用于骨缺损修复的活性微管道网络生物结构体3D打印复合成形机理与方法及试验

Building bioactive micro-pipeline network structure with rich cells and growth factors through biological manufacturing technology has great significance for thoroughly repairing bone defects and thus shows tremendous potential appliation in many fields. However, deficients in manufacturing technology and equipment are also obvious. Aiming at solving these key technologies and basing on the 3D printing that integrate extrusion forming with electrospinning,this research project comes up with the idea of combining the characteristics of many technologies such as controlled cell assembling,micro-pipeline forming,cell migration and coaxial electrospinning.Combining theories such as rheology, diffusion with numerical simulation and experimental technology, the mechanism of integrated forming cells and micro-pipeline,and the three-dimension controlled assembly method of the achieved structure are both studied, the concentration gradient math model for the growth factors in micro-pipeline is also established. Based on electro-hydraulic dynamics and interface theory, the sustained release behaivor of the coaxial nanofiber carrier for growth factor delivery is studied, the method for combining coaxial nanofiber carrier with macro bioactive structure is also probed. Through methods of hybrid modeling, decoupling controlling and motion controlling, the regulation mechanism and strategy for integrately 3D printing bioactive micro-pipeline network structure are studied. Finally, after having successfully built the required experimental platform, the validity of aforementioned theories and technologies is tested.

通过生物制造技术体外构建富含细胞和生长因子的活性微管道网络生物结构体，对于彻底解决骨缺损修复问题具有非常重要的意义，也表现出巨大应用潜力，但目前在制备工艺及装备技术方面还都存在局限。本项目正是锁定该关键技术领域，以生物3D打印挤出成形结合静电纺丝的复合成形方法为基础,并综合细胞直接受控组装,微管道成形，细胞迁移以及同轴静电纺丝的技术特点，根据流变学、扩散理论，运用数值模拟和试验方法，研究细胞与微管道结构一体化成形并三维受控组装的机理和方法,建立微管道内生长因子浓度梯度形成的数学分析模型；根据电液动力学，界面理论，研究载生长因子同轴纳米纤维载体控释行为，并探索其与宏观生物结构体可控复合的方法；通过混合建模，解耦控制方法，以及运动控制技术，研究活性微管道网络生物结构体3D打印复合成形过程的调控机理与调控方法。最后，利用研究成果建立试验平台并进行试验研究,验证研究理论和技术的正确性。

本项目围绕含细胞和生长因子的活性微管道网络生物结构体制备问题展开了深入研究，重点探索了离子交联凝胶化同轴流体成形微管道结构的机理，包括建立了数值分析模型及求解算法，揭示了离子交联同轴双相流流形演变规律，明确了成形微管道的关键参数、边界条件、以及调控离子交联凝胶化同轴流体交联度的机制，建立了基于交联度调控的微管道纤维三维搭接控制策略，给出了微管道成形尺寸控制方法；研究了同轴纳米纤维作为药物控释载体的药物控释机理及成形工艺方法，提出了多药物可控携载和梯度可控释放的工艺方法，建立了纳米纤维与凝胶网格结构可控复合方法。最后，研究构建了3D 打印复合成形试验平台，开展了含微通道网络的生物结构体制备试验，验证了建立的理论方法及技术的有效性。