Patients' experience on pain outcomes after hip arthroplasty: insights from an information tool based on registry data.

BACKGROUND: Arthroplasty registries are rarely used to inform encounters between clinician and patient. This study is part of a larger one which aimed to develop an information tool allowing both to benefit from previous patients' experience after total hip arthroplasty (THA). This study focuses on generating the information tool specifically for pain outcomes. METHODS: Data from the Geneva Arthroplasty Registry (GAR) about patients receiving a primary elective THA between 1996 and 2019 was used. Selected outcomes were identified from patient and surgeon surveys: pain walking, climbing stairs, night pain, pain interference, and pain medication. Clusters of patients with homogeneous outcomes at 1, 5, and 10 years postoperatively were generated based on selected predictors evaluated preoperatively using conditional inference trees (CITs). RESULTS: Data from 6,836 THAs were analysed and 14 CITs generated with 17 predictors found significant (p < 0.05). Baseline WOMAC pain score, SF-12 self-rated health (SRH), number of comorbidities, SF-12 mental component score, and body mass index (BMI) were the most common predictors. Outcome levels varied markedly by clusters whilst predictors changed at different time points for the same outcome. For example, 79% of patients with good to excellent SRH and less than moderate preoperative night pain reported absence of night pain at 1 year after THA; in contrast, for those with fair/poor SHR this figure was 50%. Also, clusters of patients with homogeneous levels of night pain at 1 year were generated based on SRH, Charnley, WOMAC night and pain scores, whilst those at 10 years were based on BMI alone. CONCLUSIONS: The information tool generated under this study can provide prospective patients and clinicians with valuable and understandable information about the experiences of "patients like them" regarding their pain outcomes.

Sensor-to-Bone Calibration with the Fusion of IMU and Bi-Plane X-rays.

Inertial measurement units (IMUs) need sensor-to-segment calibration to measure human kinematics. Multiple methods exist, but, when assessing populations with locomotor function pathologies, multiple limitations arise, including holding postures (limited by joint pain and stiffness), performing specific tasks (limited by lack of selectivity) or hypothesis on limb alignment (limited by bone deformity and joint stiffness). We propose a sensor-to-bone calibration based on bi-plane X-rays and a specifically designed fusion box to measure IMU orientation with respect to underlying bones. Eight patients undergoing total hip arthroplasty with bi-plane X-rays in their clinical pathway participated in the study. Patients underwent bi-plane X-rays with fusion box and skin markers followed by a gait analysis with IMUs and a marker-based method. The validity of the pelvis, thigh and hip kinematics measured with a conventional sensor-to-segment calibration and with the sensor-to-bone calibration were compared. Results showed (1) the feasibility of the fusion of bi-plane X-rays and IMUs in measuring the orientation of anatomical axes, and (2) higher validity of the sensor-to-bone calibration for the pelvic tilt and similar validity for other degrees of freedom. The main strength of this novel calibration is to remove conventional hypotheses on joint and segment orientations that are frequently violated in pathological populations.

Radiographic signs and hip pain 5 years after THA with a cemented stem predict future revision for aseptic loosening: a prospective cohort study.

BACKGROUND AND PURPOSE: We aimed to evaluate the long-term predictive value of radiographic abnormality and/or hip pain assessed 5 years following primary total hip arthroplasty (THA) and the occurrence of revision for aseptic loosening between 5 and 25 years postoperatively. PATIENTS AND METHODS: We included all primary THAs performed between 1996 and 2011 (same uncemented cup, polyethylene-ceramic bearing, 28 mm head, cemented stem) and prospectively enrolled in the institutional registry, for whom baseline and follow-up radiographs were available. At 5 years radiographically we assessed femoral osteolysis and/or stem migration. Pain was evaluated with the Harris Hip pain subscore. Kaplan-Meier survival and Cox regression analyses were performed. RESULTS: 1,317 primary THAs were included. 25 THAs (2%) were revised for aseptic stem loosening. Any abnormal radiographic sign at 5 years was present in 191 THAs (14%). Occasional hip pain was reported by 20% and slight to severe pain by 12% of patients at 5 years. In patients < 60 years, 10 of the 12 later revised for aseptic stem loosening had abnormal radiographs at 5 years vs. 5 of the 13 later revised in those ≥ 60 years. Hazard ratios (HR) were 34 (95% confidence interval [CI] 7-155) in younger vs. 4 (CI 1-11) in the older group. HR for association of hip pain at 5 years with future revision was 3 (CI 1-5). CONCLUSION: The presence of abnormal radiographic signs 5 years after THA was strongly associated with later revision for aseptic stem loosening, especially in patients < 60 years. The association between pain at 5 years and future revision was much weaker.

Reliability of the Harris Hip limping sub-score in patients undergoing total hip arthroplasty.

PURPOSE: In patients undergoing total hip arthroplasty, limping is a significant symptom, often assessed with the limping sub-score of the Harris Hip Score. However, the reliability of this sub-score has not been specifically investigated. The purpose of this study is to investigate the intra- and inter-rater reliability of this sub-score. METHODS: Thirty patients undergoing THA were recruited and performed a gait analysis before surgery and three months after surgery. In addition, 30 asymptomatic participants were included. In total, 90 visits were analysed in this study. The HHS limping sub-score was assessed for each visit using a video (front and back view side-by-side) of a ten metre walk at a self-selected speed. Two orthopaedic surgeons evaluated the limping of each video in two different grading sessions with a one week delay. To avoid recall bias, the patient's number identity was randomized and different for each grading session and each rater. The weighted Cohen's Kappa coefficient was used to quantify the intra- and inter-reliability. The reliability of three components was studied: the presence of limping, its severity, and the compensation type. RESULTS: For all components, the agreement for intra-rater reliability ranged from moderate to strong and from none to moderate for the inter-rater reliability. CONCLUSION: These results do not encourage the use of HHS-limping sub-score for data involving different raters in both clinical and research contexts. It calls for improved consensus on limping definitions or the creation of objective measures.

[Customized 3D cutting guides : what applications in orthopedic surgery ?] / Guides de coupes 3D sur mesure : quelles applications en chirurgie orthopédique?

3D printing is a technology that has been evolving rapidly over the past twenty years. It is an additive manufacturing process which allows the creation of objects without geometry restrictions. This process has applications in orthopaedic surgery through personalized cutting guides and implants which offer the possibility to treat complex pathologies such as tumoral surgery, architectural defects of the acetabulum and malunions. Although their use cannot be recommended for routine knee and hip prosthetic surgery, their value in high tibial osteotomies seems promising. Despite its high cost, this technology is of growing interest in orthopaedic surgery.

L'impression 3D est une technologie en évolution rapide depuis une vingtaine d'année. Il s'agit d'un procédé de fabrication par addition de matière permettant la réalisation d'objets sans limitation de forme. Ce procédé trouve des applications en orthopédie pour l'obtention de guides de coupes et d'implants sur mesure offrant la possibilité de traiter des pathologies complexes comme la chirurgie tumorale, les défauts architecturaux de l'acétabulum et les cals vicieux. Si leur utilisation ne peut être recommandée de façon routinière pour la chirurgie prothétique de genou et de hanche, leur intérêt dans les ostéotomies du tibia semble prometteur. Bien que d'un coût élevé, cette technologie trouve un intérêt croissant en chirurgie orthopédique.

[What surgical treatment for femoro-acetabular impingement?] / Quelle prise en charge chirurgicale pour le conflit fémoro-acétabulaire ?

Femoroacetabular impingement (FAI) is a frequent cause of hip pain in young people and athletes. It requires a complete work-up, including X-rays, hip arthro-MRI and CT coxometry with measurement of femoral torsion. The surgical management of CFA must be adapted to the morphological anomalies of the femur (cam), acetabulum (pincer) and femoral torsional disorders. Most CFA can be treated by hip arthroscopy, with correction of the cam and suture of the labrum. Some CFA with a bulky or posterior cam require surgical hip dislocation. A femoral rotation or derotation osteotomy can correct an associated torsional disorder. In cases of marked retroversion of the acetabulum, anteverting periacetabular osteotomy can reorient the acetabulum.

Le conflit fémoro-acétabulaire (CFA) est une cause fréquente de douleurs de hanche chez le sujet jeune et l'athlète. Il nécessite un bilan par radiographie, arthro-IRM de hanche, coxométrie scanographique avec torsions fémorales. La prise en charge chirurgicale du CFA doit être adaptée en fonction des anomalies morphologiques du fémur (came), du cotyle (pince) et des troubles torsionnels du fémur. La majorité des CFA peuvent être traitées par arthroscopie de hanche avec correction de la came et suture du labrum. Certains CFA avec une came volumineuse ou postérieure nécessitent une prise en charge par luxation chirurgicale de hanche. Une ostéotomie fémorale de rotation ou dérotation peut corriger un trouble torsionnel associé. En cas de rétroversion marquée du cotyle, une ostéotomie périacétabulaire d'antéversion permet de réorienter le cotyle.

In vitro-generated human muscle reserve cells are heterogeneous for Pax7 with distinct molecular states and metabolic profiles.

BACKGROUND: The capacity of skeletal muscles to regenerate relies on Pax7+ muscle stem cells (MuSC). While in vitro-amplified MuSC are activated and lose part of their regenerative capacity, in vitro-generated human muscle reserve cells (MuRC) are very similar to quiescent MuSC with properties required for their use in cell-based therapies. METHODS: In the present study, we investigated the heterogeneity of human MuRC and characterized their molecular signature and metabolic profile. RESULTS: We observed that Notch signaling is active and essential for the generation of quiescent human Pax7+ MuRC in vitro. We also revealed, by immunofluorescence and flow cytometry, two distinct subpopulations of MuRC distinguished by their relative Pax7 expression. After 48 h in differentiation medium (DM), the Pax7High subpopulation represented 35% of the total MuRC pool and this percentage increased to 61% after 96 h in DM. Transcriptomic analysis revealed that Pax7High MuRC were less primed for myogenic differentiation as compared to Pax7Low MuRC and displayed a metabolic shift from glycolysis toward fatty acid oxidation. The bioenergetic profile of human MuRC displayed a 1.5-fold decrease in glycolysis, basal respiration and ATP-linked respiration as compared to myoblasts. We also observed that AMPKα1 expression was significantly upregulated in human MuRC that correlated with an increased phosphorylation of acetyl-CoA carboxylase (ACC). Finally, we showed that fatty acid uptake was increased in MuRC as compared to myoblasts, whereas no changes were observed for glucose uptake. CONCLUSIONS: Overall, these data reveal that the quiescent MuRC pool is heterogeneous for Pax7 with a Pax7High subpopulation being in a deeper quiescent state, less committed to differentiation and displaying a reduced metabolic activity. Altogether, our data suggest that human Pax7High MuRC may constitute an appropriate stem cell source for potential therapeutic applications in skeletal muscle diseases.

Estimation of two wear factors for total hip arthroplasty: A simulation study based on musculoskeletal modelling.

BACKGROUND: Primary causes of surgical revision after total hip arthroplasty are polyethylene wear and implant loosening. These factors are particularly related to joint friction and thus patients' physical activity. Assessing implant wear over time according to patients' morphology and physical activity level is key to improve follow-up and patients' quality of life. METHODS: An approach initially proposed for tibiofemoral prosthetic wear estimation was adapted to compute two wear factors (force-velocity, directional wear intensity) using a musculoskeletal model. It was applied on 17 participants with total hip arthroplasty to compute joint angular velocity, contact force, sliding velocity, and wear factors during common daily living activities. FINDINGS: Differences were observed between gait, sitting down, and standing up tasks. An incremental increase of both global wear factors (time-integral) was observed during gait from slow to fast speeds (p ≤ 0.01). Interestingly, these two wear factors did not result in same trend for sitting down and standing up tasks. Compared to gait, one cycle of sitting down or standing up tends to induce higher friction-related wear but lower cross-shear-related wear. Depending on the wear factor, significant differences can be found between sitting down and gait at slow speed (p ≤ 0.05), and between sitting down (p ≤ 0.05) or standing up (p ≤ 0.05) and gait at fast speed. Furthermore, depending on the activity, wear can be fostered by joint contact force and/or sliding velocity. INTERPRETATION: This study demonstrated the potential of wear estimation to highlight activities inducing a higher risk of implant wear after total hip arthroplasty from motion capture data.

Extensive skin necrosis following total hip arthroplasty performed through the direct anterior approach.

BACKGROUND: Total hip arthroplasty is a widely performed surgical procedure, which enables patients to regain mobility, alleviates pain, and improves overall quality of life. Periarticular multimodal drug infiltration (PAI) is increasingly being used as an effective postoperative pain management, decreasing the systemic consumption of opioids. Extensive postoperative skin necrosis without a deep joint infection as a complication of total hip arthroplasty with PAI has not yet been described. CASE PRESENTATION: A 71-year-old patient who underwent total hip arthroplasty of the right hip for primary osteoarthritis through the Direct Anterior Approach presented postoperatively a large area of necrotic skin at the incision. Joint infection was excluded. An extensive debridement was performed and the tissue defect was reconstructed by a pedicled anterolateral thigh flap. The skin maintained a satisfactory appearance at 1 year postoperatively, and the hip was pain-free with restored ranges of motion. The patient was able to walk with no support and without limitation. CONCLUSION: We address the possible risk factors, discuss the use of epinephrine in PAI and explore possible treatment options for such a complication.

The awareness of injury prevention programmes is insufficient among French- and German-speaking sports medicine communities in Europe.

PURPOSE: Evaluate the current state of sports injury prevention perception, knowledge and practice among sports medicine professionals located in Western Europe and involved in injury prevention. METHODS: Members of two different sports medicine organizations (GOTS and ReFORM) were invited to complete a web-based questionnaire (in German and in French, respectively) addressing perception, knowledge and implementation of sports injury prevention through 22 questions. RESULTS: 766 participants from a dozen of countries completed the survey. Among them, 43% were surgeons, 23% sport physicians and 18% physiotherapists working mainly in France (38%), Germany (23%) and Belgium (10%). The sample rated the importance of injury prevention as "high" or "very high" in a majority of cases (91%), but only 54% reported to be aware of specific injury prevention programmes. The French-speaking world was characterized by lower levels of reported knowledge, unfamiliarity with existing prevention programmes and less weekly time spent on prevention as compared to their German-speaking counterparts. Injury prevention barriers reported by the respondents included mainly insufficient expertise, absence of staff support from sports organizations and lack of time. CONCLUSION: There is a lack of awareness regarding injury prevention concepts among sports medicine professionals of the European French- and German-speaking world. This gap varied according to the professional occupation and working country. Relevant future paths for improvement include specific efforts to build awareness around sports injury prevention. LEVEL OF EVIDENCE: Level IV.

The modern state of femoral, acetabular, and global offsets in total hip arthroplasty: a narrative review.

Offsets in the frontal plane are important for hip function. Research on total hip arthroplasty (THA) surgery agrees that increasing femoral offset up to 5 mm could improve functional outcome measures. The literature indicates that global offset is a key parameter that physicians should restore within 5 mm during surgery and avoid decreasing. Substantiated findings on acetabular offset are lacking despite its recognized importance, and the medialization approach must be assessed in light of its shortcomings. Future research, possibly through improved measurement, unified definitions, patient-specific surgical planning, and technology-enhanced surgical control, with specific focus on acetabular offset, is needed to better understand its impact on THA outcomes.

NADPH oxidase 4 deficiency attenuates experimental osteoarthritis in mice.

OBJECTIVE: Low-grade inflammation plays a pivotal role in osteoarthritis (OA) through exposure to reactive oxygen species (ROS). In chondrocytes, NADPH oxidase 4 (NOX4) is one of the major ROS producers. In this study, we evaluated the role of NOX4 on joint homoeostasis after destabilisation of the medial meniscus (DMM) in mice. METHODS: Experimental OA was simulated on cartilage explants using interleukin-1ß (IL-1ß) and induced by DMM in wild-type (WT) and NOX4 knockout (NOX4-/-) mice. We evaluated NOX4 expression, inflammation, cartilage metabolism and oxidative stress by immunohistochemistry. Bone phenotype was also determined by micro-CT and histomorphometry. RESULTS: Whole body NOX4 deletion attenuated experimental OA in mice, with a significant reduction of the OARSI score at 8 weeks. DMM increased total subchondral bone plate (SB.Th), epiphysial trabecular thicknesses (Tb.Th) and bone volume fraction (BV/TV) in both NOX4-/- and wild-type (WT) mice. Interestingly, DDM decreased total connectivity density (Conn.Dens) and increased medial BV/TV and Tb.Th only in WT mice. Ex vivo, NOX4 deficiency increased aggrecan (AGG) expression and decreased matrix metalloproteinase 13 (MMP13) and collagen type I (COL1) expression. IL-1ß increased NOX4 and 8-hydroxy-2'-deoxyguanosine (8-OHdG) expression in WT cartilage explants but not in NOX4-/-. In vivo, absence of NOX4 increased anabolism and decreased catabolism after DMM. Finally, NOX4 deletion decreased synovitis score, 8-OHdG and F4/80 staining following DMM. CONCLUSION: NOX4 deficiency restores cartilage homoeostasis, inhibits oxidative stress, inflammation and delays OA progression after DMM in mice. These findings suggest that NOX4 represent a potential target to counteract for OA treatment.

Articular Cartilage Repair After Implantation of Hyaline Cartilage Beads Engineered From Adult Dedifferentiated Chondrocytes: Cartibeads Preclinical Efficacy Study in a Large Animal Model.

BACKGROUND: Chondrocyte-based cell therapy to repair cartilage has been used for >25 years despite current limitations. This work presents a new treatment option for cartilage lesions. HYPOTHESIS: High-quality hyaline cartilage microtissues called Cartibeads are capable of treating focal chondral lesions once implanted in the defect, by complete fusion of Cartibeads among themselves and their integration with the surrounding native cartilage and subchondral bone. STUDY DESIGN: Controlled laboratory study. METHODS: Cartibeads were first produced from human donors and characterized using histology (safranin O staining of glycosaminoglycan [GAG] and immunohistochemistry of collagen I and II) and GAG dosage. Cartibeads from 6 Göttingen minipigs were engineered and implanted in an autologous condition in the knee (4 or 5 lesions per knee). One group was followed up for 3 months and the other for 6 months. Feasibility and efficacy were measured using histological analysis and macroscopic and microscopic scores. RESULTS: Cartibeads revealed hyaline features with strong staining of GAG and collagen II. High GAG content was obtained: 24.6-µg/mg tissue (wet weight), 15.52-µg/mg tissue (dry weight), and 35 ± 3-µg GAG/bead (mean ± SD). Histological analysis of Göttingen minipigs showed good integration of Cartibeads grafts at 3 and 6 months after implantation. The Bern Score of the histological assay comparing grafted versus empty lesions was significant at 3 months (grafted, n = 10; nongrafted, n = 4; score, 3.3 and 5.3, respectively) and 6 months (grafted, n = 11; nongrafted, n = 3; score, 1.6 and 5.1). CONCLUSION: We developed an innovative 3-step method allowing, for the first time, the use of fully dedifferentiated adult chondrocytes with a high number of cell passage (owing to the extensive amplification in culture). Cartibeads engineered from chondrocytes hold potential as an advanced therapy medicinal product for treating cartilage lesions with established efficacy. CLINICAL RELEVANCE: This successful preclinical study, combined with standardized manufacturing of Cartibeads according to good manufacturing practice guidelines, led to the approval of first-in-human clinical trial by the ethics committee and local medical authority. The generated data highlighted a promising therapy to treat cartilage lesions from a small amount of starting biopsy specimen. With our innovative cell amplification technology, very large lesions can be treated, and older active patients can benefit from it.

Definition and reliability of 3D acetabular and global offset measurements from bi-plane X-rays.

The importance of the global offset, the sum of femoral and acetabular offset, has been underlined in the literature as a key factor for the functional outcome of total hip arthroplasty (THA). However, the acetabular offset is not defined for bi-plane X-rays, a technology providing 3D measurements of the lower limb and commonly used for patients undergoing THA. The aim of this paper is to introduce a measurement method of the 3D acetabular offset with bi-plane X-rays. Our method combines the use of technical and anatomical coordinate systems. The most appropriate definition will be selected based on the best reliability and measurement error. The consequent reliability of the global offset was also assessed. Twenty-eight patients undergoing primary THA were selected retrospectively. Two operators performed three reconstructions for each patients before and after THA. Intraclass correlation (ICC) and smallest detectable change (SDC) were computed for intra-operator, inter-operator and test-retest conditions for all combinations of technical and anatomical coordinate systems. ICCs were good to excellent. One combination was more reliable than others with a moderate mean SDC of 6.3 mm (4.3-8.7 mm) for the acetabular offset and a moderate mean SDC of 6.2 mm (5.6-6.7 mm) for the global offset. This is similar to the reliability and mean SDC of the femoral offset (4.8 mm) approved for clinical use which indicates that this method of acetabular offset measurement is appropriate. This opens a research avenue to better understand the role of the acetabular offset on THA outcomes, which seems overlooked in the literature.

[Total knee arthroplasty and soft tissue defect: what are the reconstructive options?] / Prothèse totale de genou et lésion des tissus mous : quelles options pour la reconstruction ?

Wound healing issues are not rare after total knee arthroplasty. While most patients heal with local wound care, a minority is susceptible to develop serious complications such as peri-prosthetic joint infection. If direct closure is not feasible, we recommend a multidisciplinary approach based on the ortho-plastic model to determine the optimal wound closure strategy. Negative pressure wound therapy can be used while waiting for definitive coverage to optimise wound environment. Medial gastrocnemius flap is considered as the gold standard procedure for peri-prosthetic substance loss around the knee.

Les problèmes de cicatrisation ne sont pas rares après l'implantation d'une prothèse totale de genou. La plupart des patients guérissent avec des soins locaux mais une minorité d'entre eux peut développer des complications redoutables allant jusqu'à l'infection périprothétique. Hormis les situations pour lesquelles une fermeture directe de la cicatrice chirurgicale peut être réalisée, nous recommandons une approche multidisciplinaire basée sur le modèle de l'ortho-plastique afin de déterminer la stratégie de reconstruction la plus adaptée. La thérapie par pression négative peut être utilisée pour conditionner la plaie en vue d'un geste de couverture définitive. Le lambeau gastrocnémien médial est considéré comme la procédure de référence pour les pertes de substance périprothétique du genou.

[Dislocation after total hip arthroplasty : how to avoid it ?] / Luxations de prothèse de hanche : comment les éviter ?

Dislocation after hip replacement is a complication that can have dramatic consequences for the patient. The purpose of this article is to review the different parameters influencing stability and how to reduce this risk. The approach, the diameter of the femoral head, and the use of dual-mobility acetabular cups have led to a drastic reduction in the rate of dislocation, particularly in patients at risk, in cases of imbalance of the spino-pelvic complex, or in cases of revision surgery. The inclusion of patients in dedicated clinical pathways and participation in preoperative education sessions also contribute to the reduction of dislocation risk.

La luxation après prothèse de hanche est une complication qui peut avoir des conséquences dramatiques pour le patient. Cet article a pour but de revoir les différents paramètres influençant la stabilité prothétique et pouvant diminuer ce risque. La voie d'abord, le diamètre de la tête fémorale et l'usage de cotyles à double mobilité ont permis une diminution drastique du taux de luxation, en particulier chez les patients à risque, en cas de déséquilibre du complexe spino-pelvien ou en cas de reprise chirurgicale. L'inclusion des patients dans des itinéraires cliniques dédiés et la participation à des séances d'information préopératoire participent également à la réduction du risque de luxation.

Reliability of the pelvis and femur anatomical landmarks and geometry with the EOS system before and after total hip arthroplasty.

Bi-plane X-ray provides 3D measurements of the lower limb based on the identification of anatomical landmarks in sagittal and frontal X-rays. In clinical practice, such measurements involve multiple operators and sessions. This study aimed at evaluating the reliability of anatomical landmarks identification and geometric parameters of the pelvis and femur measured with bi-plane X-rays before and after total hip arthroplasty (THA). Twenty-eight patients undergoing primary THA were selected retrospectively. Two operators performed three reconstructions for each patient before and after THA. Intraclass correlation (ICC) and smallest detectable change (SDC) were computed for intra-operator, inter-operator, and test-retest conditions. Most anatomical landmark positions had good to excellent SDC (< 5 mm) apart from the centre of the sacral slope, greater trochanter, and anterior superior iliac spines (up to 7.1, 16.9, and 21.5 mm respectively). Geometric parameters had moderate to excellent SDC, apart from femoral and stem torsion, pelvic incidence, and APP inclination with poor SDC (9-12°). The sagittal view had significantly higher measurement errors than the frontal view. Test-retest and inter-operator conditions had no significant differences suggesting a low influence of patient posture. Osteoarthritis and the presence of implants did not seem to influence reliability and measurement error. This study could be used as a reference when assessing lower limb structure with bi-plane X-rays.

Hyaline Cartilage Microtissues Engineered from Adult Dedifferentiated Chondrocytes: Safety and Role of WNT Signaling.

The repair of damaged articular cartilage is an unmet medical need. Chondrocyte-based cell therapy has been used to repair cartilage for over 20 years despite current limitations. Chondrocyte dedifferentiation upon expansion in monolayer is well known and is the main obstacle to their use as cell source for cartilage repair. Consequently, current approaches often lead to fibrocartilage, which is biomechanically different from hyaline cartilage and not effective as a long-lasting treatment. Here, we describe an innovative 3-step method to engineer hyaline-like cartilage microtissues, named Cartibeads, from high passage dedifferentiated chondrocytes. We show that WNT5A/5B/7B genes were highly expressed in dedifferentiated chondrocytes and that a decrease of the WNT signaling pathway was instrumental for full re-differentiation of chondrocytes, enabling production of hyaline matrix instead of fibrocartilage matrix. Cartibeads showed hyaline-like characteristics based on GAG quantity and type II collagen expression independently of donor age and cartilage quality. In vivo, Cartibeads were not tumorigenic when transplanted into SCID mice. This simple 3-step method allowed a standardized production of hyaline-like cartilage microtissues from a small cartilage sample, making Cartibeads a promising candidate for the treatment of cartilage lesions.