面向脊髓损伤修复的多材料体素级微挤出3D打印机理及工艺研究

Spinal cord injury (SCI) is the most severe diseases. Neural stem cells (NSCs) transplantation is regarded as a promising therapeutic strategy to treat severe SCI by compensating the neuronal loss. Many inhibitors in the SCI microenvironment limit the ability of spinal cord NSCs to regenerate into neurons. A biomimetic microenvironment composed of cell,growth factors and biomaterials is needed for controlling the NSCs fate to the neuron. Hydrogel is easy to load cell and growth factor. While it is difficult to construct fine microenvironment for its high viscoelasticity property. Extruding printing process could adapt to wide viscosity range biomaterials. The multimaterials based single nozzle extruding printing process was developed.A fluid dynamics model of high viscoelasticity hydrogel in nozzle was developed. The fine discrete method based on physical model and time domain function was developed. The Mechanism of Extrued strand solidification and Interface Bonding under Temperature field and Stress field was studied for optimization of forming parameters.Based on One-dimensional Continuous printing technology，a 50-200 micronmeters precision voxel discretion and stacking. Concentration gradient of growth factors fabrication methods is conducted through growth factors controlled release. Multi-structure and multi-cell printing process will developed which achieved the Spinal cord tissue construction. This project will break through the difficulty of Spinal cord tissue construction. It will be a milestone of regenerative medicine and organ manufacturing.

脊髓损伤是最严重的组织损伤之一。神经干细胞移植被认为是目前最有希望的修复手段，为控制移植神经干向神经元定向分化，达到受损神经功能恢复的目的，需要实现细胞、因子及材料仿生微环境的精确构建，将干细胞与其微环境共同移植到损伤处修复。水凝胶可方便负载细胞及因子，但由于其强粘弹性属性难以实现精细微环境构建。本项目利用挤出技术打印粘度范围广的优点，开发单喷头多材料挤出工艺。基于高粘弹性水凝胶在打印头内的流体动力学模型，研究基于物理模型时域函数的精细离散控制方法，实现打印挤出微丝材料、体积的精准控制。研究温度场和应力场下水凝胶材料挤出丝材固化及界面粘接机理，实现成型工艺参数优化。基于一维连续无界面打印创新技术，实现水凝胶多材料50-200微米体素级精度离散及堆积。最终实现多细胞精细分区、因子浓度梯度以及微孔阵列的精细打印工艺，改变脊髓损伤修复缺乏有效手段的现状，对再生医学和器官制造具有里程碑式的意义。

项目背景：脊髓损伤是最严重的组织损伤之一。神经干细胞移植被认为是目前最有希望的修复手段，为控制移植神经干向神经元定向分化，达到受损神经功能恢复的目的，需要实现细胞、因子及材料仿生微环境的精确构建，将干细胞与其微环境共同移植到损伤处修复。水凝胶可方便负载细胞及因子，但由于其强粘弹性属性难以实现精细微环境构建。.研究内容：本项目利用挤出技术打印粘度范围广的优点，开发单喷头多材料挤出工艺。基于高黏弹性水凝胶在打印头内的流体动力学模型，研究基于物理模型时域函数的精细离散控制方法，实现打印挤出微丝材料、体积的精准控制。研究温度场和应力场下水凝胶材料挤出丝材固化及界面粘接机理，实现成型工艺参数优化。基于一维连续无界面打印创新技术，实现水凝胶多材料50-200微米体素级精度离散及堆积。最终实现多细胞精细分区、因子浓度梯度以及微孔阵列的精细打印工艺，改变脊髓损伤修复缺乏有效手段的现状，对再生医学和器官制造具有里程碑式的意义。.重要结果及关键数据：建立了基于黏弹性材料动力模型的生物墨水的输运与组装理论，提出了基于的多物理场协同调控的生物3D打印方法，设计了基于软物质输运模型的高精度生物打印头，实现了多样化生物墨水材料（包括水凝胶与熔融高分子）的高精准匹配，构建了面向组织体素化多维张量数字模型，开发了面向血管化组织体外构建的创新型设计与工艺规划软件平台BiopDesigner。开发了基于高速微阀切换控制的多材料连续式打印工艺；基于离散控制创新算法的高精度墨水启停控制打印工艺；基于模型控制的生长因子浓度梯度精准打印工艺。.科学意义：本项目提出的体素化微挤出打印方法不仅可用于脊髓损伤修复，对复杂组织器官构建也具有广泛理论和应用价值。