Mechanisms of regeneration in tissue engineered tracheal grafts

项目摘要/摘要 由于创伤、感染或其他原因，出生时或晚年可能会出现长段呼吸道缺陷。 恶毒。虽然罕见，但这些缺陷往往是致命的。目前还没有成熟的外科技术来 重建这种性质的缺陷，所以在罕见的情况下，患者存活下来，他们经常需要依赖 一种用于呼吸的长期气管切开管。如果没有重建策略，对气管的追求 替代品已经探索了使用外来材料、不能存活的组织和移植。这些 这些方法充满了复杂的情况。再生医学和组织工程学 用正常的、活的器官代替受损的器官来替换受损组织的能力。vt.给出 组织工程气管移植物(TETG)对长节段气管损伤的显著影响 在临床环境中对英勇措施的使用有限。尽管这是一种拯救生命的治疗方法 移植物狭窄和呼吸道组织再生等问题限制了TETG的临床应用。 为了探索生物人工TETG的有效性，我们建立了TETG的大型动物模型，并证明了 就像临床经验一样，移植物狭窄是最常见的并发症。 这项提议的目的是为了支持一位致力于 用于治疗复杂空气消化疾病的组织工程结构的发展。要推进 在组织工程气管置换领域，明确再生机制将是非常重要的 以及移植物狭窄。我们的假设是，这两个过程是相关的：狭窄可由 再生延迟；加速再生可减轻移植物狭窄。探索我们可以如何影响 移植物再生和最大限度地减少狭窄，我们将调整对构建 组织工程化气管：种子细胞、支架和宿主反应。我们开发了一种小鼠 TETG的模型，以满足我们的三个目标。我们的第一个目标将检查剂量依赖的影响和命运 种子细胞。我们的第二个目标将探索改变支架孔隙率和成分对 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 这些要素的相对影响不仅解决了许多不同方法的核心问题 呼吸道组织工程，但将允许我们为下一步的合理设计制定策略 产生TETG，并探索靶向治疗以优化再生。职业生涯的完成 本申请中提出的开发计划和研究将生成初步数据，这些数据将用于 作为R01资金的基础，以开发组织工程呼吸道。

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.