Predictors of fracture healing in patients with recalcitrant nonunions treated with autologous culture expanded bone marrow-derived mesenchymal stromal cells.

The study reports the prospective outcome of treating severe recalcitrant fracture nonunion in patients with autologous bone marrow-derived mesenchymal stromal cells (BMSC) from 2003 to 2010 and analyze predictors of union. Autologous BMSC were culture expanded and inserted at nonunion site with or without carriers in addition to surgical stabilization of the fracture. Radiological union was ascertained by musculoskeletal radiologists on plain radiographs and/or CT scans. A logistic regression analysis was performed with cell-expansion parameters (cell numbers, cell doubling time) and known clinical factors (e.g., smoking and diabetes) as independent variables and fracture union as the dependent variable to identify the factors that influence bony healing. An Eq5D index score assessed the effect of treatment on general quality of health. A total of 35 patients (mean age 51+/-13 years) with established nonunion (median 2.9 years, 1-33) and, at least one failed nonunion surgery (median 4,1-14) received treatment. Fracture union was achieved in 21 patients (60%; 95%CI 44-75) at 2.6 years. Multiple penalized logistic regression revealed faster cell doubling time (p = 0.07), absence of diabetes (p = 0.003), less previous surgeries (p = 0.008), and lower age at cell implantation (p = 0.02) were significant predictors for fracture union. A significant increase in Eq5D index (p = 0.01) was noted with a mean rise of the score by 0.34 units (95%CI 0.11-0.58) at 1 year following the study. In summary, the study revealed cell doubling time as a novel in vitro parameter in conjunction with age, multiple surgeries, and diabetes as being significant predictors of the fracture union. © 2018 The Authors. Journal of Orthopaedic Research® Published by Wiley Periodicals, Inc. J Orthop Res 37:1303-1309, 2019.

Efficacy and safety of autologous cell therapies for knee cartilage defects (autologous stem cells, chondrocytes or the two): randomized controlled trial design.

AIM: The main aim of this trial is to test the safety and efficacy of autologous stromal/stem cells, chondrocytes or the two combined in the treatment of knee cartilage defects. PATIENTS & METHODS: Patients with symptomatic chondral/osteochondral defects will be randomized to cell therapy treatment with one of three cell populations (1:1:1). The primary efficacy outcome is a functional knee score (Lysholm) at 15 months post-treatment and the primary safety outcome is the incidence of adverse events. Secondary objectives are to analyze repair tissues, quality of life and cost-utility assessments. Exploratory objectives are to identify predictors for success/potency and dose-response relationships. RESULTS & CONCLUSION: This trial has been carefully designed so that valuable scientific and clinical information can be gathered throughout and in the final analysis.

Autologous Bone Plug Supplemented With Autologous Chondrocyte Implantation in Osteochondral Defects of the Knee.

BACKGROUND: Structural and functional outcome of bone graft with first- or second-generation autologous chondrocyte implantation (ACI) in treating cartilage and subchondral bone defect has not been reported previously. PURPOSE: To evaluate the outcome of simultaneous transplantation of an autologous bone plug with first- or second-generation ACI for restoration of concomitant subchondral bone and full-thickness cartilage defect in the femoral condyle of the knee. STUDY DESIGN: Case series; Level of evidence, 4. METHODS: Seventeen patients (mean ± SD age, 27 ± 7 years; range, 17-40 years)-12 with osteochondritis dissecans (International Cartilage Repair Society [ICRS] grades 3 and 4) and 5 with an isolated osteochondral defect (ICRS grade 4)-had the defect reconstructed with implantation of a unicortical autologous bone graft combined with ACI (the OsPlug technique). Functional outcome was assessed with Lysholm scores obtained preoperatively and at 1 and 5 years postoperatively. The repair site was evaluated with the Oswestry Arthroscopy Score (OAS), MOCART score (magnetic resonance observation of cartilage repair tissue), and ICRS II histology score. Formation of a subchondral lamina and lateral integration of the bone grafts were evaluated from magnetic resonance imaging scans. RESULTS: The mean defect size was 4.5 ± 2.6 cm(2) (range, 1-9 cm(2)), and the mean depth was 11.3 ± 5 mm (range, 5-18 mm). The preoperative Lysholm score improved from 45 (interquartile range [IQR], 24; range, 16-79) to 77 (IQR, 28; range, 41-100) at 1 year (P = .001) and 70 (IQR, 35; range, 33-91) at 5 years (P = .009). The mean OAS of the repair site was 6.2 (range, 0-9) at a mean of 1.3 years. The mean MOCART score was 61 ± 22 (range, 20-85) at 2.6 ± 1.8 years. Histology demonstrated generally good integration of the repair cartilage with the underlying bone. Poor lateral integration of the bone graft, as assessed on magnetic resonance imaging scan, and a low OAS were significantly associated with a poor Lysholm score and failure. A total of 3 patients had treatment failure, with 1 requiring total knee replacement at 5 years (Lysholm score of 33 at failure) and the other 2 requiring further surgical intervention because of persistent symptoms at 2 and 4 years, respectively (both had Lysholm score of 45 at failure). The Lysholm score in these patients before failure were still noted to be higher than at the preoperative level. CONCLUSION: The OsPlug technique shows significant improvement of functional outcome for up to 5 years in patients with high-grade osteochondritis dissecans or osteochondral defect. This is the first report describing association of bone graft integration with functional outcome after such a procedure. It also demonstrates histologic evidence of integration of the repair cartilage with the underlying bone graft.

Midterm to long-term longitudinal outcome of autologous chondrocyte implantation in the knee joint: a multilevel analysis.

BACKGROUND: Autologous chondrocyte implantation is a cell therapeutic approach for the treatment of chondral and osteochondral defects in the knee joint. The authors previously reported on the histologic and radiologic outcome of autologous chondrocyte implantation in the short- to midterm, which yields mixed results. PURPOSE: The objective is to report on the clinical outcome of autologous chondrocyte implantation for the knee in the midterm to long term. STUDY DESIGN: Cohort study; Level of evidence, 3. METHODS: Eighty patients who had undergone autologous chondrocyte implantation of the knee with mid- to long-term follow-up were analyzed. The mean patient age was 34.6 years (standard deviation, 9.1 years), with 63 men and 17 women. Seventy-one patients presented with a focal chondral defect, with a median defect area of 4.1 cm(2) and a maximum defect area of 20 cm(2). The modified Lysholm score was used as a self-reporting clinical outcome measure to determine the following: (1) What is the typical pattern over time of clinical outcome after autologous chondrocyte implantation; and (2) Which patient-related predictors for the clinical outcome pattern can be used to improve patient selection for autologous chondrocyte implantation? RESULTS: The average follow-up time was 5 years (range, 2.7-9.3). Improvement in clinical outcome was found in 65 patients (81%), while 15 patients (19%) showed a decline in outcome. The median preoperative Lysholm score of 54 increased to a median of 78 points. The most rapid improvement in Lysholm score was over the 15-month period after operation, after which the Lysholm score remained constant for up to 9 years. The authors were unable to identify any patient-specific factors (ie, age, gender, defect size, defect location, number of previous operations, preoperative Lysholm score) that could predict the change in clinical outcome in the first 15 months. CONCLUSION: Autologous chondrocyte implantation seems to provide a durable clinical outcome in those patients demonstrating success at 15 months after operation. Comparisons between other outcome measures of autologous chondrocyte implantation should be focused on the clinical status at 15 months after surgery. The patient-reported clinical outcome at 15 months is a major predictor of the mid- to long-term success of autologous chondrocyte implantation.

Autologous chondrocyte implantation for cartilage repair: monitoring its success by magnetic resonance imaging and histology.

Autologous chondrocyte implantation is being used increasingly for the treatment of cartilage defects. In spite of this, there has been a paucity of objective, standardised assessment of the outcome and quality of repair tissue formed. We have investigated patients treated with autologous chondrocyte implantation (ACI), some in conjunction with mosaicplasty, and developed objective, semiquantitative scoring schemes to monitor the repair tissue using MRI and histology. Results indicate repair tissue to be on average 2.5 mm thick. It was of varying morphology ranging from predominantly hyaline in 22% of biopsy specimens, mixed in 48%, through to predominantly fibrocartilage, in 30%, apparently improving with increasing time postgraft. Repair tissue was well integrated with the host tissue in all aspects viewed. MRI scans provide a useful assessment of properties of the whole graft area and adjacent tissue and is a noninvasive technique for long-term follow-up. It correlated with histology (P = 0.02) in patients treated with ACI alone.