Engineered Tracheal Replacements

工程气管置换术

• 批准号: 9376650
• 负责人: LAURA E NIKLASON
• 金额: $ 64.62万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-08-15 至 2021-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9376650
• 关键词: Affect; Anastomosis - action; Animal Model; Basal Cell; Blood Vessels; Cells; Clinical; Collagen; Congenital Abnormality; Connective Tissue; Defect; Deposition; Dinoprostone; Disease; Engineering; Environment; Epithelial; Epithelium; Excision; Extravasation; Failure; Fibroblasts; Fibrosis; Goals; Immunosuppression; Implant; In Vitro; Infection; Injury; Ischemia; Lead; Length; Liquid substance; Literature; Malignant Neoplasms; Mediastinitis; Mediastinum; Mediating; Medical; Mesenchymal; Methods; Microfabrication; Nuclear; Pathway interactions; Patients; Phenotype; Physiological; Population; Primates; Production; Rattus; Reporting; Resected; Risk; Rodent; Role; Seeds; Serum; Signal Transduction; Skin; Smooth Muscle Myocytes; Stenosis; Stents; Surgeon; Techniques; Tendon structure; Testing; Tissues; Trachea; Tracheal Stenosis; Traction; Transcription Coactivator; Transforming Growth Factor beta; Traumatic injury; United States; Vascular blood supply; Work; airway epithelium; base; biomaterial compatibility; bone; design; follow-up; implantation; improved; in vivo; inhibitor/antagonist; mechanical properties; migration; novel; repaired; response; transcriptome sequencing; tumor

ABSTRACT: The overarching Goal of this proposal is to engineer a replacement airway for patients who must have their tracheas resected due to injury, infection, or cancer. Diseases of the trachea lead to approximately 4,000 tracheal excisions per year in the United States. But unlike most other connective tissues in the body - such as blood vessel, bone, skin and tendon - there currently are no replacements for tracheal tissue that are in widespread clinical use. For small tracheal defects that are less than ~ 5 cm in length, diseased tissue can generally be excised with primary re-anastomosis of the native trachea. However, this requires putting traction on the native airway that can lead to risk of ischemia, anastomotic dehiscence, and mediastinitis, which can be fatal. Furthermore, for longer tracheal defects, there is no approach at all to restore the airway. Therefore, lack of a suitable tracheal replacement is a Significant medical problem. The ideal replacement tracheal tissue would be one that has the mechanical properties of the native airway (eg. can resist both tensile and compressive forces); does not require immunosuppression; is easily implantable using standard techniques; can survive the tenuous blood supply of the tracheal environment without anastomotic failure; and is readily available. Recently, we described a novel engineered, acellular tissue that fulfills most of these requirements, and which functions for at least two months in several animal models. However, in approximately 30% of implants in rodents and primates, we have observed mid-graft fibrotic stenoses that led to airway occlusion, which contained fibroblasts and abundant collagen matrix deposition, but little epithelial repopulation. The underlying Premise of this application is that undesirable host remodeling responses lead to the airway fibrosis and stenosis that is seen in a subset of these engineered tracheas. Specifically, we hypothesize that a trigger of host fibrosis may be the supra-physiological stiffness of the engineered airways, which can impact the Hippo pathway and TGF-signaling and lead to fibroblast proliferation and collagen deposition. A second hypothesis is that inadequate epithelial re-population of the engineered trachea by host basal cells may lead to a lack of local inhibitors of fibrosis, including prostaglandin E2. This application will explore both of these hypotheses in efforts to improve the long-term functionality of engineered tracheal replacements. In the long term, the Impact of this work relates to developing a functional tracheal replacement that could help thousands of patients each year. In addition, we may Impact our understanding of tracheal stenosis that occurs in other clinical settings.

摘要： 这项提案的首要目标是为那些必须有 他们的气管因受伤、感染或癌症而被切除。气管疾病导致约4,000人 在美国，每年的气管切除手术。但与身体中的大多数其他结缔组织不同--例如 血管、骨、皮肤和肌腱-目前还没有替代气管组织的材料 广泛的临床应用。对于长度小于~5厘米的小气管缺陷，病变组织可以 一般行切除，一期气管再吻合术。然而，这需要将牵引力 会导致缺血、吻合口裂开和纵隔炎的风险，这可能是 致命的。此外，对于较长的气管缺陷，根本没有恢复呼吸道的方法。因此，缺乏 合适的气管置换是一个重大的医学问题。 理想的替代气管组织应该是具有天然气管组织的机械性能。 呼吸道(例如可以抵抗拉力和压缩力)；不需要免疫抑制；很容易 可使用标准技术植入；可以在气管环境中稀薄的血液供应中存活 无吻合口失败；且容易获得。最近，我们描述了一种新型的工程化脱细胞 满足大多数这些要求的组织，在几种动物身上至少能发挥两个月的作用 模特们。然而，在大约30%的啮齿动物和灵长类动物的植入中，我们观察到了中期移植 导致呼吸道阻塞的纤维性狭窄，其中含有成纤维细胞和丰富的胶原基质 沉积，但几乎没有上皮细胞再生。此应用程序的基本前提是不受欢迎的主机 重塑反应导致气道纤维化和狭窄，这在这些工程化的子集中可见 气管。具体地说，我们假设宿主纤维化的触发因素可能是超生理僵硬。 影响河马通路和转化生长因子-信号转导途径的工程化呼吸道，导致成纤维细胞 细胞增殖和胶原沉积。第二个假说是上皮细胞数量不足 由宿主基底细胞设计的气管可能导致缺乏包括前列腺素在内的局部纤维化抑制物 E2。这个应用程序将探索这两个假设，以努力改善 工程化的气管置换。从长远来看，这项工作的影响与开发一种功能 每年可以帮助数千名患者的气管置换术。此外，我们可能会影响我们的 了解在其他临床环境中发生的气管狭窄。