Advanced tissue engineering strategies for generating replacement tracheal tissues

气管狭窄、声门下狭窄和气管创伤需要手术切除。当涉及短节段时，初次再吻合可提供良好的结果。然而，更长的病变目前没有可接受的解决方案。有些患者需要永久性气管造口术或仅接受姑息治疗。气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，但仍有许多工作要做。组织工程解决方案，使用构建的基板，提供了一个更简单的方法，大大降低免疫原性的风险最好的希望。迄今为止，大量的工作已经取得了令人兴奋的进展，但主要集中在软骨细胞再生和结构完整性上。气道的上皮层具有几种功能：屏障功能、粘液分泌和粘膜纤毛清除吸入的病原体，但它受到的关注少得多。后一种作用需要构成整个气道树的数百万上皮细胞的纤毛同步、对齐地跳动。控制最佳上皮成熟和组织的因素几乎没有被探索，更不用说定义了。目前的合作提案将汇集一个工程师和临床医生团队，以提高我们对可以通过工程控制上皮组织和组织功能的物理因素的理解。具体来说，我们将暴露发育中的上皮细胞控制的物理力量，并检查由此产生的影响，上皮组织在二维和三维上皮层。我们假设，物理力将影响上皮细胞的生长、组织和功能成熟，所述上皮细胞从工程化基底膜上的局部祖细胞生长，并且在组织发育期间工程化特定物理力将提供用于改善细胞的质量和临床效用的新策略。

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