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Background: Hydrogel carrying exosomes shows better prospects for bone regeneration. Objective: This work investigated the effect of cross-linking N-succinyl chitosan-oxidated hyaluronic acid-based hydrogel loaded with bone marrow mesenchymal stem cell-derived exosomes on bone regeneration in cranial defects. Methods: Cross-linking N-succinyl chitosan-oxidated hyaluronic acid-based hydrogel loaded with bone marrow mesenchymal stem cell-derived exosomes was prepared, and utilized to treat bone marrow mesenchymal stem cells, human umbilical vein endothelial cells, and rats with cranial defects. Logical experiments were implemented to research the effect of the prepared hydrogel on osteogenesis and angiogenesis of cells in vitro, and on bone regeneration in rats with cranial defects. Results: Cross-linking N-succinyl chitosan-oxidated hyaluronic acid-based hydrogel loaded with bone marrow mesenchymal stem cell-derived exosomes showed good biocompatibility and self-healing property. It promoted osteogenic differentiation of bone marrow mesenchymal stem cells and angiogenesis of human umbilical vein endothelial cells, and facilitated osteogenic differentiation, angiogenesis and bone regeneration in rats with cranial defects. Conclusion: Cross-linking N-succinyl chitosan-oxidated hyaluronic acid-based hydrogel loaded with bone marrow mesenchymal stem cell-derived exosomes facilitated osteogenesis, angiogenesis and bone regeneration in rats with cranial defects. It might be an effective strategy for inducing bone regeneration in individuals with cranial defects.

Summary: Mesenchymal stem cell (MSC)-mediated coupling of osteogenesis and angiogenesis is a critical phenomenon in bone formation. Herein, we investigated the role and mechanism of SGMS1 in the osteogenic differentiation of MSCs and, in combination with osteogenesis and angiogenesis, to discover new therapeutic targets for skeletal dysplasia and bone defects. SGMS1 addition accelerated MSC osteogenic differentiation, whereas SGMS1 silencing suppressed this process. Moreover, SGMS1 overexpression inhibited ceramide (Cer) and promoted sphingomyelin (SM) levels. SM treatment neutralized the suppressive effect of shSGMS1 on osteogenesis. SGMS1 restrained PP2A activity by regulating Cer/SM metabolism and thus enhanced the levels of phosphorylated Akt, Runx2, and vascular endothelial growth factor (VEGF). Furthermore, SGMS1 transcription was regulated by Runx2. SGMS1 increased MSC-mediated angiogenesis by promoting VEGF expression. SGMS1 addition promoted rat bone regeneration in vivo. In conclusion, SGMS1 induces osteogenic differentiation of MSCs and osteogenic-angiogenic coupling through the regulation of the Cer/PP2A/Akt signaling pathway.

Background: Inflammatory-coagulation dysfunction plays an increasingly important role in sepsis associated acute kidney injury (SAKI). This study aimed to investigate whether early heparin therapy improves survival in patients with SAKI.Methods: Patients with SAKI were identified from the Medical Information Mart for Intensive Care-IV database. The patients were divided into two groups: those who received heparin subcutaneously within 48 h after intensive care unit (ICU) admission and the control group, who received no heparin. The primary endpoint was ICU mortality, the secondary outcomes were 7-day, 14-day, 28-day, and hospital mortality. Propensity score matching (PSM), marginal structural Cox model (MSCM), and E-value analyses were performed.Results: The study included 5623 individuals with SAKI, 2410 of whom received heparin and 3213 of whom did not. There were significant effects on ICU and 28-day mortality in the overall population with PSM. MSCM further reinforces the efficacy of heparin administration reduces ICU mortality in the general population. Stratification analysis with MSCM showed that heparin administration was associated with decreased ICU mortality at various AKI stages. Heparin use was also associated with reduced 28-day mortality in patients with only female, age >60 years, and AKI stage 3, with HRs of 0.79, 0.77, and 0.60, respectively (p < 0.05). E-value analysis suggests robustness to unmeasured confounding.Conclusion: Early heparin therapy for patients with SAKI decreased ICU mortality. Further analysis demonstrated that heparin therapy was associated with reduced 28-day mortality rate in patients only among female, age > 60 years and AKI stage 3.

Background: Previous studies documented that heparin can inhibit the invasion and metastasis of tumors, but its role on outcomes in patients with solid malignancy complicated sepsis remains unclear.Methods: A retrospective cohort study was conducted in critically ill patients with solid malignancy associated sepsis from the Medical Information Mart for Intensive Care (MIMIC)-IV database. The primary endpoint was intensive care unit (ICU) mortality, secondary outcomes were thrombosis and hospital mortality. Propensity score matching (PSM), marginal structural Cox model (MSCM), cox proportional hazards model, stratification analysis and E-value were used to account for baseline differences, time-varying confounding and unmeasured variables.Results: A total of 1,512 patients with solid malignancy complicated sepsis were enrolled, of which 683 in the heparin group with intensive care unit mortality, thrombosis rate and hospital mortality were 9.7%, 5.4%, 16.1%, and 829 in the non-heparin group with ICU mortality, thrombosis rate and hospital mortality were 14.6%, 12.5%, 22.6%. Similar results were observed on outcomes for patients with PSM (ICU mortality hazard ratio [HR] 0.61, 95% confidence interval [CI] 0.41–0.92), thrombosis rate (HR 0.42, 95% confidence interval 0.26–0.68); hospital mortality HR 0.70, 95% CI 0.50–0.99). marginal structural Cox model further reinforced the efficacy of heparin in reducing ICU mortality (HR 0.48, 95% CI 0.34–0.68). Logistic regression and Cox regression model showed heparin use also markedly reduced thrombosis (HR 0.42; 95% CI 0.26–0.68; p < 0.001) and hospital mortality (HR 0.70; 95% CI 0.50–0.99; p = 0.043). Stratification analysis with the MSCM showed an effect only those with digestive system cancer (HR 0.33, 95% CI 0.16–0.69).Conclusion: Early heparin therapy improved outcomes in critically ill patients with solid malignancy complicated sepsis. These results are evident especially in those with digestive system cancer. A prospective randomized controlled study should be designed to further assess the relevant findings.

Background: This study aimed to investigate whether early unfractionated heparin (UFH) administration provides a survival advantage for patients with sepsis-induced coagulopathy (SIC).Methods: Patients hospitalized with sepsis-induced coagulopathy from the Medical Information Mart for Intensive Care (MIMIC)-IV database were identified. Patients were divided into two groups, who received unfractionated heparin (UFH) subcutaneously within 24 h after intensive care unit (ICU) admission, and the control group, who received not. The primary endpoint was intensive care unit mortality, the secondary outcomes were 7, 14, and 28-day and hospital mortality. Propensity score matching (PSM) the marginal structural Cox model (MSCM) and E-value analysis were used to account for baseline differences, time-varying and unmeasured confounding factors.Results: A total of 3,377 patients with sepsis-induced coagulopathy were enrolled in the study, of which 815 in unfractionated heparin group and 2,562 in control group. There was significant effect on primary and secondary outcomes with unfractionated heparin after propensity score matching (intensive care unit mortality, hazard ratio [HR] 0.69, 95% confidence interval [CI] 0.52–0.92; 7-day, HR 0.70, 95% CI 0.49–0.99; 14-day, HR 0.68.95% CI 0.50–0.92; 28-day, HR 0.72, 95% CI 0.54–0.96; hospital mortality, HR 0.74, 95% CI 0.57–0.96), marginal structural Cox model manifested unfractionated heparin associated with decreased intensive care unit mortality in all populations (HR 0.64, 95% CI 0.49–0.84), and stratification with the marginal structural Cox model indicated analysis further indicated the survival advantage only among patients with an sepsis-induced coagulopathy score of 4 (HR 0.56, 95% CI 0.38–0.81). Further analysis showed that treatment with 6,250–13750 IU/day of unfractionated heparin associated with a decreased risk of intensive care unit mortality. Similar results were replicated in subgroup analysis with propensity score matching only for patients with an sepsis-induced coagulopathy score of 4 (intensive care unit mortality, HR 0.51, 95% CI 0.34–0.76).Conclusion: This study found early unfractionated heparin therapy to patients with sepsis-induced coagulopathy appears to be associated with improved outcomes. Subgroup analysis further demonstrates heparin therapy decreased intensive care unit mortality primarily in patients only with SIC score of 4.

Background: Bone tissue defect, one of the common orthopaedicdiseases, is traumatizing and affects patient’s lifestyle. Although autologous and xenograft bone transplantations are performed in bone tissue engineering, clinical development of bone transplantation is limited because ofvarious factors, such as varying degrees of immune rejection, lack of bone sources, and secondary damage to bone harvesting.Methods: We synthesised a heparinised gelatine-hydroxyapatite-tricalcium phosphate (HG-HA-TCP) scaffold loaded with sustained-release vascular endothelial growth factor (VEGF) analysed their structure, mechanical properties, and biocompatibility. Additionally, the effects of HG-HA-TCP (VEGF) scaffolds on osteogenic differentiation and vascularisation of stem cells from human exfoliated deciduous teeth (SHED) in vitro and bone regeneration in vivo were investigated.Results: HG-HA-TCP scaffold possessed good pore structure, mechanical properties, and biocompatibility. HG-HA-TCP scaffold loaded with VEGF could effectively promote SHED proliferation, migration, and adhesion. Moreover, HG-HA-TCP (VEGF) scaffold increased the expression of osteogenesis- and angiogenesis-related genes and promoted osteogenic differentiation and vascularisation in cells. In vivo results demonstrated that VEGF-loaded HG-HA-TCP scaffold improved new bone regeneration and enhanced bone mineral density, revealed byhistological, micro-CT and histochemical straining analyses. Osteogenic and angiogenic abilities of the three biological scaffolds wereranked as follows: HG-HA-TCP (VEGF) > G-HA-TCP (VEGF) > G-HA-TCP.Conclusion: HG-HA-TCP (VEGF) scaffold with good biocompatibility could create an encouraging osteogenic microenvironment that could accelerate vessel formation and osteogenesis, providing an effective scaffold for bone tissue engineering and developing new clinical treatment strategies for bone tissue defects.

BackgroundIn updated international guidelines, combined albumin resuscitation is recommended for septic shock patients who receive large volumes of crystalloids, but minimal data exist on albumin use and the optimal timing in those with cardiogenic shock (CS). The objective of this study was to evaluate the relationship between resuscitation with a combination of albumin within 24 h and 30-day mortality in CS patients.MethodsWe screened patients with CS from the Medical Information Mart for Intensive Care IV (MIMIC-IV) database. Multivariable Cox proportional hazards models and propensity score matching (PSM) were employed to explore associations between combined albumin resuscitation within 24 h and 30-day mortality in CS. Models adjusted for CS considered potential confounders. E-value analysis suggested for unmeasured confounding.ResultsWe categorized 1,332 and 254 patients into crystalloid-only and early albumin combination groups, respectively. Patients who received the albumin combination had decreased 30-day and 60-day mortality (21.7 vs. 32.4% and 25.2 vs. 34.2%, respectively, P < 0.001), and the results were robust after PSM (21.3 vs. 44.7% and 24.9 vs. 47.0%, respectively, P < 0.001) and following E-value. Stratified analysis showed that only ≥ 60 years old patients benefited from administration early albumin. In the early albumin combination group, the hazard ratios (HRs) of different adjusted covariates remained significant (HRs of 0.45–0.64, P < 0.05). Subgroup analysis showed that resuscitation with combination albumin was significantly associated with reduced 30-day mortality in patients with maximum sequential organ failure assessment score≥10, with acute myocardial infarction, without an Impella or intra-aortic balloon pump, and with or without furosemide and mechanical ventilation (HRs of 0.49, 0.58, 0.65, 0.40, 0.65 and 0.48, respectively; P < 0.001).ConclusionThis study found, compared with those given crystalloid-only, resuscitation with combination albumin within 24 h is associated with lower 30-day mortality of CS patients aged≥60. The results should be conducted to further assess in randomized controlled trials.