基于细胞归巢的组织工程新方法及其在骨再生中的应用

As a traditional engineering strategy, transplanted cells alone or combined with one or more growth factors may be satisfactory for repairing small-sized tissue defects. However, cell transplantation has encountered crucial barriers in therapeutic translation, including possible immune rejection, pathogen transmission, potential tumorigenesis, issues with packaging, storage, and shipping, and difficulties in clinical adoption and regulatory approval. Moreover, as a passive/forced regenerative process, delivered cells may not survive due to nutrient diffusion limit and the resultant regeneration thus derails because the therapy doesn't harness the host's innate capacity for repair. Tissue regeneration by recruiting host's endogenous stem and progenitor cells is an emerging idea and considered as an alternative. The chemotactic factor released from an implanted device will attract the host's stem/progenitor cells to the injured tissue and make preparation for proliferation and differentiations into projected tissues. In this way, all the problems associated with cell transplantation will be solved and currently available tissue engineering strategies can be readily applied. However, how to coordinate cell recruitment and proliferation of endogenous cells, and subsequent differentiations is a bottleneck in translating this novel regeneration strategy into clinical applications. The multi-step process of spontaneous repair is always regulated by a series of growth factors. This suggests that a sequential release of multiple factors in vivo from a scaffold, which mimics the complex temporal microenvironment presented in nature, will become critical for a successful regeneration strategy. However, in modern design, most delivery systems only accounts for a single factor, limiting the overall efficacy. As a regeneration model, bone repair is essentially a multistage process that is regulated by a serial of growth factors, such as PDGF and BMPs. Each factor requires its specific time scale and concentration profile according to the nature of the repair process. Herein, we suggest a brand new "smart" material loaded with three key factors in tissue repair, which releases growth factors in a sequential manner. This could enable the development of more clinically relevant treatment devices for bone regeneration and the principles of cell homing-based therapy from the bone regeneration model can be readily applied to regenerating other tissues.

基于细胞移植的传统组织工程技术存在明显的缺陷，譬如细胞死亡、病原菌传播、可能的免疫排斥和潜在的肿瘤病变。这些缺陷造成医疗监管困难，严重阻碍了组织工程技术向临床应用的转化。基于细胞归巢的组织工程技术归避了细胞移植，充分调动自身细胞的修复潜能，是再生医学的新思维，但是否能够精确调控细胞归巢、繁殖和分化是此新方法能否被普遍应用的关键点。当前的生物支架大多利用单一的生物活性因子，组织再生效果欠佳。为了模拟自发的修复过程，植入的支架最好按时间顺序程序性地释放一系列生物因子，分别调控细胞归巢、增殖和分化，引导归巢细胞形成所期望的组织。本项目将以骨再生为模型筛选正确的细胞趋化因子，探讨三生长因子协调作用的必要性和优越性，构建全新的三生长因子释放体系，并通过动物实验验证基于细胞归巢的组织工程新技术应用于骨再生的可行性。

以探索基于细胞归巢的骨组织工程为研究目标，通过考察干细胞的PDGFR表面改性对干细胞迁移的影响、生物材料的拓扑结构对干细胞浸润的影响、以及生物因子的协同作用对干细胞增殖和骨分化的影响，发展了基于自体干细胞的迁移为基础的骨组织工程新技术。具体而言，我们建立了基于干细胞的PDGFR表面改性诱导干细胞迁移的技术体系；开发了基于同向纤维的多孔支架诱导干细胞的黏附、迁移和分化；开发了基于核-壳结构高分子微球的双因子控释体系；利用核-壳结构的双因子控释微球研究了增殖因子和分化因子的协同作用对骨再生的影响（体外细胞实验和动物实验）。通过项目的完成取得了一批具有重要意义的研究成果，在Journal of Materials Chemistry B、Journal of Biomedical Materials Research Part A、Chemical Engineering Science等国际学术期刊上发表学术论文5篇，申请专利3项，独立培养硕士、博士研究生共12人。其中2人已通过硕士学位论文答辩，1人获国家奖学金（博士生）。同时，项目负责人在项目执行期间，获得了湖南省自然科学杰出青年基金的资助，并与国内外有关单位开展了多层次、多方位的科研合作和学术交流，围绕生物材料和组织工程的研究建立了良好的合作关系；日本NIMS组织再生材料中心主任陈国平（Guoping Chen）教授、北京大学生物医学工程系教授戴志飞教授、中国科学院上海硅酸盐研究所吴成铁教授专家应邀到项目组访问和讲学；项目负责人在2013 TERMIS-AP（上海、乌镇）、2014 ISOMRM （长庚大学）、2014 Asian BioCeramics Symposium （上海）、第六届全国组织工程与再生医学大会（西安）, 第十四届全国生物材料大会（西安）等国际、国内会议报道了相关研究成果。

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