Identifying knee osteoarthritis (OA) patient phenotypes is relevant to assessing treatment efficacy, yet biomechanical variability has not been applied to phenotyping. This study aimed to identify demographic and gait related groups (clusters) among total knee arthroplasty (TKA) candidates, and examine inter-cluster differences in gait feature improvement post-TKA. Knee OA patients scheduled for TKA underwent three-dimensional gait analysis one-week pre and one-year post-TKA, capturing lower-limb external ground reaction forces and kinematics using a force platform and optoelectronic motion capture. Principal component analysis was applied to frontal and sagittal knee angle and moment waveforms (n=135 pre-TKA, n=106 post-TKA), resulting in a new uncorrelated dataset of subject PCscores and PC vectors, describing major modes of variability throughout one gait cycle (0–100%). Demographics (age, gender, body mass index (BMI), gait speed), and gait angle and moment PCscores were standardized and assessed for outliers. One patient exceeding Tukey's outer (3IQR) fence was removed. Two-dimensional multidimensional scaling followed by k-medoids clustering was applied to scaled demographics and pre-TKA PCscores [134×15]. Number of clusters (k=2:10) were assessed by silhouette coefficients, s, and stability by Adjusted Rand Indices (ARI) of 100 data subsets. Clusters were validated by examining inter-cluster differences at baseline, and inter-cluster gait changes (PostPCscore–PrePCscore, n=105) by k-way ANOVA and Tukey's honestly significant difference (HSD) criterion. Four (k=4) TKA candidate groups yielded optimum clustering metrics (s = 0.4, ARI=0.75). Cluster 1 was all-males (male:female=19:0) who walked with faster gait speeds (1>2,3), larger flexion angle magnitudes and stance-phase angle range (PC1 & PC4 1>2,3,4), and more flexion (PC2 1>2,3,4) and adduction moment (PC2 & PC3 1>2,3) range patterns. Cluster 1 had the most dynamic kinematics and kinetic loading/unloading range amongst the clusters, representing a higher-functioning (less “stiff”) male subset. Cluster 2 captured older (2>1,3) males (31:1) with slower gait speeds (2 4), and lower flexion angle magnitude (PC1 3 2,3) and less stiff kinematic and kinetic patterns relative to Clusters 2 and 3, representing a higher-functioning female subset. Radiographic severity did not differ between clusters (Kellgren-Lawrence Grade, p=0.9, n=102), and after removing demographics and re-clustering, gender differences remained (p < 0 .04). Pre-TKA, higher-functioning clusters (1&4) had more dynamic loading/un-loading kinetic patterns. Post-TKA, high-functioning clusters experienced less gait improvement (flexion angle PC2, 1,4 < 3, p≥0.004, flexion moment PC2, 4 < 2,3), with some sagittal range patterns decreasing postoperatively. TKA candidates can be characterized by four clusters, differing by demographics and biomechanical severity features. Post-TKA, functional gains were cluster-specific, stiff-gait clusters experienced more improvement, while higher-functioning clusters experienced less gain and showed some decline. Results suggest the presence of cohorts who may not benefit functionally from TKA. Cluster profiling may support triaging and developing targeted OA treatment strategies, meeting individual function needs

Previous study reported that intra-articular injection of MgSO4 could alleviate pain related behaviors in a collagenase induced OA model in rats. It provided us a good description on the potential of Mg2+ in OA treatment. However, the specific efficiency of Mg2+ on OA needs to be further explored and confirmed. The underlying mechanisms should be elucidated as well. Increasing attention has been paid on existence of synovial fluid MSCs (SF-MSCs) (not culture expanded) which may participate in endogenous reparative capabilities of the joint. On the other hand, previous studies demonstrated that Mg2+ not only promoted the expression of integrins but also enhanced the strength of fibronectin-integrin bonds that indicated the promotive effect of Mg2+ on cell adhesion, moreover, Mg2+ was proved could enhance chondrogenic differentiation of synovial membrane derived MSCs by modulating integrins. Based on these evidence, we hypothesize herein intra-articular injection of Mg2+ can attenuate cartilage degeneration in OA rat through modulating the biological behavior of SF-MSCs. Human and rat SF-MSCs were collected after obtaining Experimental Ethics approval. The biological behaviors of both human and rat SF-MSCs including multiple differentiation, adhesion, colony forming, proliferation, etc. were determined in vitro in presence or absence of Mg2+ (10 mmol/L). Male SD rats (body weight: 450–500 g) were used to establish anterior cruciate ligament transection and partial medial meniscectomy (ACLT+PMM) OA models. The rats received ACLT+PMM were randomly divided into saline (control) group and MgCl2 (0.5 mol/L) group (n=6 per group). Intra-articular injection was performed on week 4 post-operation, twice per week for two weeks. Knee samples were harvested on week 2, 4, 8, 12 and 16 after injection for histological analysis for assessing the progression of OA. On week 2 and 4 after injection, the rat SF-MSCs were also isolated before the rats were sacrificed for assessing the abilities of chondrogenic differentiation, colony forming and adhesion in vitro. Statistical analysis was done using Graphpad Prism 6.01. Unpaired t test was used to compare the difference between groups. Significant difference was determined at P < 0 .05. The adhesion and chondrogenic differentiation ability of both human and rat SF-MSCs were significantly enhanced by Mg2+ (10 mmol/L) supplementation in vitro. However, no significant effects of Mg2+ (10 mmol/L) on the osteogenic and adipogenic differentiation as well as the colony forming and proliferation. In the animal study, histological analysis by Saffranin O and Toluidine Blue indicated the cartilage degeneration was significantly alleviated by intra-articular injection of Mg2+, in addition, the expression of Col2 in cartilage was also increased in MgCl2 group with respect to control group indicated by immunohistochemistry. Moreover, the OARSI scoring was decreased in MgCl2 group as well. Histological analysis and RT-qPCR indicated that the chondrogenic differentiation of SF-MSCs isolated from Mg2+ treated rats were significantly enhanced compare to control group. In the current study, we have provided direct evidence supporting that Mg2+ attenuated the progression of OA. Except for the effect of Mg2+ on preventing cartilage degeneration had been demonstrated in this study, for the first time, we demonstrated the promoting effect of Mg2+ on adhesion and chondrogenic differentiation of endogenous SF-MSCs within knee joint that may favorite cartilage repair. We have confirmed that the anti-osteoarthritic effect of Mg2+ involves the multiple actions which refer to prevent cartilage degeneration plus enhance the adhesion and chondrogenic differentiation of SF-MSCs in knee joint to attenuate the progression of OA. These multiple actions of Mg2+ may be more advantage than traditional products. Besides, this simple, widely available and inexpensive administration of Mg2+ has the potential on reducing the massive heath economic burden of OA. However, the current data just provided a very basic concept, the exact functions and underlying mechanisms of Mg2+ on attenuating OA progression still need to be further explored both in vitro and in vivo. Formula of Mg2+ containing solution also need to be optimized, for example, a sustained and controlled release delivery system need to be developed for improving the long-term efficacy

Joint load reduction is effective for alleviating OA pain. Treatment options for joint unloading include braces and HTO, both of which may be impractical for patients. The purpose of the present study was to examine the biomechanical rationale of a practical, partial unloading implant (KineSpring® System, Moximed) for knee OA. Device durability was tested by cyclically loading bone-implant constructs through simulated use for at least 10 million cycles. Joint load reduction with the implant was quantified by measuring changes in medial and lateral knee compartment loads generated by cadaver knees in simulated gait. Safety of the device was tested by 3, 6, and 12 month follow-up of implants in an in vivo ovine model. Surgical technique and device safety and efficacy were assessed in human clinical studies. The unloader device survived over 15 million cycles of simulated use without failure. In the simulated gait cadaver model, the unloading device significantly reduced medial compartment (29 ± 13 lbs, p<0.05) and overall knee joint loads during the stance phase of gait testing but did not significantly increase lateral compartment loading. Chronic ovine implants demonstrated good tolerance of the implant with normal wound healing and secure device fixation. Clinical experience (n=49) demonstrated uneventful device implantation. Unlike HTO, the implantation technique for the unloader does not alter joint alignment. This surgical technique avoids removal of bone, ligament, and cartilage, thus preserving future primary arthroplasty, if required. Early-term clinical experience also demonstrates good outcomes for patients, the earliest of whom are beyond 2.6 years with the implant. This unloading device offers a practical and attractive treatment option for patients with medial knee OA: load reduction without load transfer, durability, preservation of downstream treatment options, safety, and early-term efficacy