基于环状结构促进大动物长段气管缺损修复

修复长段气管缺损是国际难题，关键在于缺乏理想的气管替代物。组织工程技术有望构建具有生命活性的气管替代物，但受仿生力学特性（径向刚性和纵向柔韧性）、血管化、上皮化等难题制约，至今未取得临床突破。本课题设计“环状结构”构建方案，先联合3D生物打印技术及生物力学反应器构建具有高力学强度的仿生软骨环，再对负载促血管因子的胶原环内环表面接种上皮细胞；随后通过硅胶管串联形成“软骨环-胶原环”交替排列的嵌合体，植入体内后包裹带血供肌肉组织，随着胶原环的逐步降解，软骨环之间的支架材料逐渐由结缔组织及血管替代长入，且长入内腔的血供会促进上皮的增生和迁移完成上皮化，最终形成“软骨环-结缔组织环”交替排列的仿生气管组织，一并解决仿生力学特性、血管化及上皮化的三大难题。最后，整合上述多种方案并改进前期已有修复技术，进行羊长段气管缺损修复和移植物结构、功能长期评估，为组织工程技术修复长段气管缺损的临床转化奠定基础。

Reconstruction of large segmental trachea defect is an international dilemma and the key challenge is the lack of an ideal tracheal substitute. Tissue engineering technology is expected to build a bioactive tracheal substitute, but it is still restricted by a series of thorny problems such as biomimetic mechanical properties (radial rigidity and longitudinal flexibility), vascularization, and epithelialization, so no clinical breakthrough has been achieved until now. This project designed a "ring structure" construction scheme, we firstly combined 3D bioprinting technology and biomechanical reactors to build a cartilage ring with high mechanical strength; Then, the collagen ring is loaded with angiogenic factor and its inner surface is colonized with epithelial cells; A chimera of cartilage ring/ collagen ring alternate structure is fabricated by silicon tube. Afterwards, the chimera is implanted into muscle tissue with abundant blood supply. With gradually degrade of the collagen rings, the collagen materials between cartilage rings is gradually replaced by connective tissue and blood vessels. The blood supply that penetrating into the lumen will promote the proliferation and migration of the epithelium, and eventually forms a biomimetic tracheal tissue featured with cartilage ring/connective tissue alternately structure, simultaneously solving the major problems of biomimetic mechanical properties, vascularization and epithelialization. Finally, we combine the above-mentioned multiple schemes with improved repair technology to perform long segmental tracheal defect repair and evaluate long-term structure and function of the graft. The current study provides a technical and theoretical basis for the clinical translation of repairing long-term tracheal defects by tissue engineering technology.