时间-空间可控生物活性分子释放的胶原支架用于脊髓损伤神经网络重建的研究

项目名称： 时间-空间可控生物活性分子释放的胶原支架用于脊髓损伤神经网络重建的研究

项目编号： No.81471276

项目类型： 面上项目

立项/批准年度： 2015

项目学科： 医药、卫生

项目作者： 李晓然

作者单位： 中国科学院苏州纳米技术与纳米仿生研究所

项目金额： 80万元

中文摘要： 神经干细胞移植为脊髓损伤修复带来希望，但仍面临挑战。主要包括损伤急性期胶质细胞活化并分泌抑制因子，修复期缺乏空间分布的神经营养因子。因此，构建生物活性分子时间、空间协同释放的支架载体，才能满足脊髓损伤修复不同阶段、位置的需求。本项目拟将表皮生长因子受体(EGFR)抗体和脑源性神经营养因子(BDNF)的时空控释引入胶原支架，一方面，EGFR抗体、BDNF顺序释放抑制急性期胶质细胞活化，促进修复期神经干细胞向神经元分化；另一方面，EGFR抗体梯度释放阻断抑制因子作用，BDNF梯度释放诱导轴突长距离延伸。为此，我们采用融合胶原特异结合短肽(CBD)的EGFR抗体，利用CBD改造分子与微球担载因子释放速度不同实现顺序释放；最终通过CBD-EGFR抗体静电喷雾梯度涂覆和BDNF-PLGA微球梯度担载实现CBD-EGFR抗体/BDNF梯度、顺序释放。加深脊髓损伤修复时空调控的认识，为临床应用奠定基础。

中文关键词： 脊髓损伤；神经干细胞；功能胶原支架；梯度释放；顺序释放

英文摘要： Neural stem cell (NSC) transplantation offer potential therapeutic strategies for spinal cord injury (SCI) repair. However, it will not be sufficient to achieve complete functional restoration. The poor axonal regeneration is due to the presence of axonal growth inhibitors and lack of temporal and spatial expression of neurotrophic factors. Functionalized scaffolds which can provide temporally and spatially controlled biomolecule delivery for NSC tranplantion are becoming increasingly attractive. We propose here a strategy based on gradient and sequential delivery of epidermal growth factor receptor (EGFR) antibody and brain-derived neurotrophic factor (BDNF) from collagen scaffolds. On the one hand, a sequential delivery of EGFR antibody and BDNF was supposed to reduce the activation of glial cells during the acute phase response, and further promote neuronal differentiation of NSCs during the long-term regeneration. On the other hand, a gradient delivery of EGFR antibody was supposed to attenuate spatially the effect of myelin associated inhibitors, and, BDNF gradient delivery was supposed to promote long-distance axonal regeneration. In order to achieve the gradient and sequential delivery, the EGFR antibody fused with a collagen-binding domain (CBD) derived from collagenase was electrosprayed gradiently on the three-dimensional collagen scaffolds incorporated with spatially distributed BDNF-poly (lactide-co-glycolide) (PLGA) microspheres. The present study will contribute to a better understanding of temporal and spatial regulation following NSC transplantation after SCI repair, and provide valuable information for its clinical use.

英文关键词： Spinal cord injury;Neural stem cell;Functionalized collagen scaffold;Gradient delivery;Sequential delivery