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Posttraumatic osteoarthritis (PTOA) patients are often diagnosed by X-ray imaging at a middle-late stage when drug interventions are less effective. Early PTOA is characterized by overexpressed matrix metalloprotease 13 (MMP13). Herein, we constructed an integrated diagnosis and treatment micelle modified with MMP13 enzyme-detachable, cyanine 5 (Cy5)-containing PEG, black hole quencher-3 (BHQ3), and cRGD ligands and loaded with siRNA silencing MMP13 (siM13), namely ERMs@siM13. ERMs@siM13 could be cleaved by MMP13 in the diseased cartilage tissues to detach the PEG shell, causing cRGD exposure. Accordingly, the ligand exposure promoted micelle uptake by the diseased chondrocytes by binding to cell surface αvβ3 integrin, increasing intracellular siM13 delivery for on-demand MMP13 downregulation. Meanwhile, the Cy5 fluorescence was restored by detaching from the BHQ3-containing micelle, precisely reflecting the diseased cartilage state. In particular, the intensity of Cy5 fluorescence generated by ERMs@siM13 that hinged on the MMP13 levels could reflect the PTOA severity, enabling the physicians to adjust the therapeutic regimen. Finally, in the murine PTOA model, ERMs@siM13 could diagnose the early-stage PTOA, perform timely interventions, and monitor the OA progression level during treatment through a real-time detection of MMP13. Therefore, ERMs@siM13 represents an appealing approach for early-stage PTOA theranostics.

The healing of large skin defects remains a significant challenge in clinical settings. The lack of epidermal sources, such as autologous skin grafting, limits full-thickness skin defect repair and leads to excessive scar formation. Skin organoids have the potential to generate a complete skin layer, supporting in-situ skin regeneration in the defect area. In this study, skin organoid spheres, created with human keratinocytes, fibroblasts, and endothelial cells, showed a specific structure with a stromal core surrounded by surface keratinocytes. We selected an appropriate bioink and innovatively combined an extrusion-based bioprinting technique with dual-photo source cross-linking technology to ensure the overall mechanical properties of the 3D bioprinted skin organoid. Moreover, the 3D bioprinted skin organoid was customized to match the size and shape of the wound site, facilitating convenient implantation. When applied to full-thickness skin defects in immunodeficient mice, the 3D bioprinted human-derived skin organoid significantly accelerated wound healing through in-situ regeneration, epithelialization, vascularization, and inhibition of excessive inflammation. The combination of skin organoid and 3D bioprinting technology can overcome the limitations of current skin substitutes, offering a novel treatment strategy to address large-area skin defects.

Osteoarthritis (OA), a common degenerative disease, is characterized by high disability and imposes substantial economic impacts on individuals and society. Current clinical treatments remain inadequate for effectively managing OA. Organoids, miniature 3D tissue structures from directed differentiation of stem or progenitor cells, mimic native organ structures and functions. They are useful for drug testing and serve as active grafts for organ repair. However, organoid construction requires extracellular matrix-like 3D scaffolds for cellular growth. Hydrogel microspheres, with tunable physical and chemical properties, show promise in cartilage tissue engineering by replicating the natural microenvironment. Building on prior work on SF-DNA dual-network hydrogels for cartilage regeneration, we developed a novel RGD-SF-DNA hydrogel microsphere (RSD-MS) via a microfluidic system by integrating photopolymerization with self-assembly techniques and then modified with Pep-RGDfKA. The RSD-MSs exhibited uniform size, porous surface, and optimal swelling and degradation properties. In vitro studies demonstrated that RSD-MSs enhanced bone marrow mesenchymal stem cells (BMSCs) proliferation, adhesion, and chondrogenic differentiation. Transcriptomic analysis showed RSD-MSs induced chondrogenesis mainly through integrin-mediated adhesion pathways and glycosaminoglycan biosynthesis. Moreover, in vivo studies showed that seeding BMSCs onto RSD-MSs to create cartilage organoid precursors (COPs) significantly enhanced cartilage regeneration. In conclusion, RSD-MS was an ideal candidate for the construction and long-term cultivation of cartilage organoids, offering an innovative strategy and material choice for cartilage regeneration and tissue engineering.

Segmental bone defects, stemming from trauma, infection, and tumors, pose formidable clinical challenges. Traditional bone repair materials, such as autologous and allogeneic bone grafts, grapple with limitations including source scarcity and immune rejection risks. The advent of nucleic acid nanotechnology, particularly the use of DNA hydrogels in tissue engineering, presents a promising solution, attributed to their biocompatibility, biodegradability, and programmability. However, these hydrogels, typically hindered by high gelation temperatures (∼46 °C) and high construction costs, limit cell encapsulation and broader application. Our research introduces a novel polymer-modified DNA hydrogel, developed using nucleic acid nanotechnology, which gels at a more biocompatible temperature of 37 °C and is cost-effective. This hydrogel then incorporates tetrahedral Framework Nucleic Acid (tFNA) to enhance osteogenic mineralization. Furthermore, considering the modifiability of tFNA, we modified its chains with Aptamer02 (Apt02), an aptamer known to foster angiogenesis. This dual approach significantly accelerates osteogenic differentiation in bone marrow stromal cells (BMSCs) and angiogenesis in human umbilical vein endothelial cells (HUVECs), with cell sequencing confirming their targeting efficacy, respectively. In vivo experiments in rats with critical-size cranial bone defects demonstrate their effectiveness in enhancing new bone formation. This innovation not only offers a viable solution for repairing segmental bone defects but also opens avenues for future advancements in bone organoids construction, marking a significant advancement in tissue engineering and regenerative medicine.

Abstract Background Osteoporosis is characterized by an imbalance in bone homeostasis, resulting in the excessive dissolution of bone minerals due to the acidified microenvironment mediated by overactive osteoclasts. Oroxylin A (ORO), a natural flavonoid, has shown potential in reversing osteoporosis by inhibiting osteoclast-mediated bone resorption. The limited water solubility and lack of targeting specificity hinder the effective accumulation of Oroxylin A within the pathological environment of osteoporosis. Results Osteoclasts’ microenvironment-responsive nanoparticles are prepared by incorporating Oroxylin A with amorphous calcium carbonate (ACC) and coated with glutamic acid hexapeptide-modified phospholipids, aiming at reinforcing the drug delivery efficiency as well as therapeutic effect. The obtained smart nanoparticles, coined as OAPLG, could instantly neutralize acid and release Oroxylin A in the extracellular microenvironment of osteoclasts. The combination of Oroxylin A and ACC synergistically inhibits osteoclast formation and activity, leading to a significant reversal of systemic bone loss in the ovariectomized mice model. Conclusion The work highlights an intelligent nanoplatform based on ACC for spatiotemporally controlled release of lipophilic drugs, and illustrates prominent therapeutic promise against osteoporosis.

Summary: Patients with diabetes often experience fragile fractures despite normal or higher bone mineral density (BMD), a phenomenon termed the diabetic bone paradox (DBP). The pathogenesis and therapeutics opinions for diabetic bone disease (DBD) are not fully explored. In this study, we utilize two preclinical diabetic models, the leptin receptor-deficient db/db mice (DB) mouse model and the streptozotocin-induced diabetes (STZ) mouse model. These models demonstrate higher BMD and lower mechanical strength, mirroring clinical observations in diabetic patients. Advanced glycation end products (AGEs) accumulate in diabetic bones, causing higher non-enzymatic crosslinking within collagen fibrils. This inhibits intrafibrillar mineralization and leads to disordered mineral deposition on collagen fibrils, ultimately reducing bone strength. Guanidines, inhibiting AGE formation, significantly improve the microstructure and biomechanical strength of diabetic bone and enhance bone fracture healing. Therefore, targeting AGEs may offer a strategy to regulate bone mineralization and microstructure, potentially preventing the onset of DBD.

α-Ketoglutarate (AKG), a crucial intermediate in the tricarboxylic acid cycle, has been demonstrated to mitigate hyperlipidemia-induced dyslipidemia and endothelial damage. While hyperlipidemia stands as a major trigger for non-alcoholic fatty liver disease, the protection of AKG on hyperlipidemia-induced hepatic metabolic disorders remains underexplored. This study aims to investigate the potential protective effects and mechanisms of AKG against hepatic lipid metabolic disorders caused by acute hyperlipidemia. Our observations indicate that AKG effectively alleviates hepatic lipid accumulation, mitochondrial dysfunction, and loss of redox homeostasis in P407-induced hyperlipidemia mice, as well as in palmitate-injured HepG2 cells and primary hepatocytes. Mechanistic insights reveal that the preventive effects are mediated by activating the AMPK-PGC-1α/Nrf2 pathway. In conclusion, our findings shed light on the role and mechanism of AKG in ameliorating abnormal lipid metabolic disorders in hyperlipidemia-induced fatty liver, suggesting that AKG, an endogenous mitochondrial nutrient, holds promising potential for addressing hyperlipidemia-induced fatty liver conditions.

Lipid nanovehicles are currently the most advanced vehicles used for RNA delivery, as demonstrated by the approval of patisiran for amyloidosis therapy in 2018. To illuminate the unique superiority of lipid nanovehicles in RNA delivery, in this review, we first introduce various RNA therapeutics, describe systemic delivery barriers, and explain the lipid components and methods used for lipid nanovehicle preparation. Then, we emphasize crucial advances in lipid nanovehicle design for overcoming barriers to systemic RNA delivery. Finally, the current status and challenges of lipid nanovehicle-based RNA therapeutics in clinical applications are also discussed. Our objective is to provide a comprehensive overview showing how to utilize lipid nanovehicles to overcome multiple barriers to systemic RNA delivery, inspiring the development of more high-performance RNA lipid nanovesicles in the future.

Organoids, miniature and simplified in vitro model systems that mimic the structure and function of organs, have attracted considerable interest due to their promising applications in disease modeling, drug screening, personalized medicine, and tissue engineering. Despite the substantial success in cultivating physiologically relevant organoids, challenges remain concerning the complexities of their assembly and the difficulties associated with data analysis. The advent of AI-Enabled Organoids, which interfaces with artificial intelligence (AI), holds the potential to revolutionize the field by offering novel insights and methodologies that can expedite the development and clinical application of organoids. This review succinctly delineates the fundamental concepts and mechanisms underlying AI-Enabled Organoids, summarizing the prospective applications on rapid screening of construction strategies, cost-effective extraction of multiscale image features, streamlined analysis of multi-omics data, and precise preclinical evaluation and application. We also explore the challenges and limitations of interfacing organoids with AI, and discuss the future direction of the field. Taken together, the AI-Enabled Organoids hold significant promise for advancing our understanding of organ development and disease progression, ultimately laying the groundwork for clinical application.

ABSTRACTIn bone tissue engineering, the search for improved repair methods is crucial, given the drawbacks of traditional strategies like donor site issues and immune rejection. Addressing these challenges, this paper introduces an innovative GelMA/Bentonite composite bioink for 3D bioprinting, designed to create scaffolds that closely emulate native bone tissue. GelMA is selected for its biocompatibility and modifiable mechanics, while Bentonite's mineral richness and ion exchange capacity are harnessed to enhance scaffold structure and promote an osteogenic microenvironment. This research marks the inaugural incorporation of Bentonite into a bioink, a significant stride forward given its established safety in pharmaceuticals and versatility across industries. This bioink formulation signifies a breakthrough in bone tissue engineering, aiming to improve the osteointegration and regeneration of bone tissue. Combining Bentonite with GelMA marks a key step in creating bioinks that enhance bone healing, potentially transforming scaffold-based bone regeneration and pioneering the use of natural nanomaterials in medicine.

In confronting the global prevalence of bone-related disorders, bone tissue engineering (BTE) has developed into a critical discipline, seeking innovative materials to revolutionize treatment paradigms. Quantum dots (QDs), nanoscale semiconductor particles with tunable optical properties, are at the cutting edge of improving bone regeneration. This comprehensive review delves into the multifaceted roles that QDs play within the realm of BTE, emphasizing their potential to not only revolutionize imaging but also to osteogenesis, drug delivery, antimicrobial strategies and phototherapy. The customizable nature of QDs, attributed to their size-dependent optical and electronic properties, has been leveraged to develop precise imaging modalities, enabling the visualization of bone growth and scaffold integration at an unprecedented resolution. Their nanoscopic scale facilitates targeted drug delivery systems, ensuring the localized release of therapeutics. QDs also possess the potential to combat infections at bone defect sites, preventing and improving bacterial infections. Additionally, they can be used in phototherapy to stimulate important bone repair processes and work well with the immune system to improve the overall healing environment. In combination with current trendy artificial intelligence (AI) technology, the development of bone organoids can also be combined with QDs. While QDs demonstrate considerable promise in BTE, the transition from laboratory research to clinical application is fraught with challenges. Concerns regarding the biocompatibility, long-term stability of QDs within the biological environment, and the cost-effectiveness of their production pose significant hurdles to their clinical adoption. This review summarizes the potential of QDs in BTE and highlights the challenges that lie ahead. By overcoming these obstacles, more effective, efficient, and personalized bone regeneration strategies will emerge, offering new hope for patients suffering from debilitating bone diseases.

Abstract Osteoporosis (OP) is a systematic bone disease characterized by low bone mass and fragile bone microarchitecture. Conventional treatment for OP has limited efficacy and long‐term toxicity. Synthetic biology makes bacterial extracellular vesicle (BEVs)‐based therapeutic strategies a promising alternative for the treatment of OP. Here, we constructed a recombinant probiotics Escherichia coli Nissle 1917‐pET28a‐ClyA‐BMP‐2‐CXCR4 (ECN‐pClyA‐BMP‐2‐CXCR4), in which BMP‐2 and CXCR4 were overexpressed in fusion with BEVs surface protein ClyA. Subsequently, we isolated engineered BEVs‐BMP‐2‐CXCR4 (BEVs‐BC) for OP therapy. The engineered BEVs‐BC exhibited great bone targeting in vivo. In addition, BEVs‐BC had good biocompatibility and remarkable ability to promote osteogenic differentiation of BMSCs. Finally, the synthetic biology‐based BEVs‐BC significantly prevented the OP in an ovariectomized (OVX) mouse model. In conclusion, we constructed BEVs‐BC with both bone‐targeting and bone‐forming in one‐step using synthetic biology, which provides an effective strategy for OP and has great potential for industrialization.

Traditional hydrogel design and optimization methods usually rely on repeated experiments, which is time-consuming and expensive, resulting in a slow-moving of advanced hydrogel development. With the rapid development of artificial intelligence (AI) technology and increasing material data, AI-energized design and optimization of hydrogels for biomedical applications has emerged as a revolutionary breakthrough in materials science. This review begins by outlining the history of AI and the potential advantages of using AI in the design and optimization of hydrogels, such as prediction and optimization of properties, multi-attribute optimization, high-throughput screening, automated material discovery, optimizing experimental design, and etc. Then, we focus on the various applications of hydrogels supported by AI technology in biomedicine, including drug delivery, bio-inks for advanced manufacturing, tissue repair, and biosensors, so as to provide a clear and comprehensive understanding of researchers in this field. Finally, we discuss the future directions and prospects, and provide a new perspective for the research and development of novel hydrogel materials for biomedical applications.

Diabetes mellitus is a chronically inflamed disease that predisposes to delayed fracture healing. Macrophages play a key role in the process of fracture healing by undergoing polarization into either M1 or M2 subtypes, which respectively exhibit pro-inflammatory or anti-inflammatory functions. Therefore, modulation of macrophage polarization to the M2 subtype is beneficial for fracture healing. Exosomes perform an important role in improving the osteoimmune microenvironment due to their extremely low immunogenicity and high bioactivity. In this study, we extracted the M2-exosomes and used them to intervene the bone repair in diabetic fractures. The results showed that M2-exosomes significantly modulate the osteoimmune microenvironment by decreasing the proportion of M1 macrophages, thereby accelerating diabetic fracture healing. We further confirmed that M2-exosomes induced the conversion of M1 macrophages into M2 macrophages by stimulating the PI3K/AKT pathway. Our study offers a fresh perspective and a potential therapeutic approach for M2-exosomes to improve diabetic fracture healing.

Articular cartilage injury is a frequent worldwide disease, while effective treatment is urgently needed. Due to lack of blood vessels and nerves, the ability of cartilage to self-repair is limited. Despite the availability of various clinical treatments, unfavorable prognoses and complications remain prevalent. However, the advent of tissue engineering and regenerative medicine has generated considerable interests in using biomaterials for articular cartilage repair. Nevertheless, there remains a notable scarcity of comprehensive reviews that provide an in-depth exploration of the various strategies and applications. Herein, we present an overview of the primary biomaterials and bioactive substances from the tissue engineering perspective to repair articular cartilage. The strategies include regeneration, substitution, and immunization. We comprehensively delineate the influence of mechanically supportive scaffolds on cellular behavior, shedding light on emerging scaffold technologies, including stimuli-responsive smart scaffolds, 3D-printed scaffolds, and cartilage bionic scaffolds. Biologically active substances, including bioactive factors, stem cells, extracellular vesicles (EVs), and cartilage organoids, are elucidated for their roles in regulating the activity of chondrocytes. Furthermore, the composite bioactive scaffolds produced industrially to put into clinical use, are also explicitly presented. This review offers innovative solutions for treating articular cartilage ailments and emphasizes the potential of biomaterials for articular cartilage repair in clinical translation.

Abstract The regeneration of weight-bearing bone defects and critical-sized cartilage defects remains a significant challenge. A wide range of nano-biomaterials are available for the treatment of bone/cartilage defects. However, their poor compatibility and biodegradability pose challenges to the practical applications of these nano-based biomaterials. Natural biomaterials inspired by the cell units (e.g., nucleic acids and proteins), have gained increasing attention in recent decades due to their versatile functionality, compatibility, biodegradability, and great potential for modification, combination, and hybridization. In the field of bone/cartilage regeneration, natural nano-based biomaterials have presented an unparalleled role in providing optimal cues and microenvironments for cell growth and differentiation. In this review, we systematically summarize the versatile building blocks inspired by the cell unit used as natural nano-based biomaterials in bone/cartilage regeneration, including nucleic acids, proteins, carbohydrates, lipids, and membranes. In addition, the opportunities and challenges of natural nano-based biomaterials for the future use of bone/cartilage regeneration are discussed.

The necessity of disease models for bone/cartilage related disorders is well-recognized, but the barrier between ex-vivo cell culture, animal models and the real human body has been pending for decades. The organoid-on-a-chip technique showed opportunity to revolutionize basic research and drug screening for diseases like osteoporosis and arthritis. The bone/cartilage organoid on-chip (BCoC) system is a novel platform of multi-tissue which faithfully emulate the essential elements, biologic functions and pathophysiological response under real circumstances. In this review, we propose the concept of BCoC platform, summarize the basic modules and current efforts to orchestrate them on a single microfluidic system. Current disease models, unsolved problems and future challenging are also discussed, the aim should be a deeper understanding of diseases, and ultimate realization of generic ex-vivo tools for further therapeutic strategies of pathological conditions.

The skeletal system is responsible for weight-bearing, organ protection, and movement. Bone diseases caused by trauma, infection, and aging can seriously affect a patient's quality of life. Bone targeted biomaterials are suitable for the treatment of bone diseases. Biomaterials with bone-targeted properties can improve drug utilization and reduce side effects. A large number of bone-targeted micro-nano materials have been developed. However, only a few studies addressed bone-targeted hydrogel. The large size of hydrogel makes it difficult to achieve systematic targeting. However, local targeted hydrogel still has significant prospects. Molecules in bone/cartilage extracellular matrix and bone cells provide binding sites for bone-targeted hydrogel. Drug delivery systems featuring microgels with targeting properties is a key construction strategy for bone-targeted hydrogel. Besides, injectable hydrogel drug depot carrying bone-targeted drugs is another strategy. In this review, we summarize the bone-targeted hydrogel through application environment, construction strategies and disease applications. We hope this article will provide a reference for the development of bone-targeted hydrogels. We also hope this article could increase awareness of bone-targeted materials.

Abstract Despite enormous advances in the generation of organoids, robust and stable protocols of organoids are still a major challenge to researchers. Research for assessing structures of organoids and the evaluations of their functions on in vitro or in vivo is often limited by precision strategies. A growing interest in assessing organoids has arisen, aimed at standardizing the process of obtaining organoids to accurately resemble human‐derived tissue. The complex microenvironment of organoids, intricate cellular crosstalk, organ‐specific architectures and further complicate functions urgently quest for high‐through schemes. By utilizing multi‐omics analysis and single‐cell analysis, cell‐cell interaction mechanisms can be deciphered, and their structures can be investigated in a detailed view by histological analysis. In this review, we will conclude the novel approaches to study the molecular mechanism and cell heterogeneity of organoids and discuss the histological and morphological similarity of organoids in comparison to the human body. Future perspectives on functional analysis will be developed and the organoids will become mature models.

Treatment of large bone defects represents a great challenge in orthopedic and craniomaxillofacial surgery. Traditional strategies in bone tissue engineering have focused primarily on mimicking the extracellular matrix (ECM) of bone in terms of structure and composition. However, the synergistic effects of other cues from the microenvironment during bone regeneration are often neglected. The bone microenvironment is a sophisticated system that includes physiological (e.g., neighboring cells such as macrophages), chemical (e.g., oxygen, pH), and physical factors (e.g., mechanics, acoustics) that dynamically interact with each other. Microenvironment-targeted strategies are increasingly recognized as crucial for successful bone regeneration and offer promising solutions for advancing bone tissue engineering. This review provides a comprehensive overview of current microenvironment-targeted strategies and challenges for bone regeneration and further outlines prospective directions of the approaches in construction of bone organoids.

Skeletal muscle disorders have posed great threats to health. Selective delivery of drugs and oligonucleotides to skeletal muscle is challenging. Aptamers can improve targeting efficacy. In this study, for the first time, the human skeletal muscle-specific ssDNA aptamers (HSM01, etc.) were selected and identified with Systematic Evolution of Ligands by Exponential Enrichment (SELEX). The HSM01 ssDNA aptamer preferentially interacted with human skeletal muscle cells in vitro. The in vivo study using tree shrews showed that the HSM01 ssDNA aptamer specifically targeted human skeletal muscle cells. Furthermore, the ability of HSM01 ssDNA aptamer to target skeletal muscle cells was not affected by the formation of a disulfide bond with nanoliposomes in vitro or in vivo, suggesting a potential new approach for targeted drug delivery to skeletal muscles via liposomes. Therefore, this newly identified ssDNA aptamer and nanoliposome modification could be used for the treatment of human skeletal muscle diseases.

Abstract As the integration of artificial intelligence (AI) into our daily lives and educational environments becomes increasingly prevalent, it is necessary to understand the way in which these technologies impact cognitive functions. AI models such as ChatGPT hold immense promise for advancing the field of education, making it easier than ever for educators to support personalized learning and for students to access information. However, there are risks associated with increased AI engagement; individuals may become over‐reliant on AI, resulting in a reduced capacity for critical thinking, or a decline in memory retention. This article provides a comprehensive survey of these potential impacts, emphasizing the need for the judicious utilization of AI, and advocating for an integration approach that supplements, rather than supplants, human cognitive functions. The paper concludes by encouraging further research into the long‐term cognitive effects of interacting with advanced AI models such as ChatGPT.

Abstract Osteoporosis is a systemic and degenerative disease characterized by low bone mass and fragile microarchitecture, which predispose patients to fragility fractures, also known as osteoporotic fractures (OPF). OPF have become a major social problem that threaten the health of the elderly. Over the past decade, organoids and organoids extracellular vesicles (OEVs) play a significant role in OPF repair. Organoids have been widely used for fractures treatment. Moreover, EVs are promising nanocarriers due to their cell‐free system, stable drug loading capacity, nanometer size, and good biocompatibility. Importanly, compared with traditional EVs, OEVs have more quantity, better physiological effects, and better therapeutic effects. Therefore, the development of organoid and OEVs in the treatment of OPF is of great significance. Here, we summarize the current status and future perspectives of organoids and OEVs, which will provide innovative solutions to OPF repair.

Abstract Recently, the interest in extracellular vesicles released by bacteria has rapidly increased. Bacterial extracellular vesicles (BEVs) have been involved in bacteria‐bacteria and bacteria‐host interactions, which strengthen health or bring about various pathologies. However, BEV separation, characterization, and functional studies require the establishment of guidelines and further optimization in order to stimulate the development of science in BEV research and a following successful transformation into clinical applications. This position paper is authored by the Microbial Vesicles Task Force of the Chinese Society for Extracellular Vesicles (CSEV) composed of experienced medical laboratory specialists, microbiologists, virologists, biologists and material biologists who are actively engaged in BEV research. Herein, we present a concise description of BEV research and discover challenges and critical gaps in current BEV‐based analyses for clinical applications. Finally, we also offer suggestions and considerations to improve experimental reproducibility and interoperability in BEV research to promote progress in the field.

Bone defects repair and regeneration by various causes such as tumor resection, trauma, degeneration, etc. have always been a key issue in the clinics. As one of the few organs that can regenerate after adulthood, bone itself has a strong regenerative ability. In recent decades, bone tissue engineering technology provides various types of functional scaffold materials and seed cells for bone regeneration and repair, which significantly accelerates the speed and quality of bone regeneration, and many clinical problems are gradually solved. However, the bone metabolism mechanism is complicated, the research duration is long and difficult, which significantly restricts the progress of bone regeneration and repair research. Organoids as a new concept, which is built in vitro with the help of tissue engineering technology based on biological theory, can simulate the complex biological functions of organs in vivo. Once proposed, it shows broad application prospects in the research of organ development, drug screening, mechanism study, and so on. As a complex and special organ, bone organoid construction itself is quite challenging. This review will introduce the characteristics of bone microenvironment, the concept of organoids, focus on the research progress of bone organoids, and propose the strategies for bone organoid construction, study direction, and application prospects.

Nanosized extracellular vesicles derived from bacteria contain diverse cargo and transfer intercellular bioactive molecules to cells. Due to their favorable intercellular interactions, cell membrane-derived bacterial extracellular vesicles (BEVs) have great potential to become novel drug delivery platforms. In this review, we summarize the biogenesis mechanism and compositions of various BEVs. In addition, an overview of effective isolation and purification techniques of BEVs is provided. In particular, we focus on the application of BEVs as bioactive nanocarriers for drug delivery. Finally, we summarize the advances and challenges of BEVs after providing a comprehensive discussion in each section. We believe that a deeper understanding of BEVs will open new avenues for their exploitation in drug delivery applications.

Background: Bone fracture healing is a postnatal regenerative process in which fibrocartilaginous callus formation and bony callus formation are important. Bony callus formation requires osteoblastic differentiation of MSCs. Materials and methods: The formation of callus was assessed by μCT, Safranin-O, H&E and Masson trichrome staining. Osteogenesis of MSCs was analyzed by ALP staining, ARS staining, qRT-PCR and WB. And we also used IF and TOP/FOP Flash luciferase reporter to assess the nuclear translocation of PP65. Results: In this study, we found Bcl-3 showed a significant correlation with bone fracture healing. Results of μCT showed that loss of Bcl-3 delays bone fracture healing. Safranin-O, H&E and Masson trichrome staining confirmed that loss of Bcl-3 impacted the formation of cartilage and woven bone in callus. Further experiments in vitro manifested that Bcl-3-knockdown could inhibit MSCs osteoblastic differentiation through releasing the inhibition on NF-κB signaling by Co-IP, IF staining and luciferase reporter assay. Conclusions: We unveiled that loss of Bcl-3 could lead to inhibited osteogenic differentiation of MSCs via promoting PP65 nuclear translocation. The translational potential of this article: Our data demonstrated that overexpression of Bcl-3 accelerates bone fracture healing, which serves as a promising therapeutic target for bone fracture treatment.

Bone tissue engineering has emerged as a significant research area that provides promising novel tools for the preparation of biomimetic hydrogels applied in bone-related diseases (e.g., bone defects, cartilage damage, osteoarthritis, etc.). Herein, thermal sensitive polymers (e.g., PNIPAAm, Soluplus, etc.) were introduced into main chains to fabricate biomimetic hydrogels with injectability and compatibility for those bone defect need minimally invasive surgery. Mineral ions (e.g., calcium, copper, zinc, and magnesium), as an indispensable role in maintaining the balance of the organism, were linked with polymer chains to form functional hydrogels for accelerating bone regeneration. In the chemically triggered hydrogel section, advanced hydrogels crosslinked by different molecular agents (e.g., genipin, dopamine, caffeic acid, and tannic acid) possess many advantages, including extensive selectivity, rapid gel-forming capacity and tunable mechanical property. Additionally, photo crosslinking hydrogel with rapid response and mild condition can be triggered by different photoinitiators (e.g., I2959, LAP, eosin Y, riboflavin, etc.) under specific wavelength of light. Moreover, enzyme triggered hydrogels were also utilized in the tissue regeneration due to its rapid gel-forming capacity and excellent biocompatibility. Particularly, some key factors that can determine the therapy effect for bone tissue engineering were also mentioned. Finally, brief summaries and remaining issues on how to properly design clinical-oriented hydrogels were provided in this review.

Rapid and effective repair of injured or diseased bone defects remains a major challenge due to shortages of implants. Smart hydrogels that respond to internal and external stimuli to achieve therapeutic actions in a spatially and temporally controlled manner have recently attracted much attention for bone therapy and regeneration. These hydrogels can be modified by introducing responsive moieties or embedding nanoparticles to increase their capacity for bone repair. Under specific stimuli, smart hydrogels can achieve variable, programmable, and controllable changes on demand to modulate the microenvironment for promoting bone healing. In this review, we highlight the advantages of smart hydrogels and summarize their materials, gelation methods, and properties. Then, we overview the recent advances in developing hydrogels that respond to biochemical signals, electromagnetic energy, and physical stimuli, including single, dual, and multiple types of stimuli, to enable physiological and pathological bone repair by modulating the microenvironment. Then, we discuss the current challenges and future perspectives regarding the clinical translation of smart hydrogels.

The cellular composition and underlying spatiotemporal transformation processes of subchondral bone in osteoarthritis (OA) remain unknown. Herein, various cell subsets from tibial plateau of patients with OA are identified, and the mechanism of subchondral microstructure alteration is elaborated using single-cell RNA sequencing technique. We identified two novel endothelial cell (EC) populations characterised by either exosome synthesis and inflammation response or vascular function and angiogenesis. Three osteoblast (OB) subtypes are introduced, separately related to vascularisation, matrix manufacturing and matrix mineralisation. The distinct roles and functions of these novel phenotypes in OA development are further discussed as well as interaction network between these subpopulations. The variation tendency of each population is testified in a destabilisation of the medial meniscus mouse model. The identification of cell types demonstrates a novel taxonomy and mechanism for ECs and OBs inside subchondral bone area provides new insights into the physiological and pathological behaviours of subchondral bone in OA pathogenesis.

Osteoporotic fractures, also known as fragility fractures, are prevalent in the elderly and bring tremendous social burdens. Poor bone quality, weak repair capacity, instability, and high failure rate of internal fixation are main characteristics of osteoporotic fractures. Osteoporotic bone defects are common and need to be repaired by appropriate materials. Proximal humerus, distal radius, tibia plateau, calcaneus, and spine are common osteoporotic fractures with bone defect. Here, the consensus from the Osteoporosis Group of Chinese Orthopaedic Association concentrates on the epidemiology, characters, and management strategies of common osteoporotic fractures with bone defect to standardize clinical practice in bone repair of osteoporotic fractures.

The differentiation shift from osteogenesis to adipogenesis of bone marrow mesenchymal stem cells (BMSCs) characterizes many pathological bone loss conditions. Stromal cell-derived factor-1 (SDF1) is highly enriched in the bone marrow for C-X-C motif chemokine receptor 4 (CXCR4)-positive hematopoietic stem cell (HSC) homing and tumor bone metastasis. In this study, we displayed CXCR4 on the surface of exosomes derived from genetically engineered NIH-3T3 cells. CXCR4+ exosomes selectively accumulated in the bone marrow. Then, we fused CXCR4+ exosomes with liposomes carrying antagomir-188 to produce hybrid nanoparticles (NPs). The hybrid NPs specifically gathered in the bone marrow and released antagomir-188, which promoted osteogenesis and inhibited adipogenesis of BMSCs and thereby reversed age-related trabecular bone loss and decreased cortical bone porosity in mice. Taken together, this study presents a novel way to obtain bone-targeted exosomes via surface display of CXCR4 and a promising anabolic therapeutic approach for age-related bone loss.

The past decade has become an important strategy in precision medicine for the targeted therapy of many diseases, expecially various types of cancer. As a promising targeted element, nucleic acid aptamers are single-stranded functional oligonucleotides which have specific abilities to bind with various target molecules ranging from small molecules to entire organisms. They are often named ‘chemical antibody’ and have aroused extensive interest in diverse clinical studies on account of their advantages, such as considerable biostability, versatile chemical modification, low immunogenicity and quick tissue penetration. Thus, aptamer-embedded drug delivery systems offer an unprecedented opportunity in bioanalysis and biomedicine. In this short review, we endeavor to discuss the recent advances in aptamer-based targeted drug delivery platforms for cancer therapy. Some perspectives on the advantages, challenges and opportunities are also presented.

Osteoarthritis (OA) is a degenerative disease of the joints characterized by cartilage damage and severe pain. Despite various pharmacological and surgical interventions, current therapies fail to halt OA progression, leading to high morbidity and an economic burden. Thus, there is an urgent need for alternative therapeutic approaches that can effectively address the underlying pathophysiology of OA. Extracellular Vesicles (EVs) derived from mesenchymal stromal cells (MSCs) represent a new paradigm in OA treatment. MSC-EVs are small membranous particles released by MSCs during culture, both in vitro and in vivo. They possess regenerative properties and can attenuate inflammation, thereby promoting cartilage healing. Importantly, MSC-EVs have several advantages over MSCs as cell-based therapies, including lower risks of immune reactions and ethical issues. Researchers have recently explored different strategies, such as modifying EVs to enhance their delivery, targeting efficiency, and security, with promising results. This article reviews how MSC-EVs can help treat OA and how they might work. It also briefly discusses the benefits and challenges of using MSC-EVs and talks about the possibility of allogeneic and autologous MSC-EVs for medical use.

Calcium phosphate (CaP) is the principal inorganic constituent of bone and teeth in vertebrates and has various applications in biomedical areas. Among various types of CaPs, amorphous calcium phosphate (ACP) is considered to have superior bioactivity and biodegradability. With regard to the instability of ACP, the phosphorus-containing molecules are usually adopted to solve this issue, but the specific roles of the molecules in the formation of nano-sized CaP have not been clearly clarified yet. Herein, alendronate, cyclophosphamide, zoledronate, and foscarnet are selected as the model molecules, and theoretical calculations were performed to elucidate the interaction between calcium ions and different model molecules. Subsequently, CaPs were prepared with the addition of the phosphorus-containing molecules. It is found that cyclophosphamide has limited influence on the generation of CaPs due to their weak interaction. During the co-precipitation process of Ca2+ and PO43-, the competitive relation among alendronate, zoledronate, and foscarnet plays critical roles in the produced inorganic-organic complex. Moreover, the biocompatibility of CaPs was also systematically evaluated. The DFT calculation provides a convincing strategy for predicting the structure of CaPs with various additives. This work is promising for designing CaP-based multifunctional drug delivery systems and tissue engineering materials.

In aging society, osteoporotic fractures have become one major social problem threatening the health of the elderly population in China. Compared with conventional fractures, low bone mass, bone defect and retarded healing issues of osteoporotic fractures lead to great difficulties in treatment and rehabilitation. Addressing major concerns in clinical settings, we proposed the “three in one” bone repair strategy focusing on anti-osteoporosis therapies, appropriate bone grafting and fracture healing accelerating. We summarize misconceptions and repair strategies for osteoporotic fracture management, expecting improvement of prognosis and clinical outcomes for osteoporotic fractures, to further improve therapeutic effect and living quality of patients.

Targeted delivery by either systemic or local targeting of therapeutics to the bone is an attractive treatment for various bone metabolism diseases such as osteoporosis, osteoarthritis, osteosarcoma, osteomyelitis, etc. To overcome the limitations of direct drug delivery, the combination of bone-targeted agents with nanotechnology has the opportunity to provide a more effective therapeutic approach, where engineered nanoparticles cause the drug to accumulate in the bone, thereby improving efficacy and minimizing side effects. Here, we summarize the current advances in systemic or local bone-targeting approaches and nanosystem applications in bone diseases, which may provide new insights into nanocarrier-delivered drugs for the targeted treatment of bone diseases. We envision that novel drug delivery carriers developed based on nanotechnology will be a potential vehicle for the treatment of currently incurable bone diseases and are expected to be translated into clinical applications.

Signal transducer and activator of transcription 3 (Stat3) is activated by phosphorylation and translocated to the nucleus to participate in the transcriptional regulation of DNA. Increasing evidences point that aberrant activation or deletion of the Stat3 plays a critical role in a broad range of pathological processes including immune escape, tumorigenesis, and inflammation. In the bone microenvironment, Stat3 acts as a common downstream response protein for multiple cytokines and is engaged in the modulation of cellular proliferation and intercellular interactions. Stat3 has direct impacts on disease progression by regulating mesenchymal stem cells differentiation, osteoclast activation, macrophage polarization, angiogenesis, and cartilage degradation. Here, we describe the theoretical basis and key roles of Stat3 in different bone-related diseases in combination with in vitro experiments and animal models. Then, we summarize and categorize the drugs that target Stat3, providing potential therapeutic strategies for their use in bone-related diseases. In conclusion, Stat3 could be a future target for bone-related diseases.

In-situ bone tissue regeneration, which harnesses cell external microenvironment and their regenerative potential to induce cell functions and bone reconstruction through some special properties of biomaterials, has been deeply developed. In which, hydrogel was widely applied due to its 3D network structure with high water absorption and mimicking native extracellular matrix (ECM). Additionally, exosomes can participate in a variety of physiological processes such as cell differentiation, angiogenesis and tissue repair. Therefore, a novel cell-free tissue engineering (TE) using exosome-laden hydrogels has been explored and developed for bone regeneration in recent years. However, related reviews in this field are limited. Therefore, we elaborated on the shortcomings of traditional bone tissue engineering, the challenges of exosome delivery and emphasized the advantages of exosome-laden hydrogels for in-situ bone tissue regeneration. The encapsulation strategies of hydrogel and exosomes are listed, and the research progress and prospects of bioactive hydrogel composite system for continuous delivery of exosomes for in-situ bone repair are also discussed in this review.

Abstract Osteoarthritis comprises several joint disorders characterized by articular cartilage degeneration and persistent pain, causing disability and economic burden. The incidence of osteoarthritis is rapidly increasing worldwide due to aging and obesity trends. Basic and clinical research on osteoarthritis has been carried out for decades, but many questions remain unanswered. The exact role of subchondral bone during the initiation and progression osteoarthritis remains unclear. Accumulating evidence shows that subchondral bone lesions, including bone marrow edema and angiogenesis, develop earlier than cartilage degeneration. Clinical interventions targeting subchondral bone have shown therapeutic potential, while others targeting cartilage have yielded disappointing results. Abnormal subchondral bone remodeling, angiogenesis and sensory nerve innervation contribute directly or indirectly to cartilage destruction and pain. This review is about bone-cartilage crosstalk, the subchondral microenvironment and the critical role of both in osteoarthritis progression. It also provides an update on the pathogenesis of and interventions for osteoarthritis and future research targeting subchondral bone.

Osteoporosis is a bone metabolic disease caused by the imbalance between osteoblasts and osteoclasts due to excess osteoclastogenesis, manifesting in the decrease of bone density and bone strength. Scutellariae Radix shows good anti-osteoporosis activity, but the effective component is still unclear. Cell membrane chromatography (CMC) is a biological affinity chromatography with membrane immobilized on a silica carrier as the stationary phase. It can realize a dynamical simulation of interactions between drugs and receptors on cell membrane, which is suitable for screening active compounds from complex systems. In this study, the components of Scutellariae Radix with potential anti-osteoporosis activity through inhibiting the differentiation from bone marrow mononuclear cells (BMMCs) to osteoclast were screened by a BMMC/CMC analytical system. Firstly, a new 3-mercaptopropyltrimethoxysilane (MPTS)-modified BMMC/CMC stationary phase was developed to realize covalent binding with cell membrane fractions. By investigating the retention time (tR) of the positive drug, the life span of the MPTS-modified CMC columns was significantly improved from 3 to 12 days. Secondly, 6 components of Scutellariae Radix were screened to show affinity to membrane receptors on BMMCs by a two-dimensional BMMC/CMC–TOFMS analytical system. Among them, tectochrysin demonstrated the best anti-osteoporosis effect in vitro, which has never been reported. We found that tectochrysin could inhibit the differentiation of BMMCs into osteoclasts induced by receptor activator of nuclear factor-κΒ ligand (RANKL) and macrophage colony-stimulating factor (M-CSF) in a concentration-dependent manner in vitro. In vivo, it significantly reduced the loss of bone trabeculae in ovariectomized mice, and decreased the level of C-terminal cross-linking telopeptides of type 1 collagen (CTX-1), tartrate-resistant acid phosphatase 5b (TRAP-5b), interleukin 6 (IL-6) in serum. In conclusion, tectochrysin serves as a potential candidate in the treatment of osteoporosis. The proposed two-dimensional MPTS-modified BMMC/CMC-TOFMS analytical system shows the advantages of long-life span and fast recognition ability, which is very suitable for infrequent cell lines.

Bone marrow mesenchymal stromal cells (BMSCs), identified as pericytes comprising the hematopoietic niche, are a group of heterogeneous cells composed of multipotent stem cells, including osteochondral and adipocyte progenitors. Nevertheless, the identification and classification are still controversial, which limits their application. In recent years, by lineage tracing and single-cell sequencing, several new subgroups of BMSCs and their roles in normal physiological and pathological conditions have been clarified. Key regulators and mechanisms controlling the fate of BMSCs are being revealed. Cross-talk among subgroups of bone marrow mesenchymal cells has been demonstrated. In this review, we focus on recent advances in the identification and classification of BMSCs, which provides important implications for clinical applications.

Reactive oxygen species (ROS) are the key signaling molecules in many physiological signs of progress and are associated with almost all diseases, such as atherosclerosis, aging, and cancer. Bone is a specific connective tissue consisting of cells, fibers, and mineralized extracellular components, and its quality changes with aging and disease. Growing evidence indicated that overproduced ROS accumulation may disrupt cellular homeostasis in the progress of bone modeling and remodeling, leading to bone metabolic disease. Thus, ROS-responsive biomaterials have attracted great interest from many researchers as promising strategies to realize drug release or targeted therapy for bone-related diseases. Herein, we endeavor to introduce the role of ROS in the bone microenvironment, summarize the mechanism and development of ROS-responsive biomaterials, and their completion and potential for future therapy of bone-related diseases.

Chronic skeletal disorders (CSDs), including degenerative diseases such as osteoporosis (OP) and autoimmune disorders, have become a leading cause of disability in an ageing society, with natural drugs being indispensable therapeutic options. The clinical safety evaluation (CSE) of natural drugs in CSDs has been given priority and has been intensively studied. To provide fundamental evidence for the clinical application of natural drugs in the elderly population, clinical studies of natural drugs in CSDs included in this review were selected from CNKI, Web of Science, PubMed, Science Direct and Google Scholar since 2001. Seventeen randomized controlled trials (RCTs) met our inclusion criteria: four articles were on OP, seven on osteoarthritis (OA), four on rheumatoid arthritis (RA) and two on gout. Common natural drugs used for the treatment of OP include Epimedium brevicornu Maxim [Berberidaceae], Dipsacus asper Wall ex DC [Caprifoliaceae] root, and Phalaenopsis cornu-cervi (Breda) Blume & Rchb. f[ Orchidaceae], which have been linked to several mild adverse reactions, such as skin rash, gastric dysfunction, abnormal urine, constipation and irritability. The safety of Hedera helix L [Araliaceae] extract, Boswellia serrata Roxb [Burseraceae] extract and extract from perna canaliculus was evaluated in OA and upper abdominal pain, and unstable movements were obsrerved as major side effects. Adverse events, including pneumonia, vomiting, diarrhoea and upper respiratory tract infection, were reported when RA was treated with Tripterygium wilfordii, Hook. F [Celastraceae][TwHF] polyglycosides and quercetin (Capsella bursa-pastoris (L.) Medik [Brassicaceae]). The present review aimed to summarize the CSE results of natural drugs in CSDs and could provide evidence-based information for clinicians.

Recognized for nearly 100 years, bone marrow adipocytes (BMAs) form bone marrow niches that contain hematopoietic and bone cells, the roles of which have long been underestimated. Distinct from canonical white, brown, and beige adipocytes, BMAs derived from bone marrow mesenchymal stromal cells possess unique characteristics and functions. Recent single-cell sequencing studies have revealed the differentiation pathway, and seminal works support the tenet that BMAs are critical regulators in hematopoiesis, osteogenesis, and osteoclastogenesis. In this review, we discuss the origin and differentiation of BMAs, as well as the roles of BMAs in hematopoiesis, osteogenesis, osteoclastogenesis, and immune regulation. Overall, BMAs represent a novel target for bone marrow-related diseases, including osteoporosis and leukemia.