The Fragility of Statistical Significance in Cartilage Restoration of the Knee: A Systematic Review of Randomized Controlled Trials.

OBJECTIVE: The purpose of this study was to utilize fragility analysis to assess the robustness of randomized controlled trials (RCTs) evaluating the management of articular cartilage defects of the knee. We hypothesize that the cartilage restorative literature will be fragile with the reversal of only a few outcome events required to change statistical significance. DESIGN: RCTs from 11 orthopedic journals indexed on PubMed from 2000 to 2020 reporting dichotomous outcome measures relating to the management of articular cartilage defects of the knee were included. The Fragility Index (FI) for each outcome was calculated through the iterative reversal of a single outcome event until significance was reversed. The Fragility Quotient (FQ) was calculated by dividing each FI by study sample size. Additional statistical analysis was performed to provide median FI and FQ across subgroups. RESULTS: Nineteen RCTs containing 60 dichotomous outcomes were included for analysis. The FI and FQ of all outcomes was 4 (IQR 2-7) and 0.067 (IQR 0.034-0.096), respectively. The average number of patients lost to follow-up (LTF) was 3.9 patients with 15.8% of the included studies reporting LTF greater than or equal to 4, the FI of all included outcomes. CONCLUSIONS: The orthopedic literature evaluating articular cartilage defects of the knee is fragile as the reversal of relatively few outcome events may alter the significance of statistical findings. We therefore recommend comprehensive fragility analysis and triple reporting of the P value, FI, and FQ to aid in the interpretation and contextualization of clinical findings reported in the cartilage restoration literature.

Long-Term Clinical and MRI Results of Matrix-Assisted Autologous Chondrocyte Implantation for Articular Cartilage Defects of the Knee.

OBJECTIVE: To evaluate the long-term clinical and radiological outcome of matrix-assisted autologous chondrocyte implantation (mACI) for articular cartilage defects in the knee joint. DESIGN: Clinical evaluation was assessed in 21 patients with full-thickness cartilage defects, International Cartilage Repair Society (ICRS) grade IV. Clinical scoring was performed preoperatively and 12 years after transplantation using the International Knee Documentation Committee (IKDC) score, the Lysholm score, the Knee injury and Osteoarthritis Outcome Score (KOOS), and the Noyes sports activity rating scale. Morphologic evaluation of the repair tissue was assessed by magnetic resonance imaging (MRI) in 14 patients using the Kreuz-Henderson score. RESULTS: Clinical evaluation revealed significant improvement in the IKDC, the Lysholm, the KOOS, and the Noyes score. Morphological evaluation by MRI showed moderate to complete defect filling in 10 of 14 patients, demonstrating normal to nearly normal values in mean 74.29% of all assessed parameters. Significant correlation of the parameter cartilage signal and clinical outcome was found with the IKDC, Lysholm, and KOOS subscales ADL (activities of daily living) and QoL (quality of life). CONCLUSIONS: The clinical and radiological outcomes 12 years after transplantation suggest the confirmation of the promising results of the mid-term follow-up. This study therefore provides first indications that the implantation of mACI might be a suitable option for long-term cartilage repair. Future controlled studies need to address the exact parameters influencing the long-term outcome of mACI.

Acetabular Delamination: Epidemiology, Histological Features, and Treatment.

OBJECTIVE: The International Cartilage Repair Society classification is the one mainly used to define chondral defects. However, this classification does not include delamination. The objective of the study is to describe the characteristics of this lesion to better explain its classification in the context of chondral lesions of the hip. DESIGN: We performed a retrospective analysis of 613 patients who underwent hip arthroscopy. In this group, the incidence, localization, histological characteristics, and association to femoroacetabular impingement as well as to other intraarticular lesions of acetabular delamination (AD) were analyzed. Preoperative magnetic resonance imaging accuracy and the different treatment options were also evaluated. RESULTS: In our series, the incidence of the AD was 37% (226 patients over 613). The average age of this group was significantly lower (39.3 years) than the entire group of patients. Isolated cam (P < 0.01) and pincer morphologies (P < 0.05) had a significant statistical association with the AD. This lesion was primarily localized at the acetabular chondrolabral junction, mainly on the anterosuperior quadrant. The intraarticular lesions more frequently associated to AD were labral lesions (94.25%, P < 0.01), ligamentum teres lesions (28.32%, P < 0.05), and femoral head chondral lesions (19.9%, P < 0.01). The histological examination of the AD was characterized by hypocellularity and structural disorder of the matrix, with fissures. Treatment remains controversial. CONCLUSION: AD represents an intermediate stage in chondral damage and can be classified as a "2a" grade lesion. Histological examination confirms the intermediate and progressive character of this injury.

Bilateral Hypoplasia of Both Medial and Lateral Menisci Partially Fused With the Cartilage Surface of the Tibial Plateau.

Hypoplastic meniscus is an extremely rare abnormality. The authors present the first case of meniscal hypoplasia with a partial fusion of meniscus and tibial cartilage. A 22-year-old man underwent surgery for a chronic patellar dislocation. Preoperative magnetic resonance imaging and arthroscopy incidentally revealed hypoplasia of both medial and lateral menisci. Moreover, the posterior horn of the medial meniscus and middle body of the lateral meniscus were fused with the cartilage surface of the tibia. Magnetic resonance imaging of the contralateral knee showed similar meniscal anomalies. This case presents an interesting and extremely rare abnormality of the meniscus. [Orthopedics. 2018; 41(6):e884-e887.].

Management of Articular Cartilage Defects in the Glenohumeral Joint.

Articular cartilage defects are not often encountered in the glenohumeral joint. These lesions are typically found in patients with shoulder trauma, recurrent instability, or previous surgical treatment. Diagnosis can be difficult; these defects are often found incidentally during arthroscopic or open surgical management of other pathology. Initial management of isolated glenohumeral chondral defects is nonsurgical and includes physical therapy and/or corticosteroid injections. If nonsurgical treatment is unsuccessful, patients may undergo surgery. Because these lesions occur infrequently, few studies have documented surgical techniques and outcomes. Surgical strategies include arthroscopic débridement, microfracture surgery, osteochondral autograft or allograft transplantation, autologous chondrocyte implantation, and particulated juvenile allograft cartilage implantation.

Collagen XI mutation lowers susceptibility to load-induced cartilage damage in mice.

Interactions among risk factors for osteoarthritis (OA) are not well understood. We investigated the combined impact of two prevalent risk factors: mechanical loading and genetically abnormal cartilage tissue properties. We used cyclic tibial compression to simulate mechanical loading in the cho/+ (Col11a1 haploinsufficient) mouse, which has abnormal collagen fibrils in cartilage due to a point mutation in the Col11a1 gene. We hypothesized that the mutant collagen would not alter phenotypic bone properties and that cho/+ mice, which develop early onset OA, would develop enhanced load-induced cartilage damage compared to their littermates. To test our hypotheses, we applied cyclic compression to the left tibiae of 6-month-old cho/+ male mice and wild-type (WT) littermates for 1, 2, and 6 weeks at moderate (4.5 N) and high (9.0 N) peak load magnitudes. We then characterized load-induced cartilage and bone changes by histology, microcomputed tomography, and immunohistochemistry. Prior to loading, cho/+ mice had less dense, thinner cortical bone compared to WT littermates. In addition, in loaded and non-loaded limbs, cho/+ mice had thicker cartilage. With high loads, cho/+ mice experienced less load-induced cartilage damage at all time points and displayed decreased matrix metalloproteinase (MMP)-13 levels compared to WT littermates. The thinner, less dense cortical bone and thicker cartilage were unexpected and may have contributed to the reduced severity of load-induced cartilage damage in cho/+ mice. Furthermore, the spontaneous proteoglycan loss resulting from the mutant collagen XI was not additive to cartilage damage from mechanical loading, suggesting that these risk factors act through independent pathways. © 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 36:711-720, 2018.

Overexpression of human IGF-I via direct rAAV-mediated gene transfer improves the early repair of articular cartilage defects in vivo.

Direct therapeutic gene transfer is a promising tool to treat articular cartilage defects. Here, we tested the ability of an recombinant adeno-associated virus (rAAV) insulin-like growth factor I (IGF-I) vector to improve the early repair of cartilage lesions in vivo. The vector was administered for 3 weeks in osteochondral defects created in the knee joints of rabbits compared with control (lacZ) treatment and in cells that participate in the repair processes (mesenchymal stem cells, chondrocytes). Efficient IGF-I expression was observed in the treated lesions and in isolated cells in vitro. rAAV-mediated IGF-I overexpression was capable of stimulating the biologic activities (proliferation, matrix synthesis) both in vitro and in vivo. IGF-I treatment in vivo was well tolerated, revealing significant improvements of the repair capabilities of the entire osteochondral unit. IGF-I overexpression delayed terminal differentiation and hypertrophy in the newly formed cartilage, possibly due to contrasting effects upon the osteogenic expression of RUNX2 and ß-catenin and to stimulating effects of this factor on the parathyroid hormone/parathyroid hormone-related protein pathway in this area. Production of IGF-I improved the reconstitution of the subchondral bone layer in the defects, showing increased RUNX2 expression levels in this zone. These findings show the potential of directly applying therapeutic rAAVs to treat cartilage lesions.

Comparison of articular cartilage repair with different hydrogel-human umbilical cord blood-derived mesenchymal stem cell composites in a rat model.

INTRODUCTION: The present work was designed to explore the feasibility and efficacy of articular cartilage repair using composites of human umbilical cord blood derived mesenchymal stem cells (hUCB-MSCs) and four different hydrogels in a rat model. METHODS: Full-thickness articular cartilage defects were created at the trochlear groove of femur in both knees of rats. Composites of hUCB-MSCs and four different hydrogels (group A, 4% hyaluronic acid; group B, 3% alginate:30% pluronic (1:1, v/v); group C, 4% hyaluronic acid: 3% alginate: 20% pluronic (2:1:1, v/v}; and group D, 4% hyaluronic acid:3% alginate:20% pluronic;chitosan (4:1:1:2, v/v).) were then transplanted into right knee defect in each study group (five rats/group). Left knees were transplanted with corresponding hydrogels without hUCB-MSCs as controls. At 16 weeks post-transplantation, degrees of cartilage repair were evaluated macroscopically and histologically using Masson's Trichrome, safranin-O, Sirius red staining, and type-II collagen immunostaining. RESULTS: Overall, group A with 4% hyaluronic acid hydrogel resulted in superior cartilage repair grossly and histologically and achieved a cellular arrangement and collagen organization pattern mimicking adjacent uninjured articular cartilage. Immunostaining and safranin-O staining also revealed that group A displayed the largest areas of type II collagen staining. Sirius red staining revealed that the organization pattern of collagen bundles was more similar to normal cartilage in group A. No evidence of rejection was found. CONCLUSIONS: The results of this study suggest that hUCB-MSCs could be used to repair articular cartilage defects in vivo and that hyaluronic acid is an attractive hydrogel candidate for use in combination with hUCB-MSCs.

Injectable cultured bone marrow-derived mesenchymal stem cells in varus knees with cartilage defects undergoing high tibial osteotomy: a prospective, randomized controlled clinical trial with 2 years' follow-up.

PURPOSE: To analyze the results of the use of intra-articular cultured autologous bone marrow-derived mesenchymal stem cell (MSC) injections in conjunction with microfracture and medial opening-wedge high tibial osteotomy (HTO). METHODS: Fifty-six knees in 56 patients with unicompartmental osteoarthritic knees and genu varum were randomly allocated to the cell-recipient group (n = 28) or control group (n = 28). Patients who had a joint line congruity angle of more than 2°, malalignment of the knee from femoral causes, a fixed flexion deformity, or age older than 55 years were excluded. All patients underwent HTO and microfracture. The cell-recipient group received intra-articular injection of cultured MSCs with hyaluronic acid 3 weeks after surgery, whereas the control group only received hyaluronic acid. The primary outcome measure was the International Knee Documentation Committee (IKDC) score at intervals of 6 months, 1 year, and 2 years postoperatively. Secondary outcome measures were Tegner and Lysholm clinical scores and 1-year postoperative Magnetic Resonance Observation of Cartilage Repair Tissue (MOCART) scores. RESULTS: The median age of the patients was 51 years, with a mean body mass index of 23.85. Both treatment arms achieved improvements in Tegner, Lysholm, and IKDC scores. After adjustment for age, baseline scores, and time of evaluation, the cell-recipient group showed significantly better scores. The effect of treatment showed an added improvement of 7.65 (95% confidence interval [CI], 3.04 to 12.26; P = .001) for IKDC scores, 7.61 (95% CI, 1.44 to 13.79; P = .016) for Lysholm scores, and 0.64 (95% CI, 0.10 to 1.19; P = .021) for Tegner scores. Magnetic resonance imaging scans performed 1 year after surgical intervention showed significantly better MOCART scores for the cell-recipient group. The age-adjusted mean difference in MOCART score was 19.6 (95% CI, 10.5 to 28.6; P < .001). CONCLUSIONS: Intra-articular injection of cultured MSCs is effective in improving both short-term clinical and MOCART outcomes in patients undergoing HTO and microfracture for varus knees with cartilage defects. LEVEL OF EVIDENCE: Level II, randomized controlled trial.

Descriptive epidemiology of femoroacetabular impingement: a North American cohort of patients undergoing surgery.

BACKGROUND: Symptomatic femoroacetabular impingement (FAI) is associated with hip pain, functional limitations, and secondary osteoarthritis. There is limited information from large patient cohorts defining the specific population affected by FAI. Establishing a large cohort will facilitate the identification of "at-risk" patients and will provide a population for ongoing clinical research initiatives. The authors have therefore established a multicenter, prospective, longitudinal cohort of patients undergoing surgery for symptomatic FAI. PURPOSE: To report the clinical epidemiology, disease characteristics, and contemporary surgical treatment trends in North America for patients with symptomatic FAI. STUDY DESIGN: Cross-sectional study; Level of evidence, 3. METHODS: Upon approval of the institutional review boards at 8 institutions, 12 surgeons enrolled consecutive patients undergoing surgical intervention for symptomatic FAI. Patient demographics, physical examination data, radiographic data, diagnoses, operative data, and standardized patient-reported outcome measures were collected. The first 1130 cases are summarized in this study. RESULTS: A total of 1076 consecutive patients (1130 hips) were enrolled; 55% (n = 622) were female, and 45% (n = 508) were male, with an average age of 28.4 years and average body mass index (BMI) of 25.1. Demographics revealed that 88% of patients who were predominantly treated for FAI were white, 19% reported a family history of hip surgery, 47.6% of hips had a diagnosis of cam FAI, 44.5% had combined cam/pincer FAI, and 7.9% had pincer FAI. Preoperative clinical scores (pain, function, activity level, and overall health) indicated a major dysfunction related to the hip. Surgical interventions were arthroscopic surgery (50.4%), surgical dislocation (34.4%), reverse periacetabular osteotomy (9.4%), limited open osteochondroplasty with arthroscopic surgery (5.8%), and limited open by itself (1.5%). More than 90% of the hips were noted to have labral and articular cartilage abnormalities at surgery; femoral head-neck osteochondroplasty was performed in 91.6% of the surgical procedures, acetabular rim osteoplasty in 36.7%, labral repair in 47.8%, labral debridement in 16.3%, and acetabular chondroplasty in 40.1%. CONCLUSION: This multicenter, prospective, longitudinal cohort is one of the largest FAI cohorts to date. In this cohort, FAI occurred predominantly in young, white patients with a normal BMI, and there were more female than male patients. The disease pattern of cam FAI was most common. Contemporary treatment was predominantly arthroscopic followed by surgical hip dislocation.

Is autologous chondrocyte implantation (ACI) an adequate treatment option for repair of cartilage defects in paediatric patients?

Cartilage lesions in the knee of juvenile patients require an effective repair to regain life-long functional activity of the joint. Autologous chondrocyte implantation (ACI) is discussed to be advantageous over other methods for cartilage repair regarding long-term outcome. ACI has successfully been applied in juvenile patients, although currently recommended for patients ≥18 years of age. Only few controlled clinical trials present evidence of efficacy and safety of ACI in adolescent patients. ACI products have to undergo the process of a marketing authorisation application, including the submission of a paediatric investigation plan (PIP). Data from prospective clinical studies or retrospective collection of long-term data in paediatric patients should be submitted for risk-benefit evaluation by the Paediatric Committee (PDCO).

Symptomatic carpal coalition: scaphotrapezial joint.

Carpal coalition is an uncommon congenital abnormality that arises from incomplete cavitation of the common cartilaginous precursor that forms the carpal bones. When carpal coalition is discovered, it is typically an asymptomatic incidental radiographic finding, and is often bilateral. We present a case of symptomatic unilateral carpal coalition of the scaphotrapezial joint, which was treated by excising the fibrous coalition and placing an interposition fat graft. This treatment was effective in alleviating the patient's symptoms.

[Unusual presentation of rib malformation]. / Présentation inhabituelle d'une malformation costale.

Rib malformation and anatomical variations are not well known and are still often underdiagnosed. Usually, rib malformations are fortuitously discovered. We describe here the case of a girl, 4 years and 4 months old, who presented at the emergency unit for fever and an anterior tumefaction of the ribcage, without any other symptoms. She was eupneic with a normal pulmonary auscultation and viral tonsillitis with a negative streptococcus test. The thoracic tumefaction was parasternal, painless, and fixed and measured approximately 2.5 × 2cm. Ultrasound findings consisted of a duplicated and hypoechogenic hypertrophy of the sterno-costal cartilage of the 4th left rib. Magnetic resonance imaging (MRI) confirmed the diagnosis of chondral bifidity of the sterno-costal junction of the 4th left rib. Fever, due to the viral tonsillitis, disappeared after 4 days. Rib malformations are rare, often anterior, unilateral, and preferentially located on the 3rd or the 4th rib. The main malformative rib lesions are bifid ribs, rib spurs, and widened ribs. Very rarely, they can be associated with Gorlin-Goltz syndrome or with other malformations such as VATER complex. The main differential diagnoses of these rib malformations are traumatic, tumoral, and infectious etiologies. In case of tumoral diseases, the topography of the lesion focuses the etiologic diagnosis: whereas an anterior and cartilaginous lesion is always benign, a lateral or posterior lesion can be an Ewing sarcoma. Rib malformation investigation consists in meticulous questioning, a complete clinical examination looking for any associated anomaly, completed by basic imaging explorations such as plain thoracic radiography focused on the ribcage and ultrasound. Finally, complementary computerized tomography or preferably MRI, depending on the anatomic location of the lesion, confirms the final diagnosis, as presented in our case report, and removes any uncertainty.

Hip ontogenesis: how evolution, genes, and load history shape hip morphotype and cartilotype.

BACKGROUND: Developmental hip disorders (DHDs), eg, developmental dysplasia of the hip, slipped capitis femoris epiphysis, and femoroacetabular impingement, can be considered morphology variants of the normal hip. The femoroacetabular morphology of DHD is believed to induce osteoarthritis (OA) through local cumulative mechanical overload acting on genetically controlled patterning systems and subsequent damage of joint structures. However, it is unclear why hip morphology differs between individuals with seemingly comparable load histories and why certain hips with DHD progress to symptomatic OA whereas others do not. QUESTIONS/PURPOSES: We asked (1) which mechanical factors influence growth and development of the proximal femur; and (2) which genes or genetic mechanisms are associated with hip ontogenesis. METHODS: We performed a systematic literature review of mechanical and genetic factors of hip ontogeny. We focused on three fields that in recent years have advanced our knowledge of adult hip morphology: imaging, evolution, and genetics. WHERE ARE WE NOW?: Mechanical factors can be understood in view of human evolutionary peculiarities and may summate to load histories conducive to DHD. Genetic factors most likely act through multiple genes, each with modest effect sizes. Single genes that explain a DHD are therefore unlikely to be found. Apparently, the interplay between genes and load history not only determines hip morphotype, but also joint cartilage robustness ("cartilotype") and resistance to symptomatic OA. WHERE DO WE NEED TO GO?: We need therapies that can improve both morphotype and cartilotype. HOW DO WE GET THERE?: Better phenotyping, improving classification systems of hip morphology, and comparative population studies can be done with existing methods. Quantifying load histories likely requires new tools, but proof of principle of modifying morphotype in treatment of DDH and of cartilotype with exercise is available.

The classification of degenerative hip disease.

It is probable that both genetic and environmental factors play some part in the aetiology of most cases of degenerative hip disease. Geneticists have identified some single gene disorders of the hip, but have had difficulty in identifying the genetics of many of the common causes of degenerative hip disease. The heterogeneity of the phenotypes studied is part of the problem. A detailed classification of phenotypes is proposed. This study is based on careful documentation of 2003 consecutive total hip replacements performed by a single surgeon between 1972 and 2000. The concept that developmental problems may initiate degenerative hip disease is supported. The influences of gender, age and body mass index are outlined. Biomechanical explanations for some of the radiological appearances encountered are suggested. The body weight lever, which is larger than the abductor lever, causes the abductor power to be more important than body weight. The possibility that a deficiency in joint lubrication is a cause of degenerative hip disease is discussed. Identifying the phenotypes may help geneticists to identify genes responsible for degenerative hip disease, and eventually lead to a definitive classification.

The trochlear cleft: the "black line" of the trochlear trough.

OBJECTIVE: The "cartilage black line sign" is a recently described T2 dark cartilage lesion that we have identified appearing as a cleft in the trochlear trough. The purpose of our study was to define the MR imaging characteristics of a trochlear cleft, determine its incidence, and correlate the MR findings with arthroscopy. MATERIALS AND METHODS: A total of 1,300 consecutive MR examinations of the knee were retrospectively reviewed by consensus of two fellowship-trained musculoskeletal radiologists. The MR imaging characteristics and location of a trochlear cleft were determined. Imaging results were compared to arthroscopy when available. Patient age and gender were compared to 25 randomly selected control patients without trochlear clefts. RESULTS: A total of 25 (1.9%) individuals (11 females and 14 males; age range 19­45 years; mean age 28 years) were diagnosed with a trochlear cleft. The control group consisted of 11 females and 14 males; age range 19­83 years; mean age 46 years. Mean cleft length was 7 mm (range 6­12 mm); cleft location was consistently in the lower trochlear trough. No full-thickness cartilage defects were identified in the eight individuals in whom arthroscopic correlation was available. A grade 2 cartilage lesion was identified in a single individual; another progressed from grade 0 to a full-thickness trochlear lesion over an 8-month interval. Eight individuals were athletes. No significant difference in gender was noted between the two groups, however, the study group was significantly younger p<0.0001. CONCLUSIONS: A trochlear cleft is a rare finding in young active individuals. It most likely indicates an incomplete cartilage fissure which may rarely progress to a full-thickness defect.

Muenke syndrome mutation, FgfR3P²44R, causes TMJ defects.

Muenke syndrome is characterized by various craniofacial deformities and is caused by an autosomal-dominant activating mutation in fibroblast growth factor receptor 3 (FGFR3(P250R) ). Here, using mice carrying a corresponding mutation (FgfR3(P244R) ), we determined whether the mutation affects temporomandibular joint (TMJ) development and growth. In situ hybridization showed that FgfR3 was expressed in condylar chondroprogenitors and maturing chondrocytes that also expressed the Indian hedgehog (Ihh) receptor and transcriptional target Patched 1(Ptch1). In FgfR3(P244R) mutants, the condyles displayed reduced levels of Ihh expression, H4C-positive proliferating chondroprogenitors, and collagen type II- and type X-expressing chondrocytes. Primary bone spongiosa formation was also disturbed and was accompanied by increased osteoclastic activity and reduced trabecular bone formation. Treatment of wild-type condylar explants with recombinant FGF2/FGF9 decreased Ptch1 and PTHrP expression in superficial/polymorphic layers and proliferation in chondroprogenitors. We also observed early degenerative changes of condylar articular cartilage, abnormal development of the articular eminence/glenoid fossa in the TMJ, and fusion of the articular disc. Analysis of our data indicates that the activating FgfR3(P244R) mutation disturbs TMJ developmental processes, likely by reducing hedgehog signaling and endochondral ossification. We suggest that a balance between FGF and hedgehog signaling pathways is critical for the integrity of TMJ development and for the maintenance of cellular organization.