血糖响应型、自律性靶向释药种植体改善2型糖尿病大鼠骨结合的研究

At present, China has the largest diabetes mellitus (DM) population around the world, and type 2 diabetes mellitus (T2DM) accounts for about 90%-95% of the total number of DM patients. Compared to the healthy population, diabetic patients have increased frequency of tooth loss. In recent years, dental implant has become the most ideal way to repair teeth. However, it has been confirmed that DM is associated with a relatively higher failure rate for implant and substantial risks. Therefore, DM has been considered as a relative contraindication for dental implantation. Recent studies have demonstrated that T2DM patients may benefit from functional oral reconstruction based on dental implants. In view of the large number of T2DM patients, high incidence of tooth loss in such patients and the benefits of dental implants for metabolic status of T2DM patients, how to improve the success rate of dental implants in medium and severe T2DM has become a research hotspot. In this study, we constructed a glucose-responsive, self-regulated bio-smart implant system by selective laser melting & 3D printing technology with microfluidic fabrication approach. Focusing on the shortcoming of poor osseointergration of dental implants in T2DM, this study was designed based on the novel hypothesis that glucagon-like peptide-1 receptor agonist (GLP-1 Ra) targeted regulates the relevant cells of peri-implant bone. Through in vitro and in vivo experiments, the present study is to investigate the influence of the implant system on BMSCs and its peri-implant osseointergration, and to elucidate the mechanism underlying the effects of local application of GLP-1Ra on peri-implant osseointergration. This study provides new ideas and novel strategies in order to increase the success rate of dental implants in medium and severe T2DM patients.

鉴于糖尿病患者较常人更易缺牙的倾向、种植修复对该群体代谢状况的有利影响及大量2型糖尿病患者(T2DM)处于血糖控制不佳的临床常态，如何改善该群体种植初期骨结合不良、降低其种植失败风险成为当务之急。研究证实胰高血糖素样肽-1受体激动剂(GLP-1Ra)通过其特异性受体(GLP-1R)发挥促进成骨、抑制破骨的调控作用；同时项目前期证实GLP-1R亦存在于T2DM大鼠种植体周，提示该受体作为促进T2DM骨结合潜在靶标的可能性。本项目拟以T2DM种植初期骨结合不良的直接原因为切入点，基于GLP-1Ra对骨组织的双重调控作用，结合微流控乳液模板法及选择性激光熔融技术，创新性地构建血糖敏感型、自律性靶向释药种植体。经体内外实验验证该体系对负载蛋白的响应性控释效果，明确GLP-1Ra局部控释对T2DM骨结合的影响，进而阐明其作用的具体分子信号机制，为提高中、重度T2DM患者种植成功率提供新思路和新方法。

本项目鉴于糖尿病患者较常人更易缺牙的倾向、种植修复对该群体代谢状况的有利影响及大量2 型糖尿病患者(T2DM)处于血糖控制不佳的临床常态，探究了如何改善该群体种植初期骨结合不良、降低其种植失败风险。研究已证实，糖尿病患者种植体周围的骨结合是一个复杂且长久的过程，植体植入体内后，会经历体液附着，蛋白沉积，免疫细胞识别与激活，以及干细胞附着和成骨等多个愈合阶段，受到多种因素的级联调控。本项目以T2DM种植初期骨结合不良的原因为切入点，构建具有抗菌和促成骨功效的双离子（Sr2+和Ag＋）独立控释种植体系以及负载BMP2和IL-10的血糖炎症双敏感型、自律性释药水凝胶，并构建构建了T2DM大鼠种植体周围炎模型，经体内实验分别验证了两个体系的抗菌及促进骨再生作用、对负载蛋白的响应性控释效果及促进骨缺损愈合作用。为了探究其对巨噬细胞的极化状态的调控机制，经体外试验验证了对巨噬细胞的抗炎诱导作用以及对成骨细胞的分化促进作用，阐明该体系通过调控巨噬细胞的极化状态进一步调控下游成骨前体细胞的粘附、伸展以及分化能力的生物级联调控作 用的具体分子信号机制，为提高中、重度T2DM患者种植成功率提供新思路和新方法。