Osteoarthritis (OA) is a whole-joint disease characterized by progressive structural degeneration and chronic low-grade inflammation affecting the cartilage, synovium, subchondral bone, and immune compartments. It is a complex degenerative disorder associated with substantial morbidity, heterogeneous clinical trajectories, and limited disease-modifying treatment options. Extracellular vesicles (EVs) have emerged as important mediators of intercellular communication within the OA joint microenvironment, and are implicated in pathophysiological responses to mechanical stress, inflammatory cues, and metabolic dysfunction. Through the transfer of context-dependent nucleic acid, protein, and lipid cargoes, EVs can amplify pathogenic processes in OA such as synovitis, cartilage catabolism, and cellular senescence, while also supporting reparative pathways. Understanding the mechanisms governing EV biogenesis, cargo selection, tissue targeting, and functional heterogeneity offers opportunities to identify mechanistically informed biomarkers and therapeutic strategies. This review discusses emerging concepts in EV-mediated joint communication, highlights translational potential and limitations, and outlines key priorities for advancing EV-based diagnostics and therapies in OA. However, EV-based strategies remain largely at the preclinical or experimental stage, and rigorous validation is required before they can enter routine clinical practice.

Osteoporosis management remains challenging, partly due to the poor bioavailability of drugs in bone and the systemic side effects of current treatments. To address this, we engineered a targeted nanomedicine therapy using a DNA aptamer that specifically binds RANKL, a pivotal regulator of bone resorption. The aptamer is conjugated to PEGylated mesoporous silica nanoparticles (MSNs) to create a novel agent, aptRANKL@MSN. The nanoparticle platform enhances the aptamer's stability and may promote its accumulation in bone tissue, likely through a combination of passive targeting and the intrinsic affinity of the aptamer's phosphate backbone for bone mineral. In an ovariectomized mouse model of osteoporosis, aptRANKL@MSN treatment effectively reversed bone loss, restoring bone mass, microarchitecture, and mechanical strength to levels comparable to healthy controls. The therapy demonstrated a dual action, suppressing bone resorption while also enhancing bone formation as evidenced by increased mineral apposition rate and serum P1NP levels, thereby rebalancing bone homeostasis. Crucially, this bone-accumulating approach achieved superior efficacy over free aptamer and the conventional drug alendronate, while showing no significant toxicity over the 4-week treatment period. Our findings present aptRANKL@MSN as a precise and potent therapeutic strategy with strong potential for clinical translation in osteoporosis.

Rotator cuff tears (RCT) constitute a prevalent and clinically challenging musculoskeletal pathology. Medications, such as anti-inflammatory drugs, only alleviate symptoms without addressing the underlying cause, and their delivery efficiency is relatively low. Surgical interventions often fail to restore the native gradient structure of the tendon-bone interface and are frequently associated with postoperative pain and high re-tear rates. To overcome these challenges, this study developed a silk fibroin (SF)-based nanofiber membrane. The material features a core-shell structure, with SF and P(CL@LLA) as the shell layer and PLGA as the core layer to enhance mechanical toughness. Additionally, a kartogenin (KGN) delivery system was incorporated, in which the chondrogenic factor is encapsulated within β-cyclodextrin (β-CD). This system addresses the issue of low drug utilization caused by poor solubility and mitigates the impact of burst release on long-term therapeutic efficacy. The results demonstrate that the material exhibits sustained drug release properties and exerts promising effects in promoting cell differentiation and tissue repair in both in vitro and in vivo assays.

Articular cartilage repair in osteoarthritis (OA) remains a major clinical challenge. Although approaches using mesenchymal stem cells (MSCs) have demonstrated partial efficacy in OA, the regenerated tissue is often unable to form stable hyaline-like cartilage phenotype. Here, we introduce immunity-and-matrix-regulatory cells (IMRCs), derived from human embryonic stem cells (ESCs), as an alternative cell source for OA therapy. Using a multiple-level platform including 2D chondrocytes, 3D OA cartilage organoids (OCOs), rabbit cartilage explants, and a rat OA model, we demonstrate that IMRCs significantly enhance hyaline-like matrix formation while suppressing inflammation, angiogenesis, and fibrotic remodeling. Mechanistically, IMRC-mediated cartilage repair is partially associated with MMP1-dependent matrix remodeling. This study establishes a translational evaluation strategy for IMRCs and points to their potential as an alternative cell source for inducing cartilage repair in OA. Notably, the OCOs established in this study provide a pathologically relevant in vitro platform for evaluating cartilage regeneration in OA.

Postoperative re-tear remains a prevalent challenge in rotator cuff repair. To address this, we developed a bioactive glass composite rotator cuff patch (BCP) with heterogeneous structural design to promote tendon-bone interface regeneration. The BCP features an outer barrier of hydrophobic poly (lactic acid) (PLA) electrospun membrane, which prevents infiltration of inflammatory fibrotic tissue. The inner structure, fabricated via a dual-nozzle 3D printing strategy, comprises gelatin methacryloyl (GelMA) hydrogel layers differentially loaded with zinc-doped (ZnBG) or strontium-doped (SrBG) bioactive glass, targeting the tendon and bone regions, respectively. Bioactive glass enables sustained ion release within the physiological environment, establishing distinct ionic microenvironments across the tissue interface. In vitro, ZnBG-released ions significantly promoted the proliferation and migration of tendon-derived stem cells, upregulated mature tendon matrix expression, and inhibited fibrotic scarring. Conversely, SrBG-released ions enhanced the osteogenic differentiation and mineralization potential of bone marrow mesenchymal stem cells. In vivo evaluation further demonstrated that the BCP effectively facilitated organized collagen regeneration and improved the quality of its integration with bone. Additionally, the BCP favorably modulated the local immune microenvironment toward a reparative phenotype. In summary, this study presents an innovative biomaterial strategy for achieving comprehensive structural and functional regeneration of the tendon-bone interface following rotator cuff injury.

ObjectiveThis study aims to characterize the aqueous humor (AH) microbiome in Posner–Schlossman syndrome (PSS) patients and evaluate its potential as a diagnostic and therapeutic target.MethodsMetagenomic next-generation sequencing (mNGS) was performed on 59 AH samples from patients diagnosed with PSS (n = 28) and myopia patients who underwent intraocular lens (ICL) implantation (n = 31). Taxonomic profiling and diversity analyses were conducted to characterize the microbial communities. Interactions among microbial community members were evaluated using correlation analyses.ResultsKey findings revealed that intraocular microbiomes existed in both normal and diseased eyes; however, PSS patients exhibited lower microbial diversity (Shannon index, p = 0.066; Simpson index, p = 0.065) and distinct community structures (PERMANOVA, p = 0.05). Disease-specific microbial signatures were identified: Paeniglutamicibacter was uniquely enriched in the PSS group, whereas Escherichia coli dominated in the ICL group. Moreover, ecological network analysis demonstrated contrasting interaction patterns. The microbiomes in the PSS group formed stable, tightly connected networks with balanced positive/negative correlations, whereas those in the ICL group exhibited antagonistic relationships, suggesting competitive exclusion. These results challenge the traditional view of ocular sterility and reveal dynamic microbiome shifts associated with PSS pathogenesis. The enrichment of Paeniglutamicibacter in PSS may represent an associated microbial signature that could potentially reflect compensatory responses to chronic inflammation, although experimental validation is needed to confirm this hypothesis.ConclusionOur study provides preliminary evidence supporting the concept of intraocular microbiome dysbiosis in PSS, which requires validation in future studies. These findings suggest that potential microbial biomarkers warrant further investigation for their diagnostic and therapeutic implications.

Gemcitabine resistance severely limits the therapeutic efficacy of pancreatic cancer treatments. Although non-coding RNAs (ncRNAs) have emerged as vital epigenetic orchestrators of chemoresistance, a systematic evaluation of the global intellectual architecture in this domain remains unavailable. To comprehensively map the scientific landscape, institutional collaborations, and evolutionary trajectories of ncRNA-mediated gemcitabine resistance from 2009 to 2025. Bibliographic data were systematically retrieved from the Web of Science Core Collection and Scopus databases. Following cross-database deduplication, 718 eligible documents were quantitatively analyzed using VOSviewer, CiteSpace, and the R-bibliometrix package. Annual publication output followed an exponential growth model (y = 13.814e0.2704x, R² = 0.8832). China led in productivity (387 papers, 53.9

Auxetic metamaterials have garnered significant attention in advanced industrial manufacturing due to their superior mechanical properties, which are characterized by a counterintuitive Negative Poisson's Ratio (NPR). However, traditional design approaches often rely on linear elasticity assumptions, which fail to accurately predict structural behavior under substantial strain. To satisfy stringent engineering requirements, it is imperative to integrate geometric nonlinearity into the topology optimization framework. In this work, we propose an isogeometric level set topology optimization method specifically tailored for designing geometrically nonlinear auxetic metamaterials. Firstly, the isogeometric level set method is introduced, which seamlessly integrates Computer-Aided Design (CAD) with Computer-Aided Engineering (CAE) to ensure smooth boundary representation and numerical stability. Secondly, the geometric nonlinearity isogeometric analysis (IGA) formulation is derived. By adopting the Total Lagrangian approach, we accurately model the behavior of structures under the large deformation assumption. Thirdly, the generation theory of auxetic metamaterials based on the stretchingdominated assumption is analyzed, and a robust objective function is formulated to maximize the auxetic effect. Moreover, the corresponding topology optimization model is developed, and a comprehensive sensitivity analysis scheme is utilized to guide the structural evolution. Optimization results demonstrate robust performance under large deformation conditions, while the integration of the level set method with isogeometric analysis yields smooth and well-defined structural boundaries. Comprehensive CAE analyses are performed to evaluate the mechanical responses of the optimized configurations. Finally, the effectiveness of the proposed framework is validated through a combination of high-fidelity numerical simulations and experimental testing of models fabricated via Additive Manufacturing (AM), where the experimental results demonstrate strong consistency with the simulation predictions, confirming its superior performance and practical feasibility in geometric nonlinear design.

Oral health is essential to general health. The diagnosis of dental diseases and treatment planning of dental care need to be straightforward and accurate. Recent studies have reported the use of aptamers in dentistry to achieve a simple diagnosis and facilitate therapy. Aptamers comprise nucleic acid sequences that possess a strong affinity for their target. Synthesized chemically, aptamers have several advantages, including smaller size, higher stability, and lower immunogenicity compared with monoclonal antibodies. They can be used to detect biomarkers in saliva and the presence of various pathogens, or can be used as a targeted drug delivery system for disease treatment. This review highlights current research on aptamers for dental care, especially the recent progress in oral disease diagnosis and therapeutics. The challenges and unresolved problems faced by the clinical use of aptamers are also discussed. In the future, the clinical applications of aptamers will be further extended to include, for example, dental indications and regenerative dentistry.

Porous structures, with their outstanding mechanical properties, play a crucial role in engineering applications and are an important consideration in material distribution optimization for structural dynamic performance. Recently, Isogeometric Analysis (IGA) has gained significant interest due to precise geometric representation, high-order continuity, and flexible topology evolution capabilities. Hence, this study proposes a novel infill design approach through a periodic constraint strategy in multiple Non-Uniform Rational B-Splines (NURBS) patches for two dynamic topology optimization problems, namely eigenfrequency maximization and dynamic compliance minimization. By coupling multiple NURBS patches in a conforming mesh, the complexity of the structural design domain is effectively enhanced. The Nitsche-type dynamic formulation is introduced within the IGA framework, and the theoretical analysis of the stabilization condition is performed. Furthermore, the periodic constraint strategy is imposed onto NURBS patches within the specified parameter direction, which controls the sensitivity update values of the objective function across these patches to generate a gradient porous structure. The global topology is described by the Density Distribution Function (DDF) to achieve full-scale topology optimization. The Multi-frequency Quasi-Static Ritz Vector (MQSRV) method is used to reduce the computational cost associated with dynamic problems. The mathematical models for the dynamic compliance minimization and the eigenfrequency maximization are established, where the sensitivity analysis is derived in detail. Finally, the optimized results produced by the work are fully applicable to complex structural design domains and exhibit well-defined boundaries and smooth gradient distributions. Several numerical examples are presented to demonstrate the effectiveness of the proposed multi-patch isogeometric topology optimization infill design method.

Three-dimensional (3D) culture systems have been shown to enhance cellular secretion of small extracellular vesicles (sEVs) compared to two-dimensional (2D) culture. However, the molecular mechanisms driving sEV secretion and influencing their potential for disease treatment have not been elucidated. In this study, we discovered the depolymerisation of cortical actin as a new mechanism that leads to increased sEV release, and that in 3D cultured mesenchymal stem cells (MSCs), this process was modulated by the downregulation of integrin-α1 (ITGA1) and subsequent inhibition of the RhoA/cofilin signalling pathway. Interestingly, the knockdown of Rab27A and Rab27B significantly reduced sEV secretion by MSCs to 0.5- and 0.1-fold, respectively. However, there was no difference in expression levels of Rab27A/B between MSCs cultured in 2D and 3D environments. In addition, sEVs derived from 3D cultured MSCs demonstrated enhanced therapeutic function both in vitro and in rat models of osteoarthritis (OA) and wound healing. Collectively, this study illustrates a new mechanism for enhanced secretion of sEVs, involving RhoA/cofilin pathway-dependent cortical actin depolymerisation, which is independent of Rab27A/B. These findings provide novel insights for optimising the yield of stem cell-derived sEVs, as well as their therapeutic efficacy for treating chronic diseases.

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.

Uveitis is a group of vision-threatening inflammatory diseases, and current treatment options are mainly limited to corticosteroids, which often have side effects and do not address the underlying immune dysregulation. Mesenchymal stem/stromal cells cultivated in vitro have gained attention for their immune-regulating, neurotrophic, and tissue-regenerative properties, making them a promising candidate for treating uveitis. This study investigates the safety and efficacy of human umbilical cord derived mesenchymal stem/stromal cells (HUMSCs) combined with a novel suprachoroidal microinjector for targeted delivery in a rabbit model of experimental uveitis (EU). No significant clinical or histological changes were observed following HUMSCs injection in normal Chinichilla rabbit eyes. In the EU model, treatment with HUMSCs and triamcinolone acetonide (TA) significantly alleviated uveitis symptoms compared to phosphate-buffered saline, with notable improvements in anterior chamber inflammation and vitreous opacity scores. Both treatments also reduced the levels of inflammatory cytokines (TNF-α, VEGF, MIP-1α, IL-17A, bFGF) in the aqueous humor. Histological and immunofluorescence analyses showed decreased inflammatory cell infiltration and microglial activation. Additionally, RNA sequencing revealed that HUMSCs injection downregulated key genes in the Th17 differentiation pathway, which plays a critical role in the pathogenesis of EU. These findings establish the safety and efficacy of suprachoroidal injection of HUMSCs, highlighting their potential as an effective, targeted therapeutic approach for uveitis, with results comparable to TA.

The high incidence of bone trauma has necessitated the development of multifunctional biomaterial implants with both hemostatic and osteogenic properties to address clinical challenges such as bone nonunion and immune rejection associated with nondegradable bone hemostatic materials. In this study, starch/bioactive glass/GelMA-based self-assembling composite microspheres were developed as a novel bone trauma filler exhibiting dual functions of efficient hemostasis and bone regeneration. These micron-scale composite microspheres can be applied to bone trauma sites during surgical procedures or emergency situations. Upon absorption of blood, self-assembly occurs rapidly through hydroxyl/amino-mediated interfacial interactions, preventing dispersion by blood and facilitating the formation of a stable barrier for emergency hemostasis. Furthermore, the bioactive glass component promotes osseointegration via biomineralization-mediated assembly, while the released bioactive ions enhance the proliferation and osteogenic differentiation of bone marrow mesenchymal stem cells. This composite microsphere exhibited biodegradable properties and significantly improved cranial bone defect repair in vivo.

Mesenchymal stem cells (MSCs) have shown significant potential in bone regeneration and regenerative medicine in recent years. With the advancement of tissue engineering, MSCs have been increasingly applied in bone repair and regeneration, and their clinical application potential has grown through interdisciplinary approaches involving biomaterials and genetic engineering. However, there is a lack of systematic reviews summarizing their applications in bone regeneration. To address this gap, we analyzed the latest research on MSCs for bone regeneration published from 2013 to 2023. Using the Web of Science Core Collection, we conducted a literature search in December 2024 and employed bibliometric tools like CiteSpace and VOSviewer for a comprehensive analysis of the key research trends. Our findings focus on the development of cell engineering, highlighting the advantages, limitations, and future prospects of MSC applications in bone regeneration. These insights aim to enhance understanding of MSC-based bone regeneration, inspire new research directions, and facilitate the clinical translation of MSC research.

BACKGROUND:Endochondral ossification (ECO) is essential for bone regeneration, involving cartilage formation, hypertrophy, angiogenesis, and ossification. Co-culturing mesenchymal stem cells (MSCs) with endothelial cells (ECs) shows potential to enhance bone regeneration but has not been effectively applied to ECO strategy. METHODS:We examined the synergistic effects of MSCs and ECs on chondrogenesis, osteogenesis, and angiogenesis, followed by transcriptomic analysis. ECO organoids were formed in the scaffolds, and a critical-sized calvarial bone defect model was used for in vivo evaluation. RESULTS:Co-culture of ECs and MSCs promoted osteogenic differentiation and hypertrophic chondrogenic differentiation of MSCs. The ECO organoids exhibited enhanced vascularization and improved mineralization. In vivo, the co-culture group showed superior vascularization and bone repair compared to the MSCs-only group. CONCLUSIONS:Co-culturing ECs with MSCs in ECO organoids enhances bone regeneration, offering a promising alternative to traditional tissue engineering strategies. This approach may improve therapeutic outcomes by promoting endochondral bone formation.

For a long time, the clinical management of traumatic bone injuries has been limited by the constraints of bone wax as a hemostatic material. To tackle these clinical challenges, this study has developed a ready-to-use hemostatic moldable bioactive bone putty (BP) that excels in rapid hemostasis and promotes bone regeneration. BP is a formulation made from polyethylene glycol and pre-gelatinized hydroxypropyl distarch phosphate as a molding agent, along with calcium sulfate bone cement and calcium phosphate bone cement as bioactive components. While the application method remains the same as that of bone wax, BP encourages swift thrombus formation, significantly reducing coagulation time and blood loss. Additionally, BP improves its mechanical strength through hydration reactions upon exposure to bodily fluids, providing essential support for bone tissues while completely degrading within 8 weeks of implantation. In vitro cell studies have underscored the excellent biocompatibility of BP, demonstrating its capacity to stimulate the proliferation of BMSCs, increase the expression of key osteogenic genes, and increase calcium nodule deposition. Histological analyses have further revealed the positive impact of BP on osteogenesis, whereas in vivo experiments have shown significant inhibition of inflammatory fiber formation. Overall, the BP has emerged as an innovative solution for accelerating hemostasis and facilitating regenerative repair in cases of bone injury.

Osteoarthritis (OA) is a multifactorial joint disease traditionally characterized by cartilage degradation, while growing evidence underscores the critical role of synovial fibrosis in driving disease progression. The synovium exhibits pathological remodeling in OA, primarily due to the phenotypic transition of fibroblast-like synoviocytes (FLSs) into myofibroblasts. This fibroblast–myofibroblast transition (FMT) results in excessive deposition of extracellular matrix (ECM) and increased tissue stiffness and contractility, collectively contributing to chronic inflammation and fibrotic stiffening of the joint capsule. These fibrotic changes not only impair synovial function but also exacerbate cartilage degeneration, nociceptive sensitization, and joint dysfunction, thereby amplifying OA severity. Focusing on the frequently overlooked role of the FMT of synovial fibroblasts in OA, this review introduces the biological characteristics of FLSs and myofibroblasts and systematically examines the key molecular pathways implicated in OA-related FMT, including TGF-β, Wnt/β-catenin, YAP/TAZ, and inflammatory signaling cascades. It also discusses emerging therapeutic strategies targeting synovial fibrosis and FMT and considers their implications for the clinical management of OA. By highlighting recent advances and unresolved challenges, this review provides critical insights into the fibroblast–myofibroblast axis as a central contributor to OA progression and a promising therapeutic target for modifying disease trajectory.

Three-dimensional printing (3DP) strategies in the field of meniscus and articular disc repair and regeneration have recently garnered significant attention. However, a comprehensive bibliometric assessment to evaluate the scientific progress in this area is lacking. This research aims to explore the development, key areas of focus, and new directions in 3DP techniques for meniscus and articular disc over the last 15 years, considering both structural and temporal perspectives. Academic papers on 3DP approaches for the repair and regeneration of these tissues were retrieved from the Web of Science Core Collection. Bibliometric analysis tools such as R software, CiteSpace, and VOSviewer were utilized to examine the historical patterns, topic evolution, and emerging trends in this domain. For the past 15 years, there has been a steady increase in scholarly attention toward 3DP for the repair of meniscus and articular discs, along with a notable expansion in impactful scientific partnerships. The timeline analysis of references indicates that 3DP methodologies have predominantly shaped the research agenda over the last 10 years, retaining their significance amid annual fluctuations in the focus of citations. Four emerging research subfields were identified through keyword clustering: "mesenchymal stem cells," "fabrication," "scaffolds," and "cartilage." Additionally, we mapped out the top 13 key clusters based on CiteSpace. The time zone view of keyword analysis identified three emerging research niches: "anti-inflammatory and antioxidant," "chondrogenic differentiation," and "silk-based biomaterial-ink." The insights gleaned from these bibliometric studies highlight the current state and trends in 3DP research for meniscus and articular disc, potentially assisting researchers in identifying key focal points and pioneering innovative research directions within this area.