Microfracture (MF) is widely used for cartilage repair, but it often yields limited clinical benefit because it predominantly induces fibrocartilage formation. However, the mechanisms underlying this fibrocartilaginous repair remain insufficiently defined. In this study, temporal histopathological profiling and integrative bioinformatic analyses of post-microfracture specimens revealed that early extracellular iron accumulation was positively associated with ferroptosis severity. Single-cell RNA sequencing further delineated a bifurcating differentiation trajectory of bone marrow mesenchymal stem cells (BMSCs) toward either hyaline-like chondrocytes or fibrocartilaginous chondrocytes, with ferroptosis acting as a critical regulator at the branch point. Given the antioxidant and ferroptosis-modulating activity of curcumin-derived components, we hypothesized that curcuma-derived extracellular vesicles (CDEVs) could suppress ferroptosis and bias the differentiation of BMSCs toward hyaline cartilage. Mechanistically, in vitro assays identified Pvu-miR-159 in CDEVs as a key functional cargo that attenuates ferroptosis via the PTPN12-ERK1/2-ATF4-GPX4 pathway. To enhance its translational potential, we developed an injectable reactive oxygen species (ROS)-responsive hydrogel enabling sustained CDEVs delivery, which effectively reduced ferroptosis and promoted cartilage regeneration in vivo. Together, these findings uncover a ferroptosis-driven mechanism contributing to suboptimal microfracture repair and support a plant-vesicle-based, ROS-responsive delivery strategy to reprogram BMSCs toward improved regenerative outcomes.

Objective:To review the research progress regarding the effects of the local microenvironment after meniscal injury and immunomodulatory strategies for meniscal regeneration. Methods:Relevant literature on meniscal regeneration, macrophage polarization, and tissue engineering was retrieved. The mechanisms underlying immune microenvironment imbalance after injury were summarized, and immunomodulatory interventions were analyzed from four perspectives: drugs and bioactive molecules, stem cells and exosomes, biomaterials, and external physical stimuli. Results:The highly inflammatory microenvironment dominated by M1 macrophages after injury significantly hinders tissue repair. Current studies mainly promote functional meniscal regeneration through immunomodulatory interventions in four aspects: drugs and bioactive molecules inhibit inflammatory cascades by blocking inflammatory receptors and related signaling pathways; stem cells and exosomes modulate the local immune microenvironment through paracrine effects and enhance the functions of repair-related cells; functionalized biomaterials achieve synergy between immunomodulation and mechanical support through active component delivery, physicochemical property regulation, and structural design; and external physical stimuli, such as acoustic, electrical, and magnetic stimulation, serve as non-invasive auxiliary approaches for inflammation regulation and tissue repair. Conclusion:Remodeling the immune microenvironment is critical for functional meniscal regeneration. Smart scaffolds with both mechanical support and immunomodulatory functions should be further developed.

Injury to articular cartilage remains a major clinical challenge owing to its limited self-healing capacity. Current cell-based therapies are limited by issues such as dedifferentiation and regulatory hurdles, whereas existing scaffold systems often lack the essential biochemical signals necessary for effective tissue regeneration. Consequently, biomimetic acellular strategies capable of recruiting endogenous stem cells while establishing a conducive biochemical microenvironment to direct their chondrogenic differentiation are needed. In this study, we developed a bioactive, hierarchical porous extracellular matrix (ECM) scaffold fabricated via low-temperature deposition manufacturing (LDM) and functionalized with the bone marrow-homing peptide PFS (amino acid sequence PFSSTKT) to increase in situ cartilage regeneration. The scaffold preserves the native biochemical characteristics of ECM while enabling stable functionalization with the chemoattractant peptide PFS. In vitro studies demonstrated that the PFS-functionalized ECM scaffold exhibited favorable biocompatibility and supported cell adhesion, migration, and proliferation. In vivo studies using a rabbit full-thickness cartilage defect model further showed enhanced endogenous stem cell recruitment and hyaline-like cartilage regeneration in the PFS-ECM group compared with the ECM and control groups. The regenerated tissue exhibited improved matrix composition, biomechanical properties, and histological scores. Collectively, this work presents a cell-free, biofunctional ECM-based scaffold strategy that promotes endogenous repair of articular cartilage, providing a promising approach for cartilage regeneration without exogenous cell transplantation. STATEMENT OF SIGNIFICANCE: Articular cartilage repair remains a significant clinical challenge. While current cell-based therapies face limitations such as dedifferentiation, conventional scaffolds often lack essential bioinductive signals. To address this challenge, we have developed a bioactive extracellular matrix scaffold functionalized with the chemotactic peptide PFS. In this design, the PFS peptide enhances endogenous stem cell recruitment, while the ECM provides a chondrogenic microenvironment. Experimental results confirmed that this scaffold significantly promotes stem cell migration and chondrogenic differentiation. Animal studies demonstrated that the PFS-ECM group outperformed control groups in cell recruitment, hyaline cartilage regeneration, and mechanical properties, offering a promising cell-free solution with translational potential for clinical cartilage repair.

Articular cartilage defects remain a major clinical challenge due to their poor self-repair capacity. Mesenchymal stem cell (MSC)-derived exosomes have emerged as promising cell-free therapeutics; however, conventional two-dimensional (2D) cultures yield exosomes with limited bioactivity. Here, we engineered hierarchical macro-microporous scaffolds using gelatin methacryloyl (GelMA) hydrogel and cartilage extracellular matrix (ECM) to establish biomimetic three-dimensional (3D) microenvironments for MSC culture. This approach yielded three distinct exosome types-2D-Exo, GelMA-derived exosomes (G-Exo), and ECM-derived exosomes (E-Exo). Compared with 2D-Exo, 3D-derived exosomes significantly enhanced MSC proliferation, migration, chondrogenic differentiation, immunomodulation, and chondrocyte protection under inflammatory conditions, with E-Exo exhibiting the most potent effects. In vivo, E-Exo combined with a decellularized cartilage ECM (DCM) scaffold promoted robust hyaline cartilage regeneration in a rat model. Mechanistically, we identify a key pathway by which E-Exo drives chondrogenesis: they are enriched in miR-503-5p, which suppresses Smad7 to enhance TGF-β/Smad2/3 signaling. These findings highlight ECM-based 3D culture as an effective strategy to optimize exosome bioactivity and provide a clinically translatable approach for cell-free cartilage regeneration.

The meniscus, a critical fibrocartilaginous structure in the knee joint that cushions load and stabilizes movement, suffers from poor self-healing potential following tears. This impaired repair not only fails to restore joint function but often progresses to osteoarthritis, posing significant clinical challenges. Regrettably, current therapeutic approaches, such as surgical suturing or partial resection, have limited efficacy in achieving functional regeneration of the meniscus. To address these bottlenecks, we developed a multifunctional composite hydrogel system integrating methacrylated silk fibroin (SilMA), cerium dioxide (CeO2) nanozymes and tetrahedral framework nucleic acid (tFNA)-miRNA-455. The SilMA hydrogel, leveraging photocrosslinking technology for on-demand solidification, offers injectability (enabling minimally invasive delivery), strong tissue adhesion and robust mechanical support-effectively bridging meniscal tear gaps and creating a scaffold for cell infiltration. Embedded CeO2 nanozymes act as potent reactive oxygen species (ROS) scavengers and nanozyme-mediated ROS clearance mitigates inflammation and fosters a regeneration-conducive microenvironment. Moreover, tFNAs serve as a biocompatible, stable delivery vector for miRNA-455, protecting the nucleic acid from degradation and ensuring its efficient cellular uptake. This targeted delivery drives chondrogenic differentiation of synovial mesenchymal stem cells (SMSCs), directly promoting fibrocartilage formation. This synergistic strategy unites structural reinforcement, immunomodulation and stem cell regulation, overcoming conventional carrier limitations (cytotoxicity and poor stability) and demonstrating significant potential for meniscal repair. Ultimately, it offers a promising solution for cartilage regeneration and meniscus function restoration, with broad implications for clinical translation.

ABSTRACT The integration of bioactive matrix components and precise spatial architectures represents a promising strategy for regenerating complex tissues like articular cartilage. While decellularized cartilage matrix (DCM) preserves essential regenerative cues, the optimal engineering fabrication strategy to translate its biochemical potential remains to be defined. In this study, we conducted a systematic technological screening by fabricating three distinct DCM‐based topological prototypes: randomized porous scaffolds (RPS) via traditional lyophilization, oriented porous scaffolds (OPS) via ice‐templating, and hierarchical porous scaffolds (HPS) via low‐temperature 3D printing. Our findings reveal that the HPS configuration, characterized by its multi‐scale hierarchical porosity, functions as a biophysical instructor that activates the FAK‐PI3K/AKT mechanotransduction axis. Unlike RPS and OPS, HPS uniquely reprograms the BMSC secretome into a robust paracrine factory, effectively balancing pathological homeostasis and shielding chondrogenesis from inflammatory degradation. This study establishes the hierarchical architecture as the superior engineering fabrication solution for DCM‐based regeneration, offering a new paradigm for instructive cartilage defect repair.

Articular cartilage injury poses a significant global public health challenge, with limited self-repair capacity often leading to fibrotic repair and insufficient integration following current clinical interventions. To overcome the limitations of existing hydrogels and precisely reconstruct a native-like microenvironment, this study aimed to develop a highly translational, matrix-inspired bioink. We formulated a novel bioink combining recombinant humanized type II collagen (RhCol II)—which resolves the scarcity and extraction difficulties of natural collagen—decellularized glycosaminoglycans (GAGs), and hyaluronic acid methacrylate (HAMA) for digital light processing (DLP) bioprinting of cartilage organoid precursors (COPs). Distinct from fully matured in vitro organoids, these COPs serve as highly inductive developmental blueprints designed to programmatically drive autonomous maturation post-printing. Quantitative in vitro analysis demonstrated that the bioink at the optimal RhCol II/GAGs ratio (7:3) exhibited excellent biocompatibility and significantly upregulated chondrogenic-specific genes (SOX9, ACAN, Col II) in human umbilical cord mesenchymal stem cells (hUCMSCs). Subcutaneous implantation in nude mice resulted in the maturation of COPs into cartilage-like tissue with typical lacunar structures and robust extracellular matrix (ECM) deposition. Crucially, in situ implantation in a rabbit articular cartilage defect model achieved superior hyaline cartilage regeneration, demonstrating enhanced biomechanical properties, favorable tissue integration, and subchondral bone preservation at 12 weeks. Transcriptomic and molecular analyses revealed that the biomimetic matrix components dynamically drove this chondrogenic differentiation by specifically activating the FOXO1/3 signaling pathway. This study provides an efficient, mechanistically defined platform for functional cartilage organoid construction via this novel COP strategy, offering promising potential applications in osteoarthritis modeling and cartilage tissue engineering research.

Osteonecrosis of the femoral head (ONFH) is a progressive, multifactorial bone disease characterized by ischemia-induced osteocyte death, microenvironmental imbalance, and failed tissue regeneration. According to recent advances in pathophysiological understanding, vascular injury, oxidative stress, and inflammatory storms form a pathogenic cascade leading to osteogenic dysfunction, adipogenic lineage drift of mesenchymal stem cells (MSCs), and epigenetic alterations that exacerbate bone degeneration. Despite improvements in early detection, traditional interventions-including bisphosphonates, hyperbaric oxygen therapy, and surgical decompression-have limited efficacy, particularly in the mid-to-late stages. This review systematically synthesizes emerging regenerative approaches across three domains: (1) Cellular and molecular therapies: Autologous MSC transplantation, exosomes, and apoptotic extracellular vesicles restore osteogenesis, modulate immunity, and promote angiogenesis, while gene-editing technologies such as CRISPR/Cas9 enhance MSC functionality. (2) Nanobiomaterial synergy: Enzyme-mimetic nanozymes and multifunctional polymeric scaffolds improve lesion targeting, reactive oxygen species clearance, and microenvironmental regulation. (3) Advanced bioengineering: Organoid models and 3D-bioprinted living joint prostheses enable the integration of vascularization, mechanical support, and precise drug delivery, representing transformative strategies in personalized repair. Together, these innovations highlight a future paradigm shift from passive support to active, mechanism-targeted regeneration, offering new hope for structural and functional reconstruction in ONFH. Multidisciplinary integration-bridging materials science, stem cell biology, and digital medicine-will be essential for successfully developing functional cures.

Achieving effective drug delivery and therapeutic efficacy poses significant challenges in intervertebral disc degeneration (IDD). Here, we developed a dual-pathological cascade delivery system utilizing therapeutic mesenchymal stem cell-derived apoptotic vesicles (ApoVs). These vesicles are engineered with MMP13-responsive cell-penetrating peptides (MR-ApoVs) for targeted modulation of senescence. A reactive oxygen species (ROS)-responsive hydrogel incorporating CD44 aptamers (Apt-Gel) was developed to provide high-affinity retention and spatiotemporal controlled release of MR-ApoVs. In this system, MR-ApoV release is first triggered by hydrogel degradation in response to elevated ROS levels. Subsequently, the MMP13-responsive peptides on MR-ApoVs are activated to enhance their internalization into senescent nucleus pulposus (NP) cells, thereby achieving a sequential response to pathological signals within the degenerative disc microenvironment. In a rat model of IDD, MR-ApoV@Apt-Gel effectively attenuated NP cell senescence, restored extracellular matrix homeostasis, preserved disc hydration, and maintained intervertebral disc height. This dual-pathological cascade-responsive strategy represents a promising therapeutic approach for IDD treatment.

In situ articular cartilage (AC) regeneration is a meticulously coordinated process. Microfracture has been the most extensive clinical approach in AC repair, but it faces challenges such as matrix degradation, generation, and remodeling within a local inflammatory microenvironment. So far, it remains a challenge to establish a multistage regulatory framework for coordinating these cellular events, particularly the immune response and chondrocyte proliferation in microfracture-mediated AC repair microenvironments, which is crucial for promoting AC regeneration quality. At present, the excessive inflammatory response after microfracture can chronically activate the nuclear factor-κB (NF-κB) pathway, increasing production of matrix-degrading enzymes like matrix metalloproteinases (MMPs) and aggrecanases, which in turn accelerate cartilage matrix degradation and worsen the injury. Herein, we develop a novel enzyme-responsive, self-assembling hydrogel composed of silk fibroin and an Aggrecanase-2 (ADAMTS5)-sensitive peptide. This hydrogel targets ADAMTS5, a key enzyme overexpressed in the postinjury inflammatory microenvironment, enabling dynamic drug release based on inflammation levels. We then incorporated miRNA-17-3p (miR-17-3p) into lipid nanoparticles and loaded this miRNA delivery system into the hydrogel to inhibit NF-κB signaling upstream of ADAMTS5. This strategy created a targeted positive regulatory feedback mechanism, fundamentally solving the problem of modulating the ADAMTS5-related inflammasome pathway while boosting chondrocyte expansion in the early stage. In vivo studies in microfracture-mediated cartilage repair models demonstrated that the ADAMTS5-responsive hydrogel with miR-17-3p achieves superior repair outcomes. This research offers a logic-based and multistaged strategy for chronologically regulating the inflammatory microenvironment, which has research value and practical application prospects in the treatment of AC injuries.

Apoptotic vesicles (ApoVs) have garnered considerable attention within the realm of tissue regeneration research, necessitating a comprehensive bibliometric analysis to delineate current international trends and to map out historical and contemporary developments in this domain. Methods:This study conducted a bibliometric analysis leveraging data sourced from the SCI-Expanded Web of Science (WOS) database. The analysis encompassed publications from October 1, 1991, to December 31, 2023. A total of 1209 articles focusing on ApoVs for tissue regeneration were scrutinized, considering attributes such as publication year, journal, author, institution, country/region, references, and keywords. Coauthorship, cocitation, co-occurrence analyses, network visualizations were generated using VOSviewer and CiteSpace. Results:The analysis indicated a steady annual rise in global publications pertaining to ApoVs for tissue regeneration. The United States emerged as the foremost contributor, with the highest citation count and H-index. Furthermore, University of Tehran Medical Sciences was pinpointed as the most prolific institution. The journal International Journal of Molecular Sciences issued the largest account of articles on this topic. Notable subtopics such as "regenerative medicine," "delivery," and "mesenchymal stem cells" are poised to become significant research focal points in the near future. Conclusions:Over the past 30 years, research on ApoVs for tissue regeneration has witnessed substantial growth, mirroring increasing collaboration across various countries and institutions. This study illuminates trends, collaboration patterns, research hotspots, and future trajectories in the field, providing valuable insights for researchers and practitioners.

Bone regeneration faces dual challenges of insufficient energy supply and oxidative stress, while both energy provision and reactive oxygen species levels are mitochondrially regulated and tend to increase or decrease synchronously. Conventional biomaterials fail to reconcile the high ATP demands of osteogenesis with mitochondrial dysfunction. Here, we present laponite-primed apoptotic vesicles (L@Apo) derived from bone marrow mesenchymal stem cells (BMSCs), engineered to address this bioenergetic crisis through dual-pathway mitochondrial regulation. L@Apo integrates more mitochondrial components and bioactive factors with cargo delivery to activate PINK1/Parkin-mediated mitophagy, selectively eliminating dysfunctional mitochondria while initiating biogenesis to replenish energetic capacity. Concurrent PI3K-/AKTsignaling drives metabolic rewiring, amplifying both glycolysis and oxidative phosphorylation to meet mineralization demands. A thiol-ene hydrogel (L@Apo-G/P) ensures sustained vesicle release, preserving mitochondrial integrity and bioactivity. In vitro, L@Apo promotes osteogenic differentiation, angiogenesis, and anti-inflammatory macrophage polarization while mitigating oxidative damage. In vivo, L@Apo-G/P achieves robust bone regeneration in rat femoral defects, surpassing conventional strategies in structural and functional restoration. This biomaterial platform enhances energy metabolism and reduces oxidative damage through programmable mitochondrial reprogramming, establishing a viable strategy for regenerating tissues with high metabolic demands.

Pathological subchondral bone remodeling, characterized by aberrant osteoclastogenesis, exacerbates cartilage degeneration by disrupting osteochondral homeostasis. Here, a correlation between pathological osteoclastogenesis and oxidative stress dynamics is reported in a rat cartilage defect model. On the basis of these findings, CeO2@ZIF-8 nanotherapeutics are engineered to scavenge ROS and suppress pathological osteoclastogenesis, mitigating inflammation and cartilage degeneration. The developed system integrates cerium oxide nanoparticles (CeO2) into a zeolitic imidazolate framework-8 (ZIF-8) framework, exploiting pH-responsive degradation for controlled release in acidic osteochondral niches. In vitro and in vivo assessments confirmed that CeO2@ZIF-8 attenuated osteoclastogenesis, reduced Il-1b expression, and elevated Spp1 levels, and these changes are correlated with improved cartilage regeneration. Multiomics analysis revealed that conditioned supernatants from CeO2@ZIF-8-treated osteoclasts exert protective effects on chondrocytes via the PI3K-PKCs-ERK1/2-Cyp1a1 axis, maintaining the chondrocyte phenotype and inhibiting apoptosis. In summary, the findings established the feasibility for targeting osteoclast-chondrocyte communication through nanozyme-mediated osteoclast reprogramming and provided a mechanistic understanding of orchestrate pathological communication to drive tissue regeneration.

The cellular microenvironment is an integrated complex of the extracellular matrix, cells and extracellular fluids containing numerous bioactive molecules. It is widely acknowledged that the periodontal microenvironment exerts profound effects on adjacent stem cells, affecting tissue remodeling and repair. For instance, the physiological microenvironment maintains stemness and supports tissue-specific differentiation of mesenchymal stem cells (MSCs), whereas pathological inflammation resets programmed cell fate, increases the secretion of proinflammatory factors, and may even induce MSC apoptosis. The normal remodeling or repair process is therefore dysregulated, and inflammatory conditions worsen. Modulating the stem cell-based microenvironment appears to be an effective strategy for periodontal regeneration. In this review, five types of MSCs involved in periodontal tissue remodeling and repair are introduced. Subsequently, we discuss the impact of various periodontal microenvironments on MSC fate and further summarize the latest biomaterials for use in periodontal regeneration from the aspect of microenvironmental cues. The use of multiple material design strategies to modify the inflammatory microenvironment offers valuable insights for future advancement of material-guided periodontal regeneration under pathological conditions.

Tissue engineering provides a promising avenue for treating meniscus defects. In this study, a novel polycaprolactone (PCL)/collagen type I (COL I) meniscus scaffold was fabricated using low temperature deposition manufacturing (LDM) 3D printing technology. The scaffold had a ring and radial fiber structure, and its composition and structure were double bionic of the natural meniscus. In vitro experiments showed that the scaffold had good biological properties, which could promote the proliferation of meniscus fibrochondrocytes (MFCs) and increase the secretion of collagen and glycosaminoglycan. Moreover, the scaffold had excellent mechanical properties and could withstand various stress loads from the femur and tibia. The integrity of the scaffold structure was maintained to provide sufficient time and space for tissue regeneration. The PCL/ COL I scaffold has shown good therapeutic effect in a rabbit meniscus defect model and promotes meniscus regeneration. The results of experiments in rabbits suggest that the scaffold may recruit stem cells and differentiate into fibrochondrocytes in the knee joint, which needs to be verified by further experiments. This study introduces a method of fabricating a new structural composition double bionic meniscus scaffold by LDM technology and verifies its ability to promote cell proliferation, increase the secretion of the extracellular matrix of fibrocartilage, and regulate the microenvironment of cell growth. In addition, this scaffold has achieved good results in repairing meniscus defects in small animal models. Our findings strongly indicate that the PCL/COL I biomimetic meniscus scaffold prepared using 3D-LDM technology holds great promise for repairing and regenerating damaged menisci.

High-fat diet consumption-induced obesity and metabolic alterations can accelerate the progression of osteoarthritis (OA), which is closely associated with chondrocyte lipotoxicity caused by elevated free fatty acid levels. However, antilipotoxic therapeutic strategies for dietary fat-associated OA are lacking. Here, we first identified the role of microRNA-34a-5p (miR-34a-5p) in joint destruction in dietary fat-related OA and found that miR-34a-5p inhibitors were able to exert both antilipotoxic and anti-inflammatory effects on articular chondrocytes. Furthermore, we developed a novel tetrahedral framework nucleic acid (tFNA)-based nanocomplex (P-T-M) that could efficiently deliver a miR-34a-5p inhibitor to chondrocytes through the loading of a chondrocyte-affinity peptide (CAP). P-T-M effectively preserved the chondrocyte phenotype and metabolic homeostasis in the presence of elevated fatty acid levels and inflammation while suppressing ferroptosis in chondrocytes by modulating lipid metabolism. Moreover, we developed gelatin methacryloyl (GelMA) hydrogel microspheres via microfluidic technology for sustained P-T-M delivery, which significantly mitigated joint damage in rats with high-fat diet-associated OA. Our findings establish a precision nanomedicine strategy for metabolic OA treatment that simultaneously resolves lipid metabolism disorders and ferroptosis-driven cartilage degeneration.

Osteosarcoma (OS) blooms significant clinical challenges due to risks of metastasis, recurrence and disruption of bone homeostasis (BH). This study tactically offers a multifunctional time-sequential scaffold comprising of borosilicate bioactive glass (BSG) core, Fe3O4 magnetothermal nanoparticles (FMNPs) intermediate layer, and doxorubicin-infused pH-responsive hydrogel (PRH) outer layer. BSG degradation can generate ionic and alkaline microenvironment (IAM/BSG) to fasten PRH gel state to prevent doxorubicin leakage. FMNPs-induced hyperthermia can elicit PRH gel-sol transitions under alternating magnetic field (AMF) after engagement with tumor microenvironment (TME), improving PRH infiltration into remote tumor sites. Whereas the acidic TME then cleaves Schiff base bonds generated by carboxymethyl chitosan and oxidized dextran in PRH to release doxorubicin sustainably and selectively. IAM/BSG can also reduce OS cell viability, while hyperthermia can further impair tumor cells as needed, synergistically enhancing doxorubicin release's tumor eradication effect even at lower dosages, potentially reducing chemotherapy's systemic toxicity. Subsequently, the IAM/BSG polarizes macrophages to the M2 phenotype, creating an immunoregulatory milieu promoting osteogenesis of BMSCs for optimal bone regeneration after tumor ablation. Summarily, BSG integrating with hyperthermia to manipulate pH-responsive release of chemotherapeutic agent for targeted cancer eradication and unbalanced BH reconstruction, harmonizes the challenge of efficient OS treatment with bone regeneration time-sequentially.

Poor healing outcomes following rotator cuff injury are linked to insufficient endogenous repair capacity within tendon tissue. And the ATP deficiency caused by energy metabolic imbalance in tendon stem/progenitor cells (TSPCs) is a key pathological feature. Here, we identified energy metabolic changes under the oxidative stress microenvironment of rotator cuff injury, characterized by downregulated oxidative phosphorylation (OXPHOS) and tricarboxylic acid (TCA) cycle in mitochondria, coupled with enhanced glycolysis. Our data showed that Turmeric-derived Extracellular Vesicles (Tur-EVs) rescued this energy crisis, as manifested by the restoration of mitochondrial function and enhanced energy supply, while preserving the proliferation and differentiation capacities of TSPCs. Furthermore, our study revealed that Tur-EVs enhanced mitophagy and endogenous antioxidant capacity through the AMPK-FOXO3 pathway, as a potentially functional mechanism. In rat and rabbit rotator cuff injury models, Tur-EVs-loaded microneedle significantly improved rotator cuff healing quality in terms of locomotor gait, biomechanics, and histopathological outcomes. In summary, our findings demonstrate the potential of plant-derived extracellular vesicles in regulating energy metabolism, and suggest the dysregulated energy metabolism as a crucial therapeutic target in tendon repair.

The repair of articular cartilage defects remains a major regenerative and clinical challenge. Exosomes (Exos) derived from mesenchymal stem cells (MSCs) have good application potential in cartilage tissue engineering. Numerous studies have indicated that appropriate preconditioning methods can promote the therapeutic effect of Exos. Growth differentiation factor 5 (GDF-5) plays a critical role in chondrogenesis and regeneration. In this study, GDF-5 was used to precondition synovial mesenchymal stem cells (SMSCs) to increase the chondrogenic-promoting effect of Exos (G-Exos). In addition, we demonstrated that G-Exos rich in miR-383-3p increased the chondrogenic potential of SMSCs by activating the Kdm2a/SOX2 signaling pathway. On this basis, G-Exos were loaded into a glycyrrhizic acid/methacrylate-acylated hyaluronic acid (GA/HA/G-Exos) scaffold via digital light processing (DLP) bioprinting to maintain bioactivity and sustained release. The GA/HA/G-Exos scaffolds not only presented significant biological properties in vitro but also significantly promoted the remodeling of the joint cavity regenerative microenvironment and the regeneration of articular cartilage in Sprague-Dawley rats. This study provides a promising cell-free regenerative strategy for cartilage defect repair via the use of engineered exofunctionalized biological scaffolds.

ABSTRACT Background The risk of internal fixation failure remains relatively high in stable femoral neck fracture (FNF) (Garden I or II). Preoperative sagittal displacement of the femoral head has been proposed as a potential influencing factor. This study aimed to evaluate the impact of sagittal displacement on the outcomes of cannulated screw internal fixation (CSIF) in patients with stable FNF (Garden I or II) by reconstructing the axial sagittal oblique plane of the fracture using preoperative computed tomography (CT) imaging. Methods This study included 167 patients with FNF who underwent CSIF. The sagittal tilt angle of the femoral head (STAFH) was evaluated using three‐dimensional CT (3D‐CT). The distribution of preoperative STAFH was analyzed, and its independent association with treatment failure was assessed. Treatment failure was defined as the need for revision surgery within 2 years postoperatively due to avascular necrosis, nonunion, or internal fixation failure. Results Among the 167 patients, 9 (5.4%) exhibited anterior tilt (AT) of the femoral head, 158 (94.60%) presented with posterior tilt (PT). A total of 50 patients (29.9%) demonstrated excessive sagittal displacement (AT ≥ 10° or PT ≥ 20°). In the failure group, 80.0% of patients had excessive sagittal displacement compared to 28.1% in the healed group. Excessive sagittal displacement was significantly associated with an increased risk of surgical failure (odds ratio: 11.953, 95% CI: 3.656–39.083, p < 0.05). Conclusions In patients with Garden I or II FNF, greater preoperative sagittal displacement of the femoral head was correlated with a higher likelihood of CSIF failure. AT ≥ 10° or PT ≥ 20° were identified as independent predictors of CSIF failure in FNF patients. Nevertheless, these findings still require confirmation through prospective, multi‐center clinical trials with large sample sizes.