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.

抽象的： 该提案的总体目标是为必须接受治疗的患者设计替代气道 他们的气管因受伤、感染或癌症而被切除。气管疾病导致约 4,000 美国每年进行气管切除术。但与体内大多数其他结缔组织不同 - 例如 血管、骨骼、皮肤和肌腱——目前尚无气管组织的替代品 临床广泛使用。对于长度小于 5 厘米的小气管缺损，病变组织可以 通常通过原生气管的初次再吻合来切除。然而，这需要施加牵引力 影响天然气道，可能导致缺血、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，根本没有办法恢复气道。因此，缺乏 合适的气管置换术是一个重大的医疗问题。 理想的替代气管组织是具有天然机械性能的组织 气道（例如可以抵抗拉力和压力）；不需要免疫抑制；很容易 使用标准技术可植入；可以在气管环境的微弱血液供应中生存 无吻合失败；并且很容易获得。最近，我们描述了一种新颖的工程化非细胞 满足大部分这些要求的组织，并且在几种动物中至少发挥两个月的功能 模型。然而，在啮齿类动物和灵长类动物中大约 30% 的植入物中，我们观察到移植物中期 导致气道闭塞的纤维化狭窄，其中含有成纤维细胞和丰富的胶原基质 沉积，但上皮再生很少。该应用程序的基本前提是不良主机 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。具体来说，我们假设宿主纤维化的触发因素可能是宿主的超生理僵硬。 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，上皮细胞再生不足 由宿主基底细胞改造的气管可能导致缺乏局部纤维化抑制剂，包括前列腺素 E2。该应用程序将探索这两个假设，以努力改善长期功能 工程气管置换术。从长远来看，这项工作的影响涉及开发功能性的 气管置换术每年可以帮助数千名患者。此外，我们可能会影响我们的 了解其他临床环境中发生的气管狭窄。