研制应用于不规则骨缺损修复的材料已成为临床应用的迫切需要。模仿生长因子的时序表达作用机制，研制可时空控制生长因子释放的载体材料及技术已成为研究的热点。本项目将应用双光子近红外光控技术（NIR），建立可活体内无创性的时空控制生长因子释放的方法，开发可注射性并在低能量NIR激光激发下释放生长因子的骨修复材料。BMP-2活性多肽和VEGF将分别用作模型多肽和模型蛋白。多聚谷氨酸多肽序列修饰的BMP-2活性肽将与纳米晶人工骨nHAC表面的HA组分的（002）晶面反应形成特异性生物结合，VEGF物理吸附在nHAC表面，再用光降解纳米凝胶包裹，通过前期开发的可注射性、温敏性壳聚糖将纳米凝胶顺序注射入骨缺损并成型。BMP-2活性多肽和VEGF将在程序化的NIR光照下时空控制释放。重点研究BMP-2活性多肽和VEGF的光触发释放机制，揭示新系统的时空控制释放规律、生物活性变化规律及促成骨和血管化的能力。

The limitations and morbidity associated with current surgical materials and techniques for reconstruction of irregular bone defects following the surgical removal of cysts or tumours has spurred the development of injectable bone repair materials to address these shortcomings. Injectable bone repair materials can fill irregular bone defects with minimally invasive surgery and are considered ideal delivery vehicles for growth factors. Recently, a combined therapy of various growth factors has been investigated to demonstrate the therapeutic efficacy to induce bone formation. Spatially and temporally controlled release of multiple growth factors in vivo have been noted to allow growth factors to enhance their ability for bone regeneration and vascularization. To simulate the time profile of growth factors action, the controlled release system is one of the appropriate methods. NIR light can penetrate tissues deeply with the high spatial and temporal resolution of multiphoton excitation while causing minimal damage. The objective of this research is to develop injectable bone repair materials which will spatially and temporally controlled release of multiple growth factors in response to low power two-photon near-infrared light. BMP-2-derived peptide will be used as a model peptide and the vascular endothelial growth factor (VEGF) will be used as a model protein. Firstly, the BMP-2-derived peptide is modified with polyglutamate sequence, which can react with the (002) face of hydroxyapatite crystal on the surface of nano-hydroxyapatite/collagen (nHAC),and VEGF is physically absorbed on the on the surface of nHAC, respectively. Secondly, nHAC/BMP-2-derived peptide and nHAC/VEGF complexes will be encapsulated by photodegradable nanogels. Thirdly, the nanogels will be injected to the areas needed using the former developed temperature-sensitive delivery system of chitosan/nHAC, which is injectable, biodegradable, biocompatible and osteoconductive. Lastly, BMP-2-derived peptide and the vascular endothelial growth factor (VEGF) will be spatially and temporally released by programmed irradiation with NIR light. This research will focus on the light-triggered release mechanism of BMP-2-derived peptide and VEGF, and reveal the spatially and temporally controlled release rule of this new system, the variation of biological activity, the ossification and vascularization ability of this new system.

研制应用于不规则骨缺损修复的材料已成为临床应用的迫切需要。模仿生长因子的时序表达作用机制，研制可时空控制生长因子释放的载体材料及技术已成为研究的热点。绝大多数光响应的药物递送体系都对紫外光或可见光响应,而紫外光和可见光的组织穿透性相比于近红外光较弱，限制了这些体系的生物应用。本项目应用双光子近红外光控技术（NIR），建立了可活体内无创性的时空控制生长因子释放的方法，开发了可注射性并在低能量NIR激光激发下释放生长因子的骨修复材料。在该材料中，多聚谷氨酸多肽序列修饰的BMP-2活性肽将与纳米晶人工骨nHAC表面的HA组分的（002）晶面反应形成特异性生物结合，VEGF物理吸附在nHAC表面，通过前期开发的可注射性、温敏性壳聚糖将纳米凝胶顺序注射入骨缺损并成型。体系中的光敏剂能有效吸收NIR 光并转化为热能，从而实现NIR光控响应释放。此外，该体系在 pH 和 NIR 光双刺激下，获得比单一刺激信号更高效率的响应释放。BMP-2活性多肽和VEGF在程序化的NIR光照下时空控制释放。总之，本项目制备的新型温敏性水凝胶可实现药物的时空控制释放和近红外光诱导的多次反复释放，为骨修复过程中生长因子的递送提供了一种新的思路和技术。