Jan M. Pestka

Characteristic Complications After Autologous Chondrocyte Implantation for Cartilage Defects of the Knee Joint

Background Although autologous chondrocyte implantation (ACI) is a well-established therapy for the treatment of isolated cartilage defects of the knee joint, little is known about typical complications and their treatment after ACI. Hypothesis Unsatisfactory outcome after ACI is associated with technique-related typical complications. Study Design Case series; Level of evidence, 4. Methods A total of 309 consecutive patients with 349 ACI procedures of the knee joint were analyzed. Three different ACI techniques were used: periosteum-covered ACI in 52 cases (14.9%), Chondrogide (Geistlich Biomaterials, Wolhusen, Switzerland) membrane-covered ACI in 215 cases (61.6%), and a 3-dimensional matrix-associated ACI (BioSeed-C, Biotissue Technologies, Freiburg, Germany) in 82 cases (23.5%). In 52 patients, revision surgery was performed for persistent clinical problems. These patients were analyzed for defect size and location, technique of ACI, and intraoperative findings during revision surgery. The mean time of follow-up for patients after ACI was 4.5 years (standard deviation, ±1.5). Results Four typical major complications were identified: hypertrophy of the transplant, disturbed fusion of the regenerative cartilage and the healthy surrounding cartilage, insufficient regenerative cartilage, and delamination. These diagnoses covered a total of 88.5% of the patients who underwent revision surgery. The overall complication rate was highest in the group of patients treated with periosteum-covered ACI (P = .008). The incidence of symptomatic hypertrophy was 5.2% for all techniques and defect locations; the highest incidence was in patients treated with periosteum-covered ACI (15.4%) (P = .001). The incidence of disturbed fusion was highest in the Chondrogide-covered ACI (3.7%) and the matrix-associated ACI group (4.8%). Concerning the incidence of complications by defect location, there was a tendency for increased complications in patellar defects (P = .095). Within the patellar defects group, no correlation was found for the occurrence of delamination, insufficient regeneration, and disturbed fusion. As a statistical trend, an increased rate of hypertrophy was found for patellar defects (P = .091). Conclusion A major proportion of complications after ACI can be summarized by 4 major diagnoses (symptomatic hypertrophy, disturbed fusion, delamination, and graft failure). Among those, the overall complication rate and incidence of hypertrophy of the transplant were higher for periosteum-covered ACI. Furthermore, an increased rate of symptomatic hypertrophy was found for patellar defects. Therapeutic concepts need to be developed to treat these typical complications of ACI.

Clinical Outcome of Autologous Chondrocyte Implantation for Failed Microfracture Treatment of Full-Thickness Cartilage Defects of the Knee Joint

Background: Although various factors have been identified that influence outcome after autologous chondrocyte implantation (ACI), the relevance of prior treatment of the cartilage defect and its effect concerning the outcome of second-line ACI have not been evaluated to a full extent. Hypothesis: Autologous chondrocyte implantation used as a second-line treatment after failed arthroscopic microfracturing is associated with a higher failure rate and inferior clinical results compared with ACI as a first-line treatment. Study Design: Cohort study; Level of evidence, 3. Methods: A total of 28 patients with isolated cartilage defects at the knee joint were treated with ACI after microfracture as a first-line treatment had failed (failure defined as the necessity of reintervention). These patients were assigned to group A and compared with a matched-pair cohort of patients of identical age, defect size, and defect location (group B) in which ACI was used as a first-line treatment. Failure rates in both groups were assessed. Postoperative knee status was evaluated with the International Knee Documentation Committee (IKDC) score and Knee injury and Osteoarthritis Outcome Score (KOOS), and sporting activity was assessed by use of the Activity Rating Scale. Mean follow-up times were 48.0 months (range, 15.1-75.1 months) in group A and 41.4 months (range, 15.4-83.6 months) in group B. Differences between groups A and B were analyzed by Student t test. Results: Group A had significantly greater failure rates (7 of 28 patients) in comparison with group B (1 of 28 patients; P = .0241). Mean (SD) postoperative IKDC scores revealed 58.4 (22.4) points in group A with a trend toward higher score results (69.0 [19.1] points) for patients in group B (P = .0583). Significantly different results were obtained for KOOS pain and activity of daily living subscales, whereas the remaining KOOS subscales did not show significant differences. Despite the significantly higher failure rate observed in group A, those patients did not participate in fewer activities or perform physical activity less frequently or at a lower intensity. Conclusion: Autologous chondrocyte implantation after failed microfracturing appears to be associated with a significantly higher failure rate and inferior clinical outcome when compared with ACI as a first-line treatment.

Autologous Chondrocyte Implantation for Treatment of Cartilage Defects of the Knee: What Predicts the Need for Reintervention?

Background: Autologous chondrocyte implantation (ACI) is a well-established treatment option for isolated cartilage defects of the knee joint, providing satisfying outcome. However, cases of treatment failure with the need for surgical reintervention are reported; typical patient’s individual and environmental risk factors have previously not been described. Hypothesis: The need for reintervention after ACI is associated with specific preoperative detectable individual risk factors. Study Design: Cohort study; Level of evidence, 3. Methods: A total of 413 patients following ACI (first, second, and third generation) were filtered for those who required revision surgery during their follow-up time (2-11.8 years). Factors were analyzed that might have significant effects on increased revision rate. Using preoperatively collected data, all patients were grouped according to 12 standard prognostic factors. Apart from odds ratio and Pearson χ2 test, statistical analysis of risk factors was performed with multivariate binary logistic regression models and Cox regression, the method of choice for survival time data. Results: After a follow-up of 4.4 ± 0.9 years (limited to 5 years), a total of 88 patients (21.3%) had undergone surgical revision. The time to revision surgery was 1.8 ± 1.1 years. Four prognostic factors associated with a significantly higher risk for reintervention were detected: (1) female gender (Cox survival fit: P = .033), (2) previous surgeries of the affected joint (P = .002), (3) previous bone marrow stimulation (P = .041), and (4) periosteum patch–covered ACI (P = .028). An influence of patient age, body mass index (BMI), defect number, defect size, lesion origin, lesion location, parallel treatment, or smoking on the risk for reintervention could not be observed. Conclusion: The study identifies clear facts that significantly increase the risk of revision surgery. These facts can be easily obtained preoperatively and may be taken into consideration when indicating ACI.

Influence of Cell Quality on Clinical Outcome After Autologous Chondrocyte Implantation

Background: Several factors influence clinical outcome after autologous chondrocyte implantation (ACI) for the treatment of cartilage defects of the knee joint. Hypothesis/Purpose: The aim of the present study was to investigate the influence of cell quality on clinical outcome after ACI. The hypothesis of the authors was that cell quality at the time of transplantation influences clinical outcome after ACI for cartilage defects. Study Design: Cohort study; Level of evidence, 3. Methods: A total of 80 patients were included in the present study. Knee function was assessed before surgery as well as 6, 12, and 24 months after ACI using standard instruments (International Knee Documentation Committee [IKDC], Lysholm, and Tegner scores). Cell quality was evaluated by determination of antigen expression of CD44 expression, aggrecan, collagen type II, and cell viability. A linear regression analysis including preoperative knee function, defect size, defect location, defect origin, body mass index, patient age, and other parameters was performed to evaluate the influence of these parameters on postoperative knee function. Results: Preoperative IKDC score increased from 49.6 ± 13.8 points to 75.5 ± 14.6 points at 24 months (P < .05). Postoperative IKDC score at 6, 12, and 24 months was significantly influenced by collagen type II expression, CD44 expression, and cell viability (all P < .05). No correlation between aggrecan and outcome was found. Quantitative influence of individual factors differed between different time points. Conclusion: Cell quality seems to be one of many factors that influences clinical outcome after ACI in patients with cartilage defects of the knee joint. It constitutes one aspect among various others affecting clinical outcome.

Comparison of Arthroscopic and Open Assessment of Size and Grade of Cartilage Defects of the Knee

PURPOSE The purpose of our study was to compare arthroscopic versus open measurement of cartilage defects and determination of defect grade according to the International Cartilage Repair Society (ICRS) classification. METHODS Arthroscopic determination of defect size and grade according to the ICRS classification of 450 focal cartilage defects in 407 patients who underwent autologous chondrocyte implantation was compared with definite findings at the time of open knee surgery. Results were analyzed based on defect location, defect size, and experience of the treating surgeon. RESULTS Open evaluation of all cartilage defects showed a mean size of 4.54 ± 2.11 cm², whereas arthroscopic determination resulted in a significantly larger mean defect size of 5.69 ± 1.81 cm² (P < .001, r = 0.757). This observation was found in all subgroups concerning defect location and experience of the treating surgeon (P < .001). Overestimation was pronounced among inexperienced surgeons (all P < .01) and in smaller defects (P < .01). Concerning grading of the defect according to the ICRS classification, there was a consensus in 80.9% of the cases when arthroscopic grading was compared with open grading. No differences were found based on defect location or experience of the treating surgeon (P > .05). CONCLUSIONS Although a high correlation was found between arthroscopic and open evaluation of the cartilage defect size, there is a significant overestimation of the cartilage defect size during arthroscopy. This observation is independent of defect location. Smaller defects and inexperienced surgeons are factors that make an overestimation of defect size more likely. Arthroscopic detection and estimation of the full-thickness cartilage defects according to the ICRS classification seem reliable. LEVEL OF EVIDENCE Level IV, therapeutic case series.

Decreased bone formation and increased osteoclastogenesis cause bone loss in mucolipidosis II

Mucolipidosis type II (MLII) is a severe multi‐systemic genetic disorder caused by missorting of lysosomal proteins and the subsequent lysosomal storage of undegraded macromolecules. Although affected children develop disabling skeletal abnormalities, their pathogenesis is not understood. Here we report that MLII knock‐in mice, recapitulating the human storage disease, are runted with accompanying growth plate widening, low trabecular bone mass and cortical porosity. Intralysosomal deficiency of numerous acid hydrolases results in accumulation of storage material in chondrocytes and osteoblasts, and impaired bone formation. In osteoclasts, no morphological or functional abnormalities are detected whereas osteoclastogenesis is dramatically increased in MLII mice. The high number of osteoclasts in MLII is associated with enhanced osteoblastic expression of the pro‐osteoclastogenic cytokine interleukin‐6, and pharmacological inhibition of bone resorption prevented the osteoporotic phenotype of MLII mice. Our findings show that progressive bone loss in MLII is due to the presence of dysfunctional osteoblasts combined with excessive osteoclastogenesis. They further underscore the importance of a deep skeletal phenotyping approach for other lysosomal diseases in which bone loss is a prominent feature.

Return to Sports Activity and Work After Autologous Chondrocyte Implantation of the Knee Which Factors Influence Outcomes

Background: Autologous chondrocyte implantation (ACI) has been associated with satisfying results in everyday activities. Clinical results after ACI treatment of femorotibial lesions are superior in comparison with patellofemoral lesions. There is limited information regarding at which level recreational, amateur, and professional athletes can resume sports and physical activities as well as work after ACI and what parameters influence return to work and sports. Hypothesis: Return to sports activity and work is dependent on defect characteristics such as location and size. Study Design: Case series; Level of evidence, 4. Methods: A total of 130 patients with isolated full-thickness cartilage defects of the knee joint treated with ACI between June 2000 and October 2007 were retrospectively studied by an established questionnaire that assessed sports-specific questions such as frequency, duration, and intensity. Engagement in 32 different sports disciplines was evaluated. In addition, work-specific data were evaluated according to classifications established by the REFA Association. Results were evaluated depending on patient- and defect-specific parameters. Results: The mean ± SD patient age at ACI was 36.2 ± 9.2 years, with a mean defect size of 4.4 ± 1.7 cm2. Defects were located at the femorotibial compartment in 55.7% of cases, whereas lesions of the patellofemoral compartment were found in 44.3%. Mean duration of inability to work after ACI was 13.6 ± 11.0 weeks and did not appear to be influenced by patient age. Defect location and defect size did not appear to significantly influence return-to-work rates, but work intensity before surgery significantly influenced return-to-work rates and duration of absence from work. Workplace adaptations were necessary in only 9.2% of cases postoperatively. With regard to postoperative sports activity, 73.1% of patients were able to return to sports. Neither defect location nor size significantly influenced return to physical activity. Patients participated in a mean of 2.3 different sports during their lifetime. Both duration of exercise and number of sessions per week significantly decreased from before to after surgery. Detailed analysis of 32 different sporting activities revealed that high-impact as well as start-stop sports were generally abandoned in favor of endurance and low-intensity exercises. A lifetime level of competitiveness was maintained in 31.3% of cases, while return to elite sports at the time of the survey became highly unlikely (0.8%). Conclusion: The study results illustrate that treatment of articular cartilage defects of the knee joint leads to satisfactory results concerning everyday activities. With the exception of physical labor, no essential adaptations needed to be made at work. Regarding sports activity, return to low- and moderate-intensity levels appears realistic in the majority of cases, whereas the likelihood of returning to activities with high stress applied on the knee joint is low. Neither defect location nor size appears to significantly influence postoperative sports activity or return-to-work rates.

Clinical Outcomes After Cell-Seeded Autologous Chondrocyte Implantation of the Knee When Can Success or Failure Be Predicted?

Background: Autologous chondrocyte implantation (ACI) has been associated with satisfying results. Still, it remains unclear when success or failure after ACI can be estimated. Purpose: To evaluate the clinical outcomes of cell-seeded collagen matrix–supported ACI (ACI-Cs) for the treatment of cartilage defects of the knee at 36 months and to determine a time point after ACI-Cs at which success or failure can be estimated. Study Design: Cohort study; Level of evidence, 3. Methods: A total of 80 patients with isolated full-thickness cartilage defects of the knee joint treated with ACI-Cs were prospectively assessed before surgery as well as postoperatively by use of the International Knee Documentation Committee (IKDC) score and Lysholm knee score. Results: Preoperative IKDC and Lysholm scores increased from 49.6 and 59.5, respectively, to 79.1 and 83.5, respectively, at 36 months. Only half the patients (46.6%) with poor IKDC scores (ie, <70) at 6 months postoperatively showed continued poor or fair scores at 36 months’ follow-up. The probability of poor scores at 36 months after surgery further increased to 0.61 and 0.81, respectively, when scores were persistent at 12 and 24 months. All 3 patients (100%) with good IKDC scores (ie, 81-90) at 6 months after surgery showed constant or even improved scores at 36 months’ follow-up. Ninety-one percent of patients with good and excellent scores at 12 months and 83% of patients with good and excellent scores at 24 months (a total of 23 and 37 patients, respectively) were able to maintain these scores at 36 months’ follow-up. Similar results were obtained for the Lysholm score. Conclusion: With regard to the improvements in functional outcomes after ACI-Cs at 36 months after surgery, the technique described here appears to lead to satisfying and stable clinical results. This study helps the treating physician to predict the likeliness of further clinical improvements or constant unsatisfactory results after ACI. In patients with good/excellent scores shortly after surgery, deterioration of the knee’s condition is rarely found. For patients with poor and fair postoperative scores, clinical outcomes are more difficult to predict, especially during the first year after the procedure.

CLCN7 and TCIRG1 Mutations Differentially Affect Bone Matrix Mineralization in Osteopetrotic Individuals

Osteopetrosis is an inherited disorder of impaired bone resorption, with the most commonly affected genes being CLCN7 and TCIRG1, encoding the Cl−/H+ exchanger CLC‐7 and the a3 subunit of the vacuolar H+‐ATPase, respectively. We and others have previously shown that the disease is frequently accompanied by osteomalacia, and that this additional pathology is also found in Tcirg1‐deficient oc/oc mice. The remaining question was whether osteoid enrichment is specifically associated with TCIRG1 inactivation, or whether CLCN7 mutations would also cause skeletal mineralization defects. Here we describe a complete osteologic assessment of one family carrying a novel mutation in CLCN7 (D145G), which impairs the activation and relaxation kinetics of the CLC‐7 ion transporter. The two siblings carrying the mutation in the homozygous state displayed high bone mass, increased serum levels of bone formation markers, but no impairment of calcium homeostasis when compared to the other family members. Most importantly, however, undecalcified processing of an iliac crest biopsy from one of the affected children clearly demonstrated a pathological increase of trabecular bone mass, but no signs of osteomalacia. Given the potential relevance of these findings we additionally performed undecalcified histology of iliac crest biopsies from seven additional cases with osteopetrosis caused by a mutation in TNFRSF11A (n = 1), CLCN7 (n = 3), or TCIRG1 (n = 3). Here we observed that all cases with TCIRG1‐dependent osteopetrosis displayed severe osteoid accumulation and decreased calcium content within the mineralized matrix. In contrast, there was no detectable bone mineralization defect in the cases with TNFRSF11A‐dependent or CLCN7‐dependent osteopetrosis. Taken together, our analysis demonstrates that CLCN7 and TCIRG1 mutations differentially affect bone matrix mineralization, and that there is a need to modify the current classification of osteopetrosis.

Low turnover osteoporosis in sheep induced by hypothalamic-pituitary disconnection

The hypothalamus is of critical importance in regulating bone remodeling. This is underscored by the fact that intracerebroventricular‐application of leptin in ewe leads to osteopenia. As a large animal model of osteoporosis, this approach has some limitations, such as high technical expenditure and running costs. Therefore we asked if a surgical ablation of the leptin signaling axis would have the same effects and would thereby be a more useful model. We analyzed the bone phenotype of ewe after surgical hypothalamo‐pituitary disconnection (HPD + OVX) as compared to control ewe (OVX) after 3 and 12 months. Analyses included histomorphometric characterization, micro‐CT and measurement of bone turnover parameters. Already 3 months after HPD we found osteopenic ewe with a significantly decreased bone formation (69%) and osteoclast activity (49%). After a period of 12 months the HPD group additionally developed an (preclinical) osteoporosis with significant reduction (33%) of femoral cortical thickness, as compared to controls (OVX). Taken together, HPD leads after 12 month to osteoporosis with a reduction in both trabecular and cortical bone caused by a low bone turnover situation, with reduced osteoblast and osteoclast activity, as compared to controls (OVX). The HPD‐sheep is a suitable large animal model of osteoporosis. Furthermore our results indicate that an intact hypothalamo‐pituitary axis is required for activation of bone turnover.