Because of limited self-healing ability, the treatment of articular cartilage defects is still an important clinical challenge. Hydrogel-based biomaterials have broad application prospects in articular cartilage repair. In this study, gelatin methacrylate (GelMA)and silk fibroin (SF) were combined to form a composite hydrogel with an interpenetrating network (IPN) structure under ultraviolet irradiation and ethanol treatment. Introducing silk fibroin into GelMA hydrogel significantly increased mechanical strength as compressive modulus reached 300 kPa in a GelMA/SF-5 (50 mg/mL silk fibroin) group. Moreover, composite IPN hydrogels demonstrated reduced swelling ratios and favorable biocompatibility and supported chondrogenesis of bone mesenchymal stem cells (BMSCs) at day 7 and day 14. Additionally, significantly higher gene expressions of Col-2, Acan, and Sox-9 (p < 0.01) were found in IPN hydrogel groups when compared with the GelMA group. An in vivo study was performed to confirm that the GelMA-SF IPN hydrogel could promote cartilage regeneration. The results showed partial regeneration of cartilage in groups treated with hydrogels only and satisfactory cartilage repair in groups of cell-seeded hydrogels, indicating the necessity of additional seeding cells in hydro-gel-based cartilage treatment. Therefore, our results suggest that the GelMA/SF IPN hydrogels may be a potential functional material in cartilage repair and regeneration.

The integrative regeneration of both articular cartilage and subchondral bone remains an unmet clinical need due to the difficulties of mimicking spatial complexity in native osteochondral tissues for artificial implants. Layer-by-layer fabrication strategies, such as 3D printing, have emerged as a promising technology replicating the stratified zonal architecture and varying microstructures and mechanical properties. However, the dynamic and circulating physiological environments, such as mass transportation or cell migration, usually distort the pre-confined biological properties in the layered implants, leading to undistinguished spatial variations and subsequently inefficient regenerations. This study introduced a biomimetic calcified interfacial layer into the scaffold as a compact barrier between a cartilage layer and a subchondral bone layer to facilitate osteogenic–chondrogenic repair. The calcified interfacial layer consisting of compact polycaprolactone (PCL), nano-hydroxyapatite, and tasquinimod (TA) can physically and biologically separate the cartilage layer (TA-mixed, chondrocytes-load gelatin methacrylate) from the subchondral bond layer (porous PCL). This introduction preserved the as-designed independent biological environment in each layer for both cartilage and bone regeneration, successfully inhibiting vascular invasion into the cartilage layer and preventing hyaluronic cartilage calcification owing to devascularization of TA. The improved integrative regeneration of cartilage and subchondral bone was validated through gross examination, micro-computed tomography (micro-CT), and histological and immunohistochemical analyses based on an in vivo rat model. Moreover, gene and protein expression studies identified a key role of Caveolin (CAV-1) in promoting angiogenesis through the Wnt/β-catenin pathway and indicated that TA in the calcified layer blocked angiogenesis by inhibiting CAV-1.

Osteoarthritis (OA) is the most prevalent degenerative joint disease, characterized by progressive cartilage loss, chronic inflammation, and functional decline. Current intra-articular therapies, most notably corticosteroids, provide transient pain relief but accelerate cartilage catabolism upon repeated administration. A critical need remains for steroid-free interventions that can simultaneously suppress inflammation and promote cartilage regeneration. We developed a translational strategy integrating sinomenine, a natural alkaloid with immunomodulatory properties, into bone marrow mesenchymal stem cell (BMSC)-derived cartilage organoids. The anti-inflammatory and pro-chondrogenic effects of sinomenine were evaluated under lipopolysaccharide-induced stress in vitro. The organoids treated with sinomenine were assessed for viability, extracellular matrix deposition, and phenotype stability using histology, quantitative reverse transcription–polymerase chain reaction, Western blot, and immunofluorescence. The in vivo efficacy was tested in a rat trochlear defect model. Finally, a 24-month, double-blind randomized clinical trial compared the effect of intra-articular sinomenine hydrochloride with that of triamcinolone acetonide in patients with early-stage knee OA. Sinomenine at a concentration of 20 μg/mL mitigated inflammation by suppressing the expression of tumor necrosis factor alpha and interleukin 6 while enhancing chondrogenesis in BMSCs. Sinomenine-treated organoids (sino-organoids) exhibited increased glycosaminoglycan content, reduced MMP13 expression, and stable SOX9 and COL-II expression profiles. Sino-organoids achieved superior defect filling, organized matrix deposition, and attenuated inflammatory infiltration in rat cartilage defects. Clinically, sinomenine injections were noninferior to corticosteroids across Western Ontario and McMaster Universities Osteoarthritis Index, visual analog scale, Timed Up and Go test, 20-m walk, and magnetic resonance imaging outcomes during a 24-month period, while avoiding the cartilage loss progression observed in the corticosteroid arm. This study established sinomenine-enhanced cartilage organoids as a steroid-free therapeutic platform for early OA. We united pharmacological immunomodulation with organoid-based regeneration to develop a bench-to-bedside pipeline that achieved comparable efficacy to corticosteroids while offering superior structural protection. These findings highlight a paradigm shift in OA management, suggesting that traditional bioactive compounds can be harnessed with organoid technology to deliver durable, regenerative, and clinically viable therapies. ClinicalTrials.gov Identifier: NCT05764304.

The structural failure of rotator cuff repair is largely attributed to fibrovascular scar formation driven by a persistent inflammatory microenvironment and insufficient fibrocartilage regeneration at the tendon-to-bone interface. To address this, a microfluidic-generated GelMA microsphere system co-encapsulating Zeolitic Imidazolate Framework-8 (ZIF-8) nanoparticles and bone marrow mesenchymal stem cell (BMSC)-derived small extracellular vesicles (sEVs) is developed. This composite system (ZIF-8/sEVs@MS) enables the sustained release of Zn²⁺ and sEVs, which synergistically reprogram macrophages (Mφ) from a pro-inflammatory M1 phenotype to a reparative M2 state and restore the CXCL12/CXCR4 axis for endogenous stem cell recruitment. Transcriptomic analysis elucidates that the system reactivates the PI3K/AKT signaling pathway, thereby reversing inflammation-mediated inhibition and driving chondrogenic differentiation. In a rat rotator cuff repair model, the functionalized microspheres significantly enhance fibrocartilaginous enthesis regeneration, biomechanical structural integrity, and limb function. This study establishes a dual-functional “immuno-chondrogenic” strategy that coordinates immune microenvironment modulation with tissue-specific differentiation to facilitate functional tendon-to-bone healing.

Background: Fractures involving the inferior pole of the patella can lead to postoperative patella baja. For comminuted patellar fractures that affect both the articular surface and the inferior pole, we aim to explore a new fixation method that provides reliable internal stabilization while reducing the incidence of patella baja.Methods: We conducted a finite element biomechanical study and a retrospective cohort clinical study. The finite element analysis compared the “dual tension band” technique to the traditional single tension band method using 3D models of patellar fractures. The clinical study included 66 patients with patellar fractures involving the articular surface and inferior pole, divided into two groups based on the fixation method. Outcomes were assessed using a range of motion (ROM), Böstman scores, and the Insall-Salvati Index (ISI).Results: The finite element analysis revealed that the dual tension band technique resulted in lower maximum stress on the patella and lower displacement on the fixation devices compared to the single tension band. Clinically, patients treated with the dual tension band had significantly higher postoperative ISI values (0.93 ± 0.16 vs. 0.85 ± 0.17, p < 0.05), better ROM (123.75 ± 9.58 vs. 117.63 ± 12.28, p < 0.05), and a lower incidence of patella baja (17.86% vs. 34.21%). The Böstman scores showed no significant difference between the groups.Conclusion: The dual tension band technique provides effective stabilization for patellar fractures involving the articular surface and inferior pole, reducing the incidence of postoperative patella baja and improving functional outcomes.

Background: Secondary fragility fractures remain a major complication after hip fracture surgery in older adults, yet individualized postoperative risk stratification remains challenging. We aimed to identify factors associated with secondary fragility fracture and internally validate an interpretable machine-learning model for three year refracture risk. Methods: We retrospectively analyzed adults aged ≥ 65 years who underwent surgery for a first low-energy hip fracture between 2014 and 2021. Patients were followed for three years for secondary fragility fracture. Demographic, clinical, functional, and rehabilitation variables were extracted from electronic medical records. Cox regression with multiple imputation was performed to evaluate time-to-event associations. XGBoost was developed as the primary prediction model and compared with SVM and Cox regression. Model performance was assessed using a held-out test set and decision curve analysis. Results: Among 4,418 patients, 594 (13.4%) sustained a secondary fragility fracture. Increased refracture risk was associated with older age, osteoporosis, low BMI, female sex, cardiovascular disease, visual impairment, syncope, non-standard rehabilitation, and postoperative Harris hip score < 80. In the test set, XGBoost achieved an AUC of 0.701 (95% CI, 0.657–0.743), with 61.8% sensitivity and 67.2% specificity at the default threshold. Decision curve analysis demonstrated the highest net benefit for XGBoost across threshold probabilities of approximately 7%–32%. Conclusions: Secondary fragility fractures were associated with skeletal fragility, fall-related vulnerability, and impaired postoperative recovery. The interpretable XGBoost model showed moderate discrimination and potential clinical utility as an adjunctive screening tool to identify patients who may benefit from intensified secondary prevention. External validation and prospective evaluation are required before routine clinical implementation.