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Healthy articular cartilage is characterized by extremely low friction and high compressive stiffness. This dual-functionality is tailored by its biphasic structure, whereby a fluid phase interacts with the extracellular matrix. Osteoarthritis (OA) causes structural changes, thereby altering the biomechanical and frictional properties. How the structural and functional properties of human cartilage are associated with OA remain unknown. To address this, we identified relationships between structural parameters, viscoelastic and frictional properties of degenerated human cartilage through correlation analyses. We found that cartilage friction was mainly influenced by its microscopic structure, while the viscoelastic properties were also related to the macroscopic structure. The viscoelastic and frictional properties displayed a weak correlation. These findings provide insights into the interplay between cartilage structure and its functional properties in OA, which might provide a basis for advancements in diagnosing and treating degenerated human cartilage. STATEMENT OF SIGNIFICANCE: Osteoarthritis causes changes in the cartilages biphasic structure, thereby affecting functionality by altered biomechanical and frictional properties. Currently a cartilage-preserving therapeutic option remains lacking, because the disease is not fully understood. In our correlation analyses, we investigated relationships between the structural, the viscoelastic and frictional properties of degenerated human cartilage. We found that cartilage friction was particularly dependent on the microscopic structure, while the viscoelastic properties also correlated with the macroscopic structure. The frictional properties displayed only a weak dependency with the viscoelastic properties. These new insights into the structure-function and inter-functional relationships may provide new options to advance the diagnosis and treatment of degenerated cartilage., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests of personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Osteoarthritis (OA) commonly results in compromised mobility and disability, thereby imposing a significant burden on healthcare systems. Cartilage injury is a prevalent pathological manifestation in OA and constitutes a central focus for the development of treatment strategies. Despite the considerable number of studies aimed at delaying this degenerative process, their outcomes remain unvalidated in preclinical settings. Recently, therapeutic strategies focused on angiogenesis have attracted the growing interest from researchers. Thus, we conducted a comprehensive literature review to elucidate the current progress in research and pinpoint research gaps in this domain. Additionally, it provides theoretical guidance for future research endeavors and the development of treatment strategies., Competing Interests: Declaration of competing interest The authors declare that they have no competing interests., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Purpose: This study aimed to conduct arthroscopic evaluation of cartilage electromechanical properties and establish their correlation with International Cartilage Repair Society (ICRS) grading scores., Methods: In 18 patients, quantitative parameter (QP) measurements were taken on the weight-bearing surface of the medial femoral condyle. Adjacently, the same site was graded using ICRS scores (0-4). Electromechanical QPs for ICRS grades 0 to 3 were obtained during arthroscopy, while complete grade 4 injuries were assessed using femur cartilage-bone blocks from knee arthroplasty. The QP values for ICRS grades 0 to 2 were compared with grades 3 and 4 using Welch t test. The corresponding QP values were assigned to ICRS grades 0 to 4 and compared using Welch ANOVA (analysis of variance). Pearson's coefficient evaluated QP-ICRS grade relationship., Results: Healthy grade 0 cartilage displayed a mean QP value of 10.5 (±2.8 SD, n = 4). The ICRS grade 1 and grade 2 injuries were associated with QP values of 12 (±0.7, n = 2) and 13.25 (±1.77, n = 2), respectively. The grade 3 defects had QP values of 20.43 (±4.84, n = 4), whereas complete grade 4 defects showed electromechanical values of 30.17 (±2.19, n = 6). Significant differences in QP values were observed between ICRS grades 0 to 2 (mean QP 11.56 ± 2.3, n = 8) and grades 3 and 4 (26.27 ± 6, n = 10; P < 0.0001). Pearson's correlation coefficient of 0.9 indicated a strong association between higher ICRS cartilage injury grades and elevated QP values ( P < 0.0001)., Conclusion: Arthroscopic electromechanical QP assessment robustly correlates with ICRS scores. The QP values for ICRS grades 0 to 2 are significantly lower, compared with grades 3 and 4., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Patellofemoral osteoarthritis (PFOA) is the result of degeneration and loss of articular cartilage of the patella and trochlea, and is a common cause of anterior knee pain. PFOA is triggered by insufficient adaptation to overload of the articular cartilage of the PF joint created by abnormal biomechanics. It is important to understand the pathophysiology and natural history to make the diagnosis and to plan treatment. Innate factors including malalignment, patellar instability, kinematic disorders, and acquired factors like trauma, obesity, and endocrine diseases have been found to be causes of PFOA. Genetic predisposition is also described as a contributing cause but without much scientific evidence. The diagnosis will be based on clinical manifestations, such as anterior knee pain aggravated by overloading activities, identification of risk factors, and exclusion of referred pain from other pathologies, followed by a systematic and structured physical examination. Imaging will be useful for assessing the presence of early osteoarthritis in the other compartments, for classification of the PFOA, and to identify features to establish an adequate treatment. This paper discusses varying management options for different causes of patellofemoral disease and explains the complexity of the PF joint and its often poorly understood biomechanics., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Objective: Early articular cartilage lesion (CL) is a vital sign in the onset of posttraumatic knee osteoarthritis (PTOA) in patients with anterior cruciate ligament deficiency (ACLD). Researchers have suggested that altered kinematics could accelerate CLs and, therefore, lead to the onset of PTOA. However, little is known about whether specific knee kinematics exist that lead to early CL in chronic ACLD knees. Level walking is the most frequent and relevant in vivo activity, which greatly impacts knee health. We hypothesized that the knee kinematics during level walking in chronic ACLD knees with early tibiofemoral CL would significantly differ from those of chronic ACLD knees without early tibiofemoral CL., Methods: Thirty patients with a chronic ACLD history, including 18 subjects with CLs and 12 subjects without CLs, and 35 healthy control subjects were recruited for the study from July 2020 to August 2022. The knee kinematic data during level walking were collected using a three-dimensional motion analysis system. The kinematic differences between groups were compared using statistical parametric mapping with one dimension for One-Way ANOVA. The cartilage statuses of the ACLD knees were assessed via MRI examination. The CLs distribution of subjects was evaluated using a modified Noyes scale and analyzed by chi-square tests., Results: ACLD knees with CLs had significantly greater posterior tibial translation (7.7-8.0mm, 12%-18% gait cycle GC, p = 0.014) compared to ACLD knees without CLs during level walking. ACLD knees with CLs had greater posterior tibial translation (4.6-5.5mm, 0%-23% GC, p < 0.001; 5.8-8.0mm, 86%-100% GC, p < 0.001) than healthy controls during level walking. In the group of ACLD knees with CLs, CL is mainly located in the back of the tibia plateau and front of load bearing area of the medial femoral condyle (p < 0.05)., Conclusion: Chronic anterior cruciate ligament deficient knees with cartilage lesions have increased posterior tibial translation compared to anterior cruciate ligament deficient knees without cartilage lesions and healthy subjects. The posterior tibial translation may play an important role in knee cartilage degeneration in ACLD knees. The increased posterior tibial translation and cartilage lesion characteristics may improve our understanding of the role of knee kinematics in cartilage degeneration and could be a helpful potential reference for anterior cruciate ligament deficient therapy, such as physical training to improve abnormal kinematic behavior., (© 2024 The Authors. Orthopaedic Surgery published by Tianjin Hospital and John Wiley & Sons Australia, Ltd.)

Osteoarthritis (OA) is a chronic joint disease characterized by the degeneration of articular cartilage and thickening and sclerosis of the subchondral bone. Mechanical factors play significant roles in the development and progression of OA, but it is still controversial whether exercise or rest is a more effective treatment for OA patients. In this study, we compared the effects of swimming and immobilization at different stages of OA in mice. Four weeks (the middle stage of OA) or eight weeks (the late stage of OA) after DMM (destabilization of the medial meniscus) surgery, the mice were subjected to four-week immobilization or swimming. Ink blot analysis and a beam walking test were performed to measure the gait and balance ability. Histological analysis was performed to determine the trabecular bone area, the thickness of subchondral bone, the thickness of the cartilage, the OARSI score, and the expression of MMP13 (matrix metalloproteinases) and IL-6 (interleukin). The results showed that at the middle stage of OA, both immobilization and swimming slowed down the progression of OA. Immobilization relieved OA to a certain extent by decreasing the production of regulatory factors to attenuate the degeneration of cartilage, which partly relieved the effects of DMM on gait, mainly in the hindlimb. Swimming mainly attenuated the thickening and rescued the area of subchondral bone., Competing Interests: The authors declare no conflict of interest.

Objective: To observe expression of CD38, a key modulator of nicotinamide dinucleotide (NAD+) metabolism in mice with knee osteoarthritis, and protective effect of CD38 inhibition during the osteoarthritis (OA) development., Method: The destabilization of the medial meniscus (DMM) model was performed in mice to mimic the process of OA. Immunofluorescence of CD38 was performed to evaluate its response during the OA process. Limb bud-derived mesenchymal cells were isolated for micromass culture. 100 nM or 1 μM CD38 inhibitor (78c) treatment for 14 days and CD38 sgRNA infection were then used to explore the effects of chondrogenic differentiation via Alcian blue staining. The expressions of chondrogenic markers were detected using RT-PCR and Western blot. To explore the protective effect of CD38 inhibitor on cartilage degradation during OA in vivo, a CD38 inhibitor was injected into the knee joint after DMM operations. Micro-CT analysis and Safranin O-fast green staining were used to evaluate subchondral bone micro-architecture changes and cartilage degeneration., Results: Compared to the control group, the CD38 expression in superficial cartilage was obviously increased in DMM group (P < 0.05). During the normal chondrogenic differentiation, the extracellular matrix formed and expression of Sox9, Col2, aggrecan increased apparently while CD38 expression decreased, which could be reversed with ablation of CD38 in limb bud-derived mesenchymal cells. Consistent with findings in vitro, CD38 blockage via CD38 inhibitor injection protected against osteosclerosis in medial subchondral bone and cartilage degeneration in DMM-induced experimental mice. Compared to the Sham group, DMM mice showed significantly increased values of BV and BV/TV in subchondral bone (P < 0.05) and Mankin score, which could be rescued by 78c treatment (P < 0.05). Also the CD38 inhibitor contributed to homeostasis of anabolism and catabolism by upregulating Sox9, Col2, aggrecan and downregulating Runx2, Col10 and Mmp13., Conclusion: This study primarily implicates CD38 as an important regulator of chondrogenic differentiation. Inhibition of CD38 demonstrated protection against cartilage degeneration, which suggests that CD38 could be a potential therapeutic target for OA., (© 2022 The Authors. Orthopaedic Surgery published by Tianjin Hospital and John Wiley & Sons Australia, Ltd.)

Background: Substantial evidence shows that crosstalk between cartilage and subchondral bone may play an important role in cartilage repair. Animal models have shown that hydroxyapatite-grafted-chitosan implant (HA-g-CS) and moderate-intensity exercise promote regeneration of osteochondral defects. However, no in vivo studies have demonstrated that these two factors may have a synergistic activity to facilitate subchondral bone remodeling in mice, thus supporting bone-cartilage repair. Questions: This study was to clarify whether HA-g-CS and moderate-intensity exercise might have a synergistic effect on facilitating (1) regeneration of osteochondral defects and (2) subchondral bone remodeling in a mouse model of osteochondral defects. Methods: Mouse models of osteochondral defects were created and divided into four groups. BC Group was subjected to no treatment, HC Group to HA-g-CS implantation into osteochondral defects, ME group to moderate-intensity treadmill running exercise, and HC+ME group to both HA-g-CS implantation and moderate-intensity exercise until sacrifice. Extent of subchondral bone remodeling at the injury site and subsequent cartilage repair were assessed at 4 weeks after surgery. Results: Compared with BC group, HC, ME and HC+ME groups showed more cartilage repair and thicker articular cartilage layers and HC+ME group acquired the best results. The extent of cartilage repair was correlated positively to bone formation activity at the injured site as verified by microCT and correlation analysis. Histology and immunofluorescence staining confirmed that bone remodeling activity was increased in HC and ME groups, and especially in HC+ME group. This bone formation process was accompanied by an increase in osteogenesis and chondrogenesis factors at the injury site which promoted cartilage repair. Conclusions: In a mouse model of osteochondral repair, HA-g-CS implant and moderate-intensity exercise may have a synergistic effect on improving osteochondral repair potentially through promotion of subchondral bone remodeling and generation of osteogenesis and chondrogenesis factors. Clinical Relevance: Combination of HA-g-CS implantation and moderate-intensity exercise may be considered potentially in clinic to promote osteochondral defect repair. Also, cartilage and subchondral bone forms a functional unit in an articular joint and subchondral bone may regulate cartilage repair by secreting growth factors in its remodeling process. However, a deeper insight into the exact role of HA-g-CS implantation and moderate-intensity exercise in promoting osteochondral repair in other animal models should be explored before they can be applied in clinic in the future., Competing Interests: Competing Interests: The authors have declared that no competing interest exists., (© The author(s).)

The purpose of this study was to investigate growth plate dynamics in surgical and loading murine models of osteoarthritis, to understand whether abnormalities in these dynamics are associated with osteoarthritis development. 8-week-old C57BL/6 male mice underwent destabilisation of medial meniscus (DMM) ( n = 8) surgery in right knee joints. Contralateral left knee joints had no intervention (controls). In 16-week-old C57BL/6 male mice ( n = 6), osteoarthritis was induced using non-invasive mechanical loading of right knee joints with peak force of 11N. Non-loaded left knee joints were internal controls. Chondrocyte transiency in tibial articular cartilage and growth plate was confirmed by histology and immunohistochemistry. Tibial subchondral bone parameters were measured using microCT and correlated to 3-dimensional (3D) growth plate bridging analysis. Higher expression of chondrocyte hypertrophy markers; Col10a1 and MMP13 were observed in tibial articular cartilage chondrocytes of DMM and loaded mice. In tibial growth plate, Col10a1 and MMP13 expressions were widely expressed in a significantly enlarged zone of proliferative and hypertrophic chondrocytes in DMM ( p =0.002 and p <0.0001, respectively) and loaded (both p <0.0001) tibiae of mice compared to their controls. 3D quantification revealed enriched growth plate bridging and higher bridge densities in medial compared to lateral tibiae of DMM and loaded knee joints of the mice. Growth plate dynamics were associated with increased subchondral bone volume fraction (BV/TV; %) in medial tibiae of DMM and loaded knee joints and epiphyseal trabecular bone volume fraction in medial tibiae of loaded knee joints. The results confirm articular cartilage chondrocyte transiency in a surgical and loaded murine models of osteoarthritis. Herein, we reveal spatial variation of growth plate bridging in surgical and loaded osteoarthritis models and how these may contribute to anatomical variation in vulnerability of osteoarthritis development., Competing Interests: The research leading to these results has received technical support from 3Dmagination Ltd, Didcot, UK. KM is co-founder and director of 3Dmagination Ltd in Oxfordshire, UK, a company which provides training and consultancy in 3D and 4D imaging. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Samvelyan, Madi, Törnqvist, Javaheri and Staines.)

Objective: The relationship between in vivo knee load predictions and longitudinal cartilage changes has not been investigated. We undertook this study to develop an equation to predict the medial tibiofemoral contact force (MCF) peak during walking in persons with instrumented knee implants, and to apply this equation to determine the relationship between the predicted MCF peak and cartilage loss in patients with knee osteoarthritis (OA)., Methods: In adults with knee OA (39 women, 8 men; mean ± SD age 61.1 ± 6.8 years), baseline biomechanical gait analyses were performed, and annualized change in medial tibial cartilage volume (mm 3 /year) over 2.5 years was determined using magnetic resonance imaging. In a separate sample of patients with force-measuring tibial prostheses (3 women, 6 men; mean ± SD age 70.3 ± 5.2 years), gait data plus in vivo knee loads were used to develop an equation to predict the MCF peak using machine learning. This equation was then applied to the knee OA group, and the relationship between the predicted MCF peak and annualized cartilage volume change was determined., Results: The MCF peak was best predicted using gait speed, the knee adduction moment peak, and the vertical knee reaction force peak (root mean square error 132.88N; R 2 = 0.81, P < 0.001). In participants with knee OA, the predicted MCF peak was related to cartilage volume change (R 2 = 0.35, β = -0.119, P < 0.001)., Conclusion: Machine learning was used to develop a novel equation for predicting the MCF peak from external biomechanical parameters. The predicted MCF peak was positively related to medial tibial cartilage volume loss in patients with knee OA., (© 2021 The Authors. Arthritis & Rheumatology published by Wiley Periodicals LLC on behalf of American College of Rheumatology.)

The circadian clock is a specialized cell signalling pathway present in all cells. Loss of clock function leads to tissue degeneration and premature ageing in animal models demonstrating the fundamental importance of clocks for cell, tissue and organism health. There is now considerable evidence that the chondrocyte circadian clock is altered in OA. The purpose of this review is to summarize current knowledge regarding the nature of the change in the chondrocyte clock in OA and the implications of this change for disease development. Expression of the core clock component, BMAL1, has consistently been shown to be lower in OA chondrocytes. This may contribute to changes in chondrocyte differentiation and extracellular matrix turnover in disease. Circadian clocks are highly responsive to environmental factors. Mechanical loading, diet, inflammation and oxidative insult can all influence clock function. These factors may contribute to causing the change in the chondrocyte clock in OA., (© The Author(s) 2021. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Purpose: This study aimed 1) to determine whether talar cartilage deformation measured via ultrasonography (US) after standing and hopping loading protocols differs between chronic ankle instability (CAI) patients and healthy controls and 2) to determine whether the US measurement of cartilage deformation reflects viscoelasticity between standing and hopping protocols., Methods: A total of 30 CAI and 30 controls participated. After a 60-min off-loading period, US images of the talar cartilage were acquired before and after static (2-min single-leg standing) and dynamic (60 single-leg forward hops) loading conditions. We calculated cartilage deformation by assessing the change in average thickness (mm) for overall, medial, and lateral talar cartilage. The independent variables include time (Pre60 and postloading), condition (standing and dynamic loading), and group (CAI and control). A three-way mixed-model repeated-measures ANCOVA and appropriate post hoc tests were used to compare cartilage deformation between the groups after static and dynamic loading., Results: After the static loading condition, those with CAI had greater talar cartilage deformation compared with healthy individuals for overall (-10.87% vs -6.84%, P = 0.032) and medial (-12.98% vs -5.80%, P = 0.006) talar cartilage. Similarly, the CAI group had greater deformation relative to the control group for overall (-8.59% vs -3.46%, P = 0.038) and medial (-8.51% vs -3.31%, P = 0.043) talar cartilage after the dynamic loading condition. In the combined cohort, cartilage deformation was greater after static loading compared with dynamic in overall (-8.85% vs -6.03%, P = 0.003), medial (-9.38% vs -5.91%, P = 0.043), and lateral (-7.90% vs -5.65%, P = 0.009) cartilage., Conclusion: US is capable of detecting differences in cartilage deformation between those with CAI and uninjured controls after standardized physiologic loads. Across both groups, our results demonstrate that static loading results in greater cartilage deformation compared with dynamic loading., (Copyright © 2021 by the American College of Sports Medicine.)

Reduced knee weight-bearing from prescription or sedentary lifestyles are associated with cartilage degradation; effects on the meniscus are unclear. Rodents exposed to spaceflight or hind limb unloading (HLU) represent unique opportunities to evaluate this question. This study evaluated arthritic changes in the medial knee compartment that bears the highest loads across the knee after actual and simulated spaceflight, and recovery with subsequent full weight-bearing. Cartilage and meniscal degradation in mice were measured via microCT, histology, and proteomics and/or biochemically after: (1) ~ 35 days on the International Space Station (ISS); (2) 13-days aboard the Space Shuttle Atlantis; or (3) 30 days of HLU, followed by a 49-day weight-bearing readaptation with/without exercise. Cartilage degradation post-ISS and HLU occurred at similar spatial locations, the tibial-femoral cartilage-cartilage contact point, with meniscal volume decline. Cartilage and meniscal glycosaminoglycan content were decreased in unloaded mice, with elevated catabolic enzymes (e.g., matrix metalloproteinases), and elevated oxidative stress and catabolic molecular pathway responses in menisci. After the 13-day Shuttle flight, meniscal degradation was observed. During readaptation, recovery of cartilage volume and thickness occurred with exercise. Reduced weight-bearing from either spaceflight or HLU induced an arthritic phenotype in cartilage and menisci, and exercise promoted recovery.

Articular cartilage heals poorly but experiences mechanically induced damage across a broad range of loading rates and matrix integrity. Because loading rates and matrix integrity affect cartilage mechanical responses due to poroviscoelastic relaxation mechanisms, their effects on cartilage failure are important for assessing and preventing failure. This paper investigated rate- and integrity-dependent crack nucleation in cartilage from pre- to post-relaxation timescales. Rate-dependent crack nucleation and relaxation responses were obtained as a function of matrix integrity through microindentation. Total work for crack nucleation increased with decreased matrix integrity, and with decreased loading rates. Critical energy release rate of intact cartilage was estimated as 2.39 ± 1.39 to 2.48 ± 1.26 kJ m -2 in a pre-relaxation timescale. These findings showed that crack nucleation is delayed when cartilage can accommodate localized loading through poroviscoelastic relaxation mechanisms before fracture at a given loading rate and integrity state.

Background: Delayed gadolinium-enhanced MRI of cartilage (dGEMRIC) is a validated technique for evaluating cartilage health in developmental dysplasia of the hip (DDH), which can be a helpful prognosticator for the response to surgical treatments. dGEMRIC requires intravenous injection of gadolinium contrast, however, which adds time, expense, and possible adverse reactions to the imaging procedure. Newer MRI cartilage mapping techniques such as T1 rho (ρ) and T2* have been performed in the hip without the need for any contrast, although it is unknown whether they are equivalent to dGEMRIC., Question/purpose: In this study, our purpose was to determine the correlation between the relaxation values of three cartilage mapping techniques, dGEMRIC, T1ρ, and T2*, in patients with DDH., Methods: Fifteen patients with DDH (three male, 12 female; mean age 29 ± 9 years) scheduled for periacetabular osteotomy underwent preoperative dGEMRIC, T1ρ, and T2* MRI at 3T with quantitative cartilage mapping. The outcomes of dGEMRIC, T1ρ, and T2* mapping were calculated for three regions of interest (ROI) to analyze the weightbearing cartilage of the hip: global ROI, anterior and posterior ROI, and further subdivided into medial, intermediate, and lateral to generate six smaller ROIs. The correlation between the respective relaxation time values was evaluated using the Spearman correlation coefficient (rS) for each ROI, categorized as negligible, weak, moderate, strong, or very strong. The relaxation values within the subdivided ROIs were compared for each of the three cartilage mapping techniques using the Kruskal-Wallis test., Results: There was a moderate correlation of T1ρ and T2* relaxation values with dGEMRIC relaxation values. For the global ROI, there was a moderate correlation between dGEMRIC and T2* (moderate; rS = 0.63; p = 0.01). For the anterior ROI, a moderate or strong correlation was found between dGEMRIC and both T1ρ and T2*: dGEMRIC and T1ρ (strong; rS = -0.71; p = 0.003) and dGEMRIC and T2* (moderate; rS = 0.69; p = 0.004). There were no correlations for the posterior ROI. The mean dGEMRIC, T1ρ, and T2* relaxation values were not different between the anterior and posterior ROIs nor between the subdivided six ROIs., Conclusion: Quantitative T1ρ and T2* cartilage mapping demonstrated a moderate correlation with dGEMRIC, anteriorly and globally, respectively. However, the clinical relevance of such a correlation remains unclear. Further research investigating the correlation of these two noncontrast techniques with clinical function and outcome scores is needed before broad implementation in the preoperative investigation of DDH., Level of Evidence: Level II, diagnostic study., Competing Interests: One of the authors certifies that he (PEB) has received funding, during the study period, in an amount of USD 10,000 to USD 100,000 from Zimmer Biomet. Each remaining author certifies that neither he, nor any member of his immediate family, has funding or commercial associations (consultancies, stock ownership, equity interest, patent/licensing arrangements, etc.) that might pose a conflict of interest in connection with the submitted article. All ICMJE Conflict of Interest Forms for authors and Clinical Orthopaedics and Related Research® editors and board members are on file with the publication and can be viewed on request., (Copyright © 2020 by the Association of Bone and Joint Surgeons.)

Objective: To address the need for early knee osteoarthritis (OA) markers by testing if longitudinal cartilage thickness changes are associated with specific biomechanical and biological measures acquired at a baseline test in asymptomatic aging subjects., Design: Thirty-eight asymptomatic subjects over age 45 years were studied at baseline and at an average of 7-9 year follow-up. Gait mechanics and knee MRI were measured at baseline and MRI was obtained at follow-up to assess cartilage thickness changes. A subset of the subjects (n = 12) also had serum cartilage oligomeric matrix protein measured at baseline in response to a mechanical stimulus (30-min walk) (mCOMP). Baseline measures, including the knee extension (KEM), flexion (KFM), adduction (KAM) moments and mCOMP, were tested for associations with cartilage thickness changes in specific regions of the knee., Results: Cartilage change in the full medial femoral condyle (p = 0.005) and external medial femoral region (p = 0.041) was negatively associated with larger early stance peak KEM. Similarly, cartilage change in the full medial femoral region (p = 0.009) and medial femoral external region (p = 0.043) was negatively associated with larger first peak KAM, while cartilage change in the anterior medial tibia was positively associated with larger first peak KAM (p = 0.003). Cartilage change in the anterior medial tibia was also significantly associated (p = 0.011) with mCOMP levels 5.5-h post-activity (percentage of pre-activity levels)., Conclusions: Interactions found between gait, mechanically-stimulated serum biomarkers, and cartilage thickness in an at-risk aging asymptomatic population suggest the opportunity for early detection of OA with new approaches that bridge across disciplines and scales., Competing Interests: Declaration of competing interest There are no conflicts of interest for any of the authors., (Copyright © 2021. Published by Elsevier Ltd.)

Cartilage degeneration has been reported to deteriorate osteoarthritis (OA), a prevalent joint disease caused by intrinsic and epigenetic factors. This study aimed to examine the molecular mechanism of enhancer of zeste 2 polycomb repressive complex 2 subunit (EZH2)/microRNA-138 (miR-138)/syndecan 1 (SDC1) and its epigenetic regulation in cartilage degeneration in OA. An OA cell model was induced by stimulating chondrocytes with interleukin (IL)-1β at a final concentration of 10 ng/mL, followed by alterations in EZH2 and miR-138 expression. Afterwards, cell apoptosis was analyzed using flow cytometry. The expression patterns of cartilage catabolism-related factors (MMP-13, ADAMTS-4, and ADAMTS-5) were determined using RT-qPCR and western blot analyses. The EZH2 and H3K27me3 enrichment at the miR-138 promoter region were determined using ChIP-qPCR. Finally, an OA mouse model was constructed to verify the function of EZH2 in vivo. EZH2 was expressed at high levels in OA models. EZH2 depletion ameliorated OA, as evidenced by reduced cell apoptosis in IL-1β-treated chondrocytes and decreased levels of cartilage catabolism-related factors. Moreover, EZH2 promoted histone methylation at the miR-138 promoter to suppress miR-138 expression, thereby upregulating the expression of SDC1, a target gene of miR-138. Changes in this pathway increased the expression of cartilage catabolism-related factors in vitro while promoting cartilage degeneration in vivo. Our data provided evidence that EZH2 inhibits miR-138 expression by promoting the histone methylation of its promoter, which induces cartilage degeneration in OA models by upregulating SDC1 expression, suggesting a novel mechanistic strategy for OA treatment.

Objective: To investigate the diffusion trajectory of a cationic contrast medium (CA4+) into equine articular cartilage, and to assess normal and degenerative equine articular cartilage using cationic contrast-enhanced computed tomography (CECT)., Design: In the first experiment (Exp1), equine osteochondral specimens were serially imaged with cationic CECT to establish the diffusion time constant and time to reach equilibrium in healthy articular cartilage. In a separate experiment (Exp2), articular cartilage defects were created on the femoral trochlea (defect joint) in a juvenile horse, while the opposite joint was a sham-operated control. After 7 weeks, osteochondral biopsies were collected throughout the articular surfaces of both joints. Biopsies were analyzed for cationic CECT attenuation, glycosaminoglycan (GAG) content, mechanical stiffness (E eq ), and histology. Imaging, biochemical and mechanical data were compared between defect and control joints., Results: Exp1: The mean diffusion time constant was longer for medial condyle cartilage (3.05 ± 0.1 hours) than lateral condyle cartilage (1.54 ± 0.3 hours, P = 0.04). Exp2: Cationic CECT attenuation was lower in the defect joint than the control joint ( P = 0.005) and also varied by anatomic location ( P = 0.045). Mean cationic CECT attenuation from the lateral trochlear ridge was lower in the defect joint than in the control joint (2223 ± 329 HU and 2667 ± 540 HU, respectively; P = 0.02). Cationic CECT attenuation was strongly correlated with both GAG (ρ = 0.79, P < 0.0001) and E eq (ρ = 0.61, P < 0.0001)., Conclusions: The equilibration time of CA4+ into equine articular cartilage is affected by tissue volume. Quantitative cationic CECT imaging reflects the biochemical, biomechanical and histological state of normal and degenerative equine articular cartilage.

Articular cartilage defects represent an inciting factor for future osteoarthritis (OA) and degenerative joint disease progression. Despite multiple clinically available therapies that succeed in providing short term pain reduction and restoration of limited mobility, current treatments do not reliably regenerate native hyaline cartilage or halt cartilage degeneration at these defect sites. Novel therapeutics aimed at addressing limitations of current clinical cartilage regeneration therapies increasingly focus on allogeneic cells, specifically mesenchymal stem cells (MSCs), as potent, banked, and available cell sources that express chondrogenic lineage commitment capabilities. Innovative tissue engineering approaches employing allogeneic MSCs aim to develop three-dimensional (3D), chondrogenically differentiated constructs for direct and immediate replacement of hyaline cartilage, improve local site tissue integration, and optimize treatment outcomes. Among emerging tissue engineering technologies, advancements in cell sheet tissue engineering offer promising capabilities for achieving both in vitro hyaline-like differentiation and effective transplantation, based on controlled 3D cellular interactions and retained cellular adhesion molecules. This review focuses on 3D MSC-based tissue engineering approaches for fabricating "ready-to-use" hyaline-like cartilage constructs for future rapid in vivo regenerative cartilage therapies. We highlight current approaches and future directions regarding development of MSC-derived cartilage therapies, emphasizing cell sheet tissue engineering, with specific focus on regulating 3D cellular interactions for controlled chondrogenic differentiation and post-differentiation transplantation capabilities.

Osteoarthritis (OA) is currently the most widespread musculoskeletal condition and primarily affects weight-bearing joints such as the knees and hips. Importantly, knee OA remains a multifactorial whole-joint disease, the appearance and progression of which involves the alteration of articular cartilage as well as the synovium, subchondral bone, ligaments, and muscles through intricate pathomechanisms. Whereas it was initially depicted as a predominantly aging-related and mechanically driven condition given its clear association with old age, high body mass index (BMI), and joint malalignment, more recent research identified and described a plethora of further factors contributing to knee OA pathogenesis. However, the pathogenic intricacies between the molecular pathways involved in OA prompted the study of certain drugs for more than one therapeutic target (amelioration of cartilage and bone changes, and synovial inflammation). Most clinical studies regarding knee OA focus mainly on improvement in pain and joint function and thus do not provide sufficient evidence on the possible disease-modifying properties of the tested drugs. Currently, there is an unmet need for further research regarding OA pathogenesis as well as the introduction and exhaustive testing of potential disease-modifying pharmacotherapies in order to structure an effective treatment plan for these patients.

Since its discovery in 1994, leptin has been considered as an adipokine with pleiotropic effects. In this review, we summarize the actual information about the impact of this hormone on cartilage metabolism and pathology. Leptin signalling depends on the interaction with leptin receptor LEPR, being the long isoform of the receptor (LEPRb) the one with more efficient intracellular signalling. Chondrocytes express the long isoform of the leptin receptor and in these cells, leptin signalling, alone or in combination with other molecules, induces the expression of pro-inflammatory molecules and cartilage degenerative enzymes. Leptin has been shown to increase the proliferation and activation of immune cells, increasing the severity of immune degenerative cartilage diseases. Leptin expression in serum and synovial fluid are related to degenerative diseases such as osteoarthritis (OA), rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE). Inhibition of leptin signalling showed to have protective effects in these diseases showing the key role of leptin in cartilage degeneration.

Background: Osteoarthritis (OA) is the most common joint disorder in the USA, and knee OA has the highest prevalence. Inflammation and decrease in vascularization are key factors in the degeneration of articular cartilage and the associated pain and decrease in function. To combat this process, the use of biologics including umbilical cord-derived Wharton's Jelly (UC-derived WJ) has grown. UC-derived WJ contains large quantities of regenerative factors, including growth factors (GFs), cytokines (CKs), hyaluronic acid (HA), and extracellular vesicles (EVs). The proposed study evaluates the safety and efficacy of intraarticular injection of UC-derived WJ for treatment of knee OA symptoms., Methods and Analysis: This is a non-randomized, open-label, multi-center, prospective study in which the safety and efficacy of intraarticular UC-derived WJ in patients suffering from grade II/III OA will be assessed. Twelve patients with grade II/III OA who meet the inclusion and exclusion criteria will be recruited for this study which will be conducted at up to two sites within the USA. The participants will be followed for 1 s. Participants will be assessed using the Numeric Pain Rating Scale (NPRS), Knee Injury and Osteoarthritis Outcome Score (KOOS), 36-item short form survey (SF-36), Single Assessment Numeric Evaluation (SANE), physical exams, plain radiography, and Magnetic Resonance Observation of Cartilage Repair Tissue (MOCART) score for improvements in pain, satisfaction, function, and cartilage regeneration., Discussion: This prospective study will contribute to the limited amount of data on UC-derived WJ, particularly with regard to its safety and efficacy. The outcomes from this study will also lay the groundwork for a large placebo-controlled trial of intraarticular UC-derived WJ for symptomatic knee OA., Trial Registration: ClinicalTrials.gov NCT04719793 . Registered on 22 January 2021.

Objective: Clinical trials for osteoarthritis (OA), the leading cause of global disability, are unable to pinpoint the early, potentially reversible disease with clinical technology. Hence, disease-modifying drug candidates cannot be tested early in the disease. To overcome this obstacle, we asked whether early OA-pathology detection is possible with current clinical technology., Methods: We determined the relationship between two sensitive early OA markers, atomic force microscopy (AFM)-measured human articular cartilage (AC) surface stiffness, and location-matched superficial zone chondrocyte spatial organizations (SCSOs), asking whether a significant loss of surface stiffness can be detected in early OA SCSO stages. We then tested whether current clinical technology can visualize and accurately diagnose the SCSOs using an approved probe-based confocal laser-endomicroscope and a random forest (RF) model., Results: We demonstrated a correlation between AC surface stiffness and the SCSO (r rm  = -0.91; 95%CI: -0.97, -0.73), and an extensive loss of surface stiffness specifically in those ACs with early OA-typical SCSO (95%CIs: string SCSO: 269-173 kPa, double string SCSO: 77-46 kPa). This established the SCSO as a visualizable, functionally relevant surrogate marker of early OA AC surface pathology. Moreover, SCSO-based stiffness discrimination worked well in each patient's AC. We then demonstrated feasibility of visualizing the SCSO by clinical laser-endomicroscopy and, importantly, accurate SCSO diagnosis using RF., Conclusion: We present the proof-of-concept of early OA-pathology detection with available clinical technology, introducing a future-oriented, AI-supported, non-destructive quantitative optical biopsy for early disease detection. Operationalizing SCSO recognition, this approach allows testing for correlations between local tissue architectures with other experimental and clinical read-outs, but needs clinical validation and a larger sample size for defining diagnostic thresholds., (Copyright © 2020 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Introduction: To evaluate the clinical efficacy of arthroscopic therapy with infrapatellar fat pad cell concentrates in treating knee cartilage lesions, we conducted a prospective randomized single-blind clinical study of controlled method., Methods: Sixty cases from Shanghai Changzheng Hospital from April 2018 to December 2019 were chosen and randomly divided into 2 groups equally. Patients in the experiment group were treated through knee arthroscopy with knee infrapatellar fat pad cell concentrates containing mesenchymal stromal cells, while patients in the control group were treated through regular knee arthroscopic therapy. VAS and WOMAC scores were assessed at pre-operation, and 6 weeks, 12 weeks, 6 months, and 12 months after intervention. MORCART scores were assessed at pre-operation and 12 months after intervention., Results: Twenty-nine cases in the experiment group and 28 cases in the control group were followed up. No significant difference in VAS, WOMAC, and MOCART scores were found between the two groups before surgery (P > 0.05). The WOMAC total and WOMAC function scores of the experiment group were significantly lower than those of the control group 6 months and 12 months after surgery (P < 0.05). The VAS rest and VAS motion scores of the experiment group were found significantly lower than those of the control group 12 months after surgery (P < 0.05). The MOCART scores of the experiment group were found significantly higher compared with the control group 12 months after surgery (P < 0.05). No significant difference in WOMAC stiffness scores were found between the two groups., Conclusions: The short-term results of our study are encouraging and demonstrate that knee arthroscopy with infrapatellar fat pad cell concentrates containing mesenchymal stromal cells is safe and provides assistance in reducing pain and improving function in patients with knee cartilage lesions., Trial Registration: ChiCTR1800015379. Registered on 27 March 2018, http://www.chictr.org.cn/showproj.aspx?proj=25901 .

Background: Evaluating of the articular cartilage status of the distal humeral epiphysis is difficult. Ultrasound imaging of the elbow is increasingly being used to confirm the integrity of the articular cartilage of minimally displaced lateral humeral condyle fractures in children with minimally displaced fractures. The aims of this study were to assess the correlations between ultrasound and arthrography findings for predicting the integrity of the cartilage hinge and to describe the utility of ultrasound in determining the need for pre-treatment., Methods: Thirty-nine patients with minimally displaced lateral humeral condyle fractures who underwent ultrasound and arthrography examinations before surgery from May 2018 to December 2019 were included in this study. Ultrasound and arthrography predictors of the cartilage hinge status were independently measured. The ultrasound and arthrography results were compared., Results: The mean displacement of the fractures was 3.1 mm (range, 2.0~5.0 mm). Arthrography showed incomplete fractures in 24 patients (61.5%) and complete fractures in 15 patients (38.5%). Ultrasound showed incomplete fractures in 25 patients (64.1%) and complete fractures in 14 patients (35.9%). The ultrasound and arthrography results of the integrity of the articular surface were consistent in 92.3% of the cases, including 23 that were predicted to have an intact articular surface and 13 that were predicted to have an incongruity articular surface. There was no correlation between the displacement and the fracture appearing complete on the ultrasound scan. The Pearson coefficient between ultrasound and arthrography for assessing the integrity of the articular surface was 0.837., Conclusions: Ultrasound and arthrography assessments of the integrity of the cartilage hinge status appear to be highly consistent. Ultrasound can be used as a complementary tool with arthrography to predict the integrity of the cartilage hinge status in children with minimally displaced lateral humeral condyle fractures., Level of Evidence: Prospective study; level II.

Objective: Cartilage health is maintained in response to a range of mechanical stimuli including compressive, shear and tensile strains and associated alterations in osmolality. The osmotic-sensitive ion channel Transient Receptor Potential Vanilloid 4 (TRPV4) is required for mechanotransduction. Mechanical stimuli inhibit interleukin-1β (IL-1β) mediated inflammatory signalling, however the mechanism is unclear. This study aims to clarify the role of TRPV4 in this response., Design: TRPV4 activity was modulated glycogen synthase kinase (GSK205 antagonist or GSK1016790 A (GSK101) agonist) in articular chondrocytes and cartilage explants in the presence or absence of IL-1β, mechanical (10% cyclic tensile strain (CTS), 0.33 Hz, 24hrs) or osmotic loading (200mOsm, 24hrs). Nitric oxide (NO), prostaglandin E 2 (PGE 2 ) and sulphated glycosaminoglycan (sGAG) release and cartilage biomechanics were analysed. Alterations in post-translational tubulin modifications and primary cilia length regulation were examined., Results: In isolated chondrocytes, mechanical loading inhibited IL-1β mediated NO and PGE 2 release. This response was inhibited by GSK205. Similarly, osmotic loading was anti-inflammatory in cells and explants, this response was abrogated by TRPV4 inhibition. In explants, GSK101 inhibited IL-1β mediated NO release and prevented cartilage degradation and loss of mechanical properties. Upon activation, TRPV4 cilia localisation was increased resulting in histone deacetylase 6 (HDAC6)-dependent modulation of soluble tubulin and altered cilia length regulation., Conclusion: Mechanical, osmotic or pharmaceutical activation of TRPV4 regulates HDAC6-dependent modulation of ciliary tubulin and is anti-inflammatory. This study reveals for the first time, the potential of TRPV4 manipulation as a novel therapeutic mechanism to supress pro-inflammatory signalling and cartilage degradation., (Copyright © 2020 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Objective: To determine performance and repair kinetics of the ChonDux hydrogel scaffold for treating focal articular cartilage defects in the knee over 24 months., Design: This assessor-blinded trial evaluates ChonDux hydrogel scaffold implantation in combination with microfracture in 18 patients across 6 sites. Male and female patients 18 to 65 years of age with full-thickness femoral condyle defects 2 to 4 cm 2 in area were enrolled. Eligible patients received ChonDux treatment followed by rehabilitation. Defect volume fill was evaluated after 3, 6 (primary outcome), 12, 18, and 24 months by assessor blinded magnetic resonance imaging (MRI) analysis. Secondary outcomes were T2-weighted MRI relaxation time and patient surveys via visual analogue scale (VAS) pain and International Knee Documentation Committee (IKDC) knee function scoring., Results: ChonDux maintained durable tissue restoration over 24 months with final defect percent fill of 94.2% ± 16.3% and no significant loss of fill volume at any time points. Tissues treated with ChonDux maintained T2 relaxation times similar to uninjured cartilage between 12 and 24 months. VAS pain scoring decreased between 1 and 6 weeks, and IKDC knee function scores improved by approximately 30.1 with ChonDux over 24 months., Conclusion: ChonDux treatment is a safe adjunct to microfracture therapy and promotes stable restoration of full thickness articular cartilage defects for at least 24 months.

Water, collagen, and proteoglycans determine articular cartilage functionality. If altered, susceptibility to premature degeneration is increased. This study investigated the effects of enzymatic proteoglycan depletion on cartilage functionality as assessed by advanced Magnetic Resonance Imaging (MRI) techniques under standardized loading. Lateral femoral condylar cartilage-bone samples from patients undergoing knee replacement (n = 29) were serially imaged by Proton Density-weighted and T1, T1ρ, T2, and T2* mapping sequences on a clinical 3.0 T MRI scanner (Achieva, Philips). Using pressure-controlled indentation loading, samples were imaged unloaded and quasi-statically loaded to 15.1 N and 28.6 N, and both before and after exposure to low-concentrated (LT, 0.1 mg/mL, n = 10) or high-concentrated trypsin (HT, 1.0 mg/mL, n = 10). Controls were not treated (n = 9). Responses to loading were assessed for the entire sample and regionally, i.e. sub- and peri-pistonally, and zonally, i.e. upper and lower sample halves. Trypsin effects were quantified as relative changes (Δ), analysed using appropriate statistical tests, and referenced histologically. Histological proteoglycan depletion was reflected by significant sub-pistonal decreases in T1 (p = 0.003) and T2 (p = 0.008) after HT exposure. Loading-induced changes in T1ρ and T2* were not related. In conclusion, proteoglycan depletion alters cartilage functionality and may be assessed using serial T1 and T2 mapping under loading.

Objective: To evaluate effects of a common CT contrast agent (iohexol) on the mechanical behaviors of cartilage and meniscus., Methods: Indentation responses of juvenile bovine cartilage and meniscus were monitored following exposure to undiluted contrast agent (100% CA), 50% CA/water, 50% CA/Phosphate Buffered Saline (PBS) or PBS alone, and during re-equilibration in PBS. The normalized peak force (F pk ¯), effective osmotic strain (ε osm ), and normalized effective contact modulus (E c ¯) were calculated for every cycle, with time constants determined for both exposure and recovery via mono- or biexponential fits to F pk ¯., Results: All cartilage CA groups exhibited long-term increases in F pk ¯ following exposure, although the hyperosmolal 100% CA and 50% CA/PBS groups showed an initial transient decrease. Meniscus presented opposing trends, with decreasing F pk ¯ for all CA groups. Re-equilibration in PBS for 1hr after exposure to 100% CA produced recovery to baseline F pk ¯ in cartilage but not in meniscus, and extended tests indicated that meniscus required ∼2.5 h to recover halfway. E c ¯ increased with CA exposure time for cartilage but decreased for meniscus, suggesting an increased effective stiffness for cartilage and decreased stiffness for meniscus. Long-term changes to ε osm in both tissues were consistent with changes in E c ¯., Conclusion: Exposure to iohexol solutions affected joint tissues differentially, with increased cartilage stiffness, likely relating to competing hyperosmotic and hypotonic interactions with tissue fixed charges, and decreased meniscus stiffness, likely dominated by hyperosmolarity. These altered tissue mechanics could allow non-physiological deformation during ambulatory weight-bearing, resulting in an increased risk of tissue or cell damage., (Copyright © 2020 Osteoarthritis Research Society International. Published by Elsevier Ltd. All rights reserved.)

Osteoarthritis (OA) is associated with cartilage breakdown, brought about by ADAMTS-5 mediated aggrecan degradation followed by MMP-derived aggrecan and type II collagen degradation. We investigated a novel anti-ADAMTS-5 inhibiting Nanobody ® (M6495) on cartilage turnover ex vivo. Bovine cartilage (BEX, n = 4), human osteoarthritic - (HEX, n = 8) and healthy-cartilage (hHEX, n = 1) explants and bovine synovium and cartilage were cultured up to 21 days in medium alone ( w / o ), with pro-inflammatory cytokines (oncostatin M (10 ng/mL) + TNFα (20 ng/mL) (O + T), IL-1α (10 ng/mL) or oncostatin M (50 ng/mL) + IL-1β (10 ng/mL)) with or without M6495 (1000-0.46 nM). Cartilage turnover was assessed in conditioned medium by GAG (glycosaminoglycan) and biomarkers of ADAMTS-5 driven aggrecan degradation (huARGS and exAGNxI) and type II collagen degradation (C2M) and formation (PRO-C2). HuARGS, exAGNxI and GAG peaked within the first culture week in pro-inflammatory stimulated explants. C2M peaked from day 14 by O + T and day 21 in co-culture experiments. M6495 dose dependently decreased huARGS, exAGNxI and GAG after pro-inflammatory stimulation. In HEX C2M was dose-dependently reduced by M6495. M6495 showed no effect on PRO-C2. M6495 showed cartilage protective effects by dose-dependently inhibiting ADAMTS-5 mediated cartilage degradation and inhibiting overall cartilage deterioration in ex vivo cartilage cultures.

Objective: Sympathetic blocks are used as an adjunct for pain management in the treatment of orthopedic and traumatic conditions. Stellate ganglion (ganglion stellatum) provides sympathetic innervation of the head, neck and cervicothoracic regions, and upper extremities. No study was found in the literature investigating the effects of stellate ganglion block performed in the upper extremity, on blood supply to bone, density, vascularization, and bone metabolism. Therefore, the objective of this study was to investigate the effects of stellate ganglion block on healing of closed forearm fractures that were induced in rats. Material and Methods . A total of 42 Wistar albino rats weighing between 398 and 510 g were used in this study. The rats were randomly divided into 2 groups with one group treated with stellate ganglion and the other included as the control group. In each 2 groups, a closed forearm fracture was created, confirmed with X-ray, and then stabilized by splint application. The forearm bones were examined with X-ray views on the same day and were then decalcified., Results: When histological findings of the fracture region were examined, predominantly cartilage and less woven bone were found in 7 rats, equally distributed cartilage and immature bone in 14 rats, and predominantly imitation bone and less cartilage formation in 21 rats. In the control group, the agreement between the 1st and 2nd orthopedists for the radiological evaluation of bone formation was moderate., Conclusion: The group administered stellate ganglion block showed a more significant fracture healing., Competing Interests: The authors declare no conflict of interest regarding the present study., (Copyright © 2020 Hasan Kizilay et al.)

The purpose of this study was twofold. Firstly, we proposed a measurement protocol for the atomic force microscopy (AFM) method to determine the nanomechanical properties of articular cartilage in experimental osteoarthritis in rabbits. Then, we verified if mechanical properties can be evaluated with AFM shortly after platelet-rich plasma (PRP) injection. We hypothesized that the modulus determined by AFM indentation experiments could be utilized as a progressive disease marker during the treatment of osteoarthritis. The rabbits were equally divided into three groups of six: control (group 1); injections of saline (0.5 mL) and 10% surgical talc (Talcum Pharmaceutical ® , Minsk, Belarus) were delivered into the right knee under the patella (group 2 and 3); and PRP was injected into the right knee (group 3). In group 2, the arithmetic average of absolute values (Ra) change was a 25% increase; the maximum peak height (Rp) increased by over 102%, while the mean spacing between local peaks (S) increased by 28% ( p < 0.05). In group 3, Ra increased by 14% and Rp increased by 32%, while S decreased by 75% ( p < 0.05). The Young's modulus of the surface layers decreased by 18% as a result of induced model of osteoarthritis (IMO) ( p < 0.05), and it increased by 9% ( p < 0.05) as a result of PRP therapy, which means that the mechanical properties of cartilage were partially recovered. This research demonstrates that Young's modulus utilized on a nanometer scale has potential to be a progressive disease marker during the treatment of osteoarthritis.

Objective: To determine the applicability of a minimally invasive diagnostic device to evaluate the quality of articular cartilage following autologous (OAT) and allogeneic (OCA) osteochondral graft transplantation in goat model., Design: OAT grafts were harvested from lateral femoral condyles (LFCs) and transplanted into osteochondral defects created in medial femoral condyles (MFCs) of contralateral knees. OCA grafts were transplanted into MFC condyles after in vitro storage. Autologous platelet-rich plasma (PRP) was administered intraarticularly after the surgery and at 1 and 2 months postoperatively. OAT and OCA grafts were evaluated macroscopically (Oswestry arthroscopy score [OAS]), electromechanically (quantitative parameter, QP), and histologically (O'Driscoll score, safranin O staining intensity) at 3 and 6 months after transplantation. Results were compared with preoperative graft evaluation., Results: Transplanted cartilage deteriorated within 6 months in all groups. Cartilage quality was better retained in OAT group compared with a decline in OCA group. QP and OAS scores were comparable in OAT and OCA groups at 3 months, but superior in OAT group at 6 months, according to all the methods applied. PRP injections significantly improved QP and OAS score at 6 months compared with 3 months in OAT group. QP moderately correlated with OAS, O'Driscoll score, and safranin O staining intensity., Conclusions: Grafts did not retain preoperative quality parameters at 6 months follow-up; however, OAT were superior to OCA grafts. PRP may have a beneficial effect on macroscopic and electromechanical properties of cartilage; however, histological improvement is yet to be proved. Electromechanical diagnostic device enables reliable assessment of transplanted cartilage.

Objective: The purpose of this study was to assess potential correlations between the mental component summary of the Short Form-12 (SF-12 MCS), patient characteristics or lesion morphology, and preoperative self-assessed pain and function scores in patients undergoing autologous chondrocyte implantation (ACI)., Design: A total of 290 patients underwent ACI for symptomatic cartilage lesions in the knee. One hundred and seventy-eight patients were included in this study as they completed preoperative SF-12, Knee injury and Osteoarthritis Outcome Score (KOOS), Tegner, Lysholm, and International Knee Documentation Committee (IKDC) scores. Age, sex, smoker status, body mass index, Worker's Compensation, previous surgeries, concomitant surgeries, number of defects, lesion location in the patella, and total defect size were recorded for each patient. Pearson's correlation and multivariate regression models were used to distinguish associations between these factors and preoperative knee scores., Results: The SF-12 MCS showed the strongest bivariate correlation with all KOOS subgroups ( P < 0.001) (except KOOS Symptom; P = 0.557), Tegner ( P = 0.005), Lysholm ( P < 0.001), and IKDC scores ( P < 0.001). In the multivariate regression models, the SF-12 MCS showed the strongest association with all KOOS subgroups ( P < 0.001) (except KOOS Symptom; P = 0.91), Lysholm ( P = 0.001), Tegner ( P = 0.017), and IKDC ( P < 0.001)., Conclusion: In patients with symptomatic cartilage defects of the knee, preoperative patient mental health has a strong association with self-assessed pain and functional knee scores. Further studies are needed to determine if preoperative mental health management can improve preoperative symptoms and postoperative outcomes.

Mouse models of osteoarthritis and cartilage degeneration are important and powerful tools for investigating the molecular mechanisms of the disease pathology. Because of the vast number of genetically modified mouse models that are available for research, the ability to use these models is particularly attractive for the mechanobiologic interactions in the pathogenesis of osteoarthritis. However, the very small scale of mouse articular cartilage, where the healthy tissue is only 80 µm in thickness, poses challenges in quantifying mechanical characteristics of the tissue. We introduce here a novel approach that combines experimental and analytical methods to quantify the nuanced mechanical changes during cartilage degeneration at this scale. Cyclic reference point indentation is used to directly test the murine articular cartilage to obtain the force-deformation and the phase-shift characteristics of the tissue. The cartilage zonal thicknesses are confirmed from histology. These data are then fitted to a parallel spring model to determine the depth-dependent tissue stiffness and modulus. Using this approach, we investigated the effects of trypsin degradation on the zonal mechanical behavior of mouse articular cartilage. We observe a decline of the superficial zone stiffness coupled with the loss of the superficial layer. Subsequent degradation by trypsin allowed the identification of middle- and deep- zone properties. Taken together, this approach can be a useful tool for understanding the disease mechanisms of cartilage homeostasis and degeneration, and for monitoring of therapies for osteoarthritis.

Background: Focal cartilage defects (FCDs) in the knee joint has a high prevalence. A broad range of treatment options exists for symptomatic patients. Knowledge of patient compensation claims following surgical treatment of FCDs is missing. The purpose of this study is to evaluate compensation claims filed to the Scandinavian registries for patient compensation following treatment of FCDs in the knee joint from 2010 to 2015 and identify possible areas of improvement., Methods: A cross-sectional study design was used to obtain all complaints following surgical treatment of FCDs from the Scandinavian registries from 2010 to 2015. Data such as age, gender, type of treatment, type of complaint, reason of verdict and amount of compensation were collected and systematically analyzed., Results: 103 patients filed a compensation claim. 43 had received debridement (41.7%), 54 microfracture (MF) (52.4%), 3 mosaicplasty (2.9%) and 3 autologous chondrocyte implantation (ACI) (2.9%). Of the 103 claims, 36 were granted (35%). 21 following debridement (58.3%), 13 after MF (36.1%), 1 following mosaicplasty (2.8%) and 1 after ACI (2.8%). The most common reason for complaint was infection (22.1%), of which 89% were granted. The average compensation was €24.457 (range €209 - €458.943)., Conclusion: Compensation claims following surgical treatment of knee cartilage injuries in Scandinavia are rare. Establishing nationwide cartilage registries can add further knowledge on this troublesome disease.

Background: This study aimed to evaluate the effects of vitamin D deficiency on the functional outcomes following a high tibial osteotomy (HTO)., Methods: Clinical data of 209 patients (327 knees) who underwent HTO done by a single surgeon were retrospectively registered for the study. Ninety-four patients (94 knees) who underwent HTO were analyzed. Patients were assigned into two groups according to their preoperative serum vitamin D levels (D- Deficiency and S- Sufficient); < 20 ng/ml (group D, N = 48) and ≥ 20 ng/ml (group S, N = 46) respectively. A subjective form of International Knee Documentation Committee (IKDC) score, mechanical alignment, and cartilage status before and 1 year following HTO were studied between groups., Results: The mean postoperative IKDC score was significantly higher in group S (p = 0.012). Moreover, the difference of IKDC score between pre- and post- HTO was also significantly higher in group S (p = 0.006). Preoperative vitamin D level and IKDC score did not show a significant correlation. Serum vitamin D level was found to be moderately correlated to postoperative IKDC score (r = 0.342 and, p = 0.001). A moderately positive correlation between serum vitamin D level and improvement of IKDC score following osteotomy was appreciated (r = 0.381 and, p < 0.001)., Conclusion: Patients with vitamin D deficiency had less satisfactory functional outcomes within 1 year from HTO surgery. Our results suggest that preoperative serum vitamin D level is one of the factors affecting the outcome after HTO. We recommended analyzing serum vitamin D levels as part of the routine workup in patients undergoing HTO.

Objective: The present study aimed to investigate whether experimentally induced lumbar facet-joint OA lead to degenerative changes and enhanced SP expression within the ipsilateral neurosegmentally linked tibiofemoral cartilage., Methods: Adult male Sprague-Dawley rats were assigned to left side L5-L6 facet mechanical compression injury (surgery) ( n = 6), L5-L6 facet exposure with no compression (sham) ( n = 5), or naïve (no surgery) ( n = 4) groups. The morphology of the tibiofemoral articular cartilage was assessed using a modified Mankin scoring system. Immunohistochemistry was used to examine the density of chondrocytes stained positive for SP (cells/cm 2 ) in the ipsilateral tibiofemoral cartilage at 28 days postintervention., Results: Tibiofemoral cartilage in the surgery group showed consistent loss of superficial zone chondrocytes, mild roughening of the articular surface and occasional chondrocyte clusters as well as a greater density of SP mainly in the superficial cartilage zone compared with sham and naïve groups, although they also had a basic SP-expression., Conclusion: Our results support the hypothesis that neurogenic mechanisms may mediate the spread of SP to neurosegmentally linked heterologous joints affecting the distal cartilage homeostasis. These findings contribute additional insight into the potential role of neurogenic inflammation with implications in the pathophysiology of chronic inflammatory joint disease and OA.

Objective: To explore the effects of patellectomy on the bony and cartilaginous morphology of the trochlear groove in growing rabbits., Methods: Forty-eight 4-week-old New Zealand white rabbits were randomly assigned to two groups. The control group underwent a sham surgical procedure, whereas the patellectomy group underwent patella excision surgery. Half of the rabbits in each group were sacrificed 3 months postoperatively; the rest were sacrificed 6 months postoperatively. Hematoxylin and eosin staining was performed on collected samples. Measurements included the bony and cartilaginous sulcus angles of the trochlear groove. In addition, the thickness of the articular cartilage at the deepest sulcus position (central thickness) and at the mid-position of the medial and lateral facets was measured and compared between groups., Results: Three months after surgery, histological images revealed significant differences between the control group and the patellectomy group in cartilaginous sulcus angle (144.2° ± 1.5° vs 151.9° ± 2.4°, respectively; P < 0.001). No obvious difference in bony sulcus angle was found between the groups. Six months after surgery, significant between-group differences were observed in cartilaginous sulcus angle (136.3° ± 2.5° in control group vs 160.7° ± 3.0° in patellectomy group, P < 0.001) and bony sulcus angle (136.2° ± 2.2° in control group vs 160.4° ± 2.6° in patellectomy group, P < 0.001). However, there were no significant intra-group differences between cartilaginous and bony sulcus angles in either group. Three months after surgery, significant between-group differences were detected in articular cartilage thickness at the three different positions (medial facet: 324.3 ± 14.0 μm in control group vs 391.7 ± 98.8 μm in patellectomy group, P = 0.029; central position: 362.1 ± 13.6 μm in control group vs 730.3 ± 76.8 μm in patellectomy group, P < 0.001; lateral facet: 324.6 ± 12.7 μm in control group vs 358.5 ± 38.7 μm in patellectomy group, P = 0.009). No between-group differences in cartilage thickness were found at 6 months., Conclusions: Abnormal mechanical stress (patellectomy) during a rabbit's development can cause flattening of the femoral trochlear cartilage, followed by changes in the subchondral osseous layer. Abnormal mechanical stress is a crucial factor in the development of trochlear groove dysplasia., (© 2020 The Authors. Orthopaedic Surgery published by Chinese Orthopaedic Association and John Wiley & Sons Australia, Ltd.)

Aim: This study was performed to assess the effect of the phonophoretic application of a nanoemulsion incorporating glucosamine and chondroitin sulfate (NANO-CG) associated with kinesiotherapy on the reduction of pain and stiffness in knee chondropathy. Materials & methods: NANO-CG was tested in vitro and in vivo prior to being applied in a randomized and controlled clinical trial. Results: Cell viability and hen's egg test-chorionallantonic membrane tests indicated the NANO-CG is safe for topical application. Permeation tests showed NANO-CG enhances drug permeation through the skin. There was no statistical significance between treated groups in this preliminary study, however, pain reduction and complete recovery of articular cartilage were observed in some patients treated with NANO-CG. Conclusion: We demonstrate that NANO-CG may be a promising candidate for the therapy of knee chondropathy.

Background: Obesity increases knee osteoarthritis (OA) risk through metabolic, inflammatory, and biomechanical factors, but how these systemic and local mediators interact to drive OA pathology is not well understood. We tested the effect of voluntary running exercise after chronic diet-induced obesity on knee OA-related cartilage and bone pathology in mice. We then used a correlation-based network analysis to identify systemic and local factors associated with early-stage knee OA phenotypes among the different diet and exercise groups., Methods: Male C57BL/6J mice were fed a defined control (10% kcal fat) or high fat (HF) (60% kcal fat) diet from 6 to 37 weeks of age. At 25 weeks, one-half of the mice from each diet group were housed in cages with running wheels for the remainder of the study. Histology, micro computed tomography, and magnetic resonance imaging were used to evaluate changes in joint tissue structure and OA pathology. These local variables were then compared to systemic metabolic (body mass, body fat, and glucose tolerance), inflammatory (serum adipokines and inflammatory mediators), and functional (mechanical tactile sensitivity and grip strength) outcomes using a correlation-based network analysis. Diet and exercise effects were evaluated by two-way analysis of variance., Results: An HF diet increased the infrapatellar fat pad size and posterior joint osteophytes, and wheel running primarily altered the subchondral cortical and trabecular bone. Neither HF diet nor exercise altered average knee cartilage OA scores compared to control groups. However, the coefficient of variation was ≥25% for many outcomes, and some mice in both diet groups developed moderate OA (≥33% maximum score). This supported using correlation-based network analyses to identify systemic and local factors associated with early-stage knee OA phenotypes. In wheel-running cohorts, an HF diet reduced the network size compared to the control diet group despite similar running distances, suggesting that diet-induced obesity dampens the effects of exercise on systemic and local OA-related factors. Each of the 4 diet and activity groups showed mostly unique networks of local and systemic factors correlated with early-stage knee OA., Conclusion: Despite minimal group-level effects of chronic diet-induced obesity and voluntary wheel running on knee OA pathology under the current test durations, diet and exercise substantially altered the relationships among systemic and local variables associated with early-stage knee OA. These results suggest that distinct pre-OA phenotypes may exist prior to the development of disease., (© 2019 Published by Elsevier B.V. on behalf of Shanghai University of Sport.)

Objectives: Knee joint distraction (KJD) has been evaluated as a joint-preserving treatment to postpone total knee arthroplasty in knee osteoarthritis patients in three clinical trials. Since 2014 the treatment is used in regular care in some hospitals, which might lead to a deviation from the original indication and decreased treatment outcome. In this study, baseline characteristics, complications and clinical benefit are compared between patients treated in regular care and in clinical trials., Methods: In our hospital, 84 patients were treated in regular care for 6 weeks with KJD. Surgical details, complications, and range of motion were assessed from patient hospital charts. Patient-reported outcome measures were evaluated in regular care before and one year after treatment. Trial patients (n = 62) were treated and followed as described in literature., Results: Patient characteristics were not significantly different between groups, except for distraction duration (regular care 45.3±4.3; clinical trials 48.1±8.1 days; p = 0.019). Pin tract infections were the most occurring complication (70% regular care; 66% clinical trials), but there was no significant difference in treatment complications between groups (p>0.1). The range of motion was recovered within a year after treatment for both groups. WOMAC questionnaires showed statistically and clinically significant improvement for both groups (both p<0.001 and >15 points in all subscales) and no significant differences between groups (all differences p>0.05). After one year, 70% of patients were responders (regular care 61%, trial 75%; p = 0.120). Neither regular care compared to clinical trial, nor any other characteristic could predict clinical response., Conclusions: KJD as joint-preserving treatment in clinical practice, to postpone arthroplasty for end-stage knee osteoarthritis patient below the age of 65, results in an outcome similar to that thus far demonstrated in clinical trials. Longer follow-up in regular care is needed to test whether also long-term results remain beneficial and comparable to trial data., Competing Interests: FPJG Lafeber is co-founder, co-director, and shareholder of ArthroSave BV, a medical device company involved in marketing a user-friendly knee joint distraction device. This does not alter our adherence to PLOS ONE policies on sharing data and materials.

Purpose: The main goal of this article was the analysis of the changes of mechanical properties, thickness and histology of the cartilage in different regions of the femur head in advanced stage of the osteoarthritis., Methods: The study material consisted of cylindrical specimens (9.7 mm) prepared form proximal epiphysis of the human femur bone after hip arthroplasty. The thickness was determined from the reconstruction of the specimen from microtomography (SkyScan 1172, Bruker®) images. Mechanical properties of the cartilage tissue were identified in static indentation test conducted the use of MTS® Synergie 100 testing machine. Histological study enabled us to determine cartilage total thickness as well as location and orientation of the collagen fibers., Results: Depending on the region of the head, the cartilage tissue thickness was in the range (0.74-2.23 mm). The lowest thickness values were obtained for the R5 region and the lowest for R4. Samples from R1-R4 regions differ by 24%. Measurements of cartilage tissue indentation, determined with the help of Hayes' formula, showed that the values of mechanical parameters in regions R1, R2, R3 and R5 have similar values (the difference between them is about 5.5%). Region R4, which had the smallest thickness, also had the lowest values of mechanical parameters., Conclusions: Using κ coefficients, proposed by Hayes, enabled us to obtain similar values of mechanical parameters in the regions R1, R2, R3 and R5, despite differences in cartilage tissue thickness. The R4 region, which had the weakest mechanical parameters, was characterized by the strongest reduction of the articular cartilage tissue, which was accompanied by an unformed mass of cartilage residue originating from the abraded surface and bursa fluid.

Objective: Abnormal joint movement is associated with osteoarthritis (OA). Previous studies using the controlling abnormal joint movement (CAJM) model of OA reported delayed cartilage degeneration; however, none of them focused on gait performance and the localization of matrix metalloproteinase 13 (MMP13) and tissue inhibitor of metalloproteinase-1 (TIMP-1) in chondrocytes. Therefore, we aimed to investigate the effect of controlling abnormal joint movement on gait performance and the localization of MMP13 and TIMP-1, using kinematic and histological analyses., Design: Rats were assigned to 2 groups: anterior cruciate ligament transection (ACL-T) group and CAJM group ( n = 5/group); contralateral hind limbs of ACL-T rats were designated as intact. After 1, 2, and 4 weeks, step length was analyzed, and after 2, 4, and 8 weeks, Safranin O-Fast Green staining and immunohistochemical staining for MMP13 and TIMP-1 were performed., Results: Step length did not differ significantly between the groups. However, degeneration of articular cartilage was higher in the ACL-T group than in the intact group ( P < 0.05). There was no significant difference in the CAJM group at all time points. Immunohistochemical analysis of the MMP13/TIMP-1 relationship revealed a significant increase in the expression ratio of MMP13 after 4 weeks in the ACL-T group compared to the CAJM group ( P < 0.05)., Conclusions: Controlling abnormal joint movement may reduce mechanical stress owing to kinematic elements of small articulation including joint instability and delayed cartilage degeneration, despite the lack of kinematic change in step length.

Background: Osteoarthritis (OA) affects the articular cartilage and subchondral bone of synovial joints and induces proinflammatory and anti-inflammatory pathway dysregulation, leading to pain. This study evaluated the anti-inflammatory and antiosteoarthritis effects of Alpinia oxyphylla extract (AOE) in vitro and in vivo., Methods: The anti-inflammatory effect of AOE was evaluated in vitro in lipopolysaccharide (LPS)-treated RAW264.7 cells. The antiosteoarthritis effect of AOE was investigated in a monosodium iodoacetate (MIA)-induced rat model of OA. Rats were orally administered AOE (150 mg/kg or 300 mg/kg) or the positive control drug indomethacin (1 mg/kg) 3 days before MIA injection and once daily for 21 days thereafter., Results: AOE significantly decreased the production of nitric oxide (NO, 68.2%), prostaglandin E2 (PGE2, 92.8%), interleukin-1β (IL-1β, 77.2%), interleukin-6 (IL-6, 39.9%), and tumor necrosis factor-alpha (TNF-α, 20.7%) and the activation of extracellular signal-regulated kinase (ERK), Jun N-terminal kinase (JNK) and p38 mitogen-activated protein kinase (MAPK) in LPS-treated RAW264.7 cells at a dose of 100 µg/ml. In addition, AOE attenuated joint pain, suppressed proinflammatory cytokine and mediator production and inhibited cartilage degradation in the MIA-induced rat OA model., Conclusion: These results demonstrate that AOE exerts potent anti-inflammatory effects and may be a useful therapeutic candidate against OA., (Copyright © 2019. Published by Elsevier GmbH.)

Osteoarthritis (OA) is a debilitating, degenerative joint disease characterized by progressive destruction of articular cartilage. Given the poor repair capacity of articular cartilage and the associated local destructive immune/inflammatory responses involving all joint structures, OA frequently ends up as a "whole joint failure" requiring prosthetic replacement. Current pharmacological efforts, belatedly started, mainly aim at symptomatic pain relief, underscoring the need for novel therapeutic schemes designed to modify the course of the disease. Mesenchymal stem cell (MSC)-based therapy has gained significant interest, sparking the design of multiple trials proving safety while providing promising preliminary efficacy results. MSCs possess 'medicinal signaling cell' properties related to their immunomodulatory and anti-inflammatory effects, which induce the establishment of a pro-regenerative microenvironment at the injured tissue. Those trophic effects are paralleled by the long-established chondroprogenitor capacity that can be harnessed to ex vivo fabricate engineered constructs to repair damaged articular cartilage. The present review focuses on these two aspects of the use of MSCs for articular cartilage damage, namely, cell therapy and tissue engineering, providing information on their use criteria, advancements, challenges and strategies to overcome them., (Copyright © 2019 International Society for Cell and Gene Therapy. Published by Elsevier Inc. All rights reserved.)

Traumatic joint injury is known to cause cartilage deterioration and osteoarthritis. In order to study the mechanical mechanism of damage evolution on articular cartilage, taking the fresh porcine articular cartilage as the experimental samples, the creep experiments of the intact cartilages and the cartilages with different depth defect were carried out by using the noncontact digital image correlation technology. And then, the creep constitutive equations of cartilages were established. The results showed that the creep curves of different layers changed exponentially and were not coincident for the cartilage sample. The defect affected the strain values of the creep curves. The creep behavior of cartilage was dependent on defect depth. The deeper the defect was, the larger the strain value was. The built three-parameter viscoelastic constitutive equation had a good correlation with the experimental results and could predict the creep performance of the articular cartilage. The creep values of the microdefective cartilage in the damaged early stage were different from the diseased articular cartilage. These findings pointed out that defect could accelerate the damage of cartilage. It was helpful to study the mechanical mechanism of damage evolution., Competing Interests: The authors declared that they have no conflicts of interest to this work., (Copyright © 2019 Huchen Gong et al.)

Objective: To investigate whether and how a sedentary lifestyle contributes to knee osteoarthritis (OA) incidence and severity., Design: An experiment was conducted using Hartley guinea pigs, an established idiopathic knee OA model. To simulate a sedentary lifestyle, growing animals (n = 18) were housed for 22 weeks in small cages that restricted their mobility, while another group of animals (n = 17) received daily treadmill exercise to simulate moderate physical activity. After the experiment, histological assessments, biochemical assays, and mechanical testing were conducted to compare tibial articular cartilage structure, strength, and degree of OA degeneration between sedentary and physically active animals. Groups were also compared based on body weight and composition, as well as gut microbial community composition assessed using fecal 16S rRNA gene sequencing., Results: Prevalence of knee OA was similar between sedentary and physically active animals, but severity of the disease (cartilage lesion depth) was substantially greater in the sedentary group (P = 0.02). In addition, during the experiment, sedentary animals developed cartilage with lower aggrecan quantity (P = 0.03) and accumulated more body weight (P = 0.005) and visceral adiposity (P = 0.007). Groups did not differ greatly, however, in terms of cartilage thickness, collagen quantity, or stiffness, nor in terms of muscle weight, subcutaneous adiposity, or gut microbial community composition., Conclusions: Our findings indicate that a sedentary lifestyle promotes the development of knee OA, particularly by enhancing disease severity rather than risk of onset, and this potentially occurs through multiple pathways including by engendering growth of functionally deficient joint tissues and the accumulation of excess body weight and adiposity., (Copyright © 2019 Osteoarthritis Research Society International. Published by Elsevier Ltd. All rights reserved.)

Objective: To investigate changes in response to sequential pressure-controlled loading and unloading in human articular cartilage of variable histological degeneration using serial T1ρ mapping., Method: We obtained 42 cartilage samples of variable degeneration from the medial femoral condyles of 42 patients undergoing total knee replacement. Samples were placed in a standardized artificial knee joint within an MRI-compatible whole knee-joint compressive loading device and imaged before (δ 0 ), during (δ ld1 , δ ld2 , δ ld3 , δ ld4 , δ ld5 ) and after (δ rl1 , δ rl2 , δ rl3 , δ rl4 , δ rl5 ) pressure-controlled loading to 0.663 ± 0.021 kN (94% body weight) using serial T1ρ mapping (spin-lock multigradient echo sequence; 3.0T MRI system [Achieva, Philips]). Reference assessment included histology (Mankin scoring) and conventional biomechanics (Tangent stiffness). We dichotomized sample into intact (n = 21) and degenerative (n = 21) based on histology and analyzed data using Mann Whitney, Kruskal Wallis, one-way ANOVA tests and Spearman's correlation, respectively., Results: At δ 0 , we found no significant differences between intact and degenerative samples, while the response-to-loading patterns were distinctly different. In intact samples, T1ρ increases were consistent and non-significant, while in degenerative samples, T1ρ increases were significantly higher (P = 0.004, δ0 vs δld1, δ0 vs δld3), yet undulating and variable. With unloading, T1ρ increases subsided, yet were persistently elevated beyond δ0., Conclusion: Cartilage mechanosensitivity is related to histological degeneration and assessable by serial T1ρ mapping. Unloaded, T1ρ characteristics are not significantly different in intact vs degenerative cartilage, while load bearing is organized in intact cartilage and disorganized in degenerative cartilage., (Copyright © 2019 Osteoarthritis Research Society International. Published by Elsevier Ltd. All rights reserved.)

Objective: To investigate the potential of quantitative susceptibility mapping (QSM) and T2* relaxation time mapping to determine mechanical and structural properties of articular cartilage via univariate and multivariate analysis., Methods: Samples were obtained from a cartilage repair study, in which surgically induced full-thickness chondral defects in the stifle joints of seven Shetland ponies caused post-traumatic osteoarthritis (14 samples). Control samples were collected from non-operated joints of three animals (6 samples). Magnetic resonance imaging (MRI) was performed at 9.4 T, using a 3-D multi-echo gradient echo sequence. Biomechanical testing, digital densitometry (DD) and polarized light microscopy (PLM) were utilized as reference methods. To compare MRI parameters with reference parameters (equilibrium and dynamic moduli, proteoglycan content, collagen fiber angle and -anisotropy), depth-wise profiles of MRI parameters were acquired at the biomechanical testing locations. Partial least squares regression (PLSR) and Spearman's rank correlation were utilized in data analysis., Results: PLSR indicated a moderate-to-strong correlation (ρ = 0.49-0.66) and a moderate correlation (ρ = 0.41-0.55) between the reference values and T2* relaxation time and QSM profiles, respectively (excluding superficial-only results). PLSR correlations were noticeably higher than direct correlations between bulk MRI and reference parameters. 3-D parametric surface maps revealed spatial variations in the MRI parameters between experimental and control groups., Conclusion: Quantitative parameters from 3-D multi-echo gradient echo MRI can be utilized to predict the properties of articular cartilage. With PLSR, especially the T2* relaxation time profile appeared to correlate with the properties of cartilage. Furthermore, the results suggest that degeneration affects the QSM-contrast in the cartilage. However, this change in contrast is not easy to quantify., (Copyright © 2019 The Author(s). Published by Elsevier Ltd.. All rights reserved.)