Significant improvements in clinical outcome measures and patient satisfaction after combined all-arthroscopic meniscal allograft transplantation and autologous chondrocyte implantation: A single-centre longitudinal study.

PURPOSE: The optimal treatment approach for the complex pathology of meniscal insufficiency and coexisting full-thickness cartilage defects remains unclear. The purpose of this study was to evaluate the viability, safety, and efficacy of this combined surgical approach at medium-term follow-up. METHODS: This is a single-centre longitudinal study with blinded outcome assessment. All consecutive patients treated with combined all-arthroscopic meniscal allograft transplantation (MAT) with bone bridge fixation and ACI using chondrospheres at our institution between 2001 and 2021 were eligible for inclusion. Twenty patients with an average follow-up of 72.6 ± 34.4 months were included in the statistical analysis. Clinical outcomes were assessed pre- and postoperatively using the IKDC Subjective Knee Form, Lysholm Score, Tegner Activity Scale, KOOS, and Visual Analog Scale (VAS) for patient satisfaction. Failure and reoperation rates were assessed, and cartilage regeneration tissue was evaluated on postoperative MRI. RESULTS: IKDC scores significantly improved from 52.1 ± 16.9 to 68.5 ± 16.3 (p = 0.003). Lysholm scores improved from 61.5 ± 21.7 to 78.5 ± 12.9 (p = 0.004). Tegner scores improved from 3.5 (1-4) to 4.0 (2-6) (p = 0.014). KOOS scores improved significantly across all subcategories, except 'symptoms', where improvements did not reach statistical significance. VAS for overall patient satisfaction showed improvements but did not reach statistical significance. The combined procedure was successful in 17 patients (85%). Eight patients had to undergo reoperation (40%), comprising mostly small, arthroscopic procedures. Seven reoperations were directly attributable to meniscal allograft transplantation (46.7%). Postoperative Magnetic Resonance Observation of Cartilage Repair Tissue scores were 68.9 ± 16.8 (n = 14). CONCLUSION: Combined arthroscopic MAT and autologous chondrocyte implantation (ACI) is a viable, safe, and effective treatment approach for younger patients with meniscal insufficiency and coexisting full-thickness cartilage damage, where alternative treatment options are limited. The combined surgical procedure achieved significant improvements in clinical outcome measures and patient satisfaction with acceptable failure and high arthroscopic reoperation rates. MAT is the limiting part of this combined procedure, with most failures and reoperations being attributable to MAT, as opposed to ACI. LEVEL OF EVIDENCE: Level III.

Safety and Efficacy of Matrix-Associated Autologous Chondrocyte Implantation With Spheroids for Patellofemoral or Tibiofemoral Defects: A 5-Year Follow-up of a Phase 2, Dose-Confirmation Trial.

BACKGROUND: Matrix-associated autologous chondrocyte implantation (ACI) is a well-established treatment for cartilage defects. High-level evidence at midterm follow-up is limited, especially for ACI using spheroids (spherical aggregates of ex vivo expanded human autologous chondrocytes and self-synthesized extracellular matrix). PURPOSE: To assess the safety and efficacy of 3-dimensional matrix-associated ACI using spheroids to treat medium to large cartilage defects on different locations in the knee joint (patella, trochlea, and femoral condyle) at 5-year follow-up. STUDY DESIGN: Cohort study; Level of evidence, 2. METHODS: A total of 75 patients aged 18 to 50 years with medium to large (4-10 cm2), isolated, single cartilage defects, International Cartilage Repair Society grade 3 or 4, were randomized on a single-blind basis to treatment with ACI at 1 of 3 dose levels: 3 to 7, 10 to 30, or 40 to 70 spheroids/cm2 of defect size. Outcomes were assessed via changes from baseline Knee injury and Osteoarthritis Outcome Score (KOOS), International Knee Documentation Committee score, and modified Lysholm assessments at 1- and 5-year follow-up. Structural repair was evaluated using MOCART (magnetic resonance observation of cartilage repair tissue) score. Treatment-related adverse events were assessed up to 5 years for all patients. The overall KOOS at 12 months was assessed for superiority versus baseline in a 1-sample, 2-sided t test. RESULTS: A total of 73 patients were treated: 24 in the low-dose group, 25 in the medium-dose group, and 24 in the high-dose group. The overall KOOS improved from 57.0 ± 15.2 at baseline to 73.4 ± 17.3 at 1-year follow-up (P < .0001) and 76.9 ± 19.3 at 5-year follow-up (P < .0001), independent of the applied dose. The different defect locations (patella, trochlea, and weightbearing part of the femoral condyles; P = .2216) and defect sizes (P = .8706) showed comparable clinical improvement. No differences between the various doses were observed. The overall treatment failure rate until 5 years was 4%. Most treatment-related adverse events occurred within the first 12 months after implantation, with the most frequent adverse reactions being joint effusion (n = 71), arthralgia (n = 14), and joint swelling (n = 9). CONCLUSION: ACI using spheroids was safe and effective for defect sizes up to 10 cm2 and showed maintenance of efficacy up to 5 years for all 3 doses that were investigated. REGISTRATION: NCT01225575 (ClinicalTrials.gov identifier); 2009-016816-20 (EudraCT number).

Good healing potential of patellar chondral defects after all-arthroscopic autologous chondrocyte implantation with spheroids: a second-look arthroscopic assessment.

PURPOSE: To report second-look arthroscopic assessment after all-arthroscopic autologous chondrocyte implantation (ACI) for articular cartilage defects at the patella. METHODS: A second-look arthroscopy after all-arthroscopic ACI using chondrospheres® (ACT3D) was performed in 30 patients with 30 full-thickness retropatellar cartilage defects. The mean time from ACI to second-look arthroscopy was 14.9 ± 16.3 (6-71) months. The quality of cartilage regeneration was evaluated by the International Cartilage-Repair Score (ICRS)-Cartilage Repair Assessment (CRA). RESULTS: Eleven lesions (36.7%) were classified as CRA grade I (normal) and 19 lesions (63.3%) as grade II (nearly normal). Concerning the degree of defect repair, 25 lesions (83.3%) were repaired up to the height of the surrounding articular retropatellar cartilage. Five lesions (16.7%) showed 75% repair of defect depth. The border zone was completely integrated into the surrounding articular cartilage shoulder in 28 lesions (93.3%) and demarcated within 1 mm in 2 lesions (6.7%). Macroscopically and by probing, 12 lesions (40%) had intact smooth surface, 17 lesions (56.7%) had fibrillated surface and 1 lesion (3.3%) had small, scattered fissures. A negative correlation was found between the overall repair assessment score and the defect size (r2 = - 0.430, p = 0.046) and between integration into border zone and defect size (r2 = - 0.340, p = 0.045). A positive correlation was found between macroscopic appearance and age (r2 = + 0.384, p = 0.036). CONCLUSIONS: All-arthroscopic ACI using chondrospheres® (ACT3D) for full-thickness retropatellar articular cartilage defects proved to be reproducible and reliable. The advantage of the procedure is that it is minimal invasive. Arthroscopic second-look demonstrated a high grade of normal or nearly normal cartilage regeneration. Although statistically significant differences were not observed, larger defect size and younger age may compromise the result of overall repair. LEVEL OF EVIDENCE: III.

Return to Sport After Anterior Cruciate Ligament Injury: Panther Symposium ACL Injury Return to Sport Consensus Group.

BACKGROUND: A precise and consistent definition of return to sport (RTS) after anterior cruciate ligament (ACL) injury is lacking, and there is controversy surrounding the process of returning patients to sport and their previous activity level. PURPOSE: The aim of the Panther Symposium ACL Injury Return to Sport Consensus Group was to provide a clear definition of RTS after ACL injury and a description of the RTS continuum as well as provide clinical guidance on RTS testing and decision-making. STUDY DESIGN: Consensus statement. METHODS: An international, multidisciplinary group of ACL experts convened as part of a consensus meeting. Consensus statements were developed using a modified Delphi method. Literature review was performed to report the supporting evidence. RESULTS: Key points include that RTS is characterized by achievement of the preinjury level of sport and involves a criteria-based progression from return to participation to RTS and, ultimately, return to performance. Purely time-based RTS decision-making should be abandoned. Progression occurs along an RTS continuum, with decision-making by a multidisciplinary group that incorporates objective physical examination data and validated and peer-reviewed RTS tests, which should involve functional assessment as well as psychological readiness. Consideration should be given to biological healing, contextual factors, and concomitant injuries. CONCLUSION: The resultant consensus statements and scientific rationale aim to inform the reader of the complex process of RTS after ACL injury that occurs along a dynamic continuum. Research is needed to determine the ideal RTS test battery, the best implementation of psychological readiness testing, and methods for the biological assessment of healing and recovery.

Treatment After Anterior Cruciate Ligament Injury: Panther Symposium ACL Treatment Consensus Group.

Treatment strategies for anterior cruciate ligament (ACL) injuries continue to evolve. Evidence supporting best-practice guidelines for the management of ACL injury is to a large extent based on studies with low-level evidence. An international consensus group of experts was convened to collaboratively advance toward consensus opinions regarding the best available evidence on operative versus nonoperative treatment for ACL injury. The purpose of this study was to report the consensus statements on operative versus nonoperative treatment of ACL injuries developed at the ACL Consensus Meeting Panther Symposium 2019. There were 66 international experts on the management of ACL injuries, representing 18 countries, who were convened and participated in a process based on the Delphi method of achieving consensus. Proposed consensus statements were drafted by the scientific organizing committee and session chairs for the 3 working groups. Panel participants reviewed preliminary statements before the meeting and provided initial agreement and comments on the statement via online survey. During the meeting, discussion and debate occurred for each statement, after which a final vote was then held. Ultimately, 80% agreement was defined a priori as consensus. A total of 11 of 13 statements on operative versus nonoperative treatment of ACL injury reached consensus during the symposium. Overall, 9 statements achieved unanimous support, 2 reached strong consensus, 1 did not achieve consensus, and 1 was removed because of redundancy in the information provided. In highly active patients engaged in jumping, cutting, and pivoting sports, early anatomic ACL reconstruction is recommended because of the high risk of secondary meniscal and cartilage injuries with delayed surgery, although a period of progressive rehabilitation to resolve impairments and improve neuromuscular function is recommended. For patients who seek to return to straight-plane activities, nonoperative treatment with structured, progressive rehabilitation is an acceptable treatment option. However, with persistent functional instability, or when episodes of giving way occur, anatomic ACL reconstruction is indicated. The consensus statements derived from international leaders in the field will assist clinicians in deciding between operative and nonoperative treatment with patients after an ACL injury.

Anterior Cruciate Ligament Reconstruction Using a Ribbon-Like Graft With a C-Shaped Tibial Bone Tunnel.

According to recent anatomic studies, the anterior cruciate ligament (ACL) appears to be a flat, "ribbon-like" structure, with a thin, oval-shaped insertion on the femur and a C-shaped tibial insertion. According to this anatomy, we describe an ACL-reconstruction technique that aims to approximate this natural anatomy. The basic principle of this technique is not to use conventional round tunnels but create tunnel shapes that resemble more closely the original ACL insertion sites. Using either a rectangular quadriceps tendon graft or a "flat" hamstring graft may not only provide a biomechanical advantage with increased rotational stability but also improve bone-tendon healing due to increased bone-tendon contact and decreased diffusion length. Creating a C-shaped tibial tunnel also avoids laceration of the anterior horn of the lateral meniscus, which is frequently harmed during conventional tibial tunnel drilling.

Safety and efficacy of matrix-associated autologous chondrocyte implantation with spheroid technology is independent of spheroid dose after 4 years.

PURPOSE: The aim of this study was to investigate the effect of product dose in autologous chondrocyte implantation (ACI) for the treatment of full-thickness cartilage defects of the knee and to assess its influence on clinical and morphological mid-term outcome. METHODS: Seventy-five patients were included in this single-blind, randomised, prospective, controlled clinical trial. Patients were assigned randomly to three different dose groups [low (3-7 spheroids/cm2), medium (10-30 spheroids/cm2), or high (40-70 spheroids/cm2)] and assessed using standardised clinical and morphological scoring systems (KOOS, IKDC, MOCART) for 4 years following the intervention. RESULTS: The analysis population comprised 75 patients (22 women, 53 men) aged 34 ± 9 years. Defect sizes ranged from 2 to 10 cm2 following intraoperative debridement. The assessment of the primary variable 'overall KOOS' showed a statistically significant improvement, compared with baseline, for each dose group, i.e., at baseline the mean 'overall KOOS' scores were 60.4 ± 13.6, 59.6 ± 15.4, and 51.1 ± 15.4 for the low-, medium-, and high-dose groups, respectively, and 57.0 ± 15.2 for 'all patients'. After 48 months those values improved to 80.0 ± 14.7, 84.0 ± 14.9, and 66.9 ± 21.5 in the respective dose groups and 77.1 ± 18.6 for 'all patients'. Pairwise comparisons of these dose groups did not reveal any statistically significant differences. Likewise, assessment of the subjective IKDC score revealed no statistically significant differences between the three dose groups up to the 48-month visit. However, between 12 and 48 months there was a low, but steady, improvement in the low-dose group and a substantial amelioration in the medium-dose group. The mean MOCART total scores 3 months after treatment were 59.8 ± 10.9, 64.5 ± 10.3, and 64.7 ± 9.4 for the low-, medium-, and high-dose groups, and 62.9 ± 10.3 for 'all patients'; 48 months after treatment these were 73.9 ± 13.1, 78.0 ± 12.4, and 74.3 ± 14.0 for the respective dose groups and 75.5 ± 13.1 for 'all patients'. CONCLUSIONS: Results of this study confirm the efficacy and safety of the applied "advanced therapy medicinal product"; no dose dependence was found either for the incidence or for the severity of any adverse reactions. All doses applied in the present study led to significant clinical improvement over time and can therefore be regarded as effective doses. The influence of product doses in the range investigated seems to be low and can be neglected. Thus, the authorised dose range of 10-70 spheroids/cm2 confirmed by this clinical trial offers a broad therapeutic window for the surgeon applying the product, thereby reducing the risk of over- or underdosing. LEVEL OF EVIDENCE: I.

Clinical outcome and success rates of ACI for cartilage defects of the patella: a subgroup analysis from a controlled randomized clinical phase II trial (CODIS study).

AIM: Cartilage defects of the patella are considered as a problematic entity. Purpose of the present study was to evaluate the outcome of patients treated with autologous chondrocyte implantation (ACI) for cartilage defects of the patella in comparison to patient with defects of the femoral condyles. PATIENTS AND METHODS: 73 patients with a follow-up of 5 years have been included in this subgroup analysis of the randomized controlled clinical trial (RCT). In dependence of defect location, patients were divided into two groups [patella defects (n = 45) and femoral condyle defects (n = 28)]. Clinical outcome was evaluated by the means of the KOOS score at baseline and 6 weeks, 3, 6, 12, 18, 24, 36, 48 and 60 months following ACI. RESULTS: "Responder rate" at 60 months (improvement from baseline of > 7 points in the KOOS score) in patients with patella defects was 86.2%. All scores showed a significant improvement from baseline. While overall KOOS score at 60 months was 81.9 (SD 18.6) points in femoral condyle defects, a mean of 82.6 (SD 14.0) was observed in patella defects (p = 0.2483). CONCLUSION: ACI seems an appropriate surgical treatment for cartilage defects of the patella leading to a high success rate. In this study, the clinical outcome in patients with patellar defects was even better than the already excellent results in patients with defects of the femoral condyle even though the study included relatively large defect sizes for both groups (mean defect size 6.0 ± 1.7 and 5.4 ± 1.6 for femur and patella, respectively).

Matrix-Associated Autologous Chondrocyte Implantation Is an Effective Treatment at Midterm Follow-up in Adolescents and Young Adults.

BACKGROUND: Autologous chondrocyte implantation (ACI) is an established method for treating cartilage defects in the knee of adult patients. However, less is known about its effectiveness in adolescents. HYPOTHESIS: Third-generation matrix-associated ACI (MACI) using spheroids (co.don chondrosphere/Spherox) is an effective and safe treatment for articular cartilage defects in adolescents aged 15 to 17 years, with outcomes comparable with those for young adults aged 18 to 34 years. STUDY DESIGN: Cohort study; Level of evidence, 3. METHODS: A total of 71 patients (29 adolescents, 42 young adults) who had undergone ACI using spheroids were evaluated retrospectively in this multicenter study. For adolescents, the mean defect size was 4.6 ± 2.4 cm2, and the follow-up range was 3.5 to 8.0 years (mean, 63.3 months). For young adults, the mean defect size was 4.7 ± 1.2 cm2, and the follow-up range was 3.8 to 4.3 years (mean, 48.4 months). At the follow-up assessment, outcomes were assessed by using validated questionnaires (Knee injury and Osteoarthritis Outcome Score [KOOS], International Knee Documentation Committee [IKDC] subjective knee evaluation form and current health assessment form, and modified Lysholm score), the magnetic resonance observation of cartilage repair tissue (MOCART) score, and if relevant, time to treatment failure. Safety was assessed by the treatment failure rate. RESULTS: No significant difference between the 2 study groups was found for KOOS, IKDC, or MOCART scores, with all patients achieving high functional values. A significant difference was found in the modified Lysholm score, favoring the young adult group over the adolescent group (22.3 ± 1.9 vs 21.0 ± 2.4, respectively; P = .0123). There were no differences between the rates of treatment failure, with 3% in the adolescent group and 5% in the young adult group. CONCLUSION: Third-generation MACI using spheroids is a safe and effective treatment for large cartilage defects of the knee in adolescents at midterm follow-up. Outcomes are comparable with those for young adults after ACI.

2018 International Olympic Committee Consensus Statement on Prevention, Diagnosis, and Management of Pediatric Anterior Cruciate Ligament Injuries.

In October 2017, the International Olympic Committee hosted an international expert group of physical therapists and orthopaedic surgeons who specialize in treating and researching pediatric anterior cruciate ligament (ACL) injuries. The purpose of this meeting was to provide a comprehensive, evidence-informed summary to support the clinician and help children with ACL injury and their parents/guardians make the best possible decisions. Representatives from the following societies attended: American Orthopaedic Society for Sports Medicine; European Paediatric Orthopaedic Society; European Society for Sports Traumatology, Knee Surgery, and Arthroscopy; International Society of Arthroscopy, Knee Surgery and Orthopaedic Sports Medicine; Pediatric Orthopaedic Society of North America; and Sociedad Latinoamericana de Artroscopia, Rodilla, y Deporte. Physical therapists and orthopaedic surgeons with clinical and research experience in the field and an ethics expert with substantial experience in the area of sports injuries also participated. This consensus statement addresses 6 fundamental clinical questions regarding the prevention, diagnosis, and management of pediatric ACL injuries. Injury management is challenging in the current landscape of clinical uncertainty and limited scientific knowledge. Injury management decisions also occur against the backdrop of the complexity of shared decision making with children and the potential long-term ramifications of the injury.

2018 International Olympic Committee consensus statement on prevention, diagnosis and management of paediatric anterior cruciate ligament (ACL) injuries.

In October 2017, the International Olympic Committee hosted an international expert group of physiotherapists and orthopaedic surgeons who specialise in treating and researching paediatric anterior cruciate ligament (ACL) injuries. Representatives from the American Orthopaedic Society for Sports Medicine, European Paediatric Orthopaedic Society, European Society for Sports Traumatology, Knee Surgery and Arthroscopy, International Society of Arthroscopy Knee Surgery and Orthopaedic Sports Medicine, Pediatric Orthopaedic Society of North America, and Sociedad Latinoamericana de Artroscopia, Rodilla y Deporte attended. Physiotherapists and orthopaedic surgeons with clinical and research experience in the field, and an ethics expert with substantial experience in the area of sports injuries also participated. Injury management is challenging in the current landscape of clinical uncertainty and limited scientific knowledge. Injury management decisions also occur against the backdrop of the complexity of shared decision-making with children and the potential long-term ramifications of the injury. This consensus statement addresses six fundamental clinical questions regarding the prevention, diagnosis, and management of paediatric ACL injuries. The aim of this consensus statement is to provide a comprehensive, evidence-informed summary to support the clinician, and help children with ACL injury and their parents/guardians make the best possible decisions.

2018 International Olympic Committee consensus statement on prevention, diagnosis and management of paediatric anterior cruciate ligament (ACL) injuries.

In October 2017, the International Olympic Committee hosted an international expert group of physiotherapists and orthopaedic surgeons who specialise in treating and researching paediatric ACL injuries. Representatives from the American Orthopaedic Society for Sports Medicine, European Paediatric Orthopaedic Society, European Society for Sports Traumatology, Knee Surgery & Arthroscopy, International Society of Arthroscopy Knee Surgery and Orthopaedic Sports Medicine, Pediatric Orthopaedic Society of North America and Sociedad Latinoamericana de Artroscopia, Rodilla y Deporte attended. Physiotherapists and orthopaedic surgeons with clinical and research experience in the field, and an ethics expert with substantial experience in the area of sports injuries also participated. Injury management is challenging in the current landscape of clinical uncertainty and limited scientific knowledge. Injury management decisions also occur against the backdrop of the complexity of shared decision-making with children and the potential long-term ramifications of the injury. This consensus statement addresses six fundamental clinical questions regarding the prevention, diagnosis and management of paediatric ACL injuries. The aim of this consensus statement is to provide a comprehensive, evidence-informed summary to support the clinician, and help children with ACL injury and their parents/guardians make the best possible decisions.

"I never made it to the pros " Return to sport and becoming an elite athlete after pediatric and adolescent anterior cruciate ligament injury-Current evidence and future directions.

The management of anterior cruciate ligament (ACL) injuries in the skeletally immature and adolescent patient remains an area of controversy in sports medicine. This study, therefore, summarizes and discusses the current evidence related to treating pediatric and adolescent patients who sustain an ACL injury. The current literature identifies a trend towards ACL reconstruction as the preferred treatment option for ACL injuries in the young, largely justified by the risk of further structural damage to the knee joint. Worryingly, a second ACL injury is all too common in the younger population, where almost one in every three to four young patients who sustain an ACL injury and return to high-risk pivoting sport will go on to sustain another ACL injury. The clinical experience of these patients emphasizes the rarity of an athlete who makes it to elite level after a pediatric or adolescent ACL injury, with or without reconstruction. If these patients are unable to make it to an elite level of sport, treatment should possibly be modified to take account of the risks associated with returning to pivoting and strenuous sport. The surveillance of young athletes may be beneficial when it comes to reducing injuries. Further research is crucial to better understand specific risk factors in the young and to establish independent structures to allow for unbiased decision-making for a safe return to sport after ACL injury. Level of evidence V.

Good clinical and MRI outcome after arthroscopic autologous chondrocyte implantation for cartilage repair in the knee.

PURPOSE: To analyze the clinical outcome and cartilage regeneration after all-arthroscopic Autologous Chondrocyte Implantation (ACI) using chondrospheres® (ACT3D) for the treatment of full-size articular cartilage lesions at the knee. METHODS: Thirty consecutive patients treated by all-arthroscopic ACI for full-size articular cartilage lesions in an otherwise healthy knee were enrolled. The defects were located on the femoral condyles (n = 18), in the trochlea (n = 7) and at the patella (n = 5). Follow-up consisted of a clinical evaluation with assessment of subjective scores. Patient satisfaction was evaluated on a visual analog scale (VAS). 3-Tesla MRI and T2 mapping of the operated and the contralateral healthy knees were included to control the quality of the regenerated cartilage. The MOCART score was assessed by three blinded independent radiologists. RESULTS: At the mean follow-up of 3 years ± 10.2 months 26 of the 30 patients (86.6%) were subjectively highly satisfied with the surgical result and assured they would undergo the same procedure again. The mean Lysholm score increased to 77.7 ± 14.6, the mean subjective IKDC significantly to 84.2 ± 5.6 (p < 0.05) and all five subgroups of the KOOS improved significantly (p < 0.05). The subjective outcome was not influenced by the duration of symptoms, age, location, size of defects nor dose of spheroids. The modified MOCART score was a mean of 60 ± 21 (0-80) points. Twenty-four patients (82.7%) were rated higher than 60 points. T2 mapping documented similar cartilage quality of the area of the ACI and the same location at the contralateral knee. Three patients had a MOCART score of 0 with few or no cartilage regeneration on MRI and were considered as failure of the ACI. CONCLUSION: In this small cohort of 30 patients, minimal invasive all-arthroscopic ACT 3D using spheroids led to convincing clinical short-to-mid-term results with a significant increase in patients quality of life, satisfaction, reduction of pain, and improvement in knee function. The high morphologic integrity and quality of the ACI was reconfirmed by the Mocart Score and T2 mapping. LEVEL OF EVIDENCE: IV.

Safety of three different product doses in autologous chondrocyte implantation: results of a prospective, randomised, controlled trial.

BACKGROUND: This study was conducted to assess the efficacy and safety of the three dose levels of the three-dimensional autologous chondrocyte implantation product chondrosphere® in the treatment of cartilage defects (4-10 cm2) of knee joints. We hereby report the safety results for a 36-month post-treatment observation period. METHODS: This was a prospective phase II trial with a clinical intervention comprising biopsy for culturing spheroids and their subsequent administration (level of evidence: I). Patients' knee defects were investigated by arthroscopy, and a cartilage biopsy was taken for culturing. Patients were randomised, on a single-blind basis, to treatment at the dose levels 3-7 (low), 10-30 (medium) or 40-70 (high) spheroids per square centimetre. Assessment (adverse events, vital signs, electrocardiography, physical examination, concomitant medication and laboratory values) took place 1.5, 3, 6, 12, 24 and 36 months after chondrocyte implantation. RESULTS: Seventy-five patients were included and 73 treated. The incidence of adverse events, of patients with adverse events and of patients with treatment-related adverse events showed no relevant difference between the treatment groups. There were no fatal adverse events, no adverse events led to premature withdrawal from the trial and none led to permanent sequelae. Two patients experienced serious adverse events considered related to the study treatment: arthralgia 2-3 years after implantation and chondropathy 1 and 2 years after implantation. CONCLUSIONS: The treatment with chondrosphere® was generally well tolerated. No relationship was detected between any safety criteria and the dose level: Differences between the dose groups in the incidence of any adverse events, and in numbers of patients with treatment-related adverse events, were insubstantial. TRIAL REGISTRATION: clinicaltrials.gov, NCT01225575 .

The Effect of Cell Dose on the Early Magnetic Resonance Morphological Outcomes of Autologous Cell Implantation for Articular Cartilage Defects in the Knee: A Randomized Clinical Trial.

BACKGROUND: Although autologous chondrocyte implantation (ACI) has been established as a standard treatment for large full-thickness cartilage defects, the effect of different doses of autologous chondrocyte products on structural outcomes has never been examined. HYPOTHESIS: In ACI, the dose level may have an influence on medium-term magnetic resonance morphological findings after treatment. STUDY DESIGN: Randomized controlled trial; Level of evidence, 1. METHODS: A total of 75 patients who underwent ACI using a pure, autologous, third-generation matrix-associated ACI product were divided into 3 groups representing different doses: 3 to 7 spheroids/cm(2), 10 to 30 spheroids/cm(2), and 40 to 70 spheroids/cm(2). Magnetic resonance imaging was performed at 1.5, 3, 6, and 12 months after ACI and was evaluated by the magnetic resonance observation of cartilage repair tissue (MOCART) score and the Knee injury and Osteoarthritis Outcome Score (KOOS). RESULTS: MOCART scores showed improvements after 3 months, with slight dose dependence, and further improvement after 12 months, although without significant dose dependence. The mean MOCART scores after 3 months (0 = worst, 100 = best) were 59.8, 64.5, and 64.7 for the low-, medium-, and high-dose groups, respectively, and 62.9 for all patients; at 12 months, these were 74.1, 74.5, and 68.8 for the respective dose groups and 72.4 for all patients. Several MOCART items (surface of repair tissue, structure of repair tissue, signal intensity of repair tissue, subchondral bone, and synovitis) showed a more rapid response with the medium and high doses than with the low dose, suggesting a potential dose relationship. No significant correlation between the MOCART (overall and subscores) with clinical outcomes as assessed by the overall KOOS was detected at 3- and 12-month assessments. CONCLUSION: This study reveals a trend toward earlier recovery after treatment with higher spheroid doses in terms of better defect filling for full-thickness cartilage defects of the knee, while outcomes after 12 months were similar in all dose groups. However, a correlation with clinical outcomes or the failure rate at 1 year after ACI was not found. A longer follow-up will be required for more definite conclusions on the clinical relevance of ACI cell density to be drawn. REGISTRATION: NCT01225575 (ClinicalTrials.gov identifier); 2009-016816-20 (EudraCT number).

Anatomical "C"-shaped double-bundle versus single-bundle anterior cruciate ligament reconstruction in pre-adolescent children with open growth plates.

PURPOSE: To analyse the clinical, rotational and radiological (MRI) results of paediatric anatomical "C-shaped" double-bundle (DB) anterior cruciate ligament (ACL) reconstruction with anteromedial and posteromedial bundle compared to single-bundle (SB) ACL reconstruction. METHODS: Between 2008 and 2014, 57 consecutive patients received a paediatric ACL reconstruction with open physis and were allocated into two groups, according to the surgical procedure. Transepiphyseal SB technique was used until 2012 and DB consecutively thereafter. Follow-up consisted of a clinical evaluation with assessment of the International Knee Documentation Committee (IKDC) form, the Lysholm knee score, Tegner activity score, KT-1000 arthrometer evaluation, VAS Scores for satisfaction, MRI and testing of rotational stability using a robotic system. RESULTS: The mean time from ACL reconstruction to follow-up was 48.1 ± 15.8 in the SB group (n = 17) and 23.1 ± 13.2 in the DB group (n = 16; p < 0.001). No differences were found in the subjective scores. Biomechanically, there were significant differences identified in the KT-1000 (p < 0.03) and total tibial axial rotation (p < 0.04) when evaluating the reconstructed knee only. Ten of 17 (59%) of the SB patients had a Joint Play Area within the acceptable range of the median healthy knee value compared to 100 % in the DB group. Decreased patient satisfaction was associated with increased total tibial axial rotation. No growth disturbance was observed. Overall, 98% of patients were reached and either examined or interviewed. Re-rupture rate was 3 of 21 (14.3%) for DB and 9 of 35 (25.7%) for SB. All but one re-ruptures (92%) happened in the first 16 postoperative months independent of technique. CONCLUSIONS: The re-rupture rate after pre-adolescent ACL reconstruction is too high both historically and in this mixed cohort. Anatomical transepiphyseal DB ACL reconstruction with open physis may result in a reduction in this re-rupture rate, which may be related to a tighter control of the Joint Play Area. While subjective clinical results were similar between SB and DB, decreased patient satisfaction was associated with increased total tibial axial rotation in the entire cohort. Despite the need for two transepiphyseal tunnels in the DB technique, there did not appear to be an increased risk in growth plate disturbance. Transepiphyseal DB ACL reconstruction appears to be a reasonable alternative to current techniques in pre-adolescent children with an ACL rupture. LEVEL OF EVIDENCE: IV.

Histological analysis of the tibial anterior cruciate ligament insertion.

PURPOSE: This study was performed to investigate the morphology of the tibial anterior cruciate ligament (ACL) by histological assessment. METHODS: The native (undissected) tibial ACL insertion of six fresh-frozen cadaveric knees was cut into four sagittal sections parallel to the long axis of the medial tibial spine. For histological evaluation, the slices were stained with haematoxylin and eosin, Safranin O and Russell-Movat pentachrome. All slices were digitalized and analysed at a magnification of 20×. RESULTS: The anterior tibial ACL insertion was bordered by a bony anterior ridge. The most medial ACL fibres inserted from the medial tibial spine and were adjacent to the articular cartilage of the medial tibial plateau. Parts of the bony insertions of the anterior and posterior horns of the lateral meniscus were in close contact with the lateral part of the tibial ACL insertion. A small fat pad was located just posterior to the functional ACL fibres. The anterior-posterior length of the medial ACL insertion was an average of 10.8 ± 1.1 mm compared with the lateral, which was only 6.2 ± 1.1 mm (p < 0.001). There were no central or posterolateral inserting ACL fibres. CONCLUSIONS: The shape of the bony tibial ACL insertion was 'duck-foot-like'. In contrast to previous findings, the functional mid-substance fibres arose from the most posterior part of the 'duck-foot' in a flat and 'c-shaped' way. The most anterior part of the tibial ACL insertion was bordered by a bony anterior ridge and the most medial by the medial tibial spine. No posterolateral fibres nor ACL bundles have been found histologically. This histological investigation may improve our understanding of the tibial ACL insertion and may provide important information for anatomical ACL reconstruction.