Mechanisms of regeneration in tissue engineered tracheal grafts

项目概要/摘要 长段气道缺损可在出生时或以后的生活中由于创伤、感染或 恶性肿瘤虽然罕见，但这些缺陷往往是致命的。目前还没有成熟的手术技术， 重建这种性质的缺陷，所以在罕见的情况下，病人生存，他们经常需要依靠 一种用于呼吸的长期气管切开插管。如果没有重建策略，气管的追求 替代物已经探索了外来材料、非活性组织和移植的使用。这些 各种方法都充满了复杂性。再生医学和组织工程学 有能力用正常的活体器官替代衰竭的组织，而不是治疗受损的器官。给定 长段气管损伤的显著影响，组织工程气管移植物（TETG） 在临床环境中用于英雄的措施有限。虽然这是一种挽救生命的治疗方法， 移植物狭窄和气道组织再生的一些问题限制了TETG的临床应用。 为了探索生物人工TETG的功效，我们开发了TETG的大型动物模型，并证明了其在体内的作用。 与临床经验相似，移植物狭窄是观察到的最常见并发症。 该提案的目的是支持外科医生科学家的职业发展， 开发组织工程结构来治疗复杂的呼吸消化系统疾病。推进 在组织工程气管替代领域，明确再生机制将是重要的 以及移植物变窄。我们的假设是这两个过程是相关的：狭窄可能是由于 延迟再生;加速再生可减轻移植物狭窄。探索我们如何影响 移植物再生和最大限度地减少狭窄，我们将调节对构建一个 组织工程气管：种子细胞、支架和宿主反应。我们发明了一种老鼠 TETG的模式，以满足我们的三个目标。我们的第一个目标是研究剂量依赖的影响和命运， 种子细胞我们的第二个目标是探索改变支架孔隙率和组成对 再生我们的第三个目标是确定宿主免疫反应对再生的影响。定义 这些因素中每一个的相对影响不仅解决了许多不同方法的核心问题， 气道组织工程，但将使我们能够为下一步的合理设计制定策略 TETG的产生和探索靶向治疗，以优化再生。完成职业生涯 开发计划和本申请中提出的研究将产生初步数据， 作为R 01基金开发组织工程气道的基础。

PROJECT SUMMARY / ABSTRACT Long-segment airway defects can arise at birth or later in life as a result of trauma, infection, or malignancy. Although rare, these defects are often fatal. There is currently no established surgical technique to reconstruct defects of this nature, so in the rare case in which patients survive, they frequently need to rely on a long-term tracheostomy tube for breathing. Without reconstructive strategies, the pursuits of tracheal substitutes have explored the use of foreign materials, non-viable tissues, and transplantation. These approaches have been fraught with complications. Regenerative medicine and tissue engineering have the capacity to replaced failed tissue with a normal, living organ instead of treating a compromised organ. Given the significant impact of long segment tracheal compromise, tissue engineered tracheal grafts (TETG) have had limited use in the clinical setting for heroic measures. Although this has been a life saving treatment for some, problems will graft narrowing and regrowth of airway tissue have limited the clinical translation of TETG. To explore the efficacy of a bioartificial TETG, we developed a large animal model of TETG and demonstrated that like the clinical experience, graft narrowing is the most common complication observed. This objective of this proposal is to support the career development of a surgeon scientist devoted to the development of tissue-engineered constructs to treat complex aerodigestive disorders. To advance the field of tissue engineered tracheal replacement, it will be important to define the mechanisms of regeneration as well as graft narrowing. It is our hypothesis that these two processes are related: stenosis can result from delayed regeneration; acceleration of regeneration can attenuate graft stenosis. To explore how we can affect graft regeneration and minimize stenosis, we will be modulating the constituents critical to the construction of a tissue-engineered trachea: the seeded cells, the scaffold, and the host response. We developed a mouse model of TETG to address our three aims. Our first aim will examine the dose dependent impact and fate of seeded cells. Our second aim will explore the impact of changing scaffold porosity and composition on regeneration. Our third aim will identify the impact of the host immune response on regeneration. Defining the relative impact of each of these elements not only address questions central to many different approaches to airway tissue engineering, but will allow us to strategize our approach for the rational design the next generation of TETG and explore targeted therapies to optimize regeneration. Completion of the career development plan and the research proposed in this application will generate preliminary data which will serve as a foundation for R01 funding to develop tissue engineered airways.