Tissue-engineering strategies combining mesenchymal stem cells (MSCs) or extracellular vesicles (EVs) with bone-regenerative scaffolds may improve healing of critical-size bone defects, yet their comparative efficacy remains unclear. We systematically searched PubMed, Embase, Scopus, Web of Science, and ProQuest for animal studies published up to July 1, 2025. Risk of bias was assessed using the SYRCLE tool. New bone formation was synthesized as bone volume/total volume (BV/TV) using conventional meta-analysis and Bayesian network fixed/random-effects models, reported as standardized mean difference (SMD) with 95% confidence interval (CI)/credible interval (CrI). Subgroup analyses were conducted by MSC source, EV use, scaffold type, anatomical site, and follow-up duration, with sensitivity analyses and assessment of publication bias. In total, 207 studies across 7 animal models were included. MSC-loaded scaffolds significantly enhanced bone regeneration compared with no treatment or scaffold alone, showing a strong short-term effect and consistent benefits at medium and long follow-up. Bone marrow MSC (BMSC)-laden scaffolds underperformed adipose-derived MSC (ADSC)-laden scaffolds, and BMSC-derived EVs further improved outcomes compared with cell-free scaffolds. Calvarial defect models demonstrated greater gains than long-bone models. Network meta-analysis suggested multi-component composite scaffolds had the highest potential for new bone formation among cell-free designs. Overall, MSCs/EVs combined with supportive scaffolds markedly increase bone regeneration in preclinical models, but heterogeneity in models, biomaterials, dosing, and outcome reporting limits direct clinical translation, underscoring the need for standardized protocols and core outcome sets. STATEMENT OF SIGNIFICANCE: This comprehensive meta-analysis incorporated network comparisons across diverse mesenchymal stem cells (MSCs) or extracellular vesicles (EVs) sources and biomaterial categories. It reveals that MSC-EVs, particularly when combined with scaffolds or hydrogels, are the most effective in improving BV/TV ratio (bone volume/total volume) and histological outcomes in animal bone defect models. These data indicate that MSC or EV-enhanced biomaterial strategies may be leading candidates for repairing critical-sized defects and provide a standardized roadmap for transitioning preclinical success into clinical practice.

The impaired regeneration of aged individuals presents major challenges for repairing bone defects. Within the senescent microenvironment (SME), excessive reactive oxygen species (ROS), chronic inflammation, the accumulation of senescent cells and local infection form a self-reinforcing vicious cycle that hinders healing. Here, we developed a multimodal ROS logic-gated therapeutic platform by integrating magnesium- and manganese-doped bismuth oxide with oxygen vacancies nanoparticles (MMBOx) embedded in a rapamycin (Rapa)-loaded, 3D-printed hydrogel scaffold. In vitro study, this platform combines pH-responsive peroxidase, oxidase-like activity and photothermal-enhanced sonodynamic effects, enabling on-demand ROS generation for efficient antibacterial elimination. Simultaneously, MMBOx and the hydrogel scavenge excess ROS, while Rapa promotes cellular autophagy to remove damaged mitochondria, enhances ROS regulation, and delays stem cell senescence. Moreover, MMBOx enhances glutathione (GSH) synthesis and metabolism by modulating the Keap1-Nrf2 signaling pathway, thereby boosting the intracellular GSH pool and increasing ROS tolerance to support a more youthful cellular phenotype. In vivo studies confirm that this platform alleviates infection in the infected skin defect model. Furthermore, it attenuates SME-associated chronic inflammation and cellular senescence, and promotes bone regeneration in the aged rat calvarial defect model. These findings offer a promising strategy for addressing deteriorated SME and enhancing bone repair in the elderly.

To investigate and analyze the application techniques and principles of 3D printing-based medical–engineering interaction for precision surgery of the foot and ankle, we summarized 216 patients treated at the Foot and Ankle Surgery Team of the Department of Orthopaedic Surgery, Shanghai Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine, between February 2020 and March 2025, who underwent 3D printing-assisted interventions under medical–engineering interaction. Among them, 152 patients underwent pre-operative 3D reconstruction based solely on CT/MRI imaging, 32 patients underwent deformity localization and quantitative measurements performed in the regions of interest based on these reconstruction, and 26 patients received personalized 3D-printed surgical guides for osteotomy, lesion localization, or broken implant removal. Additionally, 3 patients received customized fixation and rehabilitation orthoses, and 3 patients received personalized 3D-printed prostheses. Using 3D reconstruction, deformity localization and quantitative measurements, personalized 3D-printed surgical guides, and personalized 3D-printed prostheses, individualized treatment strategies were formulated for selected foot and ankle patients, accounting for 17.2

Articular cartilage damage, an important cause of osteoarthritis (OA), is often caused by a senescent cartilage microenvironment and insufficient repair of chondrocytes. These effects are due to limited availability and a depleted stemness phenotype of chondrocyte stem cells, leading to the failure of cartilage repair and exacerbation of symptoms. In this study, a biomimetic gradient-structured cartilage organoid (BGSC-organoid) culture system was developed using decellularized cartilage extracellular matrix infused with extracellular vesicles from SOX9-overexpressing bone marrow-derived stem cells (SBEVs) to induce the rejuvenation of senescent chondrocytes. Single-cell sequencing revealed that a subpopulation of chondrocytes could be rejuvenated in the BGSC-organoid culture system. Moreover, an ex vivo osteoarthritis-on-a-chip (OAOC) model with cyclic mechanical stimulation was constructed to simulate the mechanical microenvironment of cartilage. BGSC-organoids exhibited sustained release of chondrocyte-protective factors and good mechanical resistance through the Vimentin/14-3-3/FOXO3 pathway. Animal studies showed that BGSC-organoids preserved a hyaline-like cartilage phenotype in vivo and delayed the degeneration of articular cartilage and intervertebral discs. Efficient expansion of human cartilage organoids with enhanced regenerative capabilities represents a promising approach for joint regeneration.

Joint injuries represent a significant clinical challenge with limited regenerative options. Three-dimensional (3D) bioprinting has emerged as a transformative technology, enabling the precise fabrication of patient-specific, anatomically matched, multilayered scaffolds that replicate the complex structure and gradient of natural joint tissues. This review comprehensively summarizes advances in bioprinting techniques, cell sources, and biomaterial formulations, emphasizing cell-laden bioinks composed of biomaterials and viable cells to create functional, bioactive constructs. Beyond basic fabrication, we evaluate the functional performance of bioprinted cartilage, bone, and ligaments, and we discuss strategies for engineering osteochondral interfaces and ligament–bone interfaces to support biomimetic mechanical properties and tissue integration. We further compare major printing modalities, including extrusion-based printing, inkjet, and laser-assisted bioprinting, and we discuss how modality-specific trade-offs in resolution, viscosity window, and cell stress influence construct fidelity and repair outcomes. In addition, we examine biofunctionalization strategies that incorporate growth factors, stem cells, and exosomes to enhance regenerative signaling and matrix remodeling. Notably, 3D bioprinting for joint regeneration is transitioning from bench to bedside, and we detail the current landscape of clinical translation, including commercialized products like Nanochon and active clinical trials for knee and hip repair. However, challenges such as insufficient vascularization and the mechanical performance of the printed constructions remain significant hurdles for clinical translation. Overall, this work underscores the potential of personalized 3D bioprinted scaffolds to advance joint tissue engineering and clarifies key directions for integrating these technologies into clinical practice.

Patellar dysplasia (PD) can cause patellar dislocation and subsequent osteoarthritis (OA) development. Herein, a novel ABCA6 mutation contributing to a four-generation family with familiar patellar dysplasia (FPD) is identified. In this study, whole exome sequencing (WES) and genetic linkage analysis across a four-generation lineage presenting with six cases of FPD are conducted. A disease-causing mutation in ABCA6 is identified for FPD. Further analyses reveal a consistent correlation between ABCA6 expression downregulation and PD occurrence, chondrocyte degeneration, and OA onset. Moreover, ABCA6-KO mice demonstrate severe knee joint degeneration and accelerated OA progression. Besides, synovial mesenchymal stem cells (SMSCs) are extracted from WT, ABCA6-/+, and ABCA6-/- mice to create chondrogenic organoids in vitro, confirming ABCA6 deficiency can lead to chondrocyte degeneration via modulating cell cycle and activating cellular senescence. Moreover, transcriptome and metabolomic sequencing analysis on ABCA6-KO chondrocytes unveils that the ABCA6 deficiency inhibits cholesterol efflux, leading to intracellular cholesterol accumulation and subsequent cellular senescence and impaired chondrogenesis.A disease-causing mutation of ABCA6 is identified for FPD. ABCA6 is correlated with PD occurrence and subsequent OA progression. ABCA6 can serve as a potential target in chondrogenesis and OA treatment by orchestrated intracellular cholesterol efflux and delayed cellular senescence.

Barium titanate (BaTiO3) is a conventional piezoelectric material, but its biocompatibility is limited. Besides, its piezoelectric property is significantly different from that of natural bone tissue. To address this, we have developed an innovative coating material that mimics the piezoelectric characteristics of natural bone with a d33 coefficient of 7.8 pm/V. The material was fabricated by replacing titanium (Ti) in the BaTiO3 crystal lattice with copper (Cu), a strategy that not only augments the piezoelectric response but also harnesses the osteogenic potential of Cu. BaCuxTi1-xO3 reveals an enhanced piezoelectric performance and actively promotes the adhesion, proliferation, and differentiation of MC3T3-E1 cells. Moreover, doped Cu modulates osteogenic differentiation through the upregulation of the Wnt4/β-catenin/SP7/Osterix signaling pathway. The synergistical effect caused by piezoelectricity and the biological activity of Cu contributed to promoting bone regeneration in vivo; in particular, H-BaCuxTi1-xO3 led to a 15.6% increase of the bone volume percentage compared to BaTiO3. Furthermore, H-BaCuxTi1-xO3 promoted the accumulation of bone extracellular matrix components including Osteopontin (OPN) and Collagen Type I (COL-1), which, respectively, increased by 62.12 and 155%. The synergistic interplay between the piezoelectric property of BaCuxTi1-xO3 and the osteogenic influence of Cu has significantly improved the repairing process of bone defects, offering a promising advancement in the field of orthopedic implant coatings.

Bone defects caused by trauma, infection, or tumors pose significant clinical challenges, particularly in large defects with poor healing outcomes. Traditional repair methods often fail to address the complex regenerative microenvironment. This study introduces a novel biomimetic piezoelectric periosteum‐bone bilayer implant designed to remodel the osteogenic microenvironment and enhance bone defect repair. The implant comprises an upper electrospun polyvinylidene fluoride‐curcumin‐loaded magnesium metal–organic framework (PVDF‐MOF/Cur, PMC) periosteum scaffold and a lower hydroxyapatite@gelatin methacrylate (HA@GelMA) bone scaffold (PMC+HA@GelMA, PMCG). In the whole PMCG bilayer implant, the upper PMC periosteum scaffold improves the piezoelectric properties of PVDF and enables sustained drug release via Mg‐MOF loaded with Cur. Meanwhile, the lower HA@GelMA scaffold facilitates bone marrow mesenchymal stem cells osteogenic differentiation and bone regeneration. Additionally, the upper PMC scaffold further accelerates bone repair by promoting neuronal differentiation, as well as enhancing angiogenesis and regulating macrophage polarization. Transcriptome sequencing reveals that the implant activates key signaling pathways associated with angiogenesis, neurogenesis, inflammation regulation, and osteogenesis, including HIF‐1α, PI3K‐Akt, JAK‐STAT, and TGF‐β pathways. Thus, this work highlights the multifunctional capabilities of the biomimetic periosteum‐bone bilayer implant to remodify the osteogenic microenvironment to accelerate bone defect repair, which offers a promising platform for advancing tissue repair.

INTRODUCTION:Developmental dysplasia of hip (DDH) is a hip joint disorder leading to subsequent osteoarthritis. Previous studies suggested collagen XI alpha 1 (COL11A1) as a potential gene in hip dysplasia and chondrocyte degeneration. However, no genetic association has reported COL11A1-related cellular therapy as treatment of DDH and joint degeneration. METHODS AND RESULTS:We report identified genetic association between COL11A1 locus and DDH with genome-wide association study (GWAS). Further exome sequencing for familial DDH patients was conducted in different populations to identify potential pathogenic Col11A1 variants for familiar DDH. Further studies demonstrated involvement of COL11A1 expression was down-regulated in femoral head cartilage of DDH patients and Col11a1-KO mice with induced DDH. Col11a1-KO mice demonstrated aggravated joint degeneration and severe OA phenotype. To explore the underlying mechanism of Col11a1 in cartilage and DDH development, we generated scRNA-seq profiles for DDH and Col11a1-KO cartilage, demonstrating disrupted chondrocyte homeostasis and cellular senescence caused by Col11a1-HIF1α-mediated glycolysis-OXPHOS shift in chondrocytes. Genetically and biologically inspired, we further fabricated an intra-articular injection therapy to preventing cartilage degeneration by generating a Col11a1-over-expressed (OE) SMSC mini-organoids. Col11a1-OE organoids demonstrated superior chondrogenesis and ameliorated cartilage degeneration in DDH mice via regulating cellular senescence by up-regulated Col11a1/HIF1α-mediated glycolysis in chondrocytes. CONCLUSION:We reported association between COL11A1 loci and DDH with GWAS and exome sequencing. Further studies demonstrated involvement of COL11A1 in DDH patients and Col11a1-KO mice. ScRNA-seq for DDH and Col11a1-KO cartilage demonstrated disrupted chondrocyte homeostasis and cellular senescence caused by Col11a1-HIF1α-mediated glycolysis-OXPHOS shift in chondrocytes. Genetically and biologically inspired, an intra-articular injection therapy was fabricated to prevent cartilage degeneration with Col11a1-OE SMSC organoids. Col11a1-OE organoids ameliorated cartilage degeneration in DDH mice via regulating cellular senescence by up-regulated Col11a1/HIF1α-mediated glycolysis in chondrocytes.

3D-printing technology, a leading example of advanced additive manufacturing, has revolutionized the treatment of clinical orthopedic diseases, ushering in a new era of personalized medicine. Since the 1980s, the orthopedic team led by Prof. Kerong Dai at Shanghai Ninth People's Hospital, affiliated with Shanghai Jiao Tong University School of Medicine, has effectively advanced the research, development, and implementation of customized artificial joints through medical collaboration. This work laid the foundation for the application of domestic 3D-printing in orthopedics. Continuous innovations—from fundamental research to clinical practice, from metal prosthesis implantation to customized bioactive bone product replacement, and from the traditional standardized diagnostic and treatment paradigm to the transformation of personalized medical models-underscore the pivotal role of 3D-printing technology. It has promoted personalized medicine, enhanced surgical precision, minimized the risk of infection, and accelerated bone integration. Prof. Yongqiang Hao's group has further expanded and deepened the application of three-dimensional printing technology in orthopedics. Significant breakthroughs have been achieved in domestic bioactive metals, metal orthopedic implants, and 3D-printed biological implants. The protocols for personalized internal fixation and novel pelvic reconstruction prostheses are now internationally recognized in clinical practice. This study provides a comprehensive overview of the innovative research and applications of personalized and customized 3D-printed orthopedic implants.

Melt electrospinning writing (MEW) combines the fundamental principles of electrospinning, a fiber forming technology, and 3D printing. The process, however, is highly complex and the quality of the fabricated structures strongly depends on the interplay of key printing parameter settings including processing temperature, applied voltage, collection speed, and applied pressure. These parameters act in unison, comprising the principal forces on the electrified jet: pushing the viscous polymer out of the nozzle and mechanically and electrostatically dragging it for deposition towards the collector. This article will reveal the correlation between the printing process parameters and the fiber morphology for curved printing fibers below the critical translation speed (CTS), and prepare controllable curved scaffolds by adjusting the electric field strength, which have fully interconnected pores and allow cells to migrate and proliferate. Furthermore, the study verified the advantages of these scaffolds through mechanical and in vitro culture experiments. The results showed that compared with the linearly printed scaffolds, the curved printed scaffolds exhibited better mechanical properties and enhanced cell attachment and proliferation.

Introduction: Cartilage defect (CD) is a common complication in osteoarthritis (OA). Impairment of chondrogenesis and cellular senescence are considered as hallmarks of OA development and caused failure of cartilage repair in most clinical CD cases. Exploring markers for cellular senescence in CD patients might provide new perspectives for osteoarthritic CD patients. In the present study, we aim to explore senescent markers in CD patients with OA to fabricate a senescence-targeted SMSC organoid hydrogel for cartilage repair. Methods: Clinical cartilage samples from cartilage defect patients were collected. Immunofluorescence staining of senescent markers and SA-β-Gal staining were used to detect the senescence state of SMSCs and chondrocytes in cartilage defect and OA patients. MicroRNA expression profiles of SMSC organoids and H2O2-treated SMSC organoids were analyzed and compared with high-throughput microRNA sequencing. Fluorescent in situ hybridization of miRNA were used to determine the expression level of miR-24 in SMSC organoids and cartilage samples. Interaction between miR-24 and its downstream target was analyzed via qRT-PCR, immunofluorescence and luciferase assay. Senescence-targeted miR-24 μS/SMSC organoid hydrogel (MSOH) was constructed for cartilage repair. Anti-senescence properties and chondrogenesis were determined in vitro for MSOH. Rats were used to evaluate the cartilage repair capacity of the MSOH hydrogel in vivo. Results: In this study, we found Osteoarthritic cartilage defect patients demonstrated upregulated cellular senescence in joint cartilage. MicroRNA sequencing demonstrated senescence marker miR-24 was negatively associated with cartilage impairment and cellular senescence in osteoarthritic CD patients. Moreover, miR-24 mimics alleviates cellular senescence to promote chondrogenesis by targeting downstream TAOK1. Also, miR-24 downregulated TAOK1 expression and promoted chondrogenesis in SMSC organoids. Senescence-targeted miR-24 μS/SMSC organoid hydrogel (MSOH) was constructed and demonstrated superior chondrogenesis in vitro. Animal experiments demonstrated that MSOH hydrogel showed better cartilage repairing effects and better maintained joint function at 24 weeks with low intra-articular inflammatory response after transplantation in rat joint. Single-cell RNA-seq of generated cartilage indicated that implanted MSOH could affect chondrocyte homeostatic state and alter the chondrocyte cluster frequency by regulating cellular glycolysis and OXPHOS, impacting cell cycle and ferroptosis to alleviate cellular senescence and prevent joint degeneration. Conclusion: Osteoarthritic cartilage defect patients demonstrated upregulated cellular senescence in joint cartilage. Senescence marker miR-24 was negatively associated with cartilage impairment in osteoarthritic CD patients. miR-24 attenuates chondrocytes senescence and promotes chondrogenesis in SMSC organoids through targeting TAOK1. Senescence-targeted miR-24 microsphere/SMSC organoid composite hydrogel could successfully repair cartilage defect in osteoarthritic microenvironment via enhanced miR-24/TAOK1 signaling pathway, suggesting MSOH might be a novel therapy for cartilage repair in osteoarthritic CD patients.

Marrow niches in osteosarcoma (OS) are a specialized microenvironment that is essential for the maintenance and regulation of OS cells. However, existing animal xenograft models are plagued by variability, complexity, and high cost. Herein, we used a decellularized osteosarcoma extracellular matrix (dOsEM) loaded with extracellular vesicles from human bone marrow-derived stem cells (hBMSC-EVs) and OS cells as a bioink to construct a micro-osteosarcoma (micro-OS) through 3D printing. The micro-OS was further combined with a microfluidic system to develop into an OS-on-a-chip (OOC) with a built-in recirculating perfusion system. The OOC system successfully integrated bone marrow niches, cell‒cell and cell–matrix crosstalk, and circulation, allowing a more accurate representation of OS characteristics in vivo. Moreover, the OOC system may serve as a valuable research platform for studying OS biological mechanisms compared with traditional xenograft models and is expected to enable precise and rapid evaluation and consequently more effective and comprehensive treatments for OS.

Physiologically relevant electrical microenvironments play an integral role in manipulating bone metabolism. Although implanted biomaterials using conductive or piezoelectric materials to mimic natural tissue electrical properties have been introduced into the field of bone regeneration, the use of electret materials to provide stable and durable electrical stimulation has rarely been studied in biomaterial design. In this study, the ZnO/PCL composite scaffolds with in-situ electret were fabricated using melt electro-writing to explore its efficacy in bone regeneration. By adjusting the electret concentration, the surface potential of the composite scaffolds could be tuned to the biopotential for promoting bone regeneration, and the prepared scaffolds exhibited good electrical stability over an observation period of up to 42 days. In vitro biological experiments showed that the in-situ electret scaffolds promoted the cell viability and osteogenic differentiation of mesenchymal stem cells. At the same time, the in-situ electret composite scaffolds can induce the phenotype transformation of RAW 264.7 cells from M1 to M2, creating a favorable microenvironment for bone tissue regeneration. The composite scaffolds significantly promoted bone regeneration in vivo through sustained endogenous electrical stimulation. These findings suggest that the in-situ electret scaffolds that maintain a stable and physiological electrical microenvironment are promising candidates for enhanced bone regeneration.

Introduction: Osteoarthritis (OA) is the most prevalent degenerative disease worldwide and commonly occurs among the elderly. At present, there is no effective treatment for OA. When OA develops to the end stage, arthroplasty is generally operated to improve the life quality of patients. Targeting senescence has been considered as a therapeutic approach for OA in recent years. Methods & results: In this study, we have identified P16 gene as a novel target for anti-senescence strategy and harnessed small interfering RNA (siRNA) technology to fabricate P16-siRNA encapsulated PLGA microspheres. We combined this with our previously successful three-dimensional (3D) culture of functionally bioengineered chondrogenic synovial mesenchymal stromal cell (SMSC) organoids. This served as the primary component of the bio-ink for 3D bioprinting, culminating in the creation of P16-siRNA PLGA mu S and SMSC organoid hydrogelpolymer composite scaffold (PPSOH). Its superior capabilities of cartilage repair were confirmed through in vivo and in vitro experimentations. In the rabbit model of knee cartilage defects, PPSOH not only restored the superior characteristics of native healthy hyaline cartilage but also maintained post-implanted joint function. It prevented development of joint degeneration resulting from cartilage defects by mitigating intra-articular inflammatory responses and cellular senescence. Our usage of miRNA and RNA sequencing reveals that PPSOH targets the miR-23b/ELOVL5 axis and rewired cellular metabolism, therefore regulating glycolysis and fatty acid oxidation. This effectively alleviates cellular senescence, promotes relief from OA, and facilitates cartilage regeneration. Conclusion: PPSOH scaffold could effectively alleviate cellular senescence, foster relief from OA, and facilitate cartilage regeneration. Further experiments disclosed that PPSOH targets the miR-23b/ELOVL5 axis and rewired cellular metabolism by regulating glycolysis and fatty acid oxidation. Therefore, PPSOH could be used as potential therapy for cartilage repair in osteoarthritic patients.

The essential role of the neural network in enhancing bone regeneration has often been overlooked in biomaterial design, leading to delayed or compromised bone healing. Engineered mesenchymal stem cells (MSCs)-derived exosomes are becoming increasingly recognized as potent cell-free agents for manipulating cellular behavior and improving therapeutic effectiveness. Herein, MSCs are stimulated with nerve growth factor (NGF) to regulate exosomal cargoes to improve neuro-promotive potential and facilitate innervated bone regeneration. In vitro cell experiments showed that the NGF-stimulated MSCs-derived exosomes (N-Exos) obviously improved the cellular function and neurotrophic effects of the neural cells, and consequently, the osteogenic potential of the osteo-reparative cells. Bioinformatic analysis by miRNA sequencing and pathway enrichment revealed that the beneficial effects of N-Exos may partly be ascribed to the NGF-elicited multicomponent exosomal miRNAs and the subsequent regulation and activation of the MAPK and PI3K-Akt signaling pathways. On this basis, N-Exos were delivered on the micropores of the 3D-printed hierarchical porous scaffold to accomplish the sustained release profile and extended bioavailability. In a rat model with a distal femoral defect, the N-Exos-functionalized hierarchical porous scaffold significantly induced neurovascular structure formation and innervated bone regeneration. This study provided a feasible strategy to modulate the functional cargoes of MSCs-derived exosomes to acquire desirable neuro-promotive and osteogenic potential. Furthermore, the developed N-Exos-functionalized hierarchical porous scaffold may represent a promising neurovascular-promotive bone reparative scaffold for clinical translation.

Healing of fractures or bone defects is significantly hindered by overactivated osteoclasts and inhibited osteogenesis in patients with abnormal bone metabolism. Current clinical approaches using titanium alloys or stainless steel provide mechanical support but have no biological effects on bone regeneration. Therefore, designing and fabricating degradable metal materials with sufficient mechanical strength and bidirectional regulation of both osteoblasts and osteoclasts is a substantial challenge. Here, this study first reported an adaptive biodegradable Zn-0.8 Mg alloy with bidirectional regulation of bone homeostasis, which promotes osteogenic differentiation by activating the Pi3k/Akt pathway and inhibits osteoclast differentiation by inhibiting the GRB2/ERK pathway. The anti-osteolytic ability of the Zn-0.8 Mg alloy was verified in a mouse calvarial osteolysis model and its suitability for internal fracture fixation with high-strength screws was confirmed in the rabbit femoral condyle fracture model. Furthermore, in an aged postmenopausal rat femoral condyle defect model, 3D printed Zn-0.8 Mg scaffolds promoted excellent bone regeneration through adaptive structures with good mechanical properties and bidirectionally regulated bone metabolism, enabling personalized bone defect repair. These findings demonstrate the substantial potential of the Zn-0.8 Mg alloy for treating fractures or bone defects in patients with aberrant bone metabolism.

The restoration of cartilage injuries remains a formidable challenge in orthopedics, chiefly attributed to the absence of vascularization and innervation in cartilage. Decellularized extracellular matrix (dECM) derived from cartilage, following antigenic removal through decellularization processes, has exhibited remarkable biocompatibility and bioactivity, rendering it a viable candidate for cartilage repair. Additionally, extracellular vesicles (EVs) generated from cartilage have demonstrated a synergistic effect when combined with dECM, potentially mitigating the inhibitory impact on protein synthesis by phosphorylating 4ebp, thereby promoting the synthesis of cartilage-related proteins such as collagen. In pursuit of this objective, we have innovated a novel bioink and repair scaffold characterized by exceptional biocompatibility, bioactivity, and biodegradability, establishing a tissue-specific microenvironment conducive to chondrogenesis. Within rat osteochondral defects, the biologically active scaffold successfully prompted the formation of transparent cartilage, featuring adequate mechanical strength, favorable elasticity, and dECM deposition indicative of cartilage. In summary, this study has effectively engineered a hydrogel bioink tailored for cartilage repair and devised a bioactive cartilage repair scaffold proficient in instigating cell differentiation and fostering cartilage repair.

Lactate (LA) undergoes abnormal metabolism in the microenvironment of rheumatoid arthritis (RA), and its excessive accumulation activates a cascade of intracellular signals, acting as an inflammatory enhancer. Clearing LA while simultaneously regulating the polarization of macrophage cells can improve long-term therapeutic outcomes. Here, we developed photocatalytic biomimetic nano enzymes to address multiple factors in RA by generating hydrogen to control innate immunity and reducing LA to restore the immune system. Heterostructured nanocrystals using plasmonic copper and zinc monosulfide could be explored for anomalous plasmon-induced electron transfer for NIR-induced photocatalytic activity in the hydrogen evolution reaction. In our study, overexpressed LA as a sacrificial agent for NIR photocatalytic therapy is depleted; generated hydrogen could scavenge intracellular reactive oxygen species, regulate polarization of M1 to M2 macrophages that could inhibit cytokine storms, thus alleviating inflammation of collagen induced mouse model. This “two-for-one” photocatalytic biomimetic nanoenzyme strategy of oxidative consumption of LA and targeted delivery of hydrogen opens up a potential strategy for treating progressive arthritis.