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Diabetes mellitus is a chronically inflamed disease that predisposes to delayed fracture healing. Macrophages play a key role in the process of fracture healing by undergoing polarization into either M1 or M2 subtypes, which respectively exhibit pro-inflammatory or anti-inflammatory functions. Therefore, modulation of macrophage polarization to the M2 subtype is beneficial for fracture healing. Exosomes perform an important role in improving the osteoimmune microenvironment due to their extremely low immunogenicity and high bioactivity. In this study, we extracted the M2-exosomes and used them to intervene the bone repair in diabetic fractures. The results showed that M2-exosomes significantly modulate the osteoimmune microenvironment by decreasing the proportion of M1 macrophages, thereby accelerating diabetic fracture healing. We further confirmed that M2-exosomes induced the conversion of M1 macrophages into M2 macrophages by stimulating the PI3K/AKT pathway. Our study offers a fresh perspective and a potential therapeutic approach for M2-exosomes to improve diabetic fracture healing.

Diabetes mellitus impairs fracture healing and function of stem cells related to bone regeneration; thus, effective bone tissue engineering therapies can intervene with those dysfunctions. Nanohydroxyapatite/polyamide 66 (n-HA/PA66) scaffold has been used in fracture healing, whereas the low bioactivity limits its further application. Herein, we developed a novel bone morphogenetic protein-2- (BMP-2) and vascular endothelial growth factor- (VEGF) derived peptides-decorated n-HA/PA66 (BVHP66) scaffold for diabetic fracture. The n-HA/PA66 scaffold was functionalized by covalent grafting of BMP-2 and VEGF peptides to construct a dual peptide sustained-release system. The structural characteristics and peptide release profiles of BVHP66 scaffold were tested by scanning electron microscopy, Fourier transform infrared spectroscopy, and fluorescence microscope. Under high glucose (HG) condition, the effect of BVHP66 scaffold on rat bone marrow mesenchymal stem cells’ (rBMSCs) adherent, proliferative, and differentiate capacities and human umbilical vein endothelial cells’ (HUVECs) proliferative and tube formation capacities was assessed. Finally, the BVHP66 scaffold was applied to fracture of diabetic rats, and its effect on osteogenesis and angiogenesis was evaluated. In vitro, the peptide loaded on the BVHP66 scaffold was in a sustained-release mode of 14 days. The BVHP66 scaffold significantly promoted rBMSCs’ and HUVECs’ proliferation and improved osteogenic differentiation of rBMSCs and tube formation of HUVECs in HG environment. In vivo, the BVHP66 scaffold enhanced osteogenesis and angiogenesis, rescuing the poor fracture healing in diabetic rats. Comparing with single peptide modification, the dual peptide-modified scaffold had a synergetic effect on bone regeneration in vivo. Overall, this study reported a novel BVHP66 scaffold with excellent biocompatibility and bioactive property and its application in diabetic fracture.

Diabetes mellitus is a chronically inflamed disease that predisposes to delayed fracture healing. Macrophages play a key role in the process of fracture healing by undergoing polarization into either M1 or M2 subtypes, which respectively exhibit pro-inflammatory or anti-inflammatory functions. Therefore, modulation of macrophage polarization to the M2 subtype is beneficial for fracture healing. Exosomes perform an important role in improving the osteoimmune microenvironment due to their extremely low immunogenicity and high bioactivity. In this study, we extracted the M2-exosomes and used them to intervene the bone repair in diabetic fractures. The results showed that M2-exosomes significantly modulate the osteoimmune microenvironment by decreasing the proportion of M1 macrophages, thereby accelerating diabetic fracture healing. We further confirmed that M2-exosomes induced the conversion of M1 macrophages into M2 macrophages by stimulating the PI3K/AKT pathway. Our study offers a fresh perspective and a potential therapeutic approach for M2-exosomes to improve diabetic fracture healing., Competing Interests: The authors declare no conflict of interest., (© 2023 The Authors.)

Diabetics are at increased risk for fracture, and experience severely impaired skeletal healing characterized by delayed union or nonunion of the bone. The periosteum harbors osteochondral progenitors that can differentiate into chondrocytes and osteoblasts, and this connective tissue layer is required for efficient fracture healing. While bone marrow-derived stromal cells have been studied extensively in the context of diabetic skeletal repair and osteogenesis, the effect of diabetes on the periosteum and its ability to contribute to bone regeneration has not yet been explicitly evaluated. Within this study, we utilized an established murine model of type I diabetes to evaluate periosteal cell differentiation capacity, proliferation, and availability under the effect of a diabetic environment. Periosteal cells from diabetic mice were deficient in osteogenic differentiation ability in vitro , and diabetic mice had reduced periosteal populations of mesenchymal progenitors with a corresponding reduction in proliferation capacity following injury. Additionally, fracture callus mineralization and mature osteoblast activity during periosteum-mediated healing was impaired in diabetic mice compared to controls. We propose that the effect of diabetes on periosteal progenitors and their ability to aid in skeletal repair directly impairs fracture healing. Unlabelled Image • Periosteum-specific effects contribute to impaired diabetic fracture healing. • Diabetes induces a long-term loss of progenitor osteogenic differentiation capacity. • Diabetes causes loss of periosteal proliferation/differentiation post-fracture. • Advanced glycation end products do not alter periosteal chondrogenic potential. [ABSTRACT FROM AUTHOR]

Diabetes mellitus impairs fracture healing and function of stem cells related to bone regeneration; thus, effective bone tissue engineering therapies can intervene with those dysfunctions. Nanohydroxyapatite/polyamide 66 (n-HA/PA66) scaffold has been used in fracture healing, whereas the low bioactivity limits its further application. Herein, we developed a novel bone morphogenetic protein-2- (BMP-2) and vascular endothelial growth factor- (VEGF) derived peptides-decorated n-HA/PA66 (BVHP66) scaffold for diabetic fracture. The n-HA/PA66 scaffold was functionalized by covalent grafting of BMP-2 and VEGF peptides to construct a dual peptide sustained-release system. The structural characteristics and peptide release profiles of BVHP66 scaffold were tested by scanning electron microscopy, Fourier transform infrared spectroscopy, and fluorescence microscope. Under high glucose (HG) condition, the effect of BVHP66 scaffold on rat bone marrow mesenchymal stem cells' (rBMSCs) adherent, proliferative, and differentiate capacities and human umbilical vein endothelial cells' (HUVECs) proliferative and tube formation capacities was assessed. Finally, the BVHP66 scaffold was applied to fracture of diabetic rats, and its effect on osteogenesis and angiogenesis was evaluated. In vitro , the peptide loaded on the BVHP66 scaffold was in a sustained-release mode of 14 days. The BVHP66 scaffold significantly promoted rBMSCs' and HUVECs' proliferation and improved osteogenic differentiation of rBMSCs and tube formation of HUVECs in HG environment. In vivo , the BVHP66 scaffold enhanced osteogenesis and angiogenesis, rescuing the poor fracture healing in diabetic rats. Comparing with single peptide modification, the dual peptide-modified scaffold had a synergetic effect on bone regeneration in vivo . Overall, this study reported a novel BVHP66 scaffold with excellent biocompatibility and bioactive property and its application in diabetic fracture., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Li, Wei, Li, Liu, Sun and Qiao.)