动态调控巨噬细胞极化以促进种植体骨整合的葡甘聚糖涂层及其作用机制研究

Titanium dental implants are used as the first choice for the clinical treatment of tooth loss. However, the impaired bone condition of the jawbone may lead to compromised osseointegration between the implant and surrounding bone tissue. During the bone development and bone healing process, macrophages have been demonstrated as an indispensable dynamic regulator. In the applicant's previous studies, acetyl-modified glucomannan (acGM) exhibits a remarkable affinity towards macrophages, activates them to present a pro-inflammatory phenotype and release pro-osteogenic/angiogenic cytokines. In this project, alendronate (ALN) will be adopted as an environment-responsive molecule to cross-link acGM on the surface of titanium implants. We expect that, at the early stage of repair, acGM could stimulate macrophages to transform into an M1-like phenotype, thereby initiate the full-scale osteogenesis process; and to the middle/late stage of repair, the progressively accumulated alkaline phosphatase (ALP) in the reparative environment could break the phosphoester bonds to release ALN-acGM complex, which could afterward regulate the phenotypic transformation of macrophages and inhibit the activity of osteoclasts through the endocytosis mediated by pattern recognition receptors, thus stabilizing the newly forming bone tissue. In this project, the fixed-released state transition of composite coating components is designed to stimulate different signaling/ endocytic receptors during the early and late bone repair process, regulate phenotypic transformation, consequently promote the osseointegration quality of the implant under the condition of osteoporosis. Taken together, this design provides a new settlement strategy for the dynamic regulation of macrophage phenotypes and its engineering application.

牙科钛种植体是临床上治疗牙齿缺失的首选方案。但骨质受损的牙槽骨往往导致种植体表面骨整合不佳。在骨发育和修复过程中，巨噬细胞被证实发挥了不可或缺的动态调控作用。申请人的前期研究发现乙酰化葡甘聚糖（acGM）可以亲和巨噬细胞，激活其促炎表型并释放促成骨/成血管细胞因子。本项目拟利用阿仑膦酸钠（ALN）作为环境响应分子，将acGM共价交联到种植体表面。在修复早期，acGM涂层界面有望诱导巨噬细胞的偏M1型极化，全面启动成骨进程；在修复中后期，累积的碱性磷酸酶（ALP）切割磷酸酯键释放ALN-acGM复合物，通过相关模式识别受体介导的内吞作用，调控巨噬细胞表型转变并抑制破骨细胞活性，稳定新生骨组织。本设计利用涂层成分的固定-游离形态转变，在修复前后阶段激活巨噬细胞的不同信号/内吞受体，调节表型转换，促进骨质疏松情况下种植体表面的骨整合，为巨噬细胞的动态极化调控及其工程化应用提供了全新的解决策略。

口腔种植体是解决牙齿缺失的重要技术手段。然而，其临床使用仍然面临一个迫切的挑战：即众多基础性疾病，如骨质疏松患者，其骨密度较低，机械固定力不足，使得植入的种植体不能形成稳定的骨整合，从而出现种植体松动致使手术失败。该类患者在进行种植体植入时，需要解决更严苛的临床需求，有必要针对其特殊的病理微环境，发展一种可动态操纵种植体活性接口的生物材料，以动态、可控、符合生物学机理的方式促进种植体骨整合与牙槽骨修复。..基于这样的设计理念，本项目利用前期发现的具有巨噬细胞调节活性的乙酰化白及葡甘聚糖（acBSP），再由阿仑膦酸钠（ALN）偶联至金属钛合金种植体的表面。acBSP具有启动巨噬细胞释放促成骨生长因子的作用。而ALN，既是acBSP化学交联至钛表面的中间物，又是可抑制破骨细胞活性的临床药物。此外，ALN交联形成的磷酸酯键，恰是成骨过程中不断分泌的碱性磷酸酶（ALP）的底物。在修复早期，涂层中的acBSP特异诱导巨噬细胞促进骨整合，改善成骨微环境；在修复的中后期，ALP不断增多，切割磷酸酯键并逐渐释放出ALN，抑制巨噬/破骨细胞活性，稳固新生骨组织。本设计利用涂层中这两类分子在骨修复前后阶段的不同生理作用，调节骨质疏松情况下局部的成骨/破骨活性平衡，促进了牙槽骨在种植体表面的骨整合，为临床的治疗提供了新的思路借鉴和应用指导。