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： 该提案的首要目标是为必须使用呼吸道的患者设计一种替代气道。 他们的气管因受伤、感染或癌症而被切除。气管疾病导致大约4000 气管切除手术的数量。但与体内大多数其他结缔组织不同的是， 血管，骨骼，皮肤和肌腱-目前还没有替代气管组织， 广泛的临床应用。对于长度小于5 cm的小气管缺损，病变组织可 通常在原生气管的初次再吻合的情况下切除。然而，这需要把牵引力 可能导致局部缺血、吻合口裂开和纵隔炎的风险， 致命的此外，对于较长的气管缺损，根本没有恢复气道的方法。因此，缺乏 合适的气管替代物是一个重要的医学问题。 理想的替代气管组织将是具有天然力学性能的组织 气道（例如，可以抵抗拉伸力和压缩力）;不需要免疫抑制;容易 使用标准技术植入;可以在气管环境的稀薄血液供应中存活 没有吻合失败;并且容易获得。最近，我们描述了一种新的工程化的，无细胞的， 满足这些要求中的大部分，并且在几种动物中至少作用两个月的组织 模型然而，在啮齿动物和灵长类动物中约30%的植入物中，我们观察到移植物中期 导致气道阻塞的纤维化狭窄，其中含有成纤维细胞和丰富的胶原基质 沉积，但很少上皮再生。此应用程序的潜在缺点是， 重塑反应导致气道纤维化和狭窄， 气管具体来说，我们假设宿主纤维化的触发因素可能是超生理硬度， 工程气道，可以影响Hippo通路和TGF-β信号传导，并导致成纤维细胞 增殖和胶原沉积。第二个假设是，上皮细胞的重新增殖不足， 由宿主基底细胞构建的气管可能导致缺乏纤维化的局部抑制剂，包括前列腺素 E2.本申请将探讨这两种假设，以努力提高长期的功能， 人工气管替代品从长远来看，这项工作的影响涉及到开发一个功能 每年可以帮助成千上万的病人。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。