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•  Introduction: the impaired repair capacity of cartilage and the beginning of cell therapy ‐  Autologous chondrocyte implantation ‐  Combination products ‐  Randomized controlled studies •  Choice of cell types •  Regulating cellular activities ‐  Influence of growth factors on chondrogenic differentiation ‐  Influence of growth factors on matrix deposition ‐  Supportive effect of biomaterials •  Interference of inflammation with cartilage repair •  Tracking of transplanted cells in vivo •  Conclusion and future directions Since the first cell therapeutic study to repair articular cartilage defects in the knee in 1994, several clinical studies have been reported. An overview of the results of clinical studies did not conclusively show improvement over conventional methods, mainly because few studies reach level I of evidence for effects on middle or long term. However, these explorative trials have provided valuable information about study design, mechanisms of repair and clinical outcome and have revealed that much is still unknown and further improvements are required. Furthermore, cellular and molecular studies using new technologies such as cell tracking, gene arrays and proteomics have provided more insight in the cell biology and mechanisms of joint surface regeneration. Besides articular cartilage, cartilage of other anatomical locations as well as progenitor cells are now considered as alternative cell sources. Growth Factor research has revealed some information on optimal conditions to support cartilage repair. Thus, there is hope for improvement. In order to obtain more robust and reproducible results, more detailed information is needed on many aspects including the fate of the cells, choice of cell type and culture parameters. As for the clinical aspects, it becomes clear that careful selection of patient groups is an important input parameter that should be optimized for each application. In addition, the study outcome parameters should be improved. Although reduced pain and improved function are, from the patient's perspective, the most important outcomes, there is a need for more structure/tissue‐related outcome measures. Ideally, criteria and/or markers to identify patients at risk and responders to treatment are the ultimate goal for these more sophisticated regenerative approaches in joint surface repair in particular, and regenerative medicine in general.

Objectives: To compare the efficacy between platelet-rich plasma (PRP) and corticosteroids (CS) in improving magnetic resonance imaging (MRI)-detected synovitis in correlation with clinical complaints among patients with lumbar facet joint (FJ) disease. Methods: This study was carried out at Eldemerdash Hospital, Cairo, Egypt between September 2019 and January 2021. A prospective, randomized, comparative, single blinded study included 30 patients with lumbar FJ disease, divided into 2 equal groups, received PRP and CS injections. Patients were comparatively assessed before and after the intervention according to number of tender lumbar FJs, maximum active lumbar extension range of motion, LBP visual analogue score, LBP functional disability questionnaires and MRI lumbar FJ detected synovitis and their grading. Results: Both groups showed a significant improvement in all mentioned parameters at follow-up after 3 months. However, PRP injections promoted better performance in terms of MRI synovitis grade in all lumbar FJ levels compared to CS injections. Conclusion: Both PRP and CS injections were effective in improving MRI-detected FJ synovitis while concurrently improving all examined parameters at follow-up after 3 months. However, PRP promoted better improvement in MRI-detected synovitis grade, suggesting that it may be a better treatment option for longer duration efficacy. TRN: NCT04860531- 1/3/2021 Keywords: platelet rich plasma, corticosteroids, synovitis, lumbar facet joint [phrase omitted]

BackgroundCurrent methods used to restore the joint surface in patients with localized articular cartilage defects include transplantation of an autologous osteochondral cylinder and implantation of autologous chondrocytes. The purpose of this study was to evaluate the clinical and histological outcomes of these two techniques.MethodsWe performed a prospective clinical study to investigate the two-year outcomes in forty patients with an articular cartilage lesion of the femoral condyle who had been randomly treated with either transplantation of an autologous osteochondral cylinder or implantation of autologous chondrocytes. Biopsy specimens from representative patients of both groups were evaluated with histological staining, immunohistochemistry, and scanning electron microscopy.ResultsAccording to the postoperative Lysholm score, the recovery after autologous chondrocyte implantation was slower than that after osteochondral transplantation at six months (p ≤ 0.015), twelve months (p ≤ 0.001), and twenty-four months (p ≤ 0.012). On the basis of the Meyers score and the Tegner activity score, the results were equally good with the two methods two years after treatment. Histomorphological evaluation of biopsy specimens within two years after autologous chondrocyte implantation demonstrated a complete, mechanically stable resurfacing of the defect in all patients. The tissue consisted mainly of fibrocartilage, while localized areas of hyaline-like regenerative cartilage could be detected close to the subchondral bone. Although a gap remained at the site of the transplantation in all five biopsy specimens examined as long as two years after osteochondral cylinder transplantation, histomorphological analysis and scanning electron microscopy revealed no differences between the osteochondral transplants and the surrounding original cartilage.ConclusionsBoth treatments resulted in a decrease in symptoms. However, the improvement provided by the autologous chondrocyte implantation lagged behind that provided by the osteochondral cylinder transplantation. Histologically, the defects treated with autologous chondrocyte implantation were primarily filled with fibrocartilage, whereas the osteochondral cylinder transplants retained their hyaline character, although there was a persistent interface between the transplant and the surrounding original cartilage. Limitations of our study included the small number of patients, the relatively short (two-year) follow-up, and the absence of a control group.Level of EvidenceTherapeutic study, Level II-2 (poor-quality randomized controlled trial [e.g., <80% follow-up]). See Instructions to Authors for a complete description of levels of evidence.

The purpose of this study was to compare the knee extensor mechanics in persons with and without patella alta. Thirteen subjects with patella alta and 14 subjects with normal patellar position participated in the study. Sagittal and axial MR images of the knee were acquired at 0°, 20°, 40°, and 60° of knee flexion. Measurements of actual moment arm, patellar ligament/quadriceps tendon force ratio, quadriceps effective moment arm, and joint reaction force/quadriceps force ratio were obtained. There were no differences between groups in terms of actual moment arm. However, subjects with patella alta had significantly larger patellar ligament/quadriceps tendon force ratios (1.04±0.02 vs. 0.92±0.02) and quadriceps effective moment arms (4.40±0.09 vs. 4.00±0.09 cm) when averaged across the range of knee flexion angles tested. There was no difference in the joint reaction force/quadriceps force ratio between groups. The observed differences in knee extensor mechanics suggest that individuals with patella alta have a more efficient knee extensor mechanism and would be expected to generate similar joint reaction forces per unit quadriceps force compared to subjects with normal patellar position. Therefore, persons with patella alta may experience less patellofemoral joint reaction force to overcome the same knee flexion moment in the range of 0°–60° of knee flexion.

Lyme disease, caused by Borrelia burgdorferi, B. afzelii and B. garinii, is a chronic, multi-systemic infection and the spectrum of tissues affected can vary with the Lyme disease strain. For example, whereas B. garinii infection is associated with neurologic manifestations, B. burgdorferi infection is associated with arthritis. The basis for tissue tropism is poorly understood, but has been long hypothesized to involve strain-specific interactions with host components in the target tissue. OspC (outer surface protein C) is a highly variable outer surface protein required for infectivity, and sequence differences in OspC are associated with variation in tissue invasiveness, but whether OspC directly influences tropism is unknown. We found that OspC binds to the extracellular matrix (ECM) components fibronectin and/or dermatan sulfate in an OspC variant-dependent manner. Murine infection by isogenic B. burgdorferi strains differing only in their ospC coding region revealed that two OspC variants capable of binding dermatan sulfate promoted colonization of all tissues tested, including joints. However, an isogenic strain producing OspC from B. garinii strain PBr, which binds fibronectin but not dermatan sulfate, colonized the skin, heart and bladder, but not joints. Moreover, a strain producing an OspC altered to recognize neither fibronectin nor dermatan sulfate displayed dramatically reduced levels of tissue colonization that were indistinguishable from a strain entirely deficient in OspC. Finally, intravital microscopy revealed that this OspC mutant, in contrast to a strain producing wild type OspC, was defective in promoting joint invasion by B. burgdorferi in living mice. We conclude that OspC functions as an ECM-binding adhesin that is required for joint invasion, and that variation in OspC sequence contributes to strain-specific differences in tissue tropism displayed among Lyme disease spirochetes.

Exosomes are a subset of small, membrane-bound extracellular vesicles that are important for communication among cells. They originate from the cell membrane during endocytic internalization, and are stable in biological fluids, including blood and synovial fluids. Increasing knowledge is emerging about exosomes in joint diseases, including osteoarthritis, rheumatoid arthritis, osteonecrosis of the femoral head, and others. Exosomes in synovial fluid can lead to inflammation, degeneration of cartilage, and destruction of joints. Exosomes in blood have diagnostic value in the early disease stage or for complicated conditions of joint diseases. Exosomes from stem cells could delay diseases and repair joints. For a comprehensive understanding about the emerging role of exosomes in joint diseases, we introduced the isolation and verification of exosomes from synovial fluid, reviewed the physiological and pathological effects of exosomes on joints, and discussed the diagnostic value and therapeutic potential of exosomes in joint diseases. In the future, immunologically active exosomes and engineered exosomes will of interest in the joint diseases. Challenges in the field of exosomes in joint-disease research include complex and expensive isolation, detection of contributing molecular, effectiveness and safety evaluation. In summary, challenges remain, but the field of exosomes in joint diseases has potential, including in mechanisms, diagnoses and therapies.

The IL-36 family of cytokines were first identified in 2000 based on their sequence homology to IL-1 cytokines. Over subsequent years, the ability of these cytokines to either agonise or antagonise an IL-1R homologue, now known as the IL-36 Receptor (IL-36R), was identified and these cytokines went through several cycles of renaming with the current nomenclature being proposed in 2010. Despite being identified over 20 years ago, it is only during the last decade that the function of these cytokines in health and disease has really begun to be appreciated, with both homeostatic functions in wound healing and response to infection, as well as pathological functions now ascribed. In the disease context, over activation of IL-36 has now been associated with many inflammatory diseases including Psoriasis and inflammatory bowel diseases, with roles in cancer also now being investigated. This review summarises the current knowledge of IL-36 biology, its role in inflammatory diseases and focuses on an emerging role for IL-36 in cancer.

Background Pseudotumor-like periprosthetic tissue reactions around metal-on-metal (M-M) hip replacements can cause pain and lead to revision surgery. The cause of these reactions is not well understood but could be due to excessive wear, or metal hypersensitivity or an as-yet unknown cause. The tissue features may help distinguish reactions to high wear from those with suspected metal hypersensitivity. Questions/purposes We therefore examined the synovial lining integrity, inflammatory cell infiltrates, tissue organization, necrosis and metal wear particles of pseudotumor-like tissues from M-M hips revised for suspected high wear related and suspected metal hypersensitivity causes. Methods Tissue samples from 32 revised hip replacements with pseudotumor-like reactions were studied. A 10-point histological score was used to rank the degree of aseptic lymphocytic vasculitis-associated lesions (ALVAL) by examination of synovial lining integrity, inflammatory cell infiltrates, and tissue organization. Lymphocytes, macrophages, plasma cells, giant cells, necrosis and metal wear particles were semiquantitatively rated. Implant wear was measured with a coordinate measuring machine. The cases were divided into those suspected of having high wear and those suspected of having metal hypersensitivity based on clinical, radiographic and retrieval findings. The Mann-Whitney test was used to compare the histological features in these two groups. Results The tissues from patients revised for suspected high wear had a lower ALVAL score, fewer lymphocytes, but more macrophages and metal particles than those tissues from hips revised for pain and suspected metal hypersensitivity. The highest ALVAL scores occurred in patients who were revised for pain and suspected metal hypersensitivity. Component wear was lower in that group. Conclusions Pseudotumor-like reactions can be caused by high wear, but may also occur around implants with low wear, likely because of a metal hypersensitivity reaction. Histologic features including synovial integrity, inflammatory cell infiltrates, tissue organization, and metal particles may help differentiate these causes. Clinical Relevance Painful hips with periprosthetic masses may be caused by high wear, but if this can be ruled out, metal hypersensitivity should be considered.

Connective tissues within the synovial joints are characterized by their dense extracellular matrix and sparse cellularity. With injury or disease, however, tissues commonly experience an influx of cells owing to proliferation and migration of endogenous mesenchymal cell populations, as well as invasion of the tissue by other cell types, including immune cells. Although this process is critical for successful wound healing, aberrant immune-mediated cell infiltration can lead to pathological inflammation of the joint. Importantly, cells of mesenchymal or haematopoietic origin use distinct modes of migration and thus might respond differently to similar biological cues and microenvironments. Furthermore, cell migration in the physiological microenvironment of musculoskeletal tissues differs considerably from migration in vitro. This Review addresses the complexities of cell migration in fibrous connective tissues from three separate but interdependent perspectives: physiology (including the cellular and extracellular factors affecting 3D cell migration), pathophysiology (cell migration in the context of synovial joint autoimmune disease and injury) and tissue engineering (cell migration in engineered biomaterials). Improved understanding of the fundamental mechanisms governing interstitial cell migration might lead to interventions that stop invasion processes that culminate in deleterious outcomes and/or that expedite migration to direct endogenous cell-mediated repair and regeneration of joint tissues.

Knowledge of how the joint functions as an integrated unit in health and disease requires an understanding of the stromal cells populating the joint mesenchyme, including fibroblasts, tissue-resident macrophages and endothelial cells. Knowledge of the physiological and pathological mechanisms that involve joint mesenchymal stromal cells has begun to cast new light on why joint inflammation persists. The shared embryological origins of fibroblasts and endothelial cells might shape the behaviour of these cell types in diseased adult tissues. Cells of mesenchymal origin sustain inflammation in the synovial membrane and tendons by various mechanisms, and the important contribution of newly discovered fibroblast subtypes and their associated crosstalk with endothelial cells, tissue-resident macrophages and leukocytes is beginning to emerge. Knowledge of these mechanisms should help to shape the future therapeutic landscape and emphasizes the requirement for new strategies to address the pathogenic stroma and associated crosstalk between leukocytes and cells of mesenchymal origin.