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Background: Diabetes mellitus (DM) is considered to be an important factor for bone degeneration disorders such as bone defect nonunion, which is characterized by physical disability and tremendous economy cost to families and society. Exosomal miRNAs of BMSCs have been reported to participate in osteoblastogenesis and modulating bone formation. However, their impacts on the development of bone degeneration in DM are not yet known. The role of miRNAs in BMSCs exosomes on regulating hyperglycemia bone degeneration was investigated in the present study. Results: The osteogenic potential in bone defect repair of exosomes derived from diabetes mellitus BMSCs derived exosomes (DM-Exos) were revealed to be lower than that in normal BMSCs derived exosomes (N-Exos) in vitro and in vivo. Here, we demonstrate that miR-140-3p level was significantly altered in exosomes derived from BMSCs, ADSCs and serum from DM rats. In in vitro experiments, upregulated miR-140-3p exosomes promoted DM BMSCs differentiation into osteoblasts. The effects were exerted by miR-140-3p targeting plxnb1, plexin B1 is the receptor of semaphoring 4D(Sema4D) that inhibited osteocytes differentiation, thereby promoting bone formation. In DM rats with bone defect, miR-140-3p upregulated exosomes were transplanted into injured bone and accelerated bone regeneration. Besides, miR-140-3p in the exosomes was transferred into BMSCs and osteoblasts and promoted bone regeneration by targeting the plexin B1/RohA/ROCK signaling pathway. Conclusions: Normal-Exos and miR-140-3p overexpressed-Exos accelerated diabetic wound healing by promoting the osteoblastogenesis function of BMSCs through inhibition plexin B1 expression which is the receptor of Sema4D and the plexin B1/RhoA/ROCK pathway compared with diabetes mellitus-Exos. This offers a new insight and a new therapy for treating diabetic bone unhealing. [ABSTRACT FROM AUTHOR]

After an osteosarcoma excision, recurrence and bone defects are significant challenges for clinicians. In this study, the curcumin (Cur) loaded chitosan (CS) nanoparticles (CCNP) encapsulated silk fibroin (SF)/hyaluronic acid esterified by methacrylate (HAMA) (CCNPs-SF/HAMA) hydrogel for the osteosarcoma therapy and bone regeneration was developed by photocuring and ethanol treatment. The micro or nanofibers networks were observed in the CCNPs-SF/HAMA hydrogel. The FTIR results demonstrated that alcohol vapor treatment caused an increase in β-sheets of SF, resulting in the high compression stress and Young's modulus of CCNPs-SF/HAMA hydrogel. According to the water uptake analysis, SF caused a slight decrease in water uptake of CCNPs-SF/HAMA hydrogel while CCNPs could enhance the water uptake of it. The swelling kinetic results showed that both the CCNPs and the SF increased the swelling ratio of CCNPs-SF/HAMA hydrogel. The accumulative release profile of CCNPs-SF/HAMA hydrogel showed that the release of Cur from CCNPs-SF/HAMA hydrogel was accelerated when pH value was decreased from 7.4 to 5.5. Besides, compared with CCNPs, the CCNPs-SF/HAMA hydrogel had a more sustainable drug release, which was beneficial for the long-term treatment of osteosarcoma. In vitro assay results indicated that CCNPs-SF/HAMA hydrogel with equivalent Cur concentration of 150 μg/mL possessed both the effect of anti-cancer and promoting the proliferation of osteoblasts. These results suggest that CCNPs-SF/HAMA hydrogel with superior physical properties and the bifunctional osteosarcoma therapy and bone repair may be an excellent candidate for local cancer therapy and bone regeneration. [ABSTRACT FROM AUTHOR]

Bone regeneration is a highly synchronized process that requires multiple biochemical, bioelectrical, mechanical, and other physiological cues. The restoration and delivery of electrical cues locally through piezoelectric materials have been demonstrated to facilitate osteogenesis in vitro and bone repair in vivo. However, the underlying mechanism by which piezoelectric stimulation promotes osteogenesis and bone repair remains unclear yet, limiting the design and clinical application of piezoelectric materials for bone repair. Herein, a piezoelectric BaTiO3/Ti6Al4V (BT/Ti) scaffold was prepared by hydrothermal synthesis of a uniform BaTiO3 layer on three dimensionally printed Ti6Al4V scaffold. The BT/Ti scaffolds exhibited piezoelectricity and favorable biocompatibility with RAW264.7 macrophages after polarization. In vitro results demonstrated that the piezoelectric effects of the poled BT/Ti scaffolds promoted M2 polarization of macrophages and immunoregulatory osteogenesis of MC-3T3 osteoblasts. In a subcutaneous implantation model, a higher proportion of CD68+ CD206+ M2 macrophages was observed in the tissues around the poled BT/Ti scaffolds under low intensity pulsed ultrasound (LIPUS) stimulation. Improvements in macrophage M2 polarization and bone regeneration were further identified in a sheep cervical corpectomy model. RNA sequencing and mechanistic investigation revealed that the piezoelectric BT/Ti (poled) scaffolds inhibited the inflammatory MAPK/JNK signaling cascade and activated oxidative phosphorylation (OXPHOS) and ATP synthesis in macrophages. Collectively, our study provides a promising method for regulating the immune microenvironment and enhancing bone regeneration using polarized piezoelectric BT/Ti scaffolds. (A) Fabrication of porous Ti6Al4V scaffolds coated with piezoelectric barium titanate and scaffolds implantation in a sheep cervical en-bloc spondylectomy model. (B) Piezoelectric BT/Ti (poled) artificial vertebrae bodies promoted M2 polarization of macrophages and bone repair process. (C) Piezoelectric stimulation inhibited MAPK/JNK signaling and activated OXPHOS of macrophages. [Display omitted] [ABSTRACT FROM AUTHOR]