be protected from the possible risks of premature translation of a research finding (Petrini, 2011). Quality standards of the experimental medicinal products and balancing of the risk of to treatment with the potential benefits of the research are paramount (Petrini, 2010). In clinical research there is a danger that the emphasis on advancements in scientific knowledge might prevail over the protection of the people who participate in research (Petrini, 2011). The risk of this danger can introduce complications in the regulations governing the use of materials obtained from clinical patients for medical research. In addition, the international exchange of data must follow the laws and regulations of the country of origin (Riegman and van Veen, 2011). Furthermore, the importance of possible surrogate end-points of clinical efficacy is currently being discussed and platforms for defining and identifying categories of responding patients remain to be developed. These advancements necessitate special regulatory approvals and heightened uncertainty regarding the approval of clinical protocols, which need to be positively addressed to promote clinical experimentation in standardized and controlled conditions (Belardelli et al., 2011). Key to evidence-based medicine, clinical treatment guidelines highlight the importance of international, randomized, blinded, multi-center, placebo-controlled trials; however, this study design is generally used in the confirmatory phase of a development program. Due to the rigid design and criteria for trials that are submitted for regulatory approval, the results of such studies may not predict the effectiveness of a product or technology in the clinical practice setting, leading to frustrations from practitioners (Belardelli et al., 2011; Schmidt, 2007). Ongoing initiatives

for the implementation of new discoveries and advances in translational science are expected to lead to address these ethical issues and stressful regulatory limitations. A careful examination of current translational regenerative research reveals that the true hurdles between bench and bedside lie in translational medicine and not in regenerative medicine. Over the last 10 years, the concept of translational medicine and the promotion of its ideas have enhanced the transformation of regenerative research, while it has guided changes in government policy and funding support. However, this finding does not indicate that translational regenerative medicine has paved the avenue for success. At this stage, the concept of translational regenerative medicine has just been formed and will continuously evolve (Katz, 2008; Mankoff et al.,2004; Newnham and Page, 2010). The full implementation of translational research faces some practical problems, such as an unclear idea or concept, a nonstandardized process, a lack of a unified, standardized criteria and arbitrary and sometimes utilitarian application. There still remains a lack of communication and cooperation between basic researchers (cell biologists/biomaterial scientists) and clinicians (Kreeger, 2003; Ledford, 2008; Moore, 2008). The ethical issues involved in the process of clinical translation of stem cells and/or tissue replacements/constructs should be further addressed. Clinical medicine and social prevention are not yet in sync. These measures must be addressed during the exploratory process (Kreeger, 2003; Moore, 2008). Translational regenerative medicine is not a traditional scientific discipline. It involves knowledge and research results from various fields and disciplines. Fragmentation, inefficiency, lack of orderliness and incoherence are the main obstacles to the development of effective and practical translational research. In terms of globalization, the fragmentation problem requires a global solution (Albani and Prakken, 2009). In other words, we need a holistic concept to develop new treatment methods and a means to cultivate the development and management process. More important is the cooperation of researchers in various fields, and the optimization and integration of research resources to solve practical problems. The difficulties faced in translational regenerative medicine are largely due to the lack of translational medicine professionals (Albani et al., 2010; Wolf, 1974). Among the researchers who participate in translational regenerative medicine, there should be a group of professionals with a global perspective who are well versed in international regulations and are responsible for directing the entire development process. This talent is urgently needed and, unfortunately, is nearly absent today. Further education is required to train these “vanguards” to lead the development of translational regenerative medicine (Lenfant, 2003). We cannot ask for each of the translational practitioners to be versatile and proficient in all scientific areas. However, they should have an international holistic vision, with good communication and coordination skills. Translational practitioners should be proficient in standard translation procedures and be familiar with the constitution of translational research. Such training is tailored to the scope of translational medical expertise. Currently, however, there is not a complete knowledge system for this field (Carpenter, 2007). At the management level, academic research institutions and government departments should adapt to the development of translational medicine and re-establish a set of management practices. Good, effective communication channels should be established between the various departments to properly resolve their conflicts and differences. With the continuous accumulation of translational and regenerative medical knowledge, from an individual point of view and from the public's perspective, problems and difficulties faced today should be solvable in the future. 6. Closing remarks The challenges and opportunities associated with the clinical use of stem cells and cell-based products have been reviewed elsewhere

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(Bianco, 2011; Cuende and Izeta, 2010; Daley and Scadden, 2008; Mosna et al., 2010; Parekkadan and Milwid, 2010; Rayment and Williams, 2010; Salem and Thiemermann, 2010). Substantial data on specific translational fields, such as diabetes therapy (Hussain and Theise, 2004; Procházka et al., 2010; Reddi et al., 2010), skeletal repair (Gómez-Barrena et al., 2011; Griffin et al., 2011; Kagami et al., 2011; Kraus and Kirker-Head, 2006), cardiac regeneration (Howe et al., 2011; Madonna and De Caterina, 2011; Malliaras and Marbán, 2011; Nunes et al., 2011) and the treatment of neural and Parkinson's diseases (Lindvall and Kokaia, 2009; Sanberg et al., 2005; Vidaltamayo et al., 2010), muscular dystrophy (Meng et al., 2011; Meregalli et al., 2010) and Alzheimer's disease (Sugaya et al., 2007), have been comprehensively discussed in the mounting literature. To avoid duplicated efforts, these data are not detailed in this conceptual paper; the readers are pointed to these contributions for more information. Translational regenerative medicine shoulders heavy responsibilities and has great potential for regeneration of a multitude of tissues, although its exact definition is still being discussed in the scientific community. Establishment of a platform for translational medical research, practice and personnel training is necessary for the future development of regenerative medicine and education reform. The most important tasks of translational medicine are the strengthening and promotion of the combination of basic and clinical research, the operation mechanism and the model of a unified system of medical teaching and research, and the establishment of translational medical centers, thereby leading to the translation of medical research and medical findings. Cultivation in medical philosophy encourages researchers and clinicians to communicate in both directions, enabling translational results and practical applications to serve a more important role in twenty-first century medical development. In today's medical research society, the development of translational medicine is designed to promote basic research and a deep integration of resource optimization, thereby rapidly increasing the original biopharmaceutical research and development innovation capability and ultimately enhance human healthcare. Translational regenerative research will promote stem cell therapy, tissue engineering, genetic engineering and new biomedical materials to improve human health services. In the field of regenerative medicine, we as scientists and clinicians cannot remain observers; we must be the “practitioners” in real translational medicine. With the further development of translational medical research, basic research results will gradually be transformed into safer, more effective clinical treatment tools and will make important contributions to prevent and treat important human diseases. Such research will play a significant role in the improvement of human health. The birth of any new diagnostic or therapeutic technique relies on substantial basic and translational research. Through continuous exploration, overcoming of difficulties, and regulatory approval, new technology will finally reach patients. Focusing on clinical demands, the translation of results from basic research to clinical diagnosis and treatment methods defines the essence of the “B2B” mode of translational medicine. Translational medicine will facilitate the impact of basic research on society, thereby justifying the endeavor of scientific research. We have reason to believe that with the maturity and development of the translational medicine concept, more regenerative technology will be developed, and the ability to prevent and treat human degenerative disease under the guidance of translational medicine will rapidly enter a new era. Acknowledgments Funding from the National Natural Science Foundation of China (81071253/H1818 and 31170912/C1002) for some of the work mentioned in the article is gratefully appreciated. We thank the anonymous reviewers of this manuscript. They made valuable remarks and very helpful suggestions.

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