Clinical experiences with cartilage repair techniques: outcomes, indications, contraindications and rehabilitation
- Eklem hastalıkları ve cerrahisi = Joint diseases & related surgery
- Published over 2 years ago
Untreated articular cartilage defects may lead to chronic joint degeneration and functional disability. In the past decade, several cartilage repair techniques have emerged for the treatment of cartilage lesions. Among these techniques, mosaicplasty was introduced by the senior author into the clinical practice in 1992. This article does not intend to give a review or a comparison of currently existing surgical techniques which aim to repair symptomatic focal defects; however, it focuses on the procedures used in the everyday practice in the authors' institute, namely microfracture, mosaicplasty, autologous chondrocyte implantation (ACI), osteochondral allograft transplantation and biodegradable osteochondral scaffolds. It gives a brief summary of these well-described techniques, summarizes the authors' clinical experience and available data on the clinical outcome, and the rehabilitation protocol following different procedures, with a special emphasis on mosaicplasty.
Osteoarthritis (OA) is a degenerative joint disease that involves the destruction of articular cartilage and eventually leads to disability. Molecules that promote the selective differentiation of multipotent mesenchymal stem cells (MSCs) into chondrocytes may stimulate the repair of damaged cartilage. Using an image-based high-throughput screen, we identified the small molecule kartogenin, which promotes chondrocyte differentiation (median effective concentration = 100 nM), shows chondroprotective effects in vitro, and is efficacious in two OA animal models. Kartogenin binds filamin A, disrupts its interaction with the transcription factor core-binding factor β subunit (CBFβ), and induces chondrogenesis by regulating the CBFβ-RUNX1 transcriptional program. This work provides new insights into the control of chondrogenesis that may ultimately lead to a stem cell-based therapy for osteoarthritis.
Cartilage therapy for focal articular lesions of the knee has been implemented for more than a decade, and it is becoming increasingly available. What do we know on the healing response of cartilage lesions? What do we know on the treatment of focal cartilage lesions of the knee and the prognostic factors involved? PubMed articles related to articular cartilage regeneration of the knee in clinical studies were searched from January 2006 to November 2012, using the following key words: articular cartilage, regeneration, clinical studies, and knee. A total of 44 reports were found. They showed the following possibilities for the treatment of focal lesions of the articular cartilage of the knee: cartilage regeneration and repair including cartilage reparation with gene-activated matrices, autologous chondrocyte implantation (ACI) and matrix-induced ACI (MACI), microfracture, osteochondral autograft transfer (mosaicplasty), biological approaches (scaffolds, mesenchymal stem cells-MSCs, platelet-rich plasma, growing factors-GF, bone morphogenetic proteins-BMPs, magnetically labeled synovium-derived cells-M-SDCs, and elastic-like polypeptide gels), osteotomies, stem-cell-coated titanium implants, and chondroprotection with pulsed electromagnetic fields. Untreated cartilage lesions on the femoral condyles had a superior healing response compared to those on the tibial plateaus, and in the patellofemoral joint. Clinical outcome regarding the treatment of medial defects is better than that of the lateral defects. Improvement from baseline was better for patients < or = 30 years compared with patients > or = 30 years. ACI, MACI, and mosaicplasty have shown similar results. The results of comparative clinical studies using ACI have shown some superiority over conventional microfracturing in medium or large defects and in long-term durability. Some biological methods such as scaffolds, MSCs, GF, M-SDCs, BMPs, and elastic-like polypeptide gels still need more research.
Bupivacaine and levobupivacaine induce apoptosis in rat chondrocyte cell cultures at ultra-low doses
- European journal of orthopaedic surgery & traumatology : orthopedie traumatologie
- Published almost 5 years ago
PURPOSE: Osteoarthritis (OA) is characterized by chondrocyte apoptosis and necrosis which play a key role during the progression of OA. Intra-articular administration of bupivacaine is a practical and effective way of postoperative pain control following various joint surgeries. 0.25 % bupivacaine showed to be safe in terms of chondrocyte toxicity. Around 200 nM of bupivacaine was shown to be effective for peripheral nerve block. This study aims to observe the possible cytotoxic effects of bupivacaine and its enantiomer levobupivacaine on chondrocyte cell culture at 7.69, 76.9, and 384.5 μM or at 0.0125, 0.0025, and 0.00025 % concentrations, respectively. METHODS: Chondrocytes were isolated from rat articular cartilage after incubating with collagenase in RPMI-1640 medium. Cells were treated with bupivacaine and levobupivacaine at 7.69, 76.9, and 384.5 μM concentrations for 6, 24, and 48 h. Treated chondrocytes were stained with acridine orange and ethidium bromide and examined under a fluorescence microscope at a 490 nm excitation wavelength for apoptotic changes. RESULTS: Study results suggest that both bupivacaine and levobupivacaine have dose-dependent chondrocyte toxicity, and this is significantly lesser at 7.69 μM dose. There was no significant difference in terms of chondrocyte apoptosis, (p > 0.05). CONCLUSIONS: Clinicians should be skeptic for the serious long-term side effects of bupivacaine and its analogs, even at ultra-low doses.
Previous experimental studies have determined local strain fields for both healthy and degenerated cartilage tissue during mechanical loading. However, the biomechanical response of chondrocytes in situ, and in particular, the response of the actin cytoskeleton to physiological loading conditions is poorly understood. In the current study, a 3D representative volume element (RVE) for cartilage tissue is created, comprising of a chondrocyte, surrounded by a pericellular matrix, and embedded in an extracellular matrix. A 3D active modelling framework incorporating actin cytoskeleton remodelling and contractility is implemented to predict the biomechanical behaviour of chondrocytes. Physiological and abnormal strain fields, based on the experimental study of Wong and Sah (Wong and Sah, J. Orthop. Res., 28:1554-61 (2010)), are applied to the RVE. Simulations demonstrate that the presence of a focal defect significantly affects cellular deformation, increases the stress experienced by the nucleus, and alters the distribution of the actin cytoskeleton. It is demonstrated that during dynamic loading, cyclic tension reduction in the cytoplasm causes continuous dissociation of the actin cytoskeleton. In contrast, during static loading significant changes in cytoplasm tension are not predicted and hence the rate of dissociation of the actin cytoskeleton is reduced. It is demonstrated that chondrocyte behaviour is affected by the stiffness of the pericellular matrix, and also by the anisotropy of the extracellular matrix. The findings of the current study are of particular importance for understanding the biomechanics underlying experimental observations such as actin cytoskeleton dissociation during the dynamic loading of chondrocytes.
Runx1, the hematopoietic lineage determining transcription factor, is present in perichondrium and chondrocytes. Here we addressed Runx1 functions, by examining expression in cartilage during mouse and human osteoarthritis (OA) progression and in response to mechanical loading.
Coronoid dysplasia (CD) or medial coronoid disease is part of canine elbow dysplasia and eventually results in osteoarthrosis. Although CD was originally attributed to disturbed endochondral ossification, more recent data point to the subchondral bone. The objective of this study was to assess dysplastic bone and cartilage of dogs that underwent unilateral or bilateral arthroscopic subtotal coronoidectomy for the treatment of CD. Arthroscopic findings and histopathology of bone and cartilage removed from elbow joints with CD were compared. The most common arthroscopic finding was fragmentation with softening of the subchondral bone of the central part of the medial coronoid process. In dogs without obvious fragmentation, CD was characterised by bone softening and chondromalacia. During arthroscopic intervention dysplastic bone and cartilage were collected for histopathological assessment. Forty-five slices of formalin-fixed, paraffin-embedded bone and cartilage samples were stained using haematoxylin and eosin and evaluated. Histopathological findings primarily consisted of osteonecrosis of subchondral bone with necrosis within the marrow spaces. Histopathological changes in the articular cartilage were characterised by fibrillation, chondrocyte clone formation, and focal cartilage necrosis. The pathology was found primarily in the subchondral bone and not in the articular cartilage. Vascular compromise may play a role in the pathogenesis of osteonecrosis in CD.
The rate of hypo-osmotic challenge influences regulatory volume decrease (RVD) and mechanical properties of articular chondrocytes
- Osteoarthritis and cartilage / OARS, Osteoarthritis Research Society
- Published about 3 years ago
Osteoarthritis (OA) is associated with a gradual reduction in the interstitial osmotic pressure within articular cartilage. The aim of this study was to compare the effects of sudden and gradual hypo-osmotic challenge on chondrocyte morphology and biomechanics.
Suppression of NF-κB activity via nanoparticle-based siRNA delivery alters early cartilage responses to injury
- Proceedings of the National Academy of Sciences of the United States of America
- Published over 1 year ago
Osteoarthritis (OA) is a major cause of disability and morbidity in the aging population. Joint injury leads to cartilage damage, a known determinant for subsequent development of posttraumatic OA, which accounts for 12% of all OA. Understanding the early molecular and cellular responses postinjury may provide targets for therapeutic interventions that limit articular degeneration. Using a murine model of controlled knee joint impact injury that allows the examination of cartilage responses to injury at specific time points, we show that intraarticular delivery of a peptidic nanoparticle complexed to NF-κB siRNA significantly reduces early chondrocyte apoptosis and reactive synovitis. Our data suggest that NF-κB siRNA nanotherapy maintains cartilage homeostasis by enhancing AMPK signaling while suppressing mTORC1 and Wnt/β-catenin activity. These findings delineate an extensive crosstalk between NF-κB and signaling pathways that govern cartilage responses postinjury and suggest that delivery of NF-κB siRNA nanotherapy to attenuate early inflammation may limit the chronic consequences of joint injury. Therapeutic benefits of siRNA nanotherapy may also apply to primary OA in which NF-κB activation mediates chondrocyte catabolic responses. Additionally, a critical barrier to the successful development of OA treatment includes ineffective delivery of therapeutic agents to the resident chondrocytes in the avascular cartilage. Here, we show that the peptide-siRNA nanocomplexes are nonimmunogenic, are freely and deeply penetrant to human OA cartilage, and persist in chondrocyte lacunae for at least 2 wk. The peptide-siRNA platform thus provides a clinically relevant and promising approach to overcoming the obstacles of drug delivery to the highly inaccessible chondrocytes.
The repair of articular cartilage needs a sufficient number of chondrocytes to replace the defect tissue, and therefore, expansion of cells is generally required. Chondrocytes derived by cellular reprogramming may provide a solution to the limitations of current (stem) cell-based therapies. In this article, two distinct approaches-induced pluripotent stem cell (iPSC)-mediated reprogramming and direct lineage conversion-are analysed and compared according to criteria that encompass the qualification of the method and the derived chondrocytes for the purpose of clinical application. Progress in iPSC generation has provided insights into the replacement of reprogramming factors by small molecules and chemical compounds. As follows, multistage chondrogenic differentiation methods have shown to improve the chondrocyte yield and quality. Nevertheless, the iPSC ‘detour’ remains a time- and cost-consuming approach. Direct conversion of fibroblasts into chondrocytes provides a slight advantage over these aspects compared to the iPSC detour. However, the requirement of constitutive transgene expression to inhibit hypertrophic differentiation limits this approach of being translated to the clinic. It can be concluded that the quality of the derived chondrocytes highly depends on the characteristics of the reprogramming method and that this is important to keep in mind during the experimental set-up. Further research into both reprogramming approaches for clinical cartilage repair has to include proper control groups and epigenetic profiling to optimize the techniques and eventually derive functionally stable articular chondrocytes.