Extensible Collagen Hydrogels for Cartilage Tissue Engineering

本研究的目的是开发具有良好延展性和韧性的组织工程化耳软骨， 天然组织。由于先天性缺陷如小耳畸形引起的儿童耳廓畸形， 临床负担，具有显著相关的心理发病率和合理的偏侧化困难。 自体软骨移植物是目前的临床护理标准，不能用于耳廓移植。 5岁以下儿童的重建，由于供体软骨不足。组织工程耳廓 形成是新软骨形成的可行策略， 护理标准。然而，用于耳软骨组织工程的材料还不能 实现原生级别的可扩展性和韧性。天然材料，如贻贝深海丝， 通过聚组氨酸-和DOPA-金属络合物形成而具有高延展性和韧性。这些复合物 在许多水凝胶系统中改善了延展性和韧性。然而，这种复杂的结构并没有被 成功应用于胶原蛋白水凝胶系统。作者的初步工作表明， 寡聚物可以与胶原分子缀合而不破坏胶原结构或功能， 导致可扩展性的显著改进。作者假设，改变 藻酸盐低聚物的缀合和那些低聚物的长度将导致在细胞中的延展性的变化。 得到的胶原凝胶。因此，目标1将确定延展性和韧性的最佳参数， 而不破坏天然结构和功能。通过改善材料的延展性和韧性， 在胶原水凝胶的基础上，作者假设体外和体内培养的机械 类似地将改进耳构造。因此，目标2是针对耳廓软骨细胞接种的构建体的制造，并测试所得的机械和生物化学发展。同样，目标3是 在小鼠皮下模型中制造耳廓软骨细胞，并分析构建体 机械、生物化学和组织学发展。结合起来，这些目标将导致耳软骨 与小耳畸形患者的弹性软骨的天然机械功能相匹配的替代物， 耳廓畸形

This study aims to develop tissue engineered auricular cartilage with extensibility and toughness matching that of native tissue. Auricular malformation in children due to congenital defects such as microtia present an unmet clinical burden, with significant associated psychological morbidities and sound lateralization difficulties. Autologous cartilage grafts, which are the current clinical standard of care, cannot be used in auricular reconstruction for children under 5 years old, due to insufficient donor cartilage. Tissue engineered auricle formation is a viable strategy for neo-cartilage formation and can be implemented in children unmet by current standards of care. However, materials for tissue engineering of auricular cartilage have not been able to achieve native levels of extensibility and toughness. Natural materials such as mussel byssal threads achieve high extensibility and toughness through poly-histidine- and DOPA-metal complex formation. These complexes improve extensibility and toughness in many hydrogel systems. However, this complex formation has not been successfully applied to collagen hydrogel systems. Preliminary work by the author has shown that alginate oligomers can be conjugated to collagen molecules without disruption of collagen structure or function and leads to significant improvements in extensibility. The authors hypothesize that changing the extent of conjugation of alginate oligomers, and the length of those oligomers, will lead to changes in extensibility in resultant collagen gels. Thus, Aim 1 will determine the optimal parameters for extensibility and toughness, without disruption of native structure and function. By improving the extensibility and toughness of the underlying collagen hydrogel, the authors hypothesize that the mechanics of in vitro and in vivo cultured auricular constructs will similarly be improved. Aim 2 is thus directed at fabrication of auricular chondrocyte-seeded constructs, with testing of resultant mechanical and biochemical development. Similarly, Aim 3 is directed at fabrication of auricular chondrocytes in a murine sub-dermal model, with analysis of construct mechanical, biochemical, and histological development. Combined, these aims will result in auricular cartilage replacements that match the native mechanical function of elastic cartilage in patients with microtia and auricular deformities.