Tissue engineering of osteochondral constructs in vitro using bioreactors

Articular cartilage is a relatively simple tissue, but has a limited capacity of restoration. Tissue engineering is a promising field that seeks to accomplish the in vitro generation of complex, functional, 3-dimensional tissues. Various cell types and scaffolds have been tested for these purposes. The results of tissue engineered cartilage and bone are as yet inferior to native tissue. Strain and perfusion have been shown to stimulate cell proliferation and differentiation of various cell phenotypes. The perfect protocol to produce articular cartilage has not been defined yet. Bioreactors could provide the environment to engineer osteochondral constructs in vitro and to provide a stress protocol. The bioreactor has to provide an economically viable approach to automated manufacture of functional grafts under clinical aspects. Composite engineered tissues, like an engineered joint, represent a future goal. Cross-disciplinary approaches are necessary in order to succeed in engineering osteochondral grafts that provide adequate primary biomechanical stability and incorporate rapidly in vivo with histological appearance close to healthy osteochondral tissue. This review surveys current clinical and experimental concepts and discusses challenges and future expectations in this advancing field of regenerative medicine focusing human osteochondral constructs in bioreactors.     

Perspectives on regenerative therapy

Organ transplantation and artificial organs are the only effective treatments for loss of organ and tissue function. These treatments, however, are associated with serious problems such as a critical shortage of donor organs, rejection, the need for life-long immunosuppression, and unstable biocompatibility. These shortcomings have stimulated the development of tissue engineering. Tissue engineering is defined as an interdisciplinary field that applies the principles of engineering and the life sciences to the development of biological substitutes that restore, retain, or improve tissue function. Tissue engineering is composed of three factors: cells; growth factors; and scaffolds. Regenerative medicine includes two important fields: tissue engineering; and regenerative biology. Regenerative therapy is a newly developed medical therapy based on the research results of regenerative medicine. The fields of regenerative therapy includes broad areas of basic and clinical sciences, bioethics, and medical economics in addition to the area of regenerative medicine. Cell sources and cell expansion are important issues in regenerative medicine. Great efforts are being made to isolate and identify the characteristics of stem cell populations of various tissues. The use of stem cells may provide an almost limitless supply of cells for transplantation. Although there are still many important issues to be resolved, regenerative medicine has been making rapid progress using a multidisciplinary approach. The success of this approach will lead to the widespread application of regenerative therapy and may ultimately be able to replace lost tissue function in the 21st century. We should, however, keep in mind the importance of bioethics in using any new therapy.     

Challenges,highlights, and opportunities in cellular transplantation: A white paper of the current landscape

Although cellular transplantation remains a relatively small field compared to solid organ transplantation, the prospects for advancement in basic science and clinical care remain bountiful. In this review, notable historical events and the current landscape of the field of cellular transplantation are reviewed with an emphasis on islets (allo- and xeno-), hepatocytes (including bioartificial liver), adoptive regulatory immunotherapy, and stem cells (SCs, specifically endogenous organ-specific and mesenchymal). Also, the nascent but rapidly evolving field of three-dimensional bioprinting is highlighted, including its major processing steps and latest achievements. To reach its full potential where cellular transplants are a more viable alternative than solid organ transplants, fundamental change in how the field is regulated and advanced is needed. Greater public and private investment in the development of cellular transplantation is required. Furthermore, consistent with the call of multiple national transplant societies for allo-islet transplants, the oversight of cellular transplants should mirror that of solid organ transplants and not be classified under the unsustainable, outdated model that requires licensing as a drug with the Food and Drug Administration. Cellular transplantation has the potential to bring profound benefit through progress in bioengineering and regenerative medicine, limiting immunosuppression-related toxicity, and providing markedly reduced surgical morbidity.     

An overview of the therapeutic potential of regenerative medicine in cutaneous wound healing

The global burden of disease associated with wounds is an increasingly significant public health concern. Current treatments are often expensive, time‐consuming and limited in their efficacy in chronic wounds. The challenge of overcoming current barriers associated with wound care requires innovative management techniques. Regenerative medicine is an emerging field of research that focuses on the repair, replacement or regeneration of cells, tissues or organs to restore impaired function. This article provides an overview of the pathophysiology of wound healing and reviews the latest evidence on the application of the principal components of regenerative medicine (growth factors, stem cell transplantation, biomaterials and tissue engineering) as therapeutic targets. Improved knowledge and understanding of the pathophysiology of wound healing has pointed to new therapeutic targets. Regenerative medicine has the potential to underpin the design of specific target therapies in acute and chronic wound healing. This personalised approach could eventually reduce the burden of disease associated with wound healing. Further evidence is required in the form of large animal studies and clinical trials to assess long‐term efficacy and safety of these new treatments.     

Researches on regenerative medicine——current state and prospect

Since 1980s,the rapid development of tissue engineering and stem cell research has pushed regenerative medicine to a new fastigium,and regenerative medicine has become a noticeable research field in th...     

Future perspectives of articular cartilage repair

Extrapolating from the current state of the art in cartilage repair technology and basic science, we describe the future of regenerative medicine in the musculoskeletal system. Crucial milestones that have been recognized include supply with competent cells from autologous to xenogeneic sources, "intelligent" or "reactive" scaffold design, optimised application of humoral factors and the introduction of advanced gene-engineering technology. Besides these technical goals, ethical and legal considerations may significantly change the way pharmacological and medical components are recruited and regulated. At the same time, governmental regulatory bodies will have to accept new realities such as the existence of adaptive medical devices and of biological combination implants that are anywhere between a drug and a transplanted organ. For cartilage replacement itself, optimism seems to be justified regarding major advances within the next decade.     

Regenerative medicine in rheumatic disease-progress in tissue engineering

Joint destruction occurs in both osteoarthritis and rheumatoid arthritis. Even in the era of biologic agents, this destruction can be delayed but not averted. As cartilage has limited ability to self-regenerate, joint arthroplasty is required. Here, we outline current tissue engineering procedures (including autologous chondrocyte implantation and in situ mesenchymal stem cell recruitment) that are routinely applied for the regenerative treatment of injured or early osteoarthritic cartilage. Potential future regenerative therapies, including administration of multipotent or pluripotent stem cells, are also discussed. In the future, cell-free, material-based (for cartilage lesions) or cell-free, factor-based (for osteoarthritic cartilage) therapies to facilitate the recruitment of repair cells and improve cartilage metabolism are likely to become more important. Moreover, delivery of anti-inflammatory factors or immunomodulatory cells could be a regenerative treatment option for rheumatoid arthritis. Tissue engineering faces a crucial phase to translate products into clinical routine and the regulatory framework for cell-based products in particular is an important issue.     

Osteochondral allograft transplantation in cartilage repair: Graft storage paradigm,translational models,and clinical applications

The treatment of articular cartilage injury and disease has become an increasingly relevant part of orthopaedic care. Articular cartilage transplantation, in the form of osteochondral allografting, is one of the most established techniques for restoration of articular cartilage. Our research efforts over the last two decades have supported the transformation of this procedure from experimental “niche” status to a cornerstone of orthopaedic practice. In this Kappa Delta paper, we describe our translational and clinical science contributions to this transformation: (1) to enhance the ability of tissue banks to process and deliver viable tissue to surgeons and patients, (2) to improve the biological understanding of in vivo cartilage and bone remodeling following osteochondral allograft (OCA) transplantation in an animal model system, (3) to define effective surgical techniques and pitfalls, and (4) to identify and clarify clinical indications and outcomes. The combination of coordinated basic and clinical studies is part of our continuing comprehensive academic OCA transplant program. Taken together, the results have led to the current standards for OCA processing and storage prior to implantation and also novel observations and mechanisms of the biological and clinical behavior of OCA transplants in vivo. Thus, OCA transplantation is now a successful and increasingly available treatment for patients with disabling osteoarticular cartilage pathology. © 2015 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 34:31–38, 2016.     

Articular cartilage repair using tissue engineering technique--novel approach with minimally invasive procedure

Articular cartilage has very limited potential to spontaneously heal, because it lacks vessels and is isolated from systemic regulation. Although there have been many attempts to treat articular cartilage defects, such as drilling, microfracture techniques, soft tissue grafts or osteochondral grafts, no treatment has managed to repair the defects with long-lasting hyaline cartilage. Recently, a regenerative medicine using a tissue engineering technique for cartilage repair has been given much attention in the orthopedic field. In 1994, Brittberg et al. introduced a new cell technology in which chondrocytes expanded in monolayer culture were transplanted into the cartilage defect of the knee. As a second generation of chondrocyte transplantation, since 1996 we have been performing transplantation of tissue-engineered cartilage made ex vivo for the treatment of osteochondral defects of the joints. This signifies a concept shift from cell transplantation to tissue transplantation made ex vivo using tissue engineering techniques. We have reported good clinical results with this surgical treatment. However, extensive basic research is vital to achieve better clinical results with this tissue engineering technique. This article describes our recent research using a minimally invasive tissue engineering technique to promote cartilage regeneration.     

Biologic approaches to articular cartilage surgery: future trends

The treatment of unicompartmental osteoarthritis and focal chondral pathologic conditions in the knee in active aging athletes has captured the interest of patients, clinicians, basic scientists, and medical industry researchers. Most would agree that a biologic solution to treating hyaline cartilage injuries and degeneration would be optimal over prosthetic joint arthroplasty. Articular cartilage resurfacing techniques and biologic surgical methods continue to evolve and have gained more acceptance in orthopedic practice. A consensus exists for the ultimate goal of achieving a more predictable and durable result after surgical tissue repair or regeneration. Numerous promising approaches are now on the horizon and although the final word is far from in, the integration of many of the anticipated advances in molecular medicine, biomedical engineering, polymer chemistry, cell biology, and clinical orthopedics contributes to an exciting and rapidly evolving field. This article reviews the current concepts of the biologic approach to articular cartilage pathologic conditions and discusses future trends and novel technologies.     

Futility in geriatric medicine, a real issue

Is futility age related? Several studies clearly demonstrate that outcome in critically ill elderly patients admitted to an intensive care unit, is more closely related to severity of illness than to age, which has little influence on prognosis. The outcome is closely associated with the severity of the illness, and age is of little influence. However, age based discrimination persists despite current recommendations from medical societies that age should not be used as a criteria for admission to intensive care. The concept of medical futility is influenced by individual or collective subjective values. Very old patients often are excluded from studies. It is difficult to apply evidence-based medicine in older people as results must be extrapolated from data in younger subjects. Thus, the true benefit of treatment is difficult to assess in the elderly. The image of the older patient, as perceived by younger health care professionals and society has a considerable impact on medical care. Medical futility is often based on clinical concepts which may lead to legal policies. It is influenced by social and economic factors. Health care professionals have a crucial role but their position, in close proximity to the patient, and its resulting emotional burden can be uncomfortable. In geriatric medicine, there is a special relationship between patients, relatives, and health professionals which requires genuine communication in order to optimise patients case. In conclusion, a balanced approach that avoids both overtreatment and therapeutic nihilism is important in order to provide old patients the best possible care.     

Quality assurance and adverse event management in regenerative medicine for knee osteoarthritis: Current concepts

The economic and human cost of knee osteoarthritis is forecast to increase. This will impact not only aging individuals, but also the working age members of emerging economies. The current treatment pathways are often costly, time-consuming, and insufficient to manage the degeneration of the knee over the ever-increasing lifespan of patients around the world. In response to the shortcomings of a focus on symptom management, international and high-impact regulators, researchers, clinicians, and most importantly patients, are increasingly interested in the possible management of knee osteoarthritis with novel therapies in the field of regenerative medicine treatments. Regenerative medicine is an emerging discipline whose adherents aim to use the tools of the human body to address underlying dysfunction, leading to lasting repair of damaged tissues and structures. The evidence base lacks consensus on issues related to safety, efficacy, cost-efficiency, and treatment specifications. In this current concepts review, we describe the potential impact of regenerative medicine for knee osteoarthritis and evaluate literature of the past decade for elements related to the quality of clinical research. Finally, we discuss strategies for improving the evidence base for the future. The results of the review reveal that the typical follow-up period for most clinical research into the area is between 6 and 12 months; local ethics board approval is commonly reported, and that Platelet-Rich Plasma is the most common option explored. However, several quality elements were lacking in this cohort of recent literature: cost efficacy data, long-term follow-up, and detailed adverse event reporting. In order to address these weaknesses in the literature, patient outcomes registries are needed, in order to satisfy the need for longer follow-up for individuals receiving regenerative treatments, in addition to further clinical trials which address larger and more diverse patient populations. Transparency will be of utmost importance in further research and clinical translation of regenerative medicine for knee osteoarthritis.     

Governmental Regulations and Increasing Food and Drug Administration Oversight of Regenerative Medicine Products: What’s New in 2020?

The United States Food and Drug Administration (FDA) is responsible for protecting and promoting public health through rules and regulations. Over the past few years, the field of regenerative medicine and cell therapy have garnered significant interest, and this evolving new biology is changing fast and challenging regulatory bodies. The FDA has published a series of guidance documents outlining steps to protect consumers against potentially dangerous and unproven treatments. The agency has offered a grace period for “stem cell clinics” until November 2020 to come into compliance by obtaining Investigational New Drug applications and working to secure premarket approval of their products. With the documentation of hundreds of “stem cell clinics,” the FDA needs to enforce the adherence to their outlined standards to protect patients. The aim of this review was to provide an overview of these FDA regulations and some current issues within the industry. The purpose is to educate and inform the musculoskeletal community about the current government regulations of this new expanding biology.Level of EvidenceLevel V, expert opinion.     

Current status and challenges of Additive manufacturing in orthopaedics: An overview

Additive manufacturing is a rapidly emerging technology which is being successfully implemented in the various field of medicine as well as in orthopaedics, where it has applications in reducing cartilage defects and treatments of bones. The technology helps through systematic collection of information about the shape of the "defects" and precise fabrication of complex 3D constructs such as cartilage, heart valve, trachea, myocardial bone tissue and blood vessels. In this paper, a large number of the relevant research papers on the additive manufacturing and its application in medical specifically orthopaedics are identified through Scopus had been studied using Bibliometric analysis and application analysis is undertaken. The bibliometric analysis shows that there is an increasing trend in the research reports on additive manufacturing applications in the field of orthopaedics. Discussions are on using technological advancement like scanning techniques and various challenges of the orthopaedic being met by additive manufacturing technology. For patient-specific orthopaedic applications, these techniques incorporate clinical practice and use for effective planning. 3D printed models printed by this technology are accepted for orthopaedic surgery such as revision of lumbar discectomy, pelvic surgery and large scapular osteochondroma. The applications of additive manufacturing in orthopaedics will experience a rapid translation in future. An orthopaedic surgeon can convert need/idea into a reality by using computer-aided design (CAD) software, analysis software to facilitate the manufacturing. Thus, AM provides a comprehensive opportunity to manufacture orthopaedic implantable medical devices.     

Gene therapy for cartilage repair

AIM: Articular cartilage has very limited intrinsic healing capacity. Although numerous attempts to repair full-thickness articular cartilage defects have been conducted, no methods have successfully regenerated long-lasting hyaline cartilage. One of the most promising procedures for cartilage repair is tissue engineering accompanied by gene therapy. METHOD: With gene therapy, genes encoding for therapeutic growth factors can be expressed at a high level in the injured site for an extended period of time. Chondrocytes have been intensively studied for cell transplantation in articular cartilage defects. RESULTS: However, recent studies have shown that chondrocytes are not the only candidate for cartilage repair. Muscle-derived cells have been found capable of delivering genes and represent a good vehicle to deliver therapeutic genes to improve cartilage repair. More importantly, recent studies have suggested the presence of pluripotent stem cells in muscle-derived cells. CONCLUSION: New techniques of cell therapy and molecular medicine for the treatment of cartilage lesions are currently undergoing clinical trials. This paper will summarize the current status of gene therapy for cartilage repair and its future application.     

Ethical issues in resuscitation and intensive care

With continued advances in resuscitation and organ support, modern intensive care medicine is redefining life and death. Yet for all our progress, more life at any costs may not be an outcome that a patient wishes or finds tolerable. As medical paternalism is stripped away and the subjective wishes of the patient becomes the focus of our care, how we offer, deliver and discontinue therapies become paramount. When our patients themselves though may not be able to communicate their wishes as a result of both their pathology and our therapies in the intensive care unit, we are presented with ethical, moral and practical dilemmas as to how we may best care for them and act in their best interests.     

Ethical issues in resuscitation and intensive care

With continued advances in resuscitation and organ support, modern intensive care medicine is redefining life and death. Yet for all our progress, more life at any costs may not be an outcome that a patient wishes or finds tolerable. As medical paternalism is stripped away and the subjective wishes of the patient becomes the focus of our care, how we offer, deliver and discontinue therapies become paramount. When our patients themselves though may not be able to communicate their wishes as a result of both their pathology and our therapies in the intensive care unit, we are presented with ethical, moral and practical dilemmas as to how we may best care for them and act in their best interests.     

Computer assisted maxillofacial surgery

Technical developments strongly influence modern medicine. This is especially obvious in imaging technology. Today, one of the most difficult tasks for surgeons is transferring all the available imaging information for their patients into one "complete picture". In the operation theatre, this picture then has to be applied to the patient. Computer-assisted surgery (CAS) promises to help in fulfilling this task and, thereby, to fully utilize the possibilities offered by modern imaging techniques. Today's standard procedures for CAS in the maxillofacial region are described in technical principles and clinical applications. They are evaluated and discussed based on the available literature and in light of practical experience of more than ten years in the field of CAS. In addition, an outlook is given into developments of the near future that have appeared in the current literature. While technical development is leading toward a complete integration of all processes surrounding the patient and his or her surgery, basic CAS has moved from research to clinical care. Before it is routinely used, more investigation about its effectiveness and benefits has to be done, especially since increasing medical care costs are an issue in all countries.     

Regenerative medicine for urological tissues: Updated review 2018

The focus of the present review on regenerative medicine is limited; first, on a few human clinical trials carried out thus far in the urology field, and second, on more basic but important biological progress that regenerative medicine has brought us. Clinical trials for the bladder, urethra and urethral sphincter have been carried out thus far. Reconstruction with autologous cell‐seeded biomaterial failed in patients in need of bladder augmentation. The strategy succeeded for urethral reconstruction in patients who might not have required this approach. Sphincter function improvement was attained by cell therapy, but did not equal the conventional standard therapy – the artificial sphincter. The radical progress in regenerative medicine is reported in more basic stem cell technology. The strategy to induce therapeutic cells from inducible pluripotent stem cells has shed novel light on developmental biology. In vitro creation of novel kidney tissue from inducible pluripotent stem cells has been attained. Other kinds of therapeutic cells could also be induced from the inducible pluripotent stem cells. Research should be encouraged to fill the gap between patient needs and what current regenerative medicine can attain.