Mechanisms of regeneration in tissue engineered tracheal grafts

组织工程气管移植物的再生机制

• 批准号: 9371368
• 负责人: Tendy Chiang
• 金额: $ 16.15万
• 依托单位: RESEARCH INST NATIONWIDE CHILDREN'S HOSP
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-07-14 至 2022-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9371368
• 关键词: Acceleration; Address; Affect; Age; Animal Model; Attenuated; Autologous; Basal Cell; Birth; Blood Vessels; Bone Marrow; Bone Marrow Purging; Bone Marrow Transplantation; Breathing; Cells; Childhood; Clinical; Complex; Complication; Data; Defect; Development; Development Plans; Disease; Dose; Elements; Epithelial; Epithelium; Foreign-Body Reaction; Foundations; Funding; Gender; Generations; Goals; Green Fluorescent Proteins; Growth; Harvest; Immune response; Implant; Infection; Infiltration; Inflammatory; Knock-out; Label; Life; Malignant Neoplasms; Measures; Mentorship; Modeling; Mononuclear; Mus; Natural regeneration; Nature; Operative Surgical Procedures; Organ; Patients; Performance; Phenotype; Porosity; Positioning Attribute; Process; Protocols documentation; Public Health; Rare Diseases; Regenerative Medicine; Research; Role; Savings; Scientist; Secretory Cell; Source; Stem cells; Stenosis; Surgeon; Techniques; Tissue Engineering; Tissue Transplantation; Tissues; Trachea; Tracheal Diseases; Tracheostomy Tube; Tracheostomy procedure; Transgenic Animals; Translating; Trauma; Vascular Graft; Wild Type Mouse; Wound Healing; base; career development; cell motility; clinical translation; design; direct application; experience; implantation; improved; macrophage; migration; mouse model; nanofiber; next generation; novel; paracrine; reconstruction; repaired; respiratory; response; scaffold; sex; targeted treatment; vascular tissue engineering

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.

项目概要/摘要 长段气道缺陷可能在出生时或晚年因创伤、感染或 恶性肿瘤。尽管很少见，但这些缺陷往往是致命的。目前尚无成熟的手术技术 重建这种性质的缺陷，因此在患者幸存的极少数情况下，他们经常需要依靠 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 替代品已经探索了使用外来材料、非活性组织和移植。这些 这些方法充满了复杂性。再生医学和组织工程具有 用正常的活器官替代衰竭组织而不是治疗受损器官的能力。给定 长段气管受损的显着影响，组织工程气管移植物（TETG） 在临床环境中英雄措施的使用有限。尽管这对患者来说是挽救生命的治疗方法 一些问题包括移植物狭窄和气道组织再生等问题限制了 TETG 的临床转化。 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 与临床经验一样，移植物狭窄是观察到的最常见的并发症。 该提案的目标是支持致力于以下领域的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疾病。为推进 在组织工程气管置换领域，定义再生机制非常重要 以及移植物变窄。我们假设这两个过程是相关的：狭窄可能是由于 延迟再生；加速再生可以减轻移植物狭窄。探索我们如何影响 移植物再生并最大限度地减少狭窄，我们将调节对构建移植物至关重要的成分 组织工程气管：接种细胞、支架和宿主反应。我们开发了鼠标 TETG 模型来实现我们的三个目标。我们的首要目标是检查剂量依赖性影响和命运 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 这些要素中的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 生成 TETG 并探索优化再生的靶向疗法。完成职业生涯 本申请中提出的发展计划和研究将产生初步数据，可用于 作为 R01 资金开发组织工程气道的基础。