Karl Almqvist

Treatment of Symptomatic Cartilage Defects of the Knee Characterized Chondrocyte Implantation Results in Better Clinical Outcome at 36 Months in a Randomized Trial Compared to Microfracture

Background Damaged articular cartilage has limited capacity for self-repair. Autologous chondrocyte implantation using a characterized cell therapy product results in significantly better early structural repair as compared with microfracture in patients with symptomatic joint surface defects of the femoral condyles of the knee. Purpose To evaluate clinical outcome at 36 months after characterized chondrocyte implantation (CCI) versus microfracture (MF). Study Design Randomized controlled trial; Level of evidence, 1. Methods Patients aged 18 to 50 years with single International Cartilage Repair Society (ICRS) grade III/IV symptomatic cartilage defects of the femoral condyles were randomized to CCI (n = 57) or MF (n = 61). Clinical outcome was measured over 36 months by the Knee injury and Osteoarthritis Outcome Score (KOOS). Serial magnetic resonance imaging (MRI) scans were scored using the Magnetic resonance Observation of Cartilage Repair Tissue (MOCART) system and 9 additional items. Gene expression profile scores associated with ectopic cartilage formation were determined by RT-PCR. Results Baseline mean overall KOOS (±SE) was comparable between the CCI and MF groups (56.30 ± 1.91 vs 59.46 ± 1.98, respectively). Mean improvement (±SE) from baseline to 36 months in overall KOOS was greater in the CCI group than the MF group (21.25 ± 3.60 vs 15.83 ± 3.48, respectively), while in a mixed linear model analysis with time as a categorical variable, significant differences favoring CCI were shown in overall KOOS (P = .048) and the subdomains of Pain (P = .044) and QoL (P = .036). More CCI- than MF-treated patients were treatment responders (83% vs 62%, respectively). In patients with symptom onset of <2 years, the mean improvement (±SE) from baseline to 36 months in overall KOOS was greater with CCI than MF (24.98 ± 4.34 vs 16.50 ± 3.99, respectively) and even greater in patients with symptom onset of <3 years (26.08 ± 4.10 vs 17.09 ± 3.77, respectively). Characterized chondrocyte implantation patients with high (>2) versus low (<2) gene profile scores showed greater improvement from baseline in mean overall KOOS (±SE) at 36 months (28.91 ± 5.69 vs 18.18 ± 5.08, respectively). Subchondral bone reaction significantly worsened over time with MF compared with CCI (P < .05). Conclusion Characterized chondrocyte implantation for the treatment of articular cartilage defects of the femoral condyles of the knee results in significantly better clinical outcome at 36 months in a randomized trial compared with MF. Time to treatment and chondrocyte quality were shown to affect outcome.

Transplantation of viable meniscal allograft. Survivorship analysis and clinical outcome of one hundred cases.

BACKGROUND Few medium-term or long-term reports on meniscal allograft transplantations are available. In this study, we present the results of a survival analysis of the clinical outcomes of our first 100 procedures involving transplantation of viable medial and lateral meniscal allografts performed in ninety-six patients. METHODS Thirty-nine medial and sixty-one lateral meniscal allografts were evaluated after a mean of 7.2 years. Survival analysis was based on specific clinical end points, with failure of the allograft defined as moderate occasional or persistent pain or as poor function. An additional survival analysis was performed to assess the results of the sixty-nine procedures that involved isolated use of a viable allograft (twenty of the thirty-nine medial allograft procedures and forty-nine of the sixty-one lateral allograft procedures) and of the thirteen viable medial meniscal allografts that were implanted in combination with a high tibial osteotomy in patients with initial varus malalignment of the lower limb. RESULTS Overall, eleven (28%) of the thirty-nine medial allografts and ten (16%) of the sixty-one lateral allografts failed. The mean cumulative survival time (11.6 years) was identical for the medial and lateral allografts. The cumulative survival rates for the medial and lateral allografts at ten years were 74.2% and 69.8%, respectively. The mean cumulative survival time and the cumulative survival rate for the medial allografts used in combination with a high tibial osteotomy were 13.0 years and 83.3% at ten years, respectively. CONCLUSIONS Transplantation of a viable meniscal allograft can significantly relieve pain and improve function of the knee joint. Survival analysis showed that this beneficial effect remained in approximately 70% of the patients at ten years. This study identified the need for a prospective study comparing patients with similar symptoms and clinical findings treated with and without a meniscal allograft and followed for a longer period with use of clinical evaluation as well as more objective documentation tools regarding the actual fate of the allograft itself and the articular cartilage.

Five-Year Outcome of Characterized Chondrocyte Implantation Versus Microfracture for Symptomatic Cartilage Defects of the Knee Early Treatment Matters

Background: Characterized chondrocyte implantation (CCI) results in significantly better early structural tissue regeneration than microfracture (MF), and CCI has a midterm clinical benefit over microfracture. Purpose: This study was undertaken to evaluate the 5-year clinical outcome of CCI in a randomized comparison with MF for the treatment of symptomatic cartilage defects of the femoral condyles of the knee. Study Design: Randomized controlled trial; Level of evidence, 1. Methods: Participants aged 18 to 50 years with a symptomatic isolated International Cartilage Repair Society (ICRS) grade III or IV cartilage lesion of the femoral condyles between 1 and 5 cm2 were randomized to either CCI or MF. Clinical outcomes were measured up to 60 months after surgery using the Knee Injury and Osteoarthritis Outcome Score (KOOS). The main outcome parameter was change from baseline in overall KOOS (oKOOS). Adverse events were monitored. Results: Fifty-one participants were treated with CCI and 61 with MF. On average, clinical benefit was maintained through the 60-month follow-up period. The average change from baseline in oKOOS was not different between both groups (least squares [LS] mean ± standard error [SE] 18.84 ± 3.58 for CCI vs 13.21 ± 5.63 for MF; P = .116). Treatment failures were comparable (n = 7 in CCI vs n = 10 in MF), although MF failures tended to occur earlier. Subgroup analysis revealed that CCI resulted in better outcome in participants with time since symptom onset of less than 3 years, which was statistically significant and clinically relevant (change in oKOOS <3 years mean ± SE 25.96 ± 3.45 for CCI vs 15.28 ± 3.17 for MF; P = .026 vs oKOOS >3 years mean ± SE 13.09 ± 4.78 for CCI vs 17.02 ± 4.50 for MF, P = .554). Other subgroup analyses such as age (cutoff 35 years) did not show a difference. Female patients showed more failures irrespective of treatment. Conclusion: At 5 years after treatment, clinical outcomes for CCI and MF were comparable. In the early treatment group, CCI obtained statistically significant and clinically relevant better results than MF. Delayed treatment resulted in less predictable outcomes for CCI. These results provide strong evidence that time since onset of symptoms is an essential variable that should be taken into account in future treatment algorithms for cartilage repair of the knee.

Transplantation of Viable Meniscal Allograft

BACKGROUND Few medium-term or long-term reports on meniscal allograft transplantations are available. In this study, we present the results of a survival analysis of the clinical outcomes of our first 100 procedures involving transplantation of viable medial and lateral meniscal allografts performed in ninety-six patients. METHODS Thirty-nine medial and sixty-one lateral meniscal allografts were evaluated after a mean of 7.2 years. Survival analysis was based on specific clinical end points, with failure of the allograft defined as moderate occasional or persistent pain or as poor function. An additional survival analysis was performed to assess the results of the sixty-nine procedures that involved isolated use of a viable allograft (twenty of the thirty-nine medial allograft procedures and forty-nine of the sixty-one lateral allograft procedures) and of the thirteen viable medial meniscal allografts that were implanted in combination with a high tibial osteotomy in patients with initial varus malalignment of the lower limb. RESULTS Overall, eleven (28%) of the thirty-nine medial allografts and ten (16%) of the sixty-one lateral allografts failed. The mean cumulative survival time (11.6 years) was identical for the medial and lateral allografts. The cumulative survival rates for the medial and lateral allografts at ten years were 74.2% and 69.8%, respectively. The mean cumulative survival time and the cumulative survival rate for the medial allografts used in combination with a high tibial osteotomy were 13.0 years and 83.3% at ten years, respectively. CONCLUSIONS Transplantation of a viable meniscal allograft can significantly relieve pain and improve function of the knee joint. Survival analysis showed that this beneficial effect remained in approximately 70% of the patients at ten years. This study identified the need for a prospective study comparing patients with similar symptoms and clinical findings treated with and without a meniscal allograft and followed for a longer period with use of clinical evaluation as well as more objective documentation tools regarding the actual fate of the allograft itself and the articular cartilage.

A Pilot Study of the Use of an Osteochondral Scaffold Plug for Cartilage Repair in the Knee and How to Deal With Early Clinical Failures

PURPOSE To present our short-term experience with an osteochondral scaffold plug (TruFit plug; Smith & Nephew, Andover, MA) for cartilage repair in the knee and, more importantly, to discuss our approach to treat early clinical failures. METHODS Twenty patients were consecutively treated for their cartilage lesions with the plug technique. These patients were prospectively clinically evaluated at 6 and 12 months of follow-up. Magnetic resonance imaging (MRI) was used for morphologic analysis of the cartilage repair. Biopsy samples were taken from 3 cases during revision surgery, allowing histologic assessment of the repair tissue. RESULTS The short-term clinical and MRI outcome of this pilot study are modest. No signs of deterioration of the repair tissue were observed. Of the 15 patients followed up during 1 year, 3 (20.0%) showed persistent clinical symptoms or even more clinical symptoms after insertion of the plug. These patients were considered as failures and therefore eligible for revision surgery. During revision surgery, the repair tissue was carefully removed. The remaining osteochondral defect was filled with autologous bone grafts. Immediate and persistent relief of symptoms was observed in all 3 patients. Histologic assessment of biopsy specimens taken during revision surgery showed fibrous vascularized repair tissue with the presence of foreign-body giant cells. CONCLUSIONS The overall short-term clinical and MRI outcome of the osteochondral scaffold plug for cartilage repair in the knee is modest. In this pilot study a modest clinical improvement became apparent at 12 months of follow-up. MRI data showed no deterioration of the repair tissue. Of the 15 patients, 3 (20%) had persistent clinical symptoms after surgery. These patients were successfully treated with removal of the osteochondral plug remnants and the application of autologous bone grafts. LEVEL OF EVIDENCE Level IV, therapeutic case series.

Silkworm and spider silk scaffolds for chondrocyte support.

Objective To create scaffolds with silkworm cocoon, spider egg sac and spider dragline silk fibres and examine their use for chondrocyte attachment and support. Methods Three different kinds of scaffolds were developed with Bombyx mori cocoon, Araneus diadematus egg sac and dragline silk fibres. The attachment of human articular cartilage cells were investigated on these bioprotein matrices. The chondrocytes produced an extracellular matrix which was studied by immunostaining. Moreover, the compression behaviour in relation to the porosity was studied. Results The compression modulus of a silkworm silk scaffold was related to its porosity. Chondrocytes were able to attach and to grow on the different fibres and in the scaffolds for several weeks while producing extracellular matrix products. Conclusion Porous scaffolds can be made out of silkworm and spider silk for cartilage regeneration. Mechanical properties are related to porosity and pore size of the construct. Cell spreading and cell expression depended on the porosity and pore-size.

Treatment of Cartilage Defects in the Knee Using Alginate Beads Containing Human Mature Allogenic Chondrocytes

Background The repair of osteochondral lesions is imperfect and transient; chondral lesions do not heal in mature cartilage. Attempts have been made to restore cartilage lesions by filling the defects with a temporary artificial biocompatible matrix. Purpose To determine whether the implantation of alginate beads containing human mature allogenic chondrocytes is feasible and safe for the treatment of symptomatic cartilage defects in the knee. Study Design Case series; Level of evidence, 4. Methods A biodegradable, alginate-based, biocompatible scaffold containing human mature allogenic chondrocytes was used for the treatment of chondral and osteochondral lesions in the knee. Twenty-one patients were clinically and prospectively evaluated with use of the Western Ontario and McMaster Universities Osteoarthritis Index and a visual analog scale for pain preoperatively and at 3, 6, 9, 12, 18, and 24 months of follow-up. Of the 21 patients, 13 consented to having a biopsy sample taken for investigative purposes from the area of implantation at 12 months of follow-up, allowing histologic assessment of the repair tissue. Results A statistically significant clinical improvement became apparent after 6 months, and patients improved during the 24 months of follow-up. Adverse reactions to the alginate/fibrin matrix seeded with the allogenic cartilage cells were not observed. Histologic analysis of the biopsy specimens rated the repair tissue as hyaline-like in 15.3% of the samples, as mixed tissue in 46.2%, as fibrocartilage in 30.8%, and as fibrous in 7.7%. Conclusion The results of this short-term pilot study show that the alginate-based scaffold containing human mature allogenic chondrocytes is feasible and safe for the treatment of symptomatic cartilage defects of the knee. The described technique provides clinical and histologic outcomes that are equal but not superior to those of other cartilage repair techniques.

Culture of chondrocytes in alginate surrounded by fibrin gel: characteristics of the cells over a period of eight weeks

OBJECTIVE To produce tissue engineered cartilage by human articular chondrocytes in vitro for further use in in vivo manipulations for the treatment of cartilage defects. METHODS Human articular chondrocytes were cultured in 0.5%, 1.0%, and 2.0% of alginate for up to four weeks. The optimal concentration of an alginate matrix for cell replication and for aggrecan synthesis by chondrocytes was determined. DNA content in the different culture conditions was measured after two and four weeks. Aggrecan synthesis rates and accumulation in the surrounding extracellular matrix were assessed by [35S]sulphate incorporation after the same periods of culture. To follow the outgrowth of chondrocytes from the alginate beads, chondrocytes were cultured for four weeks in 0.5 or 1.0% alginate surrounded by 0.25 or 0.5% fibrin gel. DNA content of each culture was measured after different culture periods. Finally, human chondrocytes in 1.0% alginate beads were embedded in 0.5% fibrin gel for eight weeks. Immunohistochemical analysis for aggrecan, type I and II collagen was performed weekly. RESULTS At two weeks the DNA content in each culture significantly increased in 0.5 and 1.0% alginate cultures in comparison with baseline values. This increase continued until week 4 at the three alginate concentrations. Aggrecan synthesis at two weeks was highest in 0.5 and 1.0% alginate cell cultures. At four weeks aggrecan synthesis rates decreased independently of the alginate concentrations. Aggrecan mainly accumulated in the interterritorial matrix. Proliferation of chondrocytes in alginate and outgrowth of these cells in the surrounding fibrin gel were evident throughout the culture period. The accumulation of aggrecan and type II collagen around the cells, in alginate as well as in fibrin gel, gradually increased over the culture period. Type I collagen appeared after six weeks in alginate and in the surrounding fibrin. CONCLUSION Human chondrocytes proliferate in this culture system, show an outgrowth into the surrounding fibrin, and synthesise a cartilage-like matrix for up to eight weeks.

Functional adaptation of knee cartilage in asymptomatic female novice runners compared to sedentary controls. A longitudinal analysis using delayed Gadolinium Enhanced Magnetic Resonance Imaging of Cartilage (dGEMRIC)

OBJECTIVE To longitudinally estimate the change in glycosaminoglycan content of knee cartilage in asymptomatic untrained female novice runners participating in a Start To Run program (STR) compared to sedentary controls. METHOD Nine females enrolling in a 10-week STR and 10 sedentary controls participated voluntarily. Prior to and after the 10-week period, both groups were subjected to dGEMRIC imaging. dGEMRIC indices of knee cartilage were determined at baseline and for the change after the 10-week period in both groups. Based on a self-reported weekly log, physical activity change during the study was depicted as decreased, unchanged or increased. The Mann-Whitney U and Kruskal-Wallis tests were applied to test the hypotheses that dGEMRIC changes occurred between groups and according to physical activity changes respectively. RESULTS No significant differences were established between groups for dGEMRIC indices at baseline (P=0.541). A significant positive change of the median dGEMRIC index in the runners group was demonstrated when compared to the controls [+11.66ms (95% CI: -25.29, 44.43) vs -9.56ms (95% CI: -29.55, 5.83), P=0.006]. The change in dGEMRIC index differed significantly according to physical activity change (P=0.014), showing an increase in dGEMRIC index with increasing physical activity. CONCLUSION Since cartilage appears to positively respond to moderate running when compared to a sedentary lifestyle, this running scheme might be considered a valuable tool in osteoarthritis prevention strategies. Caution is warranted when applying these results to a wider population and to longer training periods.

Meniscal allografts: Indications and outcomes

Meniscal allograft transplantation was introduced into clinical practice now over 20 years ago for the treatment of the symptomatic postmeniscectomy patient who has not yet developed osteoarthritis. Over the years, the indications have been fine-tuned and certain risk factors for failure have been identified. As the number of publications increases steadily, we now know that meniscal allografting significantly reduces pain and improves function. Recent data also suggest a potential chondroprotective effect in a subpopulation of patients. However, the major drawback in all meniscus allograft studies is the general lack of a control population. To improve our knowledge, future prospective studies should include objective outcome tools to evaluate the status of the allograft in addition to the clinical scoring systems. Future research should focus to elucidate the biologic and cellular processes involved in graft repopulation and remodelation.