Advanced tissue engineering strategies for generating replacement tracheal tissues

恶性肿瘤、声门下狭窄和气管外伤性损伤需要手术切除。短节段受累时，一期再吻合效果良好。然而，较长的皮损目前还没有可以接受的解决方案。一些患者需要永久性的气管切开术，或者只接受姑息治疗。呼吸道移植的最新进展为这些问题的潜在解决方案提供了新的乐观情绪，但仍有许多工作要做。使用构建的底物的组织工程解决方案最有希望实现一种简单得多的方法，并大大降低免疫原性的风险。到目前为止，大量的工作提供了令人振奋的进展，但主要集中在软骨细胞再生和结构完整性上。呼吸道上皮层具有多种功能：屏障功能、粘液分泌和清除吸入病原体的粘液纤毛，但人们对它的关注要少得多。后一种作用需要组成整个呼吸道树的数以百万计的上皮细胞的纤毛同步、排列地搏动。控制最佳的上皮成熟和组织的因素几乎没有被探索过，更不用说定义了。目前的协作提案将把工程师和临床医生团队聚集在一起，以增强我们对物理因素的理解，这些物理因素可以被设计来控制上皮组织和组织功能。具体地说，我们将把发育中的上皮暴露在可控的物理力量下，并检查由此产生的对二维和三维上皮层上皮组织的影响。我们假设，物理力将影响从工程基底膜上的局部祖细胞培养出来的上皮细胞的生长、组织和功能成熟，并且在组织发育过程中工程特定的物理力将为提高组织的质量和临床应用提供新的策略。

Malignancy, subglottic stenosis, and traumatic injury to the trachea require surgical resection. When short segments are involved, primary re-anastomosis affords excellent results. Longer lesions, however, have no currently acceptable solution. Some patients need permanent tracheostomies or receive only palliative treatment. Recent progress in airway transplantation has provided renewed optimism for potential solutions to these problems, however much remains to be done. Tissue engineered solutions, using constructed substrates, offer the best hope for a far simpler approach with much reduced risk of immunogenicity. Substantial work to date has provided exciting progress but has largely focused on chondrocyte regeneration and structural integrity. The epithelial layer of the airway has several functions: a barrier function, secretion of mucous, and mucociliary clearance of inhaled pathogens yet it has received much less attention. This latter role requires the synchronized, aligned beating of the cilia of the many millions of epithelial cells comprising the entire airway tree. The factors controlling optimal epithelial maturation and organization have barely been explored let alone defined. The present collaborative proposal will bring together a team of engineers and clinicians to enhance our understanding of physical factors that can be engineered to control epithelial organization and tissue functionality. Specifically, we will expose developing epithelium to controlled physical forces and examine the resulting effects on epithelial organization in two and three-dimensional epithelial layers. We hypothesize that physical forces will influence the growth, organization and functional maturation of the epithelial cells, grown from local progenitors on engineered basement membrane, and that engineering specific physical forces during tissue development will provide a novel strategy for improving the quality and clinical utility of