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Objective The purpose of this study was to compare the clinical and radiological efficacy of autologous adipose-derived stromal vascular fraction (SVF) versus hyaluronic acid in patients with bilateral knee osteoarthritis. Methods Sixteen patients with bilateral symptomatic knee osteoarthritis (K-L grade II to III; initial pain evaluated at four or greater on a ten-point VAS score) were enrolled in this study, which were randomized into two groups. Each patient received 4-ml autologous adipose-derived SVF treatment (group test, n  = 16) in one side of knee joints and a single dose of 4-ml hyaluronic acid treatment (group control, n  = 16) in the other side. The clinical evaluations were performed pre-operatively and post-operatively at one month, three months, six months, and 12-months follow-up visit, using the ten-point visual analog scale (VAS), the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC), and the knee range of motion (ROM). The whole-organ assessment of the knees was performed with whole-organ magnetic resonance imaging score (WORMS) based on MRI at baseline, six months and 12-months follow-up. The articular repair tissue was assessed quantitatively and qualitatively by magnetic resonance observation of cartilage repair tissue (MOCART) score based on follow-up MRI at six months and 12 months. Results No significant baseline differences were found between two groups. Safety was confirmed with no severe adverse events observed during 12-months follow-up. The SVF-treated knees showed significantly improvement in the mean VAS, WOMAC scores, and ROM at 12-months follow-up visit compared with the baseline. In contrast, the mean VAS, WOMAC scores, and ROM of the control group became even worse but not significant from baseline to the last follow-up visit. WORMS and MOCART measurements revealed a significant improvement of articular cartilage repair in SVF-treated knees compared with hyaluronic acid-treated knees. Conclusion The results of this study suggest that autologous adipose-derived SVF treatment is safe and can effectively relief pain, improve function, and repair cartilage defects in patients with knee osteoarthritis.

Purpose Autologous Matrix-Induced Chondrogenesis (AMIC ® ) utilizing a type I/III collagen membrane was compared with microfracture (MFx) alone in focal cartilage lesions of the knee at one, two and five years. Methods Forty-seven patients (aged 37 ± 10 years, mean defect size 3.6 ± 1.6 cm 2 ) were randomized and treated either with MFx, with sutured or glued AMIC ® in a prospective multicentre clinical trial. Results After improvement for the first two years in all subgroups, a progressive and significant score degradation was observed in the MFx group, while all functional parameters remained stable for least five years in the AMIC ® groups. At two and five years, MRI defect filling was more complete in the AMIC ® groups. No treatment-related adverse events were reported. Conclusions AMIC ® is an effective cartilage repair procedure in the knee resulting in stable clinical results significantly better than the MFx group at five years.

Mesenchymal stem cells (MSCs) have been the focus of an emerging treatment for osteoarthritis. However, few studies reported about outcomes of an intra‐articular injection of autologous adipose‐derived mesenchymal stem cells (AD‐MSCs). This study aimed to assess the efficacy and safety of a single intra‐articular injection of AD‐MSCs for patients with knee osteoarthritis. It was a prospective double‐blinded, randomized controlled, phase IIb clinical trial. AD‐MSCs were administered for 12 patients (MSC group), and the group was compared with 12 knees with injection of normal saline (control group) up to 6 months. All procedures were performed in the outpatient clinic. Primary outcome measure was the Western Ontario and McMaster Universities Osteoarthritis index (WOMAC) score. Secondary outcome measure included various clinical and radiologic examination, and safety after injection. Change of cartilage defect after injection was evaluated using magnetic resonance imaging (MRI). Single injection of AD‐MSCs led to a significant improvement of the WOMAC score at 6 months. In the control group, there was no significant change in the WOMAC score at 6 months. No serious adverse events were observed in both groups during the follow‐up period. In MRI, there was no significant change of cartilage defect at 6 months in MSC group whereas the defect in the control group was increased. An intra‐articular injection of autologous AD‐MSCs provided satisfactory functional improvement and pain relief for patients with knee osteoarthritis in the outpatient setting, without causing adverse events at 6 months' follow‐up. Larger sample size and long‐term follow‐up are required. Stem Cells Translational Medicine 2019;8:504–511 Autologous adipose‐derived mesenchymal stem cells (AD‐MSCs) were administered for 12 patients, and the group was compared with 12 knees with injection of normal saline up to 6 months. The procedures were performed in an outpatient clinic. An intra‐articular injection of autologous AD‐MSCs provided satisfactory functional improvement and pain relief in patients with knee osteoarthritis without causing adverse events at 6 months' follow‐up.

ObjectivesIn the phase II FGF-18 Osteoarthritis Randomized Trial with Administration of Repeated Doses (FORWARD) study, sprifermin demonstrated cartilage modification in the total femorotibial joint and in both femorotibial compartments by MRI in patients with knee osteoarthritis. Here, we evaluate whether sprifermin reduces cartilage loss and increases cartilage thickness, independent of location.MethodsPatients were randomised 1:1:1:1:1 to three once-weekly intra-articular injections of 30 µg sprifermin every 6 months (q6mo); 30 µg sprifermin every 12 months (q12mo); 100 µg sprifermin q6mo; 100 µg sprifermin q12mo; or placebo. Post-hoc analysis using thinning/thickening scores and ordered values evaluated femorotibial cartilage thickness change from baseline to 24 months independent of location. Changes were indirectly compared with those of Osteoarthritis Initiative healthy subjects.ResultsThinning scores were significantly lower for sprifermin 100 µg q6mo versus placebo (mean (95% CI) difference: 334 µm (114 to 554)), with a cartilage thinning score similar to healthy subjects. Thickening scores were significantly greater for sprifermin 100 µg q6mo, 100 µg q12mo and 30 µg q6mo versus placebo (mean (95% CI) difference: 425 µm (267 to 584); 450 µm (305 to 594) and 139 µm (19 to 259), respectively) and more than doubled versus healthy subjects.ConclusionsSprifermin increases cartilage thickness, and substantially reduces cartilage loss, expanding FORWARD primary results.Trial registration number NCT01919164.

Purpose There is limited comparative evidence on patient outcomes following cartilage repair in various knee compartments. The aim of this study was to compare clinical and imaging outcomes after treating cartilage defects in femoral condyles and trochlea with either an aragonite-based scaffold or surgical standard of care (SSoC, i.e., debridement/microfractures) in a large multicentre randomized controlled trial. Methods 247 patients with up to three knee joint surface lesions (ICRS grade IIIa or above) in the femoral condyles, trochlea or both (“mixed”), were enrolled and randomized to surgery with either a cell-free aragonite scaffold or SSoC. Patients were followed for up to 48 months by analysing subjective scores (KOOS and IKDC), radiological outcomes (defect filling on MRI), as well as treatment failure rates and adverse events. A differential analysis of outcomes for condylar, trochlear and mixed lesions was performed. Results The scaffold group significantly outperformed the SSoC group regardless of lesion location with statistically significantly better KOOS Overall scores at 24 months (all p  ≤ 0.0009) and 48 months (all p  ≤ 0.02). Similar results were observed for KOOS subscales and IKDC scores. For KOOS responder rates, superiority of the implant group was demonstrated at 24, 36, and 48 months (all p  ≤ 0.004). Higher defect filling on MRI for implants was observed for all locations. Lower treatment failure rates for the implant were observed in condylar and mixed lesions. Conclusion The aragonite-based scaffold was safe and effective regardless of the defect location, providing superior clinical and radiological outcomes compared to SSoC up to four years follow-up. Level of evidence I – Randomized controlled trial.

Purpose There is an increasing number of reports on the treatment of knee osteoarthritis (OA) using mesenchymal stem cells (MSCs). However, it is not known what would better drive osteoarthritis stabilization to postpone total knee arthroplasty (TKA): targeting the synovial fluid by injection or targeting on the subchondral bone with MSCs implantation. Methods A prospective randomized controlled clinical trial was carried out between 2000 and 2005 in 120 knees of 60 patients with painful bilateral knee osteoarthritis with a similar osteoarthritis grade. During the same anaesthesia, a bone marrow concentrate of 40 mL containing an average 5727 MSCs/mL (range 2740 to 7540) was divided in two equal parts: after randomization, one part (20 mL) was delivered to the subchondral bone of femur and tibia of one knee (subchondral group) and the other part was injected in the joint for the contralateral knee (intra-articular group). MSCs were counted as CFU-F (colony fibroblastic unit forming). Clinical outcomes of the patient (Knee Society score) were obtained along with radiological imaging outcomes (including MRIs) at two year follow-up. Subsequent revision surgeries were identified until the most recent follow-up (average of 15 years, range 13 to 18 years). Results At two year follow-up, clinical and imaging (MRI) improvement was higher on the side that received cells in the subchondral bone. At the most recent follow-up (15 years), among the 60 knees treated with subchondral cell therapy, the yearly arthroplasty incidence was 1.3% per knee-year; for the 60 knees with intra-articular cell therapy, the yearly arthroplasty incidence was higher ( p  = 0.01) with an incidence of 4.6% per knee-year. For the side with subchondral cell therapy, 12 (20%) of 60 knees underwent TKA, while 42 (70%) of 60 knees underwent TKA on the side with intra-articular cell therapy. Among the 18 patients who had no subsequent surgery on both sides, all preferred the knee with subchondral cell therapy. Conclusions Implantation of MSCs in the subchondral bone of an osteoarthritic knee is more effective to postpone TKA than injection of the same intra-articular dose in the contralateral knee with the same grade of osteoarthritis.

In order to improve the ability of clinical diagnosis to differentiate articular cartilage (AC) injury of different origins, this study explores the sensitivity of mid-infrared (MIR) spectroscopy for detecting structural, compositional, and functional changes in AC resulting from two injury types. Three grooves (two in parallel in the palmar-dorsal direction and one in the mediolateral direction) were made via arthrotomy in the AC of the radial facet of the third carpal bone (middle carpal joint) and of the intermediate carpal bone (the radiocarpal joint) of nine healthy adult female Shetland ponies (age = 6.8 ± 2.6 years; range 4–13 years) using blunt and sharp tools. The defects were randomly assigned to each of the two joints. Ponies underwent a 3-week box rest followed by 8 weeks of treadmill training and 26 weeks of free pasture exercise before being euthanized for osteochondral sample collection. The osteochondral samples underwent biomechanical indentation testing, followed by MIR spectroscopic assessment. Digital densitometry was conducted afterward to estimate the tissue's proteoglycan (PG) content. Subsequently, machine learning models were developed to classify the samples to estimate their biomechanical properties and PG content based on the MIR spectra according to injury type. Results show that MIR is able to discriminate healthy from injured AC (91%) and between injury types (88%). The method can also estimate AC properties with relatively low error (thickness = 12.7% mm, equilibrium modulus = 10.7% MPa, instantaneous modulus = 11.8% MPa). These findings demonstrate the potential of MIR spectroscopy as a tool for assessment of AC integrity changes that result from injury.

It is unclear whether the response in femoral cartilage to running at different intensities is different. To examine the acute patterns of deformation and recovery in femoral cartilage thickness during and after running at different speeds. Crossover study. Laboratory. A total of 17 healthy men (age = 23.9 ± 2.3 years, height = 173.1 ± 5.5 cm, mass = 73.9 ± 8.0 kg). Participants performed a 40-minute treadmill run at speeds of 7.5 and 8.5 km/h. Ultrasonographic images of femoral cartilage thickness (intercondylar, lateral condyle, and medial condyle) were obtained every 5 minutes during the experiment (40 minutes of running followed by a 60-minute recovery period) at each session. Data were analyzed using analysis of variance and Bonferroni- and Dunnett-adjusted post hoc t tests. To identify patterns of cartilage response, we extracted principal components (PCs) from the cartilage-thickness data using PC analysis, and PC scores were analyzed using t tests. Regardless of time, femoral cartilage thicknesses were greater for the 8.5-km/h run than the 7.5-km/h run (intercondylar: F1,656 = 24.73, P < .001, effect size, 0.15; lateral condyle: F1,649 = 16.60, P < .001, effect size, 0.16; medial condyle: F1,649 = 16.55, P < .001, effect size, 0.12). We observed a time effect in intercondylar thickness (F20,656 = 2.15, P = .003), but the Dunnett-adjusted post hoc t test revealed that none of the time point values differed from the baseline value (P > .38 for all comparisons). Although the PC1 and PC2 captured the magnitudes of cartilage thickness and time shift (eg, earlier versus later response), respectively, t tests showed that the PC scores were not different between 7.5 and 8.5 km/h (intercondylar: P ≥ .32; lateral condyle: P ≥ .78; medial condyle: P ≥ .16). Although the 40-minute treadmill run with different speeds produced different levels of fatigue, morphologic differences (<3%) in the femoral cartilage at both speeds seemed to be negligible.

Background Delayed gadolinium-enhanced MRI of cartilage (dGEMRIC) allows an objective, noninvasive, and longitudinal quantification of biochemical cartilage properties. Although dGEMRIC has been used to monitor the course of cartilage degeneration after periacetabular osteotomy (PAO) for correction of hip dysplasia, such longitudinal data are currently lacking for femoroacetabular impingement (FAI). Questions/purposes (1) How does the mean acetabular and femoral dGEMRIC index change after surgery for FAI at 1-year followup compared with a similar group of patients with FAI treated without surgery? (2) Does the regional distribution of the acetabular and femoral dGEMRIC index change for the two groups over time? (3) Is there a correlation between the baseline dGEMRIC index and the change of patient-reported outcome measures (PROMs) at 1-year followup? (4) Among those treated surgically, can dGEMRIC indices distinguish between intact and degenerated cartilage? Methods We performed a prospective, comparative, nonrandomized, longitudinal study. At the time of enrollment, the patients’ decision whether to undergo surgery or choose nonoperative treatment was not made yet. Thirty-nine patients (40 hips) who underwent either joint-preserving surgery for FAI (20 hips) or nonoperative treatment (20 hips) were included. The two groups did not differ regarding Tönnis osteoarthritis score, preoperative PROMs, or baseline dGEMRIC indices. There were more women (60% versus 30%, p = 0.003) in the nonoperative group and patients were older (36 ± 8 years versus 30 ± 8 years, p = 0.026) and had lower alpha angles (65° ± 10° versus 73° ± 12°, p = 0.022) compared with the operative group. We used a 3.0-T scanner and a three-dimensional dual flip-angle gradient-echo technique for the dGEMRIC technique for the baseline and the 1-year followup measurements. dGEMRIC indices of femoral and acetabular cartilage were measured separately on the initial and followup radial dGEMRIC reformats in direct comparison with morphologic radial images. Regions of interest were placed manually peripherally and centrally within the cartilage based on anatomic landmarks at the clockface positions. The WOMAC, the Hip disability and Osteoarthritis Outcome Score, and the modified Harris hip score were used as PROMs. Among those treated surgically, the intraoperative damage according to the Beck grading was recorded and compared with the baseline dGEMRIC indices. Results Although both the operative and the nonoperative groups experienced decreased dGEMRIC indices, the declines were more pronounced in the operative group (−96 ± 112 ms versus −16 ± 101 ms on the acetabular side and −96 ± 123 ms versus −21 ± 83 ms on the femoral side in the operative and nonoperative groups, respectively; p < 0.001 for both). Patients undergoing hip arthroscopy and surgical hip dislocation experienced decreased dGEMRIC indices; the decline in femoral dGEMRIC indices was more pronounced in hips after surgical hip dislocation (−120 ± 137 ms versus −61 ± 89 ms, p = 0.002). In the operative group a decline in dGEMRIC indices was observed in 43 of 44 regions over time. In the nonoperative group a decline in dGEMRIC indices was observed in four of 44 regions over time. The strongest correlation among patients treated surgically was found between the change in WOMAC and baseline dGEMRIC indices for the entire joint (R = 0.788, p < 0.001). Among those treated nonoperatively, no correlation between baseline dGEMRIC indices and change in PROMs was found. In the posterosuperior quadrant, the dGEMRIC index was higher for patients with intact cartilage compared with hips with chondral lesions (592 ± 203 ms versus 444 ± 205 ms, p < 0.001). Conclusions We found a decline in acetabular, femoral, and regional dGEMRIC indices for the surgically treated group at 1-year followup despite an improvement in all PROMs. We observed a similar but less pronounced decrease in the dGEMRIC index in symptomatic patients without surgical treatment indicating continuous cartilage degeneration. Although treatment of FAI is intended to alter the forces acting across the hip by eliminating impingement, its effects on cartilage biology are not clear. dGEMRIC provides a noninvasive method of assessing these effects. Longer term studies will be needed to determine whether the matrix changes of the bradytrophic cartilage seen here are permanent or clinically important. Level of Evidence Level II, therapeutic study.

ObjectivesTo evaluate changes in patellofemoral cartilage thickness over 5 years after anterior cruciate ligament (ACL) injury and to determine the impact of treatment strategy.Methods121 adults (ages 18–35 years, 26% women) had an ACL injury and participated in the KANON randomised controlled trial. Of those, 117 had available MRIs at baseline (<4 weeks post-ACL rupture) and at least one follow-up measurement (2, 5 years). Patellofemoral cartilage thickness was analysed by manual segmentation (blinded to acquisition order). Patellar, trochlear and total patellofemoral cartilage thickness changes were compared between as-randomised (rehabilitation+early ACL reconstruction (ACLR) (n=59) vs rehabilitation+optional delayed ACLR (n=58)) and as-treated groups (rehabilitation+early ACLR (n=59) vs rehabilitation +delayed ACLR (n=29) vs rehabilitation alone (n=29)).ResultsPatellofemoral cartilage thickness decreased −58 µm (95% CI −104 to –11 µm) over 5 years post-ACL rupture, with the greatest loss observed in trochlea during the first 2 years. Participants randomised to rehabilitation+early ACLR had significantly greater loss of patellar cartilage thickness compared with participants randomised to rehabilitation+optional delayed ACLR over the first 2 years (−25 µm (−52, 1 µm) vs +14 µm (−6 to 34 µm), p=0.02) as well as over 5 years (−36 µm (−78 to 5 µm) vs +18 µm (−7, 42 µm), p=0.02). There were no statistically significant differences in patellofemoral cartilage thickness changes between as-treated groups.ConclusionPatellofemoral (particularly trochlear) cartilage thickness loss was observed in young adults following acute ACL rupture. Early ACLR was associated with greater patellofemoral (particularly patellar) cartilage thickness loss over 5 years compared with optional delayed ACLR, indicating that early surgical intervention may be associated with greater short-term structural patellofemoral cartilage deterioration compared with optional delayed surgery.Trial registration number ISRCTN84752559; Post-results.