Fracture repair in renal osteodystrophy remains challenging because impaired bone quality compromises fixation stability, while current systemic therapies regulating bone metabolism do not sufficiently address the disease-specific mechanisms underlying defective repair. An integrated strategy combining early fracture stabilization with mechanism-guided local treatment is therefore needed. Here, integrated single-cell RNA sequencing and multi-omics analyses identify inflammatory macrophages as a key pathogenic population, characterized by glycolytic reprogramming driven by hypoxia-inducible factor 1 alpha and phosphofructokinase-2/fructose-2,6-bisphosphatase 3, together with acidic metabolite accumulation. We show that this inflammatory acidic niche suppresses bone formation, enhances bone resorption and impairs regeneration. Guided by this mechanism, we develop a microenvironment-responsive adhesive hydrogel formed from a gelatin–boronic acid conjugate and sodium alginate and loaded with Epimedium-derived extracellular vesicle-like nanoparticles. We demonstrate that the hydrogel provides early local stabilization, enables microenvironment-responsive nanoparticle release and regulates the pathological niche. In vitro and in vivo, we find that the system suppresses inflammatory macrophage activation, promotes osteogenesis, inhibits osteoclastogenesis and accelerates fracture healing in a renal osteodystrophy model. These findings reveal a disease-specific mechanism of defective bone repair and provide a closed-loop therapeutic strategy that integrates local stabilization with microenvironment-directed treatment for fractures associated with renal osteodystrophy. Using single-cell multi-omics, the authors uncover an inflammatory acidic environment that impairs bone repair in renal osteodystrophy. They develop a closed-loop hydrogel therapy integrating fracture stabilization with local microenvironment regulation.

Although multiple studies have confirmed the importance of chronic low-grade inflammation in the development of osteoarthritis (OA), the association between complete blood count (CBC)-derived inflammatory indicators and osteoarthritis prevalence remains unclear. The present study aims to explore the association between CBC-derived inflammatory indicators and OA prevalence. We used NHANES data from 2007 to 2020 for a cross-sectional analysis. Multivariate logistic regression models were used to evaluate the association between CBC-derived inflammatory indicators and OA prevalence. Restricted cubic spline function (RCS) and threshold analysis were used to assess potential nonlinear associations. In addition, subgroup and sensitivity analyses were performed to assess the stability of the results. Finally, we used LASSO regression to identify the variables most associated with OA outcomes to construct a prediction model, and the model's validity was verified. Among the 24,112 patients in this study, 3,195 were diagnosed with OA. In the adjusted model, multivariate logistic regression analysis showed that 5 inflammatory indicators (SII, SIRI, MLR, NMLR, NLR) were positively associated with OA prevalence. RCS and threshold analysis showed nonlinear associations between (SII, NMLR, NLR) and OA prevalence. After variable screening, we established an OA risk prediction model with an area under the curve (AUC) of 0.735 (95% CI: 0.726-0.744). Both the decision and calibration curve showed that the model had good clinical significance. The Present study suggests that CBC-derived inflammatory indicators are statistically associated with OA prevalence. Furthermore, MLR and NMLR could be valuable predictors of OA and offer novel perspectives on its assessment and treatment.

Diabetic skin wounds, a severe complication affecting over 18.6 million people globally, are characterized by high amputation and mortality rates. However, the cellular heterogeneity of diabetic wounds and the specific molecular mechanisms underlying their impaired healing remain unclear. Furthermore, treatment strategies based on medicinal plants targeting these pathological mechanisms are lacking. This study explored diabetic wound pathogenesis using single-cell RNA sequencing (scRNA-seq), revealing a 52 % reduction in vascular endothelial cells (ECs) and a decreased abundance of proliferative ECs in diabetic wound tissues, which contributed to impaired vascular repair. Network pharmacology and RT-qPCR identified E-selectin (SELE) as the key target of Panax notoginseng in the treatment of diabetic wounds, which was corroborated by molecular docking. Plant-derived extracellular vesicles (EVs) represent a class of superior bioactive nanomaterials compared to traditional extracts, exhibiting high delivery efficiency, molecular transport capacity, and biocompatibility, enabling cross-species communication essential for therapeutic applications. To further overcome limitations associated with plant-derived extracts (e.g., short half-life), we isolated Panax notoginseng EVs and subsequently loaded them into a hydrogel via dynamic borate ester bonds formed between quaternized chitosan-phenylboronic acid (QCS-BA) and konjac glucomannan (KGM), ultimately generating the QBK-2/EVs composite system. This hydrogel not only effectively encapsulated and continuously released EVs, but also exhibited good injectability, self-healing property, tissue adhesion (42.83 kPa), and ROS/pH-responsive degradation. In vitro, QBK-2/EVs enhanced human umbilical vein endothelial cell proliferation, migration, and tube formation by downregulating SELE and upregulating angiogenesis markers (CD31, F-actin). In vivo, QBK-2/EVs accelerated wound healing in diabetic mice, promoted hemostasis, increased collagen deposition, and enhanced microvessel density (CD31), while simultaneously reducing the expression of SELE. Overall, this work establishes a mechanism-driven strategy for diabetic wound treatment through synergistic exosome-mediated angiogenesis and hydrogel-based delivery.

Hemophilia poses distinct challenges to wound healing, primarily due to uncontrolled bleeding and delayed tissue repair. This study explored a novel tannic acid-thioctic acid (TATA) hydrogel, enriched with exosomes derived from bone marrow mesenchymal stem cells, as a therapeutic strategy for enhancing skin wound healing in a hemophilia model. The hydrogel exhibited robust hemostatic efficacy, potent antioxidant activity, and the capacity to modulate the inflammatory microenvironment. Both in vitro and in vivo assessments demonstrated significantly accelerated wound closure, increased collagen deposition, and pronounced angiogenesis in the TATA Hydrogel-Exosome(TATA Hydrogel-Exos) treatment group relative to controls. Rheological evaluations confirmed the self-healing properties and mechanical durability, of the hydrogel, underscoring its potential for sustained therapeutic application. Importantly, no significant systemic toxicity was observed, indicating favorable biocompatibility. These multifunctional TATA Hydrogel-Exos present a promising therapeutic avenue for hemophilia-related wounds by integrating hemostasis, inflammation regulation, and tissue regeneration.

Bone fractures, especially large and complex defects, continue to pose significant challenges in the medical field. Current treatments often rely on autografts or allografts for structural support, which can lead to problems such as reduced bioactivity, infection risks, and potential pathogen transmission. Nature herbal medicine (NHM), including herbs and herbal extracts, offers a promising alternative by effectively modulating inflammatory responses, enhancing osteoblast function, and inhibiting bone resorption, thereby facilitating fracture repair. However, traditional drug delivery methods for NHM encounter challenges such as potential drug interactions, poor tissue distribution, and reduced patient compliance. Biomaterials, engineered to interact with biological systems, play essential roles in tissue repair, mechanical support, and drug delivery. When used as drug carriers, biomaterials can be combined with NHM to form stable drug delivery systems that further promote bone regeneration. Here the applications of biomaterials are reviewed, such as hydrogels, extracellular vesicles, and bone cement, in conjunction with NHM for regulating bone homeostasis and fracture repair, aiming to provide valuable insights and guidance for future research and therapeutic strategies.

BACKGROUND:Keloids, dermal fibroproliferative disorders, frequently reemerge after surgical intervention, potentially due to skin tension, a factor often overlooked in treatment strategies. METHODS:In this study, we identified Alpha cardiac muscle 1 (ACTC1) as a key cytoskeletal target in the mechano-transduction of keloids through bioinformatic analysis and in vitro experiments. We developed an adhesive hydrogel based on lipoic acid-modified konjac glucomannan (KGM-LA), a natural polysaccharide, loaded with siACTC1. This hydrogel serves as a tension-free wound dressing to mitigate keloid proliferation. RESULTS:ACTC1 was significantly upregulated in keloid tissues and fibroblasts compared to normal controls. siACTC1 effectively reduced the proliferation, invasiveness, and levels of F-actin, α-SMA, and collagen I in keloid fibroblasts. The KGM-LA hydrogel demonstrated excellent adhesiveness, biocompatibility, injectability, and degradability, making it ideal for sustained siRNA release and tension reduction at wound sites. Notably, the siACTC1-loaded hydrogel significantly suppressed keloid growth in a mouse model by sustainably inhibiting ACTC1 and reducing mechanical tension. CONCLUSIONS:Our study demonstrates that the KGM-LA-based adhesive hydrogel loaded with siACTC1 effectively inhibits keloid growth post-surgery, highlighting its potential for future clinical applications in keloid treatment.

Background: Diabetes mellitus (DM) is a prevalent chronic condition that influences spine surgery outcomes. The impact of type I and type II DM on adverse postoperative outcomes, mortality, prolonged length of stay (LOS), and increased in-hospital costs following cervical fusion surgery remains unclear in the past decade. This study aims to determine the specific effect of different classifications of DM on postoperative complications in patients experiencing cervical fusion surgery. Method: Data from the Nationwide Inpatient Sample database was acquired between 2010 and 2019. Patients experiencing cervical fusion were included and classified as having type I DM, type II DM, or neither. Patient demographics, hospital characteristics, operative variables, comorbidities, complications, and other postoperative outcomes were assessed. Propensity score matching analysis was used to balance baseline differences. Univariate and multivariate logistic regression were employed to determine the risk of postoperative outcomes in patients with different classifications of DM. Result: A total of 267 174 cervical spinal fusions were identified (224 255 were patients without DM, 670 patients had type I DM, and 42 249 patients had type II DM). After propensity score matching, the multivariate analysis of non-DM and type I DM patients shows a significant difference in pneumonia (P=0.020). However, type II DM served as an independent predictor of an increased risk of acute cerebrovascular disease (P=0.001), acute myocardial infarction (P=0.014), pneumonia (P=0.045), continuous trauma ventilation (P=0.016), chest pain (P<0.001), urinary tract infection (P<0.001), transfusion (P=0.005) and dysphagia (P=0.013), prolonged LOS (P<0.001), and increased costs (P=0.008). Conclusion: Using non-DM patients as a reference, the type II DM group demonstrated a higher risk of postoperative complications than the type I DM group among patients receiving cervical fusion surgery. This vital distinction could enhance risk stratification and guidance for patients diagnosed with DM before cervical fusion surgery.

Bioelectrical homeostasis plays critical roles in biological processes, but disturbing it for cancer therapy remains challenging due to the difficulty in electrically controlling cancer cells. Here we show that cell-internalized electroactive nanoparticles interrupt it in cancer cells to effectively treat cancer wirelessly. Specifically, K0.5Na0.5NbO3 ferroelectric nanoparticles are polarized and then generate a voltage of approximately -60 mV in response to ultrasound. Hence, once endocytosed by cancer cells in tumors, these nanoparticles establish an intracellular electric field (iEF) under the remote activation by ultrasound irradiation (for only 3 min) from outside the body. The iEF then depolarizes cell membrane potentials, decreases mitochondrial membrane potentials, and overloads intracellular calcium ions, disturbing intracellular bioelectrical balance. This disturbance promotes cancer cell apoptosis, inhibiting the growth of different types of tumors (bone tumor and skin tumor) without adverse effects. It is noteworthy that iEF can specifically disrupt the bioelectric balance of tumor cells but has no effect on normal cells. Such wireless cancer therapy can be achieved by other ferroelectric nanoparticles (e.g., BaTiO3). This work represents the first cancer treatment paradigm by intracellularly interrupting bioelectrical homeostasis remotely to cause cancer cell dysfunctions without electrode implantation and wire connection in vivo. It can also provide biologists with new tools for studying the role of disturbed bioelectrical homeostasis in cell fates and disease progression.

The treatment of critical-size bone defects with irregular shapes remains a major challenge in the field of orthopedics. Bone implants with adaptability to complex morphological bone defects, bone-adhesive properties, and potent osteogenic capacity are necessary. Here, a shape-adaptive, highly bone-adhesive, and ultrasound-powered injectable nanocomposite hydrogel is developed via dynamic covalent crosslinking of amine-modified piezoelectric nanoparticles and biopolymer hydrogel networks for electrically accelerated bone healing. Depending on the inorganic-organic interaction between the amino-modified piezoelectric nanoparticles and the bio-adhesive hydrogel network, the bone adhesive strength of the prepared hydrogel exhibited an approximately 3-fold increase. In response to ultrasound radiation, the nanocomposite hydrogel could generate a controllable electrical output (-41.16 to 61.82 mV) to enhance the osteogenic effect in vitro and in vivo significantly. Rat critical-size calvarial defect repair validates accelerated bone healing. In addition, bioinformatics analysis reveals that the ultrasound-responsive nanocomposite hydrogel enhanced the osteogenic differentiation of bone mesenchymal stem cells by increasing calcium ion influx and up-regulating the PI3K/AKT and MEK/ERK signaling pathways. Overall, the present work reveals a novel wireless ultrasound-powered bone-adhesive nanocomposite hydrogel that broadens the therapeutic horizons for irregular bone defects.

From degeneration causing intervertebral disc issues to trauma-induced meniscus tears, diverse factors can injure the different types of cartilage. This review highlights adhesives as a promising and rapidly implemented repair strategy. Compared to traditional techniques such as sutures and wires, adhesives offer several advantages. Importantly, they seamlessly connect with the injured tissue, deliver bioactive substances directly to the repair site, and potentially alleviate secondary problems like inflammation or degeneration. This review delves into the cutting-edge advancements in adhesive technology, specifically focusing on their effectiveness in cartilage injury treatment and their underlying mechanisms. We begin by exploring the material characteristics of adhesives used in cartilage tissue, focusing on essential aspects like adhesion, biocompatibility, and degradability. Subsequently, we investigate the various types of adhesives currently employed in this context. Our discussion then moves to the unique role adhesives play in addressing different cartilage injuries. Finally, we acknowledge the challenges currently faced by this promising technology.

Hemophilic articular cartilage damage presents a significant challenge for surgeons, characterized by recurrent intraarticular bleeding, a severe inflammatory microenvironment, and limited self-repair capability of cartilage tissue. Currently, there is a lack of tissue engineering-based integrated therapies that address both early hemostasis, anti-inflammation, and long-lasting chondrogenesis for hemophilic articular cartilage defects. Herein, we developed an adhesive hydrogel using oxidized chondroitin sulfate and gelatin, loaded with exosomes derived from bone marrow stem cells (BMSCs) (Hydrogel-Exos). This hydrogel demonstrated favorable injectability, self-healing, biocompatibility, biodegradability, swelling, frictional and mechanical properties, providing a comprehensive approach to treating hemophilic articular cartilage defects. The adhesive hydrogel, featuring dynamic Schiff base bonds and hydrogen bonds, exhibited excellent wet tissue adhesiveness and hemostatic properties. In a pig model, the hydrogel could be smoothly injected into the knee joint cartilage defect site and gelled in situ under fluid-irrigated arthroscopic conditions. Our in vitro and in vivo experiments confirmed that the sustained release of exosomes yielded anti-inflammatory effects by modulating macrophage M2 polarization through the NF-κB pathway. This immunoregulatory effect, coupled with the extracellular matrix components provided by the adhesive hydrogel, enhanced chondrogenesis, promoted the cartilage repair and joint function restoration after hemophilic articular cartilage defects. In conclusion, our results highlight the significant application potential of Hydrogel-Exos for early hemostasis, immunoregulation, and long-term chondrogenesis in hemophilic patients with cartilage injuries. This innovative approach is well-suited for application during arthroscopic procedures, offering a promising solution for addressing the complex challenges associated with hemophilic articular cartilage damage.

Electroconductive hydrogels offer a promising avenue for enhancing the repair efficacy of spinal cord injuries (SCI) by restoring disrupted electrical signals along the spinal cord’s conduction pathway. Nonetheless, the application of hydrogels composed of diverse electroconductive materials has demonstrated limited capacity to mitigate the post-SCI inflammatory response. Recent research has indicated that the transplantation of M2 microglia effectively fosters SCI recovery by attenuating the excessive inflammatory response. Exosomes (Exos), small vesicles discharged by cells carrying similar biological functions to their originating cells, present a compelling alternative to cellular transplantation. This investigation endeavors to exploit M2 microglia-derived exosomes (M2-Exos) successfully isolated and reversibly bonded to electroconductive hydrogels through hydrogen bonding for synergistic promotion of SCI repair to synergistically enhance SCI repair. In vitro experiments substantiated the significant capacity of M2-Exos-laden electroconductive hydrogels to stimulate the growth of neural stem cells and axons in the dorsal root ganglion and modulate microglial M2 polarization. Furthermore, M2-Exos demonstrated a remarkable ability to mitigate the initial inflammatory reaction within the injury site. When combined with the electroconductive hydrogel, M2-Exos worked synergistically to expedite neuronal and axonal regeneration, substantially enhancing the functional recovery of rats afflicted with SCI. These findings underscore the potential of M2-Exos as a valuable reparative factor, amplifying the efficacy of electroconductive hydrogels in their capacity to foster SCI rehabilitation.

At present, effective fixation and anti-infection implant materials represent the mainstay for the treatment of open fractures. However, external fixation can cause nail tract infections and is ineffective for fixing small fracture fragments. Moreover, closed reduction and internal fixation during the early stage of injury can lead to potential bone infection, conducive to bone nonunion and delayed healing. Herein, we designed a bone adhesive with anti-infection, osteogenic and bone adhesion fixation properties to promote reduction and fixation of open fractures and subsequent soft tissue repair. It was prepared by the reaction of gelatin (Gel) and oxidized starch (OS) with vancomycin (VAN)-loaded mesoporous bioactive glass nanoparticles (MBGNs) covalently cross-linked with Schiff bases. Characterization and adhesion experiments were conducted to validate the successful preparation of the Gel-OS/VAN@MBGNs (GOVM-gel) adhesive. Meanwhile, in vitro cell experiments demonstrated its good antibacterial effects with the ability to stimulate bone marrow mesenchymal stem cell (BMSCs) proliferation, upregulate the expression of alkaline phosphatase (ALP) and osteogenic proteins (RunX2 and OPN) and enhance the deposition of calcium nodules. Additionally, we established a rat skull fracture model and a subcutaneous infection model. The histological analysis showed that bone adhesive enhanced osteogenesis, and in vivo experiments demonstrated that the number of inflammatory cells and bacteria was significantly reduced. Overall, the adhesive could promote early reduction of fractures and antibacterial and osteogenic effects, providing the foothold for treatment of this patient population.

Bone implant outcome and bone regeneration properties can be improved by the immunomodulation of exosomes (Exos) derived from bone marrow mesenchymal stem cells (BMSCs), which contain cytokines, signaling lipids, and regulatory miRNAs. Analysis of miRNAs in BMSCs-derived exosomes showed that miR-21a-5p exhibited the highest expression and was associated with the NF-κB pathway. Hence, we developed an implant with miR-21a-5p functionality to promote bone incorporation by immunoregulation. Mediated by the potent interaction between tannic acid (TA) and biomacromolecules, the tannic acid modified mesoporous bioactive glass nanoparticles coated with miR-21a-5p (miR-21a-5p@T-MBGNs) were reversibly attached to TA-modified polyetheretherketone (T-PEEK). Cocultured cells could phagocytose miR-21a-5p@T-MBGNs slowly released from miR-21a-5p@T-MBGNs loaded T-PEEK (miMT-PEEK). Moreover, miMT-PEEK boosted macrophage M2 polarization via the NF-κB pathway to increase BMSCs osteogenic differentiation. In vivo testing of miMT-PEEK in the rat air-pouch model and rat femoral drilling model indicated effective macrophage M2 polarization, new bone formation, and excellent osseointegration. Overall, the osteoimmunomodulation of the miR-21a-5p@T-MBGNs-functionalized implant promoted osteogenesis and osseointegration.

In recent years,electrically conductive hydrogel-based nerve guidance conduits(NGCs)have yielded promising results for treating peripheral nerve injuries(PNIs).However,developed ones are generally pre-manufactured and exhibit a limited ability to achieve good contact with nerve tissue with irregu-lar surfaces.Herein,we developed a plasticine-like electrically conductive hydrogel consisting of gelatin,conducting polypyrrole,and tannic acid(named GPT)and assessed its ability to promote peripheral nerve regeneration.The shape-persistent GPT hydrogel exhibited good self-healing properties and could easily be molded to form a conduit that could match any injured nerve tissue.Their electrical properties could be tuned by changing the PPy concentration.In vitro,the improved conductivity of the hydrogel pro-moted dorsal root ganglion(DRG)axonal extension.More importantly,we found that the GPT hydrogel enhanced axonal regeneration and remyelination in vivo,preventing denervation atrophy and enhancing functional recovery in a mice model of sciatic nerve injury.These results suggest that our plasticine-like NGC has huge prospects for clinical application in the repair of PNI.

Photothermal hydrogel adhesives have yielded promising results for wound closure and infected wound treatment in recent years. However, photothermal hydrogel bioadhesives with on-demand removability without additional nanomaterials-based photothermal agents have rarely been reported in the literature. In this work, an injectable intrinsic photothermal hydrogel bioadhesive with an on-demand removal trait is developed through dynamic cross-linking of gelatin (Gel), tannic acid (TA) quinone, and borax for closing skin incisions and accelerating methicillin-resistant Staphylococcus aureus (MRSA) infected wound healing. The TA quinone containing polyphenol and quinone groups with multifunctional adhesiveness and intrinsic photothermal performance confer the hydrogel adhesive with near-infrared (NIR) responsive antibacterial activity. The cross-linking of pH-sensitive boronic ester (polyphenol-B) and Schiff base bonds endow the hydrogel with great self-healing capacity and on-demand removability. Moreover, the hydrogel possesses good biocompatibility, injectability, and hemostasis. The in vivo experiment in a rat cutaneous incision model and full-thickness MRSA-infected wound model indicate that the smart hydrogel can close wounds efficiently and treat infected ones, demonstrating its superiority in noninvasive treatment of cutaneous incisions and enhancing infected full-thickness wound healing.

Characterized by nucleus pulposus (NP) cell senescenceand extracellularmatrix (ECM) degradation, disc degeneration is a common pathologyfor various degenerative spinal disorders. To date, effective treatmentsfor disc degeneration are absent. Here, we found that Glutaredoxin3(GLRX3) is an important redox-regulating molecule associated withNP cell senescence and disc degeneration. Using a hypoxic preconditioningmethod, we developed GLRX3(+) mesenchymal stem cell-derivedextracellular vehicles (EVs-GLRX3), which enhanced the cellular antioxidantdefense, thus preventing reactive oxygen species (ROS) accumulationand senescence cascade expansion in vitro. Further,a disc tissue-like biopolymer-based supramolecular hydrogel, whichwas injectable, degradable, and ROS-responsive, was proposed to deliverEVs-GLRX3 for treating disc degeneration. Using a rat model of discdegeneration, we demonstrated that the EVs-GLRX3-loaded hydrogel attenuatedmitochondrial damage, alleviated the NP senescence state, and restoredECM deposition by modulating the redox homeostasis. Our findings suggestedthat modulation of redox homeostasis in the disc can rejuvenate NPcell senescence and thus attenuate disc degeneration.

At present, surgical debridement and systematic administration of antibiotics represent the mainstay of treatment for chronic osteomyelitis. However, it is now understood that Staphylococcus aureus (S. aureus) can survive within excessively polarized M2 macrophages and evade antibiotics, accounting for the high recurrence of chronic osteomyelitis. Effective treatments for intracellular infection have rarely been reported. Herein, we designed an in situ sprayed liposomes hydrogels spray with macrophage-targeted effects and the ability to reverse polarization and eradicate intracellular bacteria to reduce the recurrence of osteomyelitis. Resiquimod (R848)-loaded and phosphatidylserine (PS)-coating nanoliposomes were introduced into fibrinogen and thrombin to form the PSL-R848@Fibrin spray. Characterization and phagocytosis experiments were performed to confirm the successful preparation of the PSL-R848@Fibrin spray. Meanwhile, in vitro cell experiments validated its ability to eliminate intracellular S. aureus by reprogramming macrophages from the M2 to the M1 phenotype. Additionally, we established a chronic osteomyelitis rat model to simulate the treatment and recurrence process. Histological analysis demonstrated a significant increase in M1 macrophages and the elimination of intracellular bacteria. Imaging revealed a significant decrease in osteomyelitis recurrence. Overall, the liposome hydrogels could target macrophages to promote antibacterial properties against intracellular infection and reduce the recurrence of chronic osteomyelitis, providing the foothold for improving the outcomes of this patient population. STATEMENT OF SIGNIFICANCE: Chronic osteomyelitis remains a high recurrence although undergoing traditional treatment of debridement and antibiotics. S. aureus can survive within the excessively polarized M2 macrophages to evade the effects of antibiotics. However, few studies have sought to investigate effective intracellular bacteria eradication. Herein, we designed a macrophage-targeted R848-containing liposomes fibrin hydrogels spray (PSL-R848@Fibrin) that can reprogram polarization of macrophages and eradicate intracellular bacteria for osteomyelitis treatment. With great properties of rapid gelation, strong adhesion, high flexibility and fit-to-shape capacity, the facile-operated immunotherapeutic in-situ-spray fibrin hydrogels exhibited huge promise of reversing polarization and fighting intracellular infections. Importantly, we revealed a hitherto undocumented treatment strategy for reducing the recurrence of chronic osteomyelitis and potentially improving the prognosis of chronic osteomyelitis patients.

Patients with osteoporotic fractures often require effective fixation and subsequent bone repair. However, currently available materials are often limited functionally, failing to improve this cohort's outcomes. Herein, kaempferol-loaded mesoporous bioactive glass nanoparticles (MBGNs)-doped orthopedic adhesives are prepared to assist osteoporotic fracture fixation and restore dysregulated bone homeostasis, including promoting osteoblast formation while inhibiting osteoclastic bone-resorbing activity to synergistically promote osteoporotic fracture healing. The injectability, reversible adhesiveness and malleable properties endowed the orthopedic adhesives with high flexibility and hemostatic performance to adapt to complex clinical scenarios. Moreover, Ca2+ and SiO4 4- ions released from MBGNs can accelerate osteogenesis via the PI3K/AKT pathway, while kaempferol mediated osteoclastogenesis inhibition and can slow down the bone resorption process through NF-κB pathway, which regulated bone regeneration and remodeling. Importantly, implementing the orthopedic adhesive is validated as an effective closed-loop management approach in restoring the dysregulated bone homeostasis of osteoporotic fractures.

Recent breakthroughs in cell transplantation therapy have revealed the promising potential of bone marrow mesenchymal stem cells (BMSCs) for promoting the regeneration of growth plate cartilage injury. However, the high apoptosis rate and the uncertainty of the differentiation direction of cells often lead to poor therapeutic effects. Cells are often grown under three-dimensional (3D) conditions in vivo, and the stiffness and components of the extracellular matrix (ECM) are important regulators of stem cell differentiation. To this end, a 3D cartilage-like ECM hydrogel with tunable mechanical properties was designed and synthesized mainly from gelatin methacrylate (GM) and oxidized chondroitin sulfate (OCS) via dynamic Schiff base bonding under UV. The effects of scaffold stiffness and composition on the survival and differentiation of BMSCs in vitro were investigated. A rat model of growth plate injury was developed to validate the effect of the GMOCS hydrogels encapsulated with BMSCs on the repair of growth plate injury. The results showed that 3D GMOCS hydrogels with an appropriate modulus significantly promoted chondrogenic differentiation of BMSCs, and GMOCS/BMSC transplantation could effectively inhibit bone bridge formation and promote the repair of damaged growth plates. Accordingly, GMOCS/BMSC therapy can be engineered as a promising therapeutic candidate for growth plate injury.