Infectious bone and soft tissue defects caused by multidrug-resistant bacteria (MDRB) represent infrequent yet challenging medical conditions. Vascularized fibular grafting constitutes a crucial treatment modality in limb reconstruction procedures, offering improved recovery by supplying nutrients and structural support, particularly in large defects and compromised vascularity. The present study assessed the long-term outcomes of flow-through fibula osteocutaneous flaps for reconstructing multidrug-resistant infected bone and soft tissue defects. Between January 2015 and January 2019, 39 patients with bone and soft tissue defects of the lower leg secondary to multidrug-resistant osteomyelitis were enrolled in this study. The study cohort comprised 23 male and 16 female participants, with a mean age of 45.33 ± 10.93 years. All limbs underwent multiple debridement procedures and were subsequently reconstructed using a flow-through fibula osteocutaneous flap combined with an external locking plate. Clinical and radiological outcomes, including flap survival, bone graft bridging, nonunion, infection recurrence, re-fracture and tibialization of the fibula, were evaluated and recorded over a minimum follow-up period of 5 years (ranging from 5 to 10 years). At the final follow-up, limb function was assessed using the Lower Extremity Functional Scale (LEFS). All the flow-through fibula osteocutaneous flaps survived well. The flow-through flap components measured a mean length of 11.72 ± 2.84 cm (95

Electrical stimulation effectively promotes nerve regeneration and functional recovery, but its clinical application faces challenges such as energy supply limitations, long-term stability issues, and implantation safety concerns. Inspired by the bioelectrogenic mechanism of electric eels, this study developed an electric-eel-inspired ionogel battery (EE-iHB) using chitosan (CS), chondroitin sulfate (CSA), and hydroxyethyl cellulose (HEC). The battery exhibits not only excellent biocompatibility but also outstanding ionic conductivity. By mimicking the intricate multilayer structure of electric eel electrocytes and employing a layer-by-layer self-assembly technique, synergistic optimization of mechanical properties and electrical conductivity was achieved in the nerve conduit. In vitro experiments confirmed the stable and continuous generation of bioelectrical signals. In vivo studies using a rat sciatic nerve injury model demonstrated that the experimental group implanted with this novel conduit showed superior nerve regeneration speed and functional recovery compared to conventional nerve conduits. Histological and electrophysiological analyses further verified that the weak current generated by the battery effectively activation of Schwann cells, guides orderly axonal growth, and promotes myelination. The use of flexible gel materials ensures seamless integration with neural tissues, guaranteeing both safety and long-term reliability in neural repair applications.

Fat embolism syndrome (FES) is a serious complication following bone fracture, primarily resulting from the release of fat microparticles into circulation. Its diagnosis remains challenging due to the absence of specific imaging techniques and laboratory tests. Near-infrared II (NIR-II, 1000-1700 nm) fluorescence imaging (FI) has gained significant attention owing to its high tissue penetration and low background signal. While FI has been widely employed in basic research and clinical practice, its application in FES has not been explored. In this study, a NIR-II organic fluorescent small molecule, FD-1080-C6, which exhibits fat affinity and viscosity responsiveness, is designed to enable FES diagnosis, for the first time. In the high-viscosity microenvironment of FES, the lipophilic molecule FD-1080-C6, which possesses a donor-acceptor-donor (D-A-D) structure, undergoes restricted single-bond rotation, promoting the formation of a rigid planar conformation and resulting in enhanced fluorescence intensity. In vitro evaluation confirms its responsiveness to lipid droplets, affinity for adipose tissue, and viscosity-dependent fluorescence changes. Furthermore, its specificity for NIR-II FI of FES is validated in the mouse. Additionally, FD-1080-C6 exhibits stable photothermal properties. FD-1080-C6 enables early diagnosis and longitudinal monitoring of disease progression in FES mice, offering a promising strategy for the management of FES.

Dysregulated osteoclast activity underlies pathological bone resorption in skeletal metastases and metabolic bone disorders such as diabetes, yet effective therapeutic strategies remain scarce. Here, we present a mesenchymal stem cell (MSC)-based cellular backpack platform for metabolism-guided and bone-targeted therapy. This biohybrid system couples MSCs with lipid-coated, biotin-streptavidin-linked nanoparticles that encapsulate the phosphoglycerate dehydrogenase (PHGDH) inhibitor NCT503 and are enriched with calcium via biomineralization. Driven by CXCR4-mediated MSC homing, the cellular backpacks selectively localize to osteoclast- and tumor-rich bone microenvironments. NCT503 inhibits the serine synthesis pathway, suppressing NFATc1-dependent osteoclastogenesis and tumor progression, while calcium ions disrupt the reciprocal metabolic coupling between osteoclasts and cancer cells. Simultaneously, calcium enrichment enhances MSC chemotaxis, migration, and osteogenic differentiation, enabling precise delivery and bone regeneration. In murine models of bone metastasis and diabetic fracture, this strategy mitigates osteolysis, restrains tumor growth, and accelerates skeletal repair. Collectively, this study introduces a multifunctional, cell-guided therapeutic platform that synergistically integrates metabolic intervention, osteoclast-tumor modulation, and regenerative repair, offering a promising avenue for the treatment of dysregulated bone diseases.

Clinical treatments for bone defects including autologous and allogeneic bone grafting are limited by donor shortages, inadequate osteo-inductive potential, and persistent inflammation. General strategies are constrained by few focus on graft-free repair and the role of osteoimmune modulation. Herein, a direct-current triboelectric nanogenerator (DC-TENG) based "triboelectric immunotherapy" is established to provide direct osteo-inductive effects and indirect osteoimmune reprogramming by mimicking bioelectronic signaling in the complex microenvironmental regenerative cues with electrical stimulation (ES). By coupling triboelectric charging with electrostatic breakdown effects, DC-TENG achieve efficient energy conversion through thin-layer electrodes to produce high-density, stable outward microcurrents (12-15 mu A), which directly activate TRPV4 ion channels to initiate osteogenic differentiation while simultaneously reprogramming macrophages toward a pro-regenerative M2 phenotype to drive osteo-immune modulation. As a result, robust bone regeneration was achieved in a rat calvarial defect model. Collectively, these findings demonstrate a controllable and biocompatible graft-free strategy that integrates both osteo-inductive and osteo-immune reprogramming capabilities, predicting a promising clinical translational alternative for the repair of bone defects.

Objective:Vascularized fibular bone grafts are an efficient method for repairing various segmental bone defects. The objective of this report is to introduce our experience with folded free vascularized fibular bone grafts for segmental femoral bone defects. Patients and methods:Clinical data collected by surgeons and the Hospital Information System (HIS) were screened. Cases with segmental femoral bone defects repaired by folded free vascularized fibular bone grafts were collected. Clinical data, including demographic characteristics, defect size, coinfection, perioperative treatment and imaging data during follow-up, were collected for analysis. Results:Twelve patients (10 males and 2 females), aged from 6 to 58, were included in this report. The defect range was 3-10 cm, with an average of 6.2 cm. Three cases were complicated with infection, and the others were not. Folded free vascularized fibular bone grafts were harvested for the reconstruction of segmental femoral bone defects. The grafts were fixed with plates in 9 cases and external fixators in 3 cases. All grafts healed uneventfully with an average healing time of 5.2 months (range 4∼8 months). Internal fixation failure occurred in one case. The follow-up time ranged from 15 to 130 months (average 58.3 months). Conclusion:Folded free fibula grafts are one of the optional methods for segmental bone defects of the femur. Through this method, patients can undergo a one-time operation to reconstruct the bone defect of the affected limb.

MRSA associated infections in skeletal and soft tissues remain formidable clinical issues with limited treatments, due to antibiotic resistance, biofilm formation and pathological hypoxia. Herein, yolk-shell nanoplatform (BMP@M) is developed for targeted mild photothermal-triggered cascade gas therapy against MRSA infections. BMP@M features a polydopamine photothermal yolk and mesoporous MnO2 shell loaded with NO donor (BNN6), enabling spatially separated heat generation and cascade NO release via gradual photothermal conduction. Macrophages are preactivated with MRSA membrane vesicles (MVs) to obtain engineered macrophage MVs with elevated Toll-like receptor 2, endowing BMP@M with MRSA-specific targeting and infectious lesion-targeting ability. The photothermal effect of BMP@M further promotes injectable thermosensitive chitosan to form tissue repair matrix (BMP@M/C). The synergistic photothermal-gas therapy effectively eradicates MRSA and disrupts biofilms. Moreover, the MnO2 shell in situ decomposes pathological H2O2 into O2, alleviating hypoxia. The coordinated release of NO and O2 restores mitochondrial function, scavenges ROS, suppresses NF-κB/NLRP3 inflammatory axis, and drives M2 polarization. In models of MRSA-induced osteomyelitis and full-thickness skin defects, BMP@M/C achieves effective infection control, anti-inflammatory, osteogenesis and angiogenesis effects. This study offers a combined antibacterial, immunomodulatory, and regenerative approach for infected tissue repair.

Effective tissue regeneration remains challenging due to persistent inflammation, insufficient angiogenesis, and impaired neuroregeneration, particularly in complex wounds such as diabetic ulcers. Although multifunctional biomaterials have shown therapeutic potential, their structural complexity often limits clinical translation, highlighting the need for simpler yet highly effective systems. Herein, we develop a chitosan-based hydrogel derived from selenolipoic acid modified chitosan (SeAMC). In contrast to conventional octenoic acid modified chitosan (OAMC) and lipoic acid modified chitosan (LAMC), the SeAMC hydrogel exhibits markedly faster gelation under UV irradiation (within 3 s) and, notably, enables efficient photocrosslinking under 495 nm blue-green light as well as natural white light, thereby substantially broadening the applicable photochemical window. The SeAMC hydrogel effectively alleviates inflammation while promoting angiogenesis and neuroregeneration, thereby facilitating wound closure and tissue regeneration in diabetic wounds. Owing to its simple composition, good photocuring performance, and integrated biofunctionality, SeAMC represents a clinically translatable strategy for high-performance tissue repair.

Due to the complex regenerative microenvironment, peripheral nerve repair poses significant challenges in clinical treatment. Severe injuries can lead to dysregulated iron homeostasis, and excessive iron produces reactive oxygen species (ROS) through the Fenton reaction. The subsequent oxidative stress further leads to mitochondrial and endoplasmic reticulum (ER) stress, which impedes nerve regeneration. In addition, insufficient vascular remodeling also limits the repair of damaged nerves. Herein, a poly(citric acid) (PCA)-loaded gelatin-lipoic acid (Gel-LA) microgel hydrogel-filled oriented electrospun fiber conduit was developed, which guides axonal alignment by topographical cues, promotes cellular infiltration and nutrient transport through a microgel cascade pore structure, and regulates the regenerative microenvironment via the ferrous ion (Fe 2+ ) chelation effect of PCA. The results demonstrate that this conduit effectively reduces the levels of Fe 2+ at the injury site, thereby alleviating mitochondrial and ER stress while promoting energy metabolism, vascular reconstruction, and nerve regeneration. This study highlights the potential of PCA in modulating the microenvironment of nerve injuries and provides new insights for developing tissue-engineered scaffolds.

Diabetic osteomyelitis, exacerbated by a hyperglycemic microenvironment, leads to increased bacterial infections and bone tissue destruction, raising the risk of amputation. Current antibiotic therapies are limited in effectiveness due to rising antibiotic resistance and biofilm barrier. In response, we developed a microgel-based hydrogel system that delivers H2Se gas combined with mild photothermal therapy (MPTT) to achieve integrated treatment for infection control, anti-inflammation, and osteogenesis. This system utilizes Fe3O4 nanoparticles as photothermal-responsive carriers to encapsulate the H2Se donor TDN1042, which is constructed into lipoic acid-modified gelatin (Gel-LA) microgels using microfluidic technology. Upon in situ injection, photocrosslink forms the TF@GL hydrogel that enables triple modulation under 808 nm NIR. First, MPTT promotes H2Se release, disrupting bacterial metabolic homeostasis and lysing biofilms. Second, H2Se scavenges excess reactive oxygen species (ROS) to alleviate cell death, simultaneously inhibiting inflammation pathways (NF-κB and NLR). Lastly, the TF@GL hydrogel promotes osteogenic differentiation by activating the TGF-β/BMP osteogenic pathway, and the porous structure enhances cell migration and nutrient diffusion, accelerating bone repair. This design provides a comprehensive therapeutic strategy for diabetic osteomyelitis through the spatiotemporal synergy of gas delivery and controlled photothermal effects, offering effective antibacterial activity, oxidative stress alleviation, and bone regeneration induction.

ABSTRACT In this paper, we develop a photothermal‐responsive hydrogel (CNB‐ePRP) based on engineered platelet‐rich plasma (PRP)/sodium alginate (SA) hydrogel integrating thrombin‐functionalized composite nanobottle (CNB) to treat diabetic wounds. Within CNB‐ePRP, the CNB consists of polydopamine nanobottle loaded with thrombin, personalized drugs and a phase‐change material. As a photothermal agent and dual‐stage controller, CNB not only enables in situ PRP activation at physiological temperature to slowly release various growth factors (GFs) via thermal‐triggered thrombin release, avoiding premature burst release of GFs, but also accelerates the release of GFs from the CNB‐ePRP hydrogel through mild photothermal heating under 808 nm laser irradiation. Meanwhile, SA enhances hydrogel stability and prolongs GF release kinetics. Consequently, CNB‐ePRP achieves on‐demand delivery of GFs, significantly promoting angiogenesis, cell proliferation and M2 macrophage polarization. Moreover, CNB‐ePRP can mitigate oxidative stress via the antioxidant activity of CNB. Furthermore, vancomycin is loaded into CNB to construct a multimodal antimicrobial hydrogel (VCNB‐ePRP) that combines antibiotic and photothermal therapy to efficiently eradicate MRSA and promote healing in MRSA‐infected diabetic mouse wounds. Collectively, this study offers a smart PRP‐derived platform, characterized by in situ PRP activation, on‐demand GFs release, personalized antimicrobial loading and multifunctional therapy, for managing diabetic wounds with great translational potential.

Age-related bone defects remain poorly repaired due to a vicious cycle involving senescent bone marrow mesenchymal stem cells (BMSCs) and pro-inflammatory macrophages. We unveil circadian disruption as the underlying driver via single-cell transcriptomics and propose an "internal clock-repairing, external immunity-reprogramming" strategy. Inspired by cardiac pacemakers that sense signals and rectify rhythms, we engineer nanocellular pacemakers (AMC) with a "sense-release-regulate" paradigm for aged bone regeneration. AMC comprises melatonin-loaded, cobalt-based metal-organic frameworks (MOF) coated with membrane vesicles derived from the new generation of probiotic Akkermansia muciniphila. The cobalt-based MOF functions as an artificial sensor that specifically senses senescence-associated signals to release melatonin in the senescent microenvironment. The targeted delivery of melatonin repairs the internal clock and rejuvenates BMSCs by precisely regulating circadian rhythms to inhibit p53 and TNF signaling pathways. While probiotic membrane on AMC actively reprograms macrophages toward a pro-regenerative M2 phenotype in the senescent niche. To enable minimally invasive delivery, a dual-network hydrogel with reactive oxygen species-responsive boronic ester bonds is developed for spatiotemporal release of AMC. In aged mice, this cascade-responsive therapeutic system fully repairs bone defects within 4 weeks by breaking the senescence-inflammation vicious cycle, offering a novel "cellular pacing" paradigm for age-related tissue repair.

Sonodynamic therapy (SDT) is a promising cancer treatment known for its deep tumor penetration and high efficacy. However, developing highly efficient sonosensitizers remains a significant challenge. Reports on SDT using aggregation-induced emission luminogens (AIEgens) are rare, highlighting the urgent need for novel AIE-active sonosensitizers. For the first time, we have developed tumor- and macrophage-targeting nano micelles, AIE/Biotin/Mannose-M (ABM-M), utilizing aggregation-induced emission polymers. The ABM-M mediate immunogenic cell death through SDT. By reprogramming tumor-associated macrophages (TAMs), they promote the conversion of M2 macrophages into M1 macrophages, reversing the tumor's immunosuppressive environment. We optimized the ratio of functional molecules to achieve maximum fluorescence intensity and reactive oxygen species (ROS) generation. The multi-targeting nature of ABM-M enables them to bind to relevant antibodies or other molecules, enhancing the capture and presentation of tumor antigens. This, in turn, activates the immune responses of dendritic cells and T cells while inhibiting angiogenesis, creating a more favorable microenvironment for antitumor therapy. Furthermore, ABM-M can be combined with immune checkpoint inhibitors, such as anti-PD-L1 antibodies, to achieve promising outcomes in cancer immunotherapy. The ABM-M nanomaterials offer multi-layered and multi-targeting immune regulation. This study provides a blueprint for developing next-generation cancer diagnostic and therapeutic strategies. Statement of Significance Our research pioneers the use of nanomicelles to simultaneously target both tumor cells and tumor-associated macrophages (TAMs), integrated with sonodynamic therapy. Through precise ratio adjustments, we engineered nanomicelles capable of multi-target regulation. These micelles uniquely induce immunogenic cell death (ICD) and repolarize macrophages from an immunosuppressive M2 phenotype to an immunostimulatory M1 phenotype, reversing the tumor's immunosuppressive microenvironment. This dual mechanism can be enhanced by combining with immune checkpoint inhibitors, such as anti-PD-L1 antibodies, offering a promising strategy to treat refractory cancers. Extensive in vitro and in vivo validation confirms their therapeutic potential, providing a solid foundation for clinical application. This innovative approach shows significant promise for revolutionizing cancer treatment and improving patient outcomes.

Following peripheral nerve injury (PNI), the early inflammatory response induces excessive production of reactive oxygen species (ROS), resulting in severe damage to the regenerative microenvironment, which poses a huge challenge to the autonomous regeneration of nerves. Exogenous nerve grafts are often needed to assist and guide nerve regeneration. In recent years, nerve conduits (NGCs) with directional structures and favorable bioactivity have made significant progress, but single-function scaffolds still cannot meet the multiple needs of reconstructing an ideal regenerative microenvironment. In this study, a construction strategy for hydrogen-releasing electroactive nerve conduit scaffolds was proposed. The system uses poly(3S-methylmorpholine-2,5-dione-co-ε-caprolactone) [P(MMD-CL)] conduits coated with helically wound metal magnesium wires as a source of gaseous transmitters that continuously release hydrogen. Under the action of an external alternating magnetic field, the magnesium wire coil can form a closed loop and generate weak electrical stimulation (ES). The conduit is further filled with photo-crosslinked lipoic acid-gelatin (Gel-LA) microgels to synergistically regulate cell behavior and assist tissue regeneration. In vitro studies have shown that the system exhibits multiple biological effects, including reducing ROS levels, regulating inflammatory responses, promoting angiogenesis, and maintaining mitochondrial function, reflecting the potential roles of H2, ES, and Mg2+ in regulating the regenerative microenvironment. In vivo, the establishment of a 15 mm sciatic nerve defect model further verified the significant efficacy of the H2 delivery system in promoting nerve morphology and functional recovery. In summary, this study constructed a multifunctional nerve conduit scaffold with gaseous transmitter delivery, electrical activity regulation, and injectable microgel filling, which provides a new therapeutic idea for improving the post-injury microenvironment and promoting peripheral nerve regeneration, and provides an experimental basis for gas molecule-guided nerve repair strategies.

The multi-territory perforator flap is a widely used microsurgical technique for repairing skin and tissue defects in diabetes. In the diabetic microenvironment, oxidative stress and inflammation from reactive oxygen species (ROS) lead to compromised blood supply to the flap, resulting in challenges for survival. The common complication of multi-territory perforator flap is distal necrosis, which is primarily attributed to the Choke zone, the critical location characterized by delayed blood supply and inadequate neovascularization. To address this issue, a ROS-responsive MSL@Z/G hydrogel is developed by encapsulating metformin-Sr-L-Arg@ZIF-90 (MSL@Z) nanoparticles into gelatine methacrylamide (GelMA), enabling the release of metformin, Sr ions and NO. The enhanced deformation resistance and compressive strength properties of the MSL@Z/G hydrogel make it suitable for tissue reconstruction and drug delivery. Additionally, the MSL@Z/G hydrogel exhibits antioxidant and anti-inflammatory effects, thereby modulating the vascular microenvironment. In the dorsal multi-territory perforated flap model of type 2 diabetic rats, the MSL@Z/G hydrogel demonstrates the ability to alleviate inflammation and promote neovascularization of the Choke zone, reducing distal necrosis, which holds great promise for improving flap survival in diabetes.

BackgroundIt is controversial whether the collateral ligaments should be repaired primarily for capitellum fractures with ligamentous injury. This research was conducted to summarize the current evidence for this issue.MethodsDatabases, including Medline, Cochrane library and EMBASE, were searched from their establishment to December 31, 2024 for clinical articles on capitellum fractures. The reference lists of the relevant studies were also checked successively. The general information including first author, publication time, location, the number of cases, treatment for the capitellum fractures with collateral ligament injury, were included. Outcomes, including the pronation and supination of the elbow, active range of motion, Mayo elbow performance score, elbow instability and complications, were extracted.ResultsFifteen studies and 220 patients were identified and analyzed. The average follow-up time ranged from 1.5 to 17 years. The fractures were managed by open reduction and internal fixation. Medial collateral ligaments (MCL) injury was reported in 4 of the 15 included reports. Among the 97 patients, 17 (17.5%) patients suffered capitellum fracture with MCL injury. For the treatment of MCL injury, the literature reports were inconsistent. Nine studies with 159 patients reported the treatment for the lateral collateral ligaments (LCL) injury. Fifty-six cases were complicated with LCL injury, of which 41 cases were primary injury and 15 LCL were released to enhance exposure. All LCL injuries were repaired primarily.ConclusionFor capitellum fractures with ligament injuries, primary repair of LCL should be performed when combined by LCL injury or LUCL release is performed during surgery. The MCL may require primary reconstruction or treatment in a hinged brace.

Featuring bacterial invasion and colonization within cells, chronic infection-induced immune suppression, and inflammatory cell infiltration, osteomyelitis is currently an intractable and recurrent bone disease. In this study, an injectable hydrogel that gels in situ and is loaded with engineered antimicrobial cells (LL37-MSC@OCAHM) is developed. This anti-inflammatory hydrogel not only maintains cell activity in the inflammatory environment but also releases magnesium ions (Mg2+) to promote the differentiation of MSCs into bone-forming cells, contributing to bone mass formation, enhancing bone repair, and accelerating bone healing. The engineered cells continuously produce antimicrobial peptides of LL37, which effectively kill both extracellular and intracellular bacteria at the osteomyelitis site. Additionally, cell hydrogel also modulates the immune response by shifting the osteomyelitis environment from pro-inflammatory to anti-inflammatory, reducing the infiltration of immune cells and myeloid-derived suppressor cells (MDSCs). We also demonstrated its ability to activate immune responses and generate immune memory, thereby preventing the recurrence of secondary infections. This study introduces an engineered cell-based approach that combines active antimicrobial effect, immune modulation, and bone repair, for effectively eliminating osteomyelitis infections and preventing recurrence.

Background:Fracture healing can be delayed or impaired in individuals with abnormal conditions, including Type 2 Diabetes Mellitus (T2DM). Mesenchymal stem cells (MSCs) are critical to the process of fracture healing and are found to be impaired in T2DM. Although some research has been conducted to address this, the specific mechanisms remain poorly understood and warrant further exploration. Methods:We downloaded transcriptomic and single-cell RNA sequencing (scRNA-seq) data, performed multiple analyses (differential expression, ssGSEA, co-expression, GO, KEGG, GSEA, and cell clustering identification), and utilized tools (GeneMINIA and Metascape) to investigate alterations in MSCs under diabetic condition. Further validation and exploration were carried out through in vitro experiments (cell transduction, flow cytometry, ALP staining, ARS, qPCR, and Western blotting) and in vivo experiments (micro-CT, histological staining, and immunohistochemistry). Results:Our study identified differentially expressed genes from fracture healing and non-union cases in human samples, suggesting abnormal immune infiltration and disrupted biological processes. ScRNA-seq analysis further revealed significant alterations in MSCs under diabetic conditions with enriched pathways, including MAPK, TGF-β, and P53 signaling pathways. Integrating with transcriptomic analysis, we identified Rbms3, which was significantly upregulated in diabetic MSCs and further validated in bone samples from patients at our institution. The upregulation of Rbms3 impaired fracture healing by modulating the MAPK signaling pathway, leading to reduced MSC osteogenic differentiation in vitro and impaired bone regeneration in vivo. Conclusion:The upregulation of Rbms3 in MSCs under diabetic conditions contributes to impaired fracture healing by modulating the MAPK signaling pathway.