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.

项目摘要 /摘要 由于创伤，感染或 恶性。尽管很少见，但这些缺陷通常是致命的。目前尚无已建立的手术技术 重建这种性质的缺陷，因此，在患者生存的极少数情况下，他们经常需要依靠 长期气管切开术呼吸。没有重建策略，对气管的追求 替代品探索了外来材料，不可行的组织和移植的使用。这些 方法充满了并发症。再生医学和组织工程具有 用正常的生物器官而不是处理受损器官，可以替换失败的组织的能力。给出 长节气管妥协的显着影响，组织工程的气管移植物（TETG）具有 在临床环境中使用有限的英雄措施。尽管这是一种挽救生命的待遇 有些问题会狭窄的问题狭窄和气道组织的再生限制了TETG的临床翻译。 为了探索生物人工TETG的功效，我们开发了一个大型的TETG动物模型，并证明了 像临床经验一样，移植狭窄是观察到的最常见并发症。 该建议的这个目标是支持专门致力于的外科医生的职业发展 组织工程构建体的发展，以治疗复杂的机修工疾病。推进 组织工程气管置换的领域，定义再生机制非常重要 以及移植物狭窄。我们的假设是这两个过程是相关的：狭窄可能是由 延迟再生；再生的加速会减弱移植狭窄。探索我们如何影响 移植物再生并最大程度地减少狭窄，我们将调节对建造至关重要的成分 组织工程的气管：种子细胞，支架和宿主反应。我们开发了一只鼠标 TETG模型以解决我们的三个目标。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讨改变脚手架孔隙和成分对 再生。我们的第三个目标将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 气道组织工程，但将允许我们在下一个理性设计制定策略 产生TETG并探索靶向疗法以优化再生。完成职业 开发计划和本应用程序中提出的研究将生成初步数据，该数据将服务 作为R01资金开发组织工程气道的基础。