A Dual Peptide Sustained-Release System Based on Nanohydroxyapatite/Polyamide 66 Scaffold for Synergistic-Enhancing Diabetic Rats' Fracture Healing in Osteogenesis and Angiogenesis.

Jian Li,Hongyu Liu,Ang Li,Jiaxing Wei,Hong Qiao,Jingxue Sun

doi:10.3389/fbioe.2021.657699

Abstract

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.

Highlights

Diabetes mellitus (DM), a chronic metabolic disease common worldwide, has profound deleterious effect on fracture healing and bone formation (Jiao et al, 2015; Marin et al, 2018; Henderson et al, 2019)
Previous studies demonstrated that the hyperglycemic environment decreased the population and functionality of bone marrow mesenchymal stem cells (BMSCs) and human umbilical vein endothelial cells (HUVECs), leading to a decrease in osteogenesis and angiogenesis that were key for bone regeneration (Januszyk et al, 2014; Sun et al, 2020; Xiang et al, 2020)
In this work, gene expression of bone morphogenetic protein-2- (BMP-2) and vascular endothelial growth factor A (VEGFA) of BMSCs was down-regulated in high glucose (HG) condition, and in order to avoid the side effects of using growth factors, so we aimed to augment their molecular signals in a favorable form

Summary

Introduction

Diabetes mellitus (DM), a chronic metabolic disease common worldwide, has profound deleterious effect on fracture healing and bone formation (Jiao et al, 2015; Marin et al, 2018; Henderson et al, 2019). Diabetic patients with fractures typically show higher rates of delayed healing and non-union than nondiabetic patients, resulting in a considerable socioeconomic burden (Sundararaghavan et al, 2017; Gortler et al, 2018). Considering the higher incidence of DM and immense healthcare-related costs generated by bone fractures, there is an urgent need to find a better strategy to efficiently augment related bioactive molecules that target diabetic-induced dysfunction of BMSCs and HUVECs to promote diabetic fracture healing (Loewenstern et al, 2019)

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