Keywords | |
| Regenerative medicine; Adult stem cell; Bone; cartilage; Tissue engineering; Preclinical studies; Translational animal model; Cell-based medicinal products; Advanced-therapy medicinal products; Physiotherapy | |
Introduction | |
| The rapid advancement of knowledge in medicine has led to the development of new concepts such as regenerative medicine, which aims to A.) expand people’s lives and B) improve quality of life. Regenerative medicine is a multidisciplinary field that attempts to facilitate to repair, replace and regenerate damaged or diseased cells, tissues and organs in order to restore impaired function resulting from congenital defects, diseases, trauma injuries or ageing [1,2]. This field includes several different research areas such as tissue engineering, stem cell biology, materials science, genetics and molecular biology, developmental biology and cell, tissue and organ transplantation (Figure 1). | |
| Regenerative medicine comprises three tools that could be used alone or in combination: A) biomaterials, which provide structural support; B) signals required to enhance cell proliferation and/or differentiation (i.e. growth factors and mechanical signals); and C) cells, such as tissue-specific cells or progenitor and stem cells [3]. In terms of clinical translation into musculoskeletal disorders, a limited number of cases using strategies combining autologous cells with a variety of synthetic scaffolds have shown some efficacy for treating long bone defects [4], fracture non-union [5] and in spinal fusion surgery [6,7]. However, there is a pressing need for additional highquality; methodologically robust studies using cell-based therapies addressing cartilage regeneration, which is probably one of the most expected applications that may benefit from regenerative medicine. | |
| Cartilage: pathology and treatment | |
| The unique biomechanical properties of articular cartilage (AC) permit nearly friction-less movement of the joint surfaces. Despite its mechanical performance, cartilage tissue lacks blood and nerve vessels and therefore chondrocytes are supplied by diffusion through the extracellular matrix (ECM). Indeed the low cell metabolic activity of cartilage protects this tissue from excessive physical stresses. On the other hand, its avascularity results in cartilaginous lesions having a low degree of spontaneous self-repair potential that can eventually lead to osteoarthritis [8]. | |
| The presence of multiple cell types and vascularity are the main differences between bone and cartilage which results in bone having a greater potential of self-repair capacity (Figure 2). Vascularity provides the bone with abundant nutrients, blood-borne proteins and cells (such as osteoclasts) that stimulate bone remodelling. Defects in bone can thus be self-repaired up to a critical size [9]. Stem cells are also present in the periosteum and bone marrow, and they can differentiate into bone-producing cells [10,11]. In contrast, cartilage lacks the ability to mount a sufficient healing response due to the lack of circulating progenitor cells and limited access to nutrients. That is the reason why even small, superficial cartilage defects fail to heal [12]. | |
| Osteoarthritis (OA) is the most common cause of arthritis worldwide and, with an ageing population, it will become an even greater public health problem over future decades. OA primarily affects knees, hips, fingers, and the lumbar and cervical spine and it may be derived from biomechanical factors, individual risk factors and/or inflammation, resulting in the degeneration of AC [13,14]. As the disease progresses, the thickness of AC decreases along with other major changes in the joints including subchondral bone sclerosis and marginal osteophyte formation. The physiopathology of OA is still largely unknown and current treatments only partially address the clinical issue. Analgesia, steroid or hyaluronan injections, combined with physiotherapy have been widely used in OA treatment, whilst standard surgical approaches have failed to successfully regenerate high-quality AC (Figure 3). | |
| Non-pharmacological therapies | |
| Non-pharmacological therapies are still considered a first-line treatment in knee and hip OA by the American College of Rheumatology (ACR), The European League Against Rheumatism (EULAR) and Osteoarthritis Research Society International (OARSI) guidelines [15-17]. They might also be used preoperatively to improve certain motion patterns that will accelerate healing processes postoperatively [18], or in a post-operative rehabilitation management program [19]. However, as the human knee cannot be fully duplicated by any animal model, post-operative management has largely been empiric. | |
| Non-pharmacological therapies include, among other treatments, pain relief by lowering weight-bearing, muscle strengthening [20], passive mobilisation of the joint [21], thermal modalities, improvement of A) joint mobility, B) muscular joint stabilization, C) joint function, and D) locomotive qualities (i.e. power, motion economy, endurance, coordination), transcutaneous electrical nerve stimulation, acupuncture [18] or dry needling [22]. Although injured cartilage will not regenerate, progressive joint degeneration processes may be decelerated by improving muscle tone and maintaining physiologic motion patterns. Physiotherapy can contribute to decrease pain and mechanical stress across the joint and restoring joint motion. Indeed, guidelines for rehabilitation after cartilage surgical repair interventions have already been proposed [19]. | |
| Pharmacological therapies | |
| Pharmacological interventions currently available for pain relief (with the fast- and slow-acting families of drugs) and slowing down cartilage degeneration (with the slow-acting drug family) are summarised in table 1. Probably, the most popular treatments involve the uptake of acetaminophen (otherwise known as paracetamol) and dietary supplements such as glucosamine and chondroitin sulfate [23-25]. | |
| The recent discovery of Kartogenin, a small molecule with chondrogenic effect on endogenous progenitor cells suggests a potentially new pharmacological approach to treat not only the symptoms of OA but to regenerate actual cartilage [26]. | |
| Surgical interventions | |
| Conventional approaches include marrow stimulation (or microfracture) that consists in a surgical micro-bleeding technique releasing progenitor/stem cells from the subchondral bone and typically results in fibrocartilage refilling of inferior quality that does not persist and has poorer biomechanical and biochemical features compared to native hyaline cartilage [27,28]. It has been widely used due to its immediate improvement of knee function, but over the first two years the fibrocartilage refilling deteriorates [29]. There are alternatives such as allografts or autografts but they present poor integration with adjacent cartilage, in addition to other drawbacks such as potential disease transmission and/or the loss of cell viability after graft storage [30,31]. Once joint failure occurs, causing intractable pain and loss of function, patients are offered major orthopaedic joint surgery (also called arthroplasty). Although total and partial knee replacements are now relatively routine surgery with high rates of success over the first 20 years therefore resulting in an improvement in quality of life [32], it is not without risks and is not universally successful. Alternative means of treating OA, such as tissue engineering, have therefore received increasing interest over recent years. | |
| Cell-based treatments | |
| Cell-based cartilage repair therapies routinely use autologous articular chondrocytes harvested from biopsies of non-weight bearing parts of the joint. [33,34]. This approach has several disadvantages such as secondary OA derived from the removal of otherwise healthy articular cartilage and the limited expansion potential of chondrocytes without acquiring a fibroblastic phenotype and their subsequent loss of physiological function [35]. | |
| The simultaneous regeneration of both cartilage and subchondral bone can also be approached by the use of porous biopolymeric scaffolds that can contribute to A) preserve the structure of the lesion area and B) absorb bone marrow, permitting bone remodelling and differentiation of neighbouring stem cells. Synthetic materials have been used extensively in tissue engineering both in vitro and in vivo due to their easy moulding characteristics, affordable production and the possibility of adjusting their bioresorption kinetics [36]. Indeed scaffolds used in combination with microfracture enhanced the quality of the new cartilage and increased fill percentage in chondral focal defects [37]. Successful results from preclinical studies using constructs made of scaffolds of different types seeded with MSC have produced cartilage of hyaline quality capable to integrate with the surrounding native cartilage and improved the repair of osteochondral defects modelled in the knee. Among natural and synthetic scaffolds, some of the most successful materials in non-clinical studies include poly-caprollactone (alone and in combination with tricalcium phosphate) [38], poly-L-lactic acid [39], and fibrin gel [40]. The nature of the neoartilage formed, whether hyaline or fibrous, and the origin of this tissue, from host or donor cells, are two of the most important questions pending to answer from these preclinical studies. Also, it is important to note that the optimal treatment of osteoarthritic cartilage may differ from that of focal defects that have not contributed yet to the degeneration of the joint (that is in early stages of OA derived from trauma injuries). In human studies, collagen and hyaluronan-based matrices are the preferred scaffolds for cartilage repair due to their high level of flexibility and resorbability. The use of autologous MSC has demonstrated substantial symptomatic improvement without any reported adverse effects from the therapy [41-43]. However, the resulting cartilage formation may be attributed either to the ex vivo expanded MSC directly or via paracrine signalling which leads either A) the inhibition of inflammatory responses or B) the stimulation of growth and/or activity of endogenous progenitors and chondrocytes [44]. | |
| Before MSC can be widely used in a clinical setting, several obstacles still need to be addressed, in particular for allogeneic approaches in which a large expansion of MSC is required in order to stock up vials with clinically relevant cell doses for off-the-shelf use. Major hurdles are replicative ageing and senescence of MSC in long-term culture [45,46]. Previous studies have implicated progressive telomere shortening associated with increasing expression of cell cycle regulators [47-49]. Cellular ageing not only affects the yield of MSC but is also associated with a decline in the multi-lineage differentiation capacity limiting differentiation of MSC towards chondrocytes [48,49]. Furthermore, there is considerable donor to donor variance with respect to frequency of MSC in primary isolates, expandability, cytokine secretion and differentiation capacity [49,50]. | |
| Challenges in the clinical translation of cell-based medicinal products | |
| Despite several open questions [51], the use of MSC is appealing for clinical exploitation and thus requires the approval by competent drug regulatory authorities (Table 2). MSC in Europe are classified as Advanced Therapy Medicinal Product (European Medicines Agency: Regulation no. 1394/2007) and therefore non-clinical product development, manufacturing, processing, and testing of cellular products has to comply with Good Laboratory/Tissue/ Manufacturing/Clinical Practice standards (GLP, GTP, GMP, GCP) that ensure that a cell-based therapy product is safe, pure and potent. Indeed, the number of clinical trials using MSC is rapidly increasing and other treatments outside the oversight of national regulatory bodies or clinical trial sites are quickly being available to many OA patients [52]. Valuable insights into trials design, patient selection, co-administration of anti-inflammatory drugs, dose, scheduling or route of administration would be gained by rigorous peer review [53]. | |
Outlook | |
| Although the control of pain is the most pressing problem in OA patients, regeneration of damaged articular cartilage is the ultimate goal. From a tissue engineering perspective, the ideal treatment would be a scaffold incorporating signalling molecules and progenitor/stem cells which would be either injected or implanted arhroscopically for patients with mild to moderate OA resulting in a reduction of pain and the regeneration of hyaline articular cartilage. Before cell-based therapies can be approved by regulatory authorities for widespread use, further clinical trials with larger numbers of patients and rigorous study design must be carried out. | |
Acknowledgements | |
| This work was supported by Spanish Government grants: Medavan, Ministerio de Economía y Competitividad (Grant number IPT-300000-2010-0017); and Medcel, Ministerio de Ciencia e Innovación (Grant number PSE-010000-2007-4//PSE-010000-2008-4). | |
References | |
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quinta-feira, 11 de junho de 2015
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