Search Results (6,307)

Stem cell therapy represents an intrinsic part of regenerative medicine, with expanding applications in orthopedic and musculoskeletal research. Although studies span from small-animal models to early-phase clinical trials, the field remains fragmented, with wide variation in stem cell types, delivery methods, and target tissues. A consolidated overview is needed to inform future directions and bridge the gap between preclinical promise and clinical application. This scoping review synthesized evidence from 500 preclinical and clinical studies, identified through systematic searches and screened in accordance with PRISMA-ScR guidelines. Data were extracted on stem cell type and source, delivery approach, targeted tissue and organ, and disease indication. We found that autologous bone marrow-derived mesenchymal stem cells were the most used, with adipose- and perinatal-derived cells gaining prominence in recent years. Small-animal models such as rats and rabbits predominated, while large-animal and human studies focused mainly on knee osteoarthritis. Intra-articular injection was the principal delivery method across both preclinical and clinical settings. By mapping prevailing practices and emerging trends, this review provides a comprehensive reference for researchers, clinicians, and regulatory stakeholders. It highlights translational pathways, identifies critical gaps, and offers evidence to guide the design of safe, effective, and scalable regenerative therapies in orthopedics. Full article

Background: Arterial hypertension (AH) is a frequent comorbidity in patients with osteoarthritis (OA). Among antihypertensive agents, angiotensin-converting enzyme (ACE) inhibitors, calcium channel blockers (CCBs), angiotensin II receptor blockers (ARBs), and beta-blockers (βBs) have been suggested to influence OA progression and symptomatology. The aim of this study was to assess whether the duration of effectiveness (DE) of viscosupplementation (VS) differs between patients with knee OA who are receiving antihypertensive treatment and those who are not. Methods: This post hoc analysis was conducted using data from a cross-sectional clinical trial (ClinicalTrials.gov Identifier: NCT04988698). The study included consecutive patients with knee OA who came for consultation at the Rheumatology Department and had received intra-articular hyaluronic acid injections within the past three years. The primary outcome was DE, self-reported by patients as the number of weeks of symptom relief. Associations between DE and various factors, including demographics, disease duration, radiographic OA severity (Kellgren–Lawrence grade and affected compartments), comorbidities, OA treatment history, antihypertensive therapy, physical activity level, and prior VS sessions, were analyzed using bivariate and multivariate models. Results: A total of 105 patients (65 women, 149 treated knees) were included. The mean age was 66.1 ± 13.2 years, and the mean body mass index (BMI) was 27.5 kg/m². Thirty-eight percent of patients were receiving antihypertensive treatment (mean number of agents: 1.9; range: 1–4), including CCBs (n = 15), ACE inhibitors (n = 13), ARBs (n = 7), βBs (n = 6), and diuretics (n = 2). The overall mean DE of VS was 48.2 ± 24.8 weeks, with a trend toward longer DE in hypertensive patients compared to non-hypertensive patients (53.1 ± 31.3 vs. 45.4 ± 19.8 weeks, p = 0.06). Bivariate analysis identified significantly longer DE in patients with BMI < 27.5 kg/m² (p = 0.002), Kellgren–Lawrence grade < 4 (p = 0.008), an active lifestyle (p = 0.005), unicompartmental OA (p = 0.01), medial tibiofemoral joint space narrowing (p = 0.046), and fewer than four prior VS sessions (p = 0.02). In multivariate analysis, AH was strongly associated with prolonged DE (p < 0.001), despite AH patients having a higher BMI (29.8 ± 5.5 vs. 25.2 ± 5.2 kg/m², p = 0.001) and being more frequently sedentary (25.5% vs. 13.8%, p = 0.07). A trend toward longer DE was observed in patients treated with βBs and ARBs but not with CCBs or ACE inhibitors. Additional independent predictors of longer DE included BMI < 27.5 kg/m² (p < 0.001), unicompartmental OA (p = 0.02), fewer than four prior VS sessions (p = 0.02), and an active lifestyle (p = 0.027). Conclusions: These findings suggest that antihypertensive treatment may extend the effectiveness of viscosupplementation in knee OA. However, the sample size was insufficient to determine whether specific classes of antihypertensive agents provide greater benefits. Further large-scale, prospective studies are warranted to clarify the potential impact of antihypertensive medications on viscosupplementation outcomes in knee OA. Full article

Osteoarthritis (OA) is a prevalent degenerative joint disease which affects millions of patients across the globe. The infrapatellar fat pad (IPFP) harbors diverse cell types with intricate intercellular interactions. Its mesenchymal stem cells (MSCs) and extracellular vesicles (EVs) possess significant biological functions and hold promising applications in regenerative medicine. IPFP exhibits active secretory capacity, releasing adipokines including leptin and adiponectin, along with various cytokines. Furthermore, it contains a rich neural network playing a crucial role in knee pain perception and sensation. Moreover, IPFP and synovium can be considered an integrated unit, exhibiting interactions both with each other and with cartilage. In imaging applications, IPFP is gaining widespread attention as an emerging biomarker. In clinical practice, the decision to resect or preserve IPFP remains a controversial topic. This article will review the latest research regarding the mechanism of IPFP in OA, and discuss its clinical applications, providing a theoretical basis for the prevention and treatment of OA. Full article

The rehabilitation training of patients with lower limb motor dysfunction highly relies on the precise control of biomimetic knee joint robots. Existing control strategies generally suffer from insufficient control accuracy and weak anti-interference ability, and an optimization plan that balances high precision and strong anti-interference has not yet been formed, which seriously affects the effectiveness of rehabilitation training. In order to improve the control accuracy and anti-interference ability of biomimetic knee joint robots for leg rehabilitation training of patients with lower limb movement disorders, the purpose of this study is to address the performance shortcomings of existing biomimetic knee joint robot control strategies. The goal is to propose a high-precision and strong anti-interference control strategy to provide more reliable rehabilitation support for patients with lower limb movement disorders. Therefore, this article proposes an optimization strategy based on the Spider Bee Algorithm (SWO) combined with fuzzy PID control. Based on a biomimetic knee joint robot model, this study simulates three common pathological states of knee joint ligament injury, meniscus injury, and muscle atrophy in patients, and compares the trajectory tracking and anti-interference performance of PID, fuzzy PID, and SWO fuzzy PID control strategies. The experimental results show that the SWO fuzzy PID control strategy has the best comprehensive performance: the overshoot of knee joint angle control is only 9.7%, and the peak angle error is reduced to 2.1948°; when simulating pathological conditions, the system takes the shortest time to recover stability: 1.068 s for ligament injuries and 0.929 s for meniscus injuries, with maximum response errors below 0.017°. Simulation experiments on healthy subjects showed that the system had a tracking error of ≤5° under two rehabilitation training modes, meeting clinical accuracy requirements, and had good performance in restoring stability under irregular vibration interference. The core contribution of this study is the proposal of the SWO fuzzy PID optimization control strategy, which effectively addresses the shortcomings of existing strategies and significantly improves the control accuracy and anti-interference ability of bionic knee joint robots, providing theoretical support and practical reference for the application of bionic knee joint robots. Full article

Background and Objectives: Medial opening wedge high tibial osteotomy (OWHTO) requires careful management of medial soft-tissue tension to achieve effective decompression and maintain knee stability. While superficial medial collateral ligament (sMCL) release is commonly performed, the role of pes anserinus release remains unclear. This study investigated the effect of pes anserinus release on postoperative pain, clinical outcomes, and medial stability in patients undergoing OWHTO. Materials and Methods: A retrospective analysis was performed on 80 knees (80 patients) that underwent OWHTO between 2012 and 2017. Patients were divided into two groups: Group A (n = 38, sMCL release only) and Group B (n = 42, sMCL + pes anserinus release). Immediate postoperative pain was assessed using visual analog scale (VAS) scores and rescue analgesic use. Clinical outcomes were evaluated with Knee Society Scores (KSSs). Radiographic medial joint opening (MJO) was measured on valgus stress radiographs preoperatively and at one year postoperatively. Results: Group B demonstrated significantly lower VAS pain scores at postoperative days (PODs) 1, 3, 5, 7, and 14 (p < 0.05) and required fewer rescue analgesics (5.5 ± 2.1 vs. 7.6 ± 3.7; p < 0.05). Both groups achieved comparable KSS improvement and radiographic correction (postoperative mechanical femorotibial angle: 2.1° valgus vs. 2.5° valgus). No significant intergroup or intragroup differences were observed in MJO at one-year follow-up (p > 0.05). Conclusions: Combined release of the superficial medial collateral ligament and pes anserinus during medial opening wedge high tibial osteotomy significantly reduces early postoperative pain and improves short-term functional recovery without compromising medial stability or alignment correction, although no significant long-term differences in functional outcomes or radiographic alignment were observed. Full article

This paper presents a data-driven modeling and sensorless angle–torque prediction method for a pneumatic soft bending actuator. The actuator contains no embedded angle or torque sensors; instead, only airflow and pressure sensors located in the external control box (standard components in pneumatic systems) are used during operation. The proposed method, and therefore eliminates the need for onboard sensing and detailed valve hysteresis modeling. Based on the ideal gas law, four continuous, monotonic, and single-valued pneumatic state equations were derived and experimentally validated. As a case study, a pneumatic soft actuator was designed to generate high torque for assisting knee and ankle extension. An experimental setup with multiple sensors collected key data on air mass, internal pressure, actuator torque, and bending angle. These additional sensors were used only during dataset generation. A data-driven modeling approach was developed with training neural networks to generate four fitting functions to predict actuator behavior, including equations for angle and torque prediction. An angle-sensorless closed-loop control simulation study, incorporating a PID controller, a proportional valve delay block, and torque prediction, demonstrated the controllability and computational feasibility of the proposed model as well as the actuator’s effectiveness in supporting additional weight during squat-to-stand motion. Full article

Background: Microgravity exposure causes muscle atrophy and bone density loss in astronauts. Traditional motion analysis provides estimations of external kinematics and muscle activation, but cannot resolve internal load. OpenSim closes this gap by applying musculoskeletal modeling to estimate internal joint mechanics. Methods: In this study, we aimed to develop an OpenSim workflow to estimate joint angles and moments using datasets from two publicly available gait studies: the Politecnico di Milano study (Dataset 1), which includes level-floor walking, walking on heels, walking on toes, and step-down-from-stairs tasks, and Maclean et al.’s walking study in reduced gravities (Dataset 2), which includes four simulated gravity levels (1.0 G, 0.76 G, 0.54 G, and 0.31 G). Marker and ground reaction force (GRF) data, along with participants’ mass, were used to prepare the first three steps of OpenSim’s workflow, including scaling, inverse kinematics (IK), and inverse dynamics (ID). Scripts using MATLAB R2025a (The MathWorks, Inc., Natick, MA, USA) were created to store, normalize, and compare OpenSim outputs with reference data on the right leg. Pearson’s correlation coefficient (PCC) was used to quantify agreement between OpenSim-derived joint angles and moments and the reference data, and root mean square error (RMSE) was used to characterize accuracy. Results: Hip and knee angles showed excellent correlation across both datasets (PCC > 0.974). Ankle angles were more variable, particularly in Dataset 1 (PCC = 0.833; RMSE = 19.797°) compared to Dataset 2 (PCC = 0.995; RMSE = 8.73°). Joint moment correlations were strong for hip and knee (PCC > 0.85), though ankle moments in Dataset 1 exhibited lower correlation (PCC = 0.677) and higher error (0.30 Nm/kg) compared to the high accuracy observed across all joints in Dataset 2. Discussion: We speculate that the lower PCC values and higher RMSE observed for ankle dorsi/plantar flexion angle and moment in Dataset 1 are mainly attributable to differences in shank segment frame definitions between the OpenSim model and the human body model used in Dataset 1. Higher ankle angle RMSEs in Dataset 2 may be due to lower weights assigned to ankle markers in the scaling and IK setup files, resulting in different ankle joint center definitions. Conclusion: In the future, we plan to improve this OpenSim workflow by including additional participants and datasets collected in simulated reduced-gravity environments and by implementing a residual reduction algorithm (RRA) and computed muscle control (CMC) to enable muscle activation estimation. Full article

Knee osteoarthritis is a leading cause of pain and functional limitation in older adults, and exercise is widely recommended as a core component of conservative management; however, the optimal frequency of aerobic and strengthening exercise remains unclear. This cross-sectional study aimed to examine the association between exercise frequency, pain, and functional outcomes in older adults with knee osteoarthritis. Participants aged ≥60 years with a clinical diagnosis of knee osteoarthritis were recruited from a tertiary university hospital in Thailand. Exercise frequency over the previous four weeks was categorized as none, 1–2 times per week, 3–6 times per week, or every day. Outcomes were assessed using the Thai version of the modified Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) and the Brief Pain Inventory. Nonparametric analyses and multivariable regression analyses adjusted for age, body mass index, and comorbidities were performed. A total of 140 participants were included, of whom 68.6% reported engaging in aerobic exercise, and 56.4% performed knee-strengthening exercises. Higher frequency of aerobic exercise was significantly associated with lower pain severity, reduced pain interference, and better WOMAC total and subdomain scores (p < 0.05). A graded association pattern was observed, with the greatest benefits seen in participants performing aerobic exercise 3–6 times per week. No significant associations were identified between knee strengthening exercise frequency and pain and functional outcomes. These findings suggest that frequent aerobic exercise is associated with reduced pain and improved function in older adults with knee osteoarthritis, supporting its role in primary care and rehabilitation management. Full article

This review develops a unified geometric framework for synthesizing global asymptotic laws, termed classical entanglement. The central tool is the entanglement operator, a Minkowski–$L_a$ metric blend that couples asymptotic regimes through an index $a>1$, producing a nonlinear global state whose intermediate region is metrically non-separable and cannot be written as a linear combination of its limits. The framework reveals a universal transition knee whose curvature scales linearly with a, independent of amplitudes or local scales. We show that this geometric mechanism encompasses Orlicz norms, weighted Hölder metrics, and iterated Hölder constructions, the latter being structurally isomorphic to self-similar root approximants. A conceptual “Rosetta Stone” links practitioner terminology, geometric meta-language, and functional-analytic structures, clarifying how classical entanglement unifies empirical blending, metric curvature, and Calderón-type interpolation. Applications to turbulence (Darcy friction factor), fractional dynamics, and scale-dependent diffusion illustrate how classical entanglement provides stable, asymptotically consistent global states across multi-scale systems. Full article

Background: Posterior cruciate ligament reconstruction (PCLR) remains one of the most technically demanding procedures in knee ligament surgery, with complication rates considerably higher than those observed for other arthroscopic procedures. Residual laxity, arthrofibrosis, neurovascular injury, tunnel-related complications, and heterotopic ossification (HO) represent the most frequent adverse events. With increasing surgical volumes and complexity—particularly in multiligament knee injuries (MLKIs)—structured, evidence-based strategies for complication avoidance are essential. The objective of this review is to provide a comprehensive, evidence-based overview of the main complications associated with PCLR and to propose a structured, reproducible protocol for complication prevention integrating current literature and high-volume institutional experience. Methods: A narrative review of the literature was conducted using PubMed and Google Scholar to identify clinical, biomechanical, and systematic studies on PCLR complications published between 2010 and 2025. Overall, 58 studies were screened and 33 were included for qualitative synthesis. Among the included studies, the level of evidence was Level I in five systematic reviews/meta-analyses, Level III–IV in seven observational clinical studies and registries, and Level V in biomechanical studies, narrative reviews, and expert consensus reports. In parallel, the recommendations were informed by the cumulative experience of a high-volume tertiary referral center with 187 PCLR procedures performed between 2010 and 2025 (136 MLKI, 51 isolated). Results: Evidence identifies several key predictors of postoperative complications: low posterior tibial slope (<6.54°), small graft diameter (<7.0 mm), untreated posterolateral corner insufficiency, excessive tibial tunnel angle, and surgical trauma at the “killer turn.” Neurovascular complications primarily arise during tibial tunnel instrumentation, with knee hyperflexion (>90°) significantly improving safety. Suture tape augmentation (STA) reduces graft elongation by 45–58% and is associated with improved biomechanical stability without increasing complication rates. Early controlled motion is critical to prevent arthrofibrosis, whereas HO—affecting up to 45% of MLKI patients—requires delayed surgical excision after maturation. Conclusions: Optimal outcomes after PCLR derive from a structured, complication-focused approach encompassing anatomical risk assessment, meticulous tunnel planning, neurovascular protection, biological augmentation, and disciplined postoperative rehabilitation. Adoption of standardized protocols—particularly in MLKIs—can substantially reduce the incidence of adverse events and improve long-term knee stability. Full article

Background/Objectives: The anterior cruciate ligament (ACL) plays a key role in knee stability, biomechanics, and proprioception, and is one of the most frequently injured and reconstructed ligaments in both athletes and the general population. The anatomical placement of femoral and tibial tunnels close to the native ACL insertion sites is critical for long-term clinical outcomes and graft survival. This study aimed to define sagittal and coronal ACL alignment and tibial footprint morphology on magnetic resonance imaging (MRI) in healthy knees, to explore sex- and side-related differences, and to provide population-specific reference values. Methods: In this retrospective cross-sectional study, knee MRIs acquired between 2018 and 2021 were screened, and knees with an intact ACL and without deformity or joint pathology that could alter alignment were included. After applying inclusion and exclusion criteria, 636 knees (320 right, 316 left) from 545 individuals (338 women, 298 men; 15–80 years, mean age 34.87 ± 11.65 years) were analyzed. On sagittal images, the sagittal ACL angle (S-ANGLE) was measured on the slice where the ligament appeared maximally visualized. The midpoints of the ACL were identified on two adjacent sagittal slices, and a line drawn through these midpoints was used to represent the central axis of the ligament; the angle between this line and the tibial plateau was recorded as the S-ANGLE. For anteroposterior localization of the tibial footprint, an anteroposterior reference distance (S-long) was defined as the length measured parallel to the tibial plateau, extending from the midpoint of the tibial tuberosity (corresponding to the insertion site of the patellar ligament and used as a topographic anterior landmark) toward the posterior aspect of the proximal tibia. A perpendicular line was drawn from the anterior end of S-long to establish the anterior reference boundary. The distance from this anterior reference line to the midpoint of the ACL tibial footprint along the same anteroposterior axis was defined as S-short. The sagittal footprint percentage (S-PERCENTAGE) was calculated as (S-short/S-long) × 100, representing the size-normalized sagittal anteroposterior position of the ACL tibial footprint midpoint. On coronal images, the ACL–tibial plateau angle (C-ANGLE), mediolateral tibial length (C-long), and distance from the medial edge to the ACL insertion (C-short) were obtained; C-PERCENTAGE was calculated analogously. Medial mechanical proximal tibial angle (mMPTA) was used to confirm physiological coronal alignment. Non-parametric tests were applied, with p < 0.05 considered statistically significant. Results: Women had significantly greater sagittal ACL angles than men, whereas anteroposterior distances measured from the midpoint of the tibial tuberosity (used as an anterior topographic landmark) and oriented parallel to the tibial plateau (S-LONG) and mediolateral tibial lengths (C-LONG) and absolute distances to the ACL tibial footprint were larger in men. In contrast, normalized sagittal and coronal footprint percentages (S-PERCENTAGE, C-PERCENTAGE) did not differ meaningfully between sexes, indicating the preservation of the relative ACL tibial insertion site despite size differences. Small but statistically significant side-to-side differences were observed in some coronal parameters; however, absolute differences were small and did not substantially modify the overall alignment pattern. Conclusions: This study provides large-sample, population-specific reference values for ACL orientation and tibial footprint location in both sagittal and coronal planes in healthy knees. The combination of higher sagittal ACL angles and shorter anteroposterior distances reference measured from the midpoint of the tibial tuberosity and oriented parallel to the tibial plateau (S-LONG) in women may represent a structural substrate contributing to the higher ACL injury rates reported in females. The morphometric data presented here may assist in individualized ACL reconstruction planning, MRI-based assessment of tibial tunnel position, and the design of knee-related biomedical implants and devices. Full article

Background/Objectives: The relationship between clinical volume and academic performance in orthopedic surgery remains understudied. The purpose of this study is to explore the characteristics of high-achieving academic orthopedic surgeons in an attempt to extrapolate patterns and trends that govern the relationship between clinical performance and academia in orthopedic surgery. Methods: The 2023 National Plan and Provider Enumeration System and Medicare claims data (2021–2022) databases were used to include all active orthopedic surgeons of different subspecialties. A publication score, based on publication volume, journal impact, and authorship position, was calculated for each included surgeon, and surgeons who scored in the top 5% were deemed high-achieving academic orthopedic surgeons. Additional data pertaining to demographic characteristics, clinical volume, relative value units (RVUs), and Healthgrades ratings were recorded and analyzed. Results: A total of 23,403 orthopedic surgeons were included in our study, with 1169 considered top researchers. There were significant disparities in multiple parameters according to gender. Moreover, there were geographic variations among orthopedic surgeons with regard to mean publication scores, clinical volume, and RVUs. The top researcher cohort had a higher mean publication score (p < 0.001) and a higher mean clinical volume (p < 0.001) when compared to the total surgeon cohort. Mean RVUs were higher in the total surgeon cohort, although not reaching significance. Hip and knee, as well as shoulder and elbow surgeons, had significantly greater clinical volumes in the top researcher cohort than in the total surgeon cohort (p < 0.001). Despite differences in clinical and research metrics, there were no significant differences in mean Healthgrades ratings and the mean number of Healthgrades ratings between the top researcher sample and the non-top researcher sample. Conclusions: Higher research productivity was not associated with lower clinical productivity, as high-achieving academic orthopedic surgeons demonstrated high academic performance while remaining clinically active. Full article

Objectives: To evaluate patient reference in paired bilateral posterior stabilized (PS) total knee arthroplasties (TKAs) with significantly different degrees of joint line obliquity (JLO) change. Methods: A retrospective review was conducted on 128 patients who underwent paired bilateral PS TKAs, with greater and smaller JLO changes (G-ΔJLO and S-ΔJLO knees; a side-to-side difference in JLO change >3° between G-ΔJLO and S-ΔJLO knees). The mean follow-up period was 3.9 years (minimum 2 years). Radiographic changes in JLO were measured according to the Coronal Plane Alignment of the Knee (CPAK) classification. Maintenance of the CPAK type and JLO direction (apex distal, neutral, and apex proximal) was investigated. Clinically, the preferred TKA out of greater and smaller JLO changes was investigated. The Hospital for Special Surgery and Western Ontario and McMaster Universities Osteoarthritis Index were evaluated. Results: The average JLO change was 10.5° in the G-ΔJLO knees and 5.5° in the S-ΔJLO knees (p < 0.001). The CPAK type and JLO direction was better maintained in the S-ΔJLO knees (p < 0.001, respectively). Regarding preference, 40 patients (31.2%) were satisfied with bilateral TKAs without a specific preference, while 44 patients (34.3%) preferred TKAs of the G-ΔJLO knee and 44 patients (34.3%) preferred the S-ΔJLO knee (p = 1.000). No significant differences were found in the patient reported outcomes between the G- and S-ΔJLO knees. Conclusions: The degree of joint line obliquity change was not associated with patient preference in bilateral PS TKAs. JLO preservation may not be a critical determinant of patient preference in PS TKA. Full article

Background: Alpine skiing imposes high biomechanical demands on the lower limbs, which are further amplified in individuals with transfemoral amputation due to prosthetic constraints. This study aimed to quantify three-dimensional knee flexion asymmetries during alpine skiing turns in transfemoral amputee skiers compared with non-disabled controls. Methods: Five unilateral transfemoral amputee skiers (intervention group) and five non-disabled ski instructors (control group) performed six left and six right turns on a skiing simulator under laboratory conditions. Knee flexion angles at the apex of each turn were analyzed using three-dimensional motion capture. Intra-individual differences between the prosthetic and intact limbs were assessed using paired comparisons, and inter-individual differences between groups were evaluated using independent statistical tests (p < 0.05), performed in IBM SPSS Statistics. Results: Intra-individual analysis revealed significant knee flexion asymmetries (p < 0.05) in almost all amputee participants at the apex of both left (mean difference = 7.74°, 95% CI: 3.38–12.09) and right turns (mean difference = 4.36°, 95% CI: 2.66–6.06). In the control group, asymmetries were smaller and reached significance only for the inside leg in both turns (mean difference = 4.02°, 95% CI: 2.51–5.54). Inter-individual comparisons demonstrated significant differences between the groups for both turning directions. During left turns (prosthetic limb on the inside), the largest difference was observed for the inside leg (26.9°, p < 0.001), while the smallest difference occurred for the outside leg (12.1°, p = 0.013). During right turns (prosthetic limb on the outside), the largest difference was found for the outside leg (19.0°, p < 0.001), with a smaller but still significant difference for the inside leg (14.0°, p < 0.001). Conclusions: Transfemoral amputee skiers exhibit a turning strategy that is qualitatively comparable to that of non-disabled skiers; however, it is characterized by a reduced knee flexion range of motion. These limitations appear to be primarily influenced by prosthesis mechanics and user-specific skill levels rather than by a fundamentally different movement strategy. Full article

Mesenchymal stem cells (MSCs) exert biological effects in part through their secretome which includes extracellular vesicles. In this study, we isolated and characterized the secretome from clinically relevant stem cell lines: human embryonic stem cell–derived mesenchymal stem cell line (ES-MSCs) and Infrapatellar fat pad derived MSC (IPFP-MSC) cultured in xeno-free medium. We assessed the biological activity of concentrated cell secretome or isolated fractions of extracellular vesicles (EVs) on cell proliferation, microvascular formation, and cartilage degradation in a human osteoarthritic (OA) ex vivo model. Serum-free conditioned medium from ES-MSC (N = 1) or IPFP-MSC (N = 2) monolayer cultures were concentrated by ultrafiltration to generate concentrated conditioned medium (CCM). Size exclusion chromatography was used to fractionate extracellular vesicles (EVs). Vesicle size, concentration, morphology, and surface markers were characterized by nanoparticle tracking analysis, transmission electron microscopy, and flow cytometry. Biological activity was evaluated by treating human umbilical vein endothelial cells (HUVECs), IPFP-MSCs, and ES-MSCs with CCM and EVs at defined particle concentrations. Endothelial network formation was tested in fibrin gels with different cell and secretome combinations. For analysis of cartilage degradation, human cartilage explants (N = 4; 3.5 mm in diameter) were harvested from patients undergoing total knee arthroplasty and subjected to IL-1β stimulation to induce an OA phenotype. Explants were treated with varying doses from CCM or EVs. Release of glycosaminoglycan in the medium and RNA analysis of catabolic genes were used as readouts. Secretome preparations yielded on average approximately 50 billion vesicles per mL with a similar particle size distribution between 50–200 nm in ES-MSC and IPFP-MSC cultures. Transmission electron microscopy confirmed vesicle morphology and flow cytometry confirmed expression of exosomal surface markers (CD9, CD63, CD81). Functionally, CCM and EVs enhanced proliferation in a dose-dependent manner. Endothelial networks formed by HUVECs in fibrin were stabilized over 7 days by CCMs, most notably by hypoxic ES-MSC CCM relative to no CCM treatment (control). In the OA cartilage model, IL-1β stimulation increased glycosaminoglycan release, whereas ES-MSC CCM treatment and EV treatment reduced glycosaminoglycan release and ES-MSC CCM reduced gene expression of IL-1β, MMP-1, and MMP-3. We isolated and characterized the concentrated secretome and the isolated vesicle-enriched fractions from xeno-free ES-MSC and IPFP-MSC and demonstrated bioactivity in promoting cell proliferation, modulating endothelial network formation, and mitigating cartilage degradation in osteoarthritic tissue. These findings support the bioactivity and therapeutic potential of stem cell–derived secretomes for OA. Full article