Bioactive nanocomposite hydrogel enhances postoperative immunotherapy and bone reconstruction for osteosarcoma treatment.

Osteosarcoma, a malignant bone tumor often characterized by high hedgehog signaling activity, residual tumor cells, and substantial bone defects, poses significant challenges to both treatment response and postsurgical recovery. Here, we developed a nanocomposite hydrogel for the sustained co-delivery of bioactive magnesium ions, anti-PD-L1 antibody (αPD-L1), and hedgehog pathway antagonist vismodegib, to eradicate residual tumor cells while promoting bone regeneration post-surgery. In a mouse model of tibia osteosarcoma, this hydrogel-mediated combination therapy led to remarkable tumor growth inhibition and hence increased animal survival by enhancing the activity of tumor-suppressed CD8+ T cells. Meanwhile, the implanted hydrogel improved the microenvironment of osteogenesis through long-term sustained release of Mg2+, facilitating bone defect repair by upregulating the expression of osteogenic genes. After 21 days, the expression levels of ALP, COL1, RUNX2, and BGLAP in the Vis-αPD-L1-Gel group were approximately 4.1, 5.1, 5.5, and 3.4 times higher than those of the control, respectively. We believe that this hydrogel-based combination therapy offers a potentially valuable strategy for treating osteosarcoma and addressing the tumor-related complex bone diseases.

Genetic polymorphisms, biomarkers and signaling pathways associated with septic shock: from diagnosis to therapeutic targets.

Septic shock is a severe form of sepsis characterized by high global mortality rates and significant heritability. Clinicians have long been perplexed by the differential expression of genes, which poses challenges for early diagnosis and prompt treatment of septic shock. Genetic polymorphisms play crucial roles in determining susceptibility to, mortality from, and the prognosis of septic shock. Research indicates that pathogenic genes are known to cause septic shock through specific alleles, and protective genes have been shown to confer beneficial effects on affected individuals. Despite the existence of many biomarkers linked to septic shock, their clinical use remains limited. Therefore, further investigation is needed to identify specific biomarkers that can facilitate early prevention, diagnosis and risk stratification. Septic shock is closely associated with multiple signaling pathways, including the toll-like receptor 2/toll-like receptor 4, tumor necrosis factor-α, phosphatidylinositol 3-kinase/protein kinase B, mitogen-activated protein kinase, nuclear factor κB, Janus kinase/signal transducer and activator of transcription, mammalian target of rapamycin, NOD-like receptor thermal protein domain-associated protein 3 and hypoxia-induced-factor-1 pathways. Understanding the regulation of these signaling pathways may lead to the identification of therapeutic targets for the development of novel drugs to treat sepsis or septic shock. In conclusion, identifying differential gene expression during the development of septic shock allows physicians to stratify patients according to risk at an early stage. Furthermore, auxiliary examinations can assist physicians in identifying therapeutic targets within relevant signaling pathways, facilitating early diagnosis and treatment, reducing mortality and improving the prognosis of septic shock patients. Although there has been significant progress in studying the genetic polymorphisms, specific biomarkers and signaling pathways involved in septic shock, the journey toward their clinical application and widespread implementation still lies ahead.

[Research on Locating Device for the Entry Point of Intramedullary Nail Based on Inertial Navigation].

Objective: To introduce a locating device for the entry point of intramedullary nail based on the inertial navigation technology, which utilizes multi-dimensional angle information to assist in rapid and accurate positioning of the ideal direction of femoral anterograde intramedullary nails' entry point, and to verify its clinical value through clinical tests. Methods: After matching the locating module with the developing board, which are the two components of the locating device, they were placed on the skin surface of the proximal femur of the affected side. Anteroposterior fluoroscopy was performed. The developing angle corresponding to the ideal direction of entry point was selected based on the X-ray image, and then the yaw angle of the locating module was reset to zero. After resetting, the locating module was combined with the surgical instrument to guide the insertion angle of the guide wire. The ideal direction of entry point was accurately located based on the angle guidance. By setting up an experimental group and a control group for clinical surgical operations, the number of guide wire insertion times, surgical time, fluoroscopy frequency, and intraoperative blood loss with or without the locating device was recorded. Results: Compared to the control group, the experimental group showed significant improvement in the number of guide wire insertion times, surgical time, fluoroscopy frequency, and intraoperative blood loss, with a statistically significant difference (P<0.01). Conclusion: The locating device can assist doctors in quickly locating the entry point of intramedullary nail, effectively reducing the fluoroscopy frequency and surgical time by improving the success rate of the guide wire insertion with one shot, improving surgical efficiency, and possessing certain clinical value.

A distinct "repair" role of regulatory T cells in fracture healing.

Regulatory T cells (Tregs) suppress immune responses and inflammation. Here, we described the distinct nonimmunological role of Tregs in fracture healing. The recruitment from the circulation pool, peripheral induction, and local expansion rapidly enriched Tregs in the injured bone. The Tregs in the injured bone displayed superiority in direct osteogenesis over Tregs from lymphoid organs. Punctual depletion of Tregs compromised the fracture healing process, which leads to increased bone nonunion. In addition, bone callus Tregs showed unique T-cell receptor repertoires. Amphiregulin was the most overexpressed protein in bone callus Tregs, and it can directly facilitate the proliferation and differentiation of osteogenic precursor cells by activation of phosphatidylinositol 3-kinase/protein kinase B signaling pathways. The results of loss- and gain-function studies further evidenced that amphiregulin can reverse the compromised healing caused by Treg dysfunction. Tregs also enriched in patient bone callus and amphiregulin can promote the osteogenesis of human pre-osteoblastic cells. Our findings indicate the distinct and nonredundant role of Tregs in fracture healing, which will provide a new therapeutic target and strategy in the clinical treatment of fractures.

Macrophage-mediated fracture healing: Unraveling molecular mechanisms and therapeutic implications using hydrogel-based interventions.

Fracture healing is a complex biological process that involves the orchestrated interplay of various cells and molecular signaling pathways. Among the key players, macrophages have emerged as critical regulators of fracture repair, influencing inflammation, tissue remodeling, and angiogenesis. Recent advances in hydrogel-based therapeutics have provided exciting opportunities to leverage the modulatory effects of macrophages for improving fracture healing outcomes. In the present study, we review the importance of macrophages in fracture repair and their potential therapeutic role in hydrogel-based interventions. We discuss the molecular mechanisms underlying macrophage-mediated effects on fracture healing, and how hydrogels can be utilized as a platform for macrophage modulation. Furthermore, we highlight the translation of hydrogel-based therapies from bench to bedside, including preclinical and clinical studies, and the challenges and opportunities in harnessing the therapeutic potential of macrophages in fracture repair. Overall, understanding the importance of macrophages in fracture healing and the potential of hydrogel-based therapeutics to modulate macrophage responses can pave the way for developing innovative approaches to improve fracture healing outcomes.

Phototherapy techniques for the management of musculoskeletal disorders: strategies and recent advances.

Musculoskeletal disorders (MSDs), which include a range of pathologies affecting bones, cartilage, muscles, tendons, and ligaments, account for a significant portion of the global burden of disease. While pharmaceutical and surgical interventions represent conventional approaches for treating MSDs, their efficacy is constrained and frequently accompanied by adverse reactions. Considering the rising incidence of MSDs, there is an urgent demand for effective treatment modalities to alter the current landscape. Phototherapy, as a controllable and non-invasive technique, has been shown to directly regulate bone, cartilage, and muscle regeneration by modulating cellular behavior. Moreover, phototherapy presents controlled ablation of tumor cells, bacteria, and aberrantly activated inflammatory cells, demonstrating therapeutic potential in conditions such as bone tumors, bone infection, and arthritis. By constructing light-responsive nanosystems, controlled drug delivery can be achieved to enable precise treatment of MSDs. Notably, various phototherapy nanoplatforms with integrated imaging capabilities have been utilized for early diagnosis, guided therapy, and prognostic assessment of MSDs, further improving the management of these disorders. This review provides a comprehensive overview of the strategies and recent advances in the application of phototherapy for the treatment of MSDs, discusses the challenges and prospects of phototherapy, and aims to promote further research and application of phototherapy techniques.

Predicting overall survival in chordoma patients using machine learning models: a web-app application.

OBJECTIVE: The goal of this study was to evaluate the efficacy of machine learning (ML) techniques in predicting survival for chordoma patients in comparison with the standard Cox proportional hazards (CoxPH) model. METHODS: Using a Surveillance, Epidemiology, and End Results database of consecutive newly diagnosed chordoma cases between January 2000 and December 2018, we created and validated three ML survival models as well as a traditional CoxPH model in this population-based cohort study. Randomly, the dataset was divided into training and validation datasets. Tuning hyperparameters on the training dataset involved a 1000-iteration random search with fivefold cross-validation. Concordance index (C-index), Brier score, and integrated Brier score were used to evaluate the performance of the model. The receiver operating characteristic (ROC) curves, calibration curves, and area under the ROC curves (AUC) were used to assess the reliability of the models by predicting 5- and 10-year survival probabilities. RESULTS: A total of 724 chordoma patients were divided into training (n = 508) and validation (n = 216) cohorts. Cox regression identified nine significant prognostic factors (p < 0.05). ML models showed superior performance over CoxPH model, with DeepSurv having the highest C-index (0.795) and the best discrimination for 5- and 10-year survival (AUC 0.84 and 0.88). Calibration curves revealed strong correlation between DeepSurv predictions and actual survival. Risk stratification by DeepSurv model effectively discriminated high- and low-risk groups (p < 0.01). The optimized DeepSurv model was implemented into a web application for clinical use that can be found at https://hust-chengp-ml-chordoma-app-19rjyr.streamlitapp.com/ . CONCLUSION: ML algorithms based on time-to-event results are effective in chordoma prediction, with DeepSurv having the best discrimination performance and calibration.

Recent advances in carboxymethyl chitosan-based materials for biomedical applications.

Chitosan (CS) and its derivatives have been applied extensively in the biomedical field owing to advantageous characteristics including biodegradability, biocompatibility, antibacterial activity and adhesive properties. The low solubility of CS at physiological pH limits its use in systems requiring higher dissolving ability and a suitable drug release rate. Besides, CS can result in fast drug release because of its high swelling degree and rapid water absorption in aqueous media. As a water-soluble derivative of CS, carboxymethyl chitosan (CMC) has certain improved properties, rendering it a more suitable candidate for wound healing, drug delivery and tissue engineering applications. This review will focus on the antibacterial, anticancer and antitumor, antioxidant and antifungal bioactivities of CMC and the most recently described applications of CMC in wound healing, drug delivery, tissue engineering, bioimaging and cosmetics.

A Whole-Course-Repair System Based on Neurogenesis-Angiogenesis Crosstalk and Macrophage Reprogramming Promotes Diabetic Wound Healing.

Diabetic wound (DW) therapy is currently a big challenge in medicine and strategies to enhance neurogenesis and angiogenesis have appeared to be a promising direction. However, the current treatments have failed to coordinate neurogenesis and angiogenesis simultaneously, leading to an increased disability rate caused by DWs. Herein, a whole-course-repair system is introduced by a hydrogel to concurrently achieve a mutually supportive cycle of neurogenesis-angiogenesis under a favorable immune-microenvironment. This hydrogel can first be one-step packaged in a syringe for later in situ local injections to cover wounds long-termly for accelerated wound healing via the synergistic effect of magnesium ions (Mg2+ ) and engineered small extracellular vesicles (sEVs). The self-healing and bio-adhesive properties of the hydrogel make it an ideal physical barrier for DWs. At the inflammation stage, the formulation can recruit bone marrow-derived mesenchymal stem cells to the wound sites and stimulate them toward neurogenic differentiation, while providing a favorable immune microenvironment via macrophage reprogramming. At the proliferation stage of wound repair, robust angiogenesis occurs by the synergistic effect of the newly differentiated neural cells and the released Mg2+ , allowing a regenerative neurogenesis-angiogenesis cycle to take place at the wound site. This whole-course-repair system provides a novel platform for combined DW therapy.

Dual-Targeted Nanodiscs Revealing the Cross-Talk between Osteogenic Differentiation of Mesenchymal Stem Cells and Macrophages.

Ongoing research has highlighted the significance of the cross-play of macrophages and mesenchymal stem cells (MSCs). Lysine-specific demethylase 6B (KDM6B) has been shown to control osteogenic differentiation of MSCs by depleting trimethylated histone 3 lysine 27 (H3K27me3). However, to date, the role of KDM6B in bone marrow-derived macrophages (BMDMs) remains controversial. Here, a chromatin immunoprecipitation assay (ChIP) proved that KDM6B derived from osteogenic-induced BMSCs could bind to the promoter region of BMDMs' brain and muscle aryl hydrocarbon receptor nuclear translocator-like protein-1 (BMAL1) gene in a coculture system and activate BMAL1. Transcriptome sequencing and experiments in vitro showed that the overexpression of BMAL1 in BMDM could inhibit the TLR2/NF-κB signaling pathway, reduce pyroptosis, and decrease the M1/M2 ratio, thereby promoting osteogenic differentiation of BMSCs. Furthermore, bone and macrophage dual-targeted GSK-J4 (KDM6B inhibitor)-loaded nanodiscs were synthesized via binding SDSSD-apoA-1 peptide analogs (APA) peptide, which indirectly proved the critical role of KDM6B in osteogenesis in vivo. Overall, we demonstrated that KDM6B serves as a positive circulation trigger during osteogenic differentiation by decreasing the ratio of M1/M2 both in vitro and in vivo. Collectively, these results provide insight into basic research in the field of osteoporosis and bone repair.

The clinical efficacy and safety of double reverse traction repositor and traction table in the reduction of unstable intertrochanteric fractures in elderly patients: a retrospective comparative study.

Background: Currently, we found that double reverse traction repositor (DRTR) is a treatment with operation convenience and fast in our clinical work. However, the clinical efficacy and safety of DRTR in the reduction of unstable intertrochanteric fractures in elderly patients remain unknown. Therefore, the study aimed to compare the clinical efficacy and safety of DRTR and traction table (TT) in the reduction of unstable intertrochanteric fractures in elderly patients. Methods: From October 2018 to December 2020, the elderly patients with unstable intertrochanteric fractures were reviewed. 22 patients treated with TT and 20 patients treated with DRTR met the inclusion criteria of this study, and baseline clinical characteristics were recorded. The reduction time, operation time, incision length and intraoperative blood loss were reviewed. The safety outcome was assessed by postoperative complications, and the efficacy outcomes were evaluated by the fracture healing time based on the radiographs conducted at each follow-up (1, 3, 6, 12 months after surgery) and hip function (hip flexion, Harris Hip Score) at the final follow-up (12 months after surgery). Results: There were no significant differences in terms of demographics and fracture characteristics of cases enrolled. In DRTR group, the average intraoperative reduction time [(34.8±7.6) min] and the average operation time [(87.1±12.2) min] were superior to those [(56.6±9.3); (123.1±15.0) min] in TT group (P<0.0001). However, there were no statistical significance in terms of the average incision lengths [(6.4±0.9) vs. (6.8±1.1) cm; P=0.1619], , the average intraoperative blood loss [(152.6±22.9) vs. (146.8±20.7) mL; P=0.3941], the average fracture healing times [(13.8±1.5) vs. (14.4±1.8) weeks; P=0.2350] and the average Harris hip score a year after operation [(84.4±6.6) vs. (82.7±7.2); P=0.4496] between the two groups. One patient in TT group experienced lower extremity intermuscular venous thrombosis postoperatively. No other operation-related complications were observed postoperatively nor during follow-up. Conclusions: Minimally invasive reduction with DRTR in unstable intertrochanteric fractures could effectively shorten the intraoperative reduction time and operation time in this study. Therefore, minimally invasive reduction with DRTR might be a good choice for intertrochanteric reduction of unstable intertrochanteric fractures.

Metformin alleviates bone loss in ovariectomized mice through inhibition of autophagy of osteoclast precursors mediated by E2F1.

BACKGROUND: Postmenopausal bone loss, mainly caused by excessive bone resorption mediated by osteoclasts, has become a global public health burden. Metformin, a hypoglycemic drug, has been reported to have beneficial effects on maintaining bone health. However, the role and underlying mechanism of metformin in ovariectomized (OVX)-induced bone loss is still vague. RESULTS: In this study, we demonstrated for the first time that metformin administration alleviated bone loss in postmenopausal women and ovariectomized mice, based on reduced bone resorption markers, increased bone mineral density (BMD) and improvement of bone microstructure. Then, osteoclast precursors administered metformin in vitro and in vivo were collected to examine the differentiation potential and autophagical level. The mechanism was investigated by infection with lentivirus-mediated BNIP3 or E2F1 overexpression. We observed a dramatical inhibition of autophagosome synthesis and osteoclast formation and activity. Treatment with RAPA, an autophagy activator, abrogated the metformin-mediated autophagy downregulation and inhibition of osteoclastogenesis. Additionally, overexpression of E2F1 demonstrated that reduction of OVX-upregulated autophagy mediated by metformin was E2F1 dependent. Mechanistically, metformin-mediated downregulation of E2F1 in ovariectomized mice could downregulate BECN1 and BNIP3 levels, which subsequently perturbed the binding of BECN1 to BCL2. Furthermore, the disconnect between BECN1 and BCL2 was shown by BNIP3 overexpression. CONCLUSION: In summary, we demonstrated the effect and underlying mechanism of metformin on OVX-induced bone loss, which could be, at least in part, ascribed to its role in downregulating autophagy during osteoclastogenesis via E2F1-dependent BECN1 and BCL2 downregulation, suggesting that metformin or E2F1 inhibitor is a potential agent against postmenopausal bone loss. Video abstract.

Femoral head metastases from primary mucinous lung adenocarcinoma with left hip pain: A case report and literature review.

Background: Primary mucinous lung adenocarcinoma, a subtype of lung adenocarcinoma, is extremely rare. Currently, as there are no specific diagnostic features, it is easy to delay the diagnosis or even to misdiagnose when atypical symptoms are present. Case summary: This case details a patient with primary mucinous lung adenocarcinoma and metastasis to the femoral head. The sole symptom was left hip pain and the initial diagnosis was isolated femoral head necrosis. Conclusions: By presenting this rare case report and the experiences learned from it, we hope to assist clinicians to identify bone metastasis cases with non-typical symptoms in order to make the correct diagnosis as soon as possible.

Traction-bed-assisted reduction and double-plate fixation for treatment of comminuted femoral intertrochanteric fractures with coronal split.

Background: A coronal comminuted femoral intertrochanteric fracture is a special type of fracture that easily leads to internal fixation failure, and the current internal fixation techniques remain controversial. This study aims to evaluate the effect of traction-bed-assisted reduction and double-plate internal fixation in the treatment of comminuted and coronally split intertrochanteric femoral fracture. Method: Retrospective analyses of the clinical data of 83 patients diagnosed with, and treated for, comminuted and coronally split intertrochanteric femoral fracture from December 2017 to November 2019 were conducted. Among the total number of 83 patients, 40 patients received traction-bed-assisted reduction and PFNA fixation (the control group), whereas 43 patients received traction-bed-assisted reduction and double-plate internal fixation (the experimental group). The major indicators for the research analysis such as the general information of patients, perioperative data, and follow-up data of both groups were collected, sorted out, and meticulously analyzed. Results: The time taken for traction-bed-assisted reduction and double-plate intern fixation in the experimental group was significantly shorter than that in the control group (P < .05). The post-operative Harris Hip Score (HHS) at 3 months and at the final follow-up after the surgery was significantly better in the experimental group compared with that in the control group, both of which were statistically significant (P < .05). However, there were statistically no significant differences between the two groups in terms of preoperative hemoglobin (Hb) level, amount of intraoperative total blood loss, immediate post-operative Hb level, incidence of wound infection within 14 days post-operatively, time taken to step up on the ground after surgery, HHS 2 weeks after surgery, time taken for fracture healing, and the incidence of complications (P > .05). Conclusion: The use of a traction bed to achieve adequate reduction, followed by internal fixation using double plates, comparatively takes less time for both reduction and operation in the treatment of comminuted and coronally split intertrochanteric femoral fractures, which also restores proper hip joint movements relatively early and hence provides better hip joint functions in the long run.

MiR-1224-5p modulates osteogenesis by coordinating osteoblast/osteoclast differentiation via the Rap1 signaling target ADCY2.

MicroRNAs (miRNAs) broadly regulate normal biological functions of bone and the progression of fracture healing and osteoporosis. Recently, it has been reported that miR-1224-5p in fracture plasma is a potential therapy for osteogenesis. To investigate the roles of miR-1224-5p and the Rap1 signaling pathway in fracture healing and osteoporosis development and progression, we used BMMs, BMSCs, and skull osteoblast precursor cells for in vitro osteogenesis and osteoclastogenesis studies. Osteoblastogenesis and osteoclastogenesis were detected by ALP, ARS, and TRAP staining and bone slice resorption pit assays. The miR-1224-5p target gene was assessed by siRNA-mediated target gene knockdown and luciferase reporter assays. To explore the Rap1 pathway, we performed high-throughput sequencing, western blotting, RT-PCR, chromatin immunoprecipitation assays and immunohistochemical staining. In vivo, bone healing was judged by the cortical femoral defect, cranial bone defect and femoral fracture models. Progression of osteoporosis was evaluated by an ovariectomy model and an aged osteoporosis model. We discovered that the expression of miR-1224-5p was positively correlated with fracture healing progression. Moreover, in vitro, overexpression of miR-1224-5p slowed Rankl-induced osteoclast differentiation and promoted osteoblast differentiation via the Rap1-signaling pathway by targeting ADCY2. In addition, in vivo overexpression of miR-1224-5p significantly promoted fracture healing and ameliorated the progression of osteoporosis caused by estrogen deficiency or aging. Furthermore, knockdown of miRNA-1224-5p inhibited bone regeneration in mice and accelerated the progression of osteoporosis in elderly mice. Taken together, these results identify miR-1224-5p as a key bone osteogenic regulator, which may be a potential therapeutic target for osteoporosis and fracture nonunion.

Clinical Application Study of Minimally Invasive Double-Reverse Traction in Complex Tibial Plateau Fractures.

The aim of this study was to evaluate the clinical application of double-reverse traction for minimally invasive reduction of complex tibial plateau fractures. A retrospective analysis was performed to identify all patients admitted to the Department of Orthopedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, from March 2017 to December 2019 with Schatzker type VI tibial plateau fractures. 12 patients were identified (7 men and 5 women) with an average age of 46.15 ± 13 (39-58) years old. All patients were treated with double-reverse traction and closed reduction. After the fracture was reduced, the bone plate was fixed by percutaneous minimally invasive implantation. Outcomes assessed in this study include operation time and intraoperative blood loss. Imaging was performed during the postoperative follow-up, and functional recovery was evaluated at the final follow-up according to the Hospital for Special Surgery (HSS) score and the International Knee Joint Literature Committee (IKDC) functional score. Patients were followed up for 12.54 ± 1.5 (8-15) months. The average operation time was 63.63 ± 21 (35-120) minutes, and the average intraoperative blood loss was 105.45 ± 21 (60-200) mL. The Rasmussen imaging score was either excellent or good in all cases. The knee joint HSS score was 86.15 ± 6 (79-90) points, and the IKDC score was 80.01 ± 11 (75-90) points. No complications, such as wound infection, incision disunion, loosening of internal fixation, and internal fixation failure, occurred. In the treatment of Schatzker VI type complex tibial plateau fracture, the dual-reverse traction minimally invasive technique has the advantages of safety and effectiveness, less soft tissue injury, and allowing early joint movement, which is worthy of clinical promotion.

Advances and perspective on animal models and hydrogel biomaterials for diabetic wound healing.

Diabetic wounds are a common complication in diabetes patients. Due to peripheral nerve damage and vascular dysfunction, diabetic wounds are prone to progress to local ulcers, wound gangrene and even to require amputation, bringing huge psychological and economic burdens to patients. However, the current treatment methods for diabetic wounds mainly include wound accessories, negative pressure drainage, skin grafting and surgery; there is still no ideal treatment to promote diabetic wound healing at present. Appropriate animal models can simulate the physiological mechanism of diabetic wounds, providing a basis for translational research in treating diabetic wound healing. Although there are no animal models that can fully mimic the pathophysiological mechanisms of diabetic wounds in humans, it is vital to explore animal simulation models used in basic research and preclinical studies of diabetic wounds. In addition, hydrogel materials are regarded as a promising treatment for diabetic wounds because of their good antimicrobial activity, biocompatibility, biodegradation and appropriate mechanical properties. Herein, we review and discuss the different animal models used to investigate the pathological mechanisms of diabetic wounds. We further discuss the promising future application of hydrogel biomaterials in diabetic wound healing.

Dual-Targeted Nanoplatform Regulating the Bone Immune Microenvironment Enhances Fracture Healing.

The immune system and skeletal system are closely linked. Macrophages are one of the most important immune cells for bone remodeling, playing a prohealing role mainly through M2 phenotype polarization. Baicalein (5,6,7-trihydroxyflavone, BCL) has been well documented to have a noticeable promotion effect on M2 macrophage polarization. However, due to the limitations in targeted delivery to macrophages and the toxic effect on other organs, BCL has rarely been used in the treatment of bone fractures. In this study, we developed mesoporous silica and Fe3O4 composite-targeted nanoparticles loaded with BCL (BCL@MMSNPs-SS-CD-NW), which could be magnetically delivered to the fracture site. This induced macrophage recruitment in a targeted manner, polarizing them toward the M2 phenotype, which was demonstrated to induce mesenchymal stem cells (MSCs) toward osteoblastic differentiation. The mesoporous silicon nanoparticles (MSNs) were prepared with surface sulfhydrylation and amination modification, and the mesoporous channels were blocked with ß-cyclodextrin. The outer layer of the mesoporous silicon was added with an amantane-modified NW-targeting peptide to obtain the targeted nanosystem. After entering macrophages, BCL could be released from nanoparticles since the disulfide linker could be cleaved by intracellular glutathione (GSH), resulting in the removal of cyclodextrin (CD) gatekeeper, which is a key element in the pro-bone-remodeling functions such as anti-inflammation and induction of M2 macrophage polarization to facilitate osteogenic differentiation. This nanosystem passively accumulated in the fracture site, promoting osteogenic differentiation activities, highlighting a potent therapeutic benefit with high biosafety.

A Versatile Nanoplatform for Broad-Spectrum Immunotherapy by Reversing the Tumor Microenvironment.

Immunotherapy is currently an important adjuvant therapy for malignant tumors besides surgical treatment. However, the heterogeneity and low immunogenicity of the tumor are two main challenges of the immunotherapy. Here, we have constructed a nanoplatform (CP@mRBC-PpIX) to realize reversion of the tumor acidosis and hypoxia through alkali and oxygen generation triggered by tumor acidosis. By targeting tumor universal features other than endogenous biomarkers, it was found that CP@mRBC-PpIX could polarize tumor-associated macrophages to anti-tumor M1 phenotype macrophages to enhance tumor immune response. Furthermore, under regional light irradiation, the reactive oxygen species produced by photosensitizers located in CP@mRBC-PpIX could increase the immunogenicity of tumors, so that tumor changes from an immunosuppressive "cold tumor" to an immunogenic "hot tumor," thereby increasing the infiltration and response of T cells, further amplifying the effect of immunotherapy. This strategy circumvented the problem of tumor heterogeneity to realize a kind of broad-spectrum immunotherapy, which could effectively prevent tumor metastasis and recurrence.

Exosomes derived from pioglitazone-pretreated MSCs accelerate diabetic wound healing through enhancing angiogenesis.

BACKGROUND: Enhanced angiogenesis can promote diabetic wound healing. Mesenchymal stem cells (MSCs)-derived exosomes, which are cell-free therapeutics, are promising candidates for the treatment of diabetic wound healing. The present study aimed to investigate the effect of exosomes derived from MSCs pretreated with pioglitazone (PGZ-Exos) on diabetic wound healing. RESULTS: We isolated PGZ-Exos from the supernatants of pioglitazone-treated BMSCs and found that PGZ-Exos significantly promote the cell viability and proliferation of Human Umbilical Vein Vascular Endothelial Cells (HUVECs) injured by high glucose (HG). PGZ-Exos enhanced the biological functions of HUVECs, including migration, tube formation, wound repair and VEGF expression in vitro. In addition, PGZ-Exos promoted the protein expression of p-AKT, p-PI3K and p-eNOS and suppressed that of PTEN. LY294002 inhibited the biological function of HUVECs through inhibition of the PI3K/AKT/eNOS pathway. In vivo modeling in diabetic rat wounds showed that pioglitazone pretreatment enhanced the therapeutic efficacy of MSCs-derived exosomes and accelerated diabetic wound healing via enhanced angiogenesis. In addition, PGZ-Exos promoted collagen deposition, ECM remodeling and VEGF and CD31 expression, indicating adequate angiogenesis in diabetic wound healing. CONCLUSIONS: PGZ-Exos accelerated diabetic wound healing by promoting the angiogenic function of HUVECs through activation of the PI3K/AKT/eNOS pathway. This offers a promising novel cell-free therapy for treating diabetic wound healing.