René Verdonk

Characterized Chondrocyte Implantation Results in Better Structural Repair When Treating Symptomatic Cartilage Defects of the Knee in a Randomized Controlled Trial Versus Microfracture

Background As the natural healing capacity of damaged articular cartilage is poor, joint surface injuries are a prime target for regenerative medicine. Characterized chondrocyte implantation uses an autologous cartilage cell therapy product that has been optimized for its biological potency to form stable cartilage tissue in vivo. Purpose To determine whether, in symptomatic cartilage defects of the femoral condyle, structural regeneration with characterized chondrocyte implantation is superior to repair with microfracture. Study Design Randomized controlled trial; Level of evidence, 1. Methods Characterized chondrocyte implantation was compared with microfracture in patients with single grade III to IV symptomatic cartilage defects of the femoral condyles in a multicenter trial. Patients aged 18 to 50 years were randomized to characterized chondrocyte implantation (n = 57) or microfracture (n = 61). Structural repair was blindly assessed in biopsy specimens taken at 1 year using (1) computerized histomorphometry and (2) evaluation of overall histological components of structural repair. Clinical outcome was measured using the self administered Knee injury and Osteoarthritis Outcome Score. Adverse events were recorded throughout the study. Results Characterized chondrocyte implantation resulted in better structural repair, as assessed by histomorphometry (P = .003) and overall histologic evaluation (P = .012). Aspects of structural repair relating to chondrocyte phenotype and tissue structure were superior with characterized chondrocyte implantation. Clinical outcome as measured by the Knee injury and Osteoarthritis Outcome Score at 12 to 18 months after characterized chondrocyte implantation was comparable with microfracture at this stage. Both treatment groups had a similar mean baseline overall Knee injury and Osteoarthritis Outcome Score (56.30 ± 13.61 and 59.53 ± 14.95 for microfracture and characterized chondrocyte implantation, respectively), which increased in both groups to 70.56 ± 12.39 and 72.63 ± 15.55 at 6 months, 73.26 ± 14.66 and 73.10 ± 16.01 at 12 months, and 74.73 ± 17.01 and 75.04 ± 14.50 at 18 months, respectively. Both techniques were generally well tolerated; the incidence of adverse events after characterized chondrocyte implantation was not markedly increased compared with that for microfracture. Conclusion One year after treatment, characterized chondrocyte implantation was associated with a tissue regenerate that was superior to that after microfracture. Short-term clinical outcome was similar for both treatments. The superior structural outcome may result in improved long-term clinical benefit with characterized chondrocyte implantation. Long-term follow-up is needed to confirm these findings.

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.

Fluorine-18 fluorodeoxyglucose-positron emission tomography: A highly accurate imaging modality for the diagnosis of chronic musculoskeletal infections.

Background: The noninvasive diagnosis of chronic musculoskeletal infections remains a challenge. Recent studies have indicated that fluorine-18 fluorodeoxyglucose-positron emission tomography is a highly accurate imaging technique and is significantly more accurate than the combination of a bone scan and a white blood-cell scan for the diagnosis of chronic infection in the central skeleton (p < 0.05). However, patients who had had surgery within the previous two years were excluded from study. It was our aim to evaluate the technique in an unselected, clinically representative population. Methods: Sixty patients with a suspected chronic musculoskeletal infection involving the central skeleton (thirty-three patients) or the peripheral skeleton (twenty-seven patients) were studied with fluorine-18 fluorodeoxyglucose-positron emission tomography. Thirty-five patients had had surgery within the previous two years. The fluorine-18 fluorodeoxyglucose-positron emission tomography studies were read in a blinded, independent manner by two experienced readers. The final diagnosis was based on histopathological studies or microbiological culture (eighteen patients) or on clinical findings after at least six months of follow-up (forty-two patients). Results: On the final composite assessment, twenty-five patients had infection and thirty-five did not. All twenty-five infections were correctly identified by both readers. There were four false-positive findings; in two of these cases, surgery had been performed less than six months prior to the study. The sensitivity, specificity, and accuracy were 100%, 88%, and 93% for the whole group; 100%, 90%, and 94% for the subgroup of patients with a suspected infection of the central skeleton; and 100%, 86%, and 93% for the subgroup of patients with a suspected infection of the peripheral skeleton. Interobserver agreement was excellent (kappa = 0.97). Conclusions: Fluorine-18 fluorodeoxyglucose-positron emission tomography is highly accurate as a single technique for the evaluation of chronic musculoskeletal infections. It is especially valuable in the evaluation of the central skeleton, where white blood-cell scans are less useful. Because of its simplicity and high degree of accuracy, it has the potential to become a standard technique for the diagnosis of chronic musculoskeletal infections. Further studies are needed to assess its ability to identify infections at the sites of total joint replacements and to distinguish infection from aseptic loosening of these prostheses.

Tissue Ingrowth After Implantation of a Novel, Biodegradable Polyurethane Scaffold for Treatment of Partial Meniscal Lesions

Background: A novel, biodegradable, aliphatic polyurethane scaffold was designed to fulfill an unmet clinical need in the treatment of patients with irreparable partial meniscal lesions. Hypothesis: Treatment of irreparable partial meniscal lesions with an acellular polyurethane scaffold supports new tissue ingrowth. Study Design: Case series; Level of evidence, 4. Methods: Fifty-two patients (with 34 medial and 18 lateral lesions) were recruited into a prospective, single-arm, multicenter, proof-of-principle study and treated with the polyurethane scaffold. The scaffold was implanted after partial meniscectomy using standard surgeon-preferred techniques for suturing. Tissue ingrowth was assessed at 3 months by dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) and at 12 months by gross examination during second-look arthroscopy, in the course of which a biopsy sample from the inner free edge of the scaffold meniscus was taken for qualitative histologic analysis. Results: Tissue ingrowth at 3 months was demonstrated on DCE-MRI in 35 of 43 (81.4%) patients. All but one 12-month second-look (43 of 44 [97.7%]) showed integration of the scaffold with the native meniscus and all biopsy specimens (44) showed fully vital material, with no signs of cell death or necrosis. Three distinct layers were observed based on morphologic structure, vessel structure presence or absence, and extracellular matrix composition. Conclusion: The DCE-MRI demonstrated successful early tissue ingrowth into the scaffold. The biopsy findings demonstrated the biocompatibility of the scaffold and ingrowth of tissue with particular histologic characteristics suggestive of meniscus-like tissue. In conclusion, these data show for the first time consistent regeneration of tissue when using an acellular polyurethane scaffold to treat irreparable partial meniscus tissue lesions.

Application of BMP-7 to tibial non-unions: A 3-year multicenter experience

SUMMARY The effective treatment of the often debilitating, longlasting and large-asset-consuming complication of fracture non-unions has been in the centre of scientific interest the last decades. The use of alternative bone substitutes to the gold standard of autologous graft includes the osteoinductive molecules named bone morphogenetic proteins (BMPs). A multicenter registry and database (bmpusergroup.co.uk) focused on the application of BMP-7/OP-1 was created in December 2005. We present the preliminary results, using the prospective case-series of aseptic tibial non-unions as an example. Sixty-eight patients fulfilled the inclusion criteria for this observational study, with a minimum follow-up of 12 months. The median duration of tibial non-union prior to BMP-7 application was 23 months (range 9-317 mo). Patients had undergone a median of 2 (range 0-11) revision procedures prior to the administration of BMP-7. In 41% the application of BMP-7 was combined with revision of the fixation at the non-union site. Non-union healing was verified in 61 (89.7%) in a median period of 6.5 months (range 3-15 mo). No adverse events or complications were associated with BMP-7 application. The safety and efficacy of BMP-7 was verified in our case series, and was comparable to the existing evidence. The establishment of multicenter networks and the systematic and long-term follow- up of these patients are expected to provide further information and significantly improve our understanding of this promising osteoinductive bone substitute.

Trochleoplasty in dysplastic knee trochlea

In patients complaining of recurrent patellar dislocations or persistent retropatellar pain due to a dysplastic femoral trochlea, we perform a Henri Dejour trochleoplasty. In this technique the femoral trochlea is deepened by removing the subchondral trochlear bone followed by incision, impaction and fixation of the cartilage flange along the trochlear groove. Between 1996 and 1999, 13 procedures were performed in 12 patients. Strictly lateral X-rays showed dysplasia of the trochlea, as defined by the “crossing sign”, whether or not in combination with patella alta. Patients were assessed using the Larsen–Lauridsen score considering pain, stiffness, osteopatellar crepitus, flexion and loss of function. Although the majority of patients scored fair and poor on an objective scoring system, we achieved 77% good to very good subjective results. Although the result was not perfect, the patients were satisfied with the procedure. This technique might be a valuable alternative in cases of frank trochlear dysplasia associated with persistent retropatellar pain or recurrent patellar dislocations.

Function of the normal meniscus and consequences of meniscal resection.

The principal functions of the meniscus are load transmission and shock absorption, based on the meniscal collagen architecture, the biochemical fluid composition, and the proteoglucan–collagen meshwork. The mobile menisci transmit 50–90% of load over the knee joint, depending on knee flexion angle, femoral translation and rotation. The meniscus contributes to knee joint proprioception and probably also to joint stability. Late consequences of total and partial meniscectomy are radiographic osteoarthritis, with a varying percentage of these patients having symptoms. Malalignment, concomitant articular cartilage lesions, and ligament instability are absolute risk factors, while age, lateral compartment, and continued sport activity are relative risk factors. Acute reinsertion of meniscal tears in the red–red or red–white zones can be performed successfully by arthroscopic technique. Also in chronic tears stable healing can be expected in most cases, if the scar tissue is resected.

Successful Treatment of Painful Irreparable Partial Meniscal Defects With a Polyurethane Scaffold Two-Year Safety and Clinical Outcomes

Background: A novel, biodegradable, polyurethane scaffold was designed to fulfill an unmet clinical need in the treatment of patients with painful irreparable partial meniscal defects. Hypothesis: The use of an acellular polyurethane scaffold for new tissue generation in irreparable partial meniscal defects provides both pain relief and improved functionality. Study Design: Case series; Level of evidence, 4. Methods: Fifty-two patients with irreparable partial meniscal defects (34 medial and 18 lateral, 88% with 1-3 previous surgeries on the index meniscus) were implanted with a polyurethane scaffold in a prospective, single-arm, multicenter, proof-of-principle study. Safety was assessed by the rate of scaffold-related serious adverse events (SAEs) and the International Cartilage Repair Society articular cartilage scoring system comparing magnetic resonance imaging (MRI) at 24 months to MRI at baseline (1 week). Kaplan-Meier time to treatment failure distributions were performed. Clinical outcomes were measured comparing visual analog scale, International Knee Documentation Committee, Knee Injury and Osteoarthritis Outcome Score (KOOS), and Lysholm scores at 24 months from baseline (entry into study). Results: Clinically and statistically significant improvements (P < .0001) compared with baseline were reported in all clinical outcome scores (baseline/24 months): visual analog scale (45.7/20.3), International Knee Documentation Committee (45.4/70.1), KOOS symptoms (64.6/78.3), KOOS pain (57.5/78.6), KOOS activities of daily living (68.8/84.2), KOOS sports (30.5/59.0), KOOS quality of life (33.9/56.6), and Lysholm (60.1/80.7), demonstrating improvements in both pain and function. The incidence of treatment failure was 9 (17.3%) patients, of which 3 patients (8.8%) had medial meniscal defects and 6 patients (33.3%) had lateral meniscal defects. There were 9 SAEs requiring reoperation. Stable or improved International Cartilage Repair Society cartilage grades were observed in 92.5% of patients between baseline and 24 months. Conclusion: At 2 years after implantation, safety and clinical outcome data from this study support the use of the polyurethane scaffold for the treatment of irreparable, painful, partial meniscal defects.

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.