基于仿生功能表面与锂离子可控释放的生物陶瓷支架构建及骨-软骨一体化修复机制研究

Articular cartilage repair is a great challenge in the field of orthopedic surgery. Previous studies have found that the bi-lineage osteochondral conducive scaffold may be an ideal substitute for articular defect. However, as a critical challenge by the different physiological and pathological characteristics of articular cartilage and subchondral bone, the scaffold capability in cell adhesion, osteochondral differentiation and the maintaining of cartilaginous phenotypic for simultaneously osteochondral regeneration is still not reliable. As a result, the insufficient osteochondral regeneration capacity limits the application of the existing scaffold, especially in large-size cartilage defect repair. As a multi-lineage conducive biofactor, it has been proven that Lithium ions (Li+) could simultaneously promote osteogenic differentiation of stem cells and the phenotypic maintenance of cartilaginous tissue. Meanwhile, inspired by the universal adhesion of Mussels, polydopamine (PDA) self-assembly nanometer layer coating may be an effective surface modification for the scaffold to promote cell adhesion and biological performance. To address the relevant issues, the current study will build up a porous bioceramics scaffold with controlled-release of Li+ ions. Meanwhile, Mussel biomimetic surface of the scaffold will be constructed using PDA coating at the surface of the scaffold for cartilage regeneration. The insights of regeneration and regulation will be provided through the observation of the synergistic effect of Li+ ions and PDA coating for stem cell biological response, including cell adhesion, differentiation, extracellular matrix accumulation, relative gene expression, and the underlying signaling pathways. The successful completion of this project will develop an integrated method for the construction of osteochondral conducive scaffold that is capable of promoting better regeneration of both articular cartilage and subchondral bone in large defect.

如何实现符合生理结构和功能的软骨修复一直是临床亟待攻克的难题。构建骨-软骨一体化修复组织工程支架被认为是实现工程化软骨修复的理想方法，但由于软骨和软骨下骨具有不同的生理、病理特点，目前的支架难以有效实现促干细胞粘附、成骨与成软骨双向诱导分化及软骨表型维持，导致支架修复性能不足，大面积软骨缺损往往存在修复缺陷。受海洋生物贻贝的广泛粘附能力和锂（Li+）离子多向诱导分化生物性能的启发，本项目拟构建Li+离子可控释放的生物陶瓷支架，并在支架成软骨层制备可控的自组装PDA纳米生物活性涂层；通过研究PDA表面修饰、控释Li+离子微环境的单独/协同调控作用对干细胞在支架粘附、增殖、分化及相关基因表达等生物学响应的影响及其机理，结合动物模型的支架在体修复效能研究，初步建立具有主动修复功能与可调控生物响应特性的骨-软骨一体化修复支架的设计和优化的理论方法，为实现稳定可控的工程化软骨修复提供理论和技术支撑。

组织工程技术是骨性关节炎治疗方面非常有潜力的方法之一，特别是利用生物支架实现骨-软骨一体化修复将可能实现稳定的软骨修复。本项目通过构建具有Li+离子可控释放、PDA仿生表面的生物陶瓷支架，研究控释Li+离子微环境、PDA仿生表面的调控作用对BMSCs在支架粘附、增殖、分化及相关基因表达等生物学响应的影响及其机理，结合支架在体修复效能研究，获得一系列研究结果，包括：（1）通过溶胶-凝胶法制备含锂钙硅酸生物陶瓷材料（Li2Ca4Si4O13，L2C4S4）的方法；（2）基于FDM 3D打印技术，通过对支架三维多孔结构的精细控制（孔大小170μm-400μm），实现了支架力学特性的控制（L2C4S4 scaffolds抗压强度15-40 MPa）及Li离子的可控释放；（3）体外研究发现，Li离子能够通过激活type II collagen、Aggrecan等相关基因，促进BMSCs的软骨分化，同时Li、Ca、Si微环境能够通过激活Runx2 、OCN等基因表达，促进BMSCs的成骨分化；（4）PDA 能够通过其自助装表面的广泛粘附性能，有效促进细胞在支架表面的粘附；（5）优化后的3D打印L2C4S4 生物陶瓷支架具有良好的促骨-软骨一体化修复效能。本项目的研究结果初步建立了一种具有稳定骨-软骨一体化再生性能的组织工程支架设计和优化的理论方法，为实现稳定可控的工程化软骨修复提供了一定的理论和技术支撑。

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