Engineering a Self-assembled, multi-tissue Tracheal Replacement

设计自组装多组织气管置换术

• 批准号: 9923657
• 负责人: Eben Alsberg
• 金额: $ 46.6万
• 依托单位: UNIVERSITY OF ILLINOIS AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-03-22 至 2023-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9923657
• 关键词: Address; Affect; Angiogenic Factor; Animal Model; Animals; Autologous; Bacterial Infections; Bioreactors; Blood Vessels; Cartilage; Cartilage Matrix; Cell Count; Cell Culture Techniques; Cell Density; Cells; Chondrogenesis; Complex; Connective Tissue; Culture Media; Custom; Defect; Development; Dimensions; Endothelial Cells; Engineering; Environment; Epithelial; Epithelial Cells; Epithelium; FGF2 gene; Failure; Gelatin; Goals; Growth Factor; Human; Implant; Individual; Interruption; Intubation; Ischemia; Length; Life; Mesenchymal Stem Cells; Microspheres; Modeling; Morphology; Natural regeneration; Necrosis; Nutrient; Operative Surgical Procedures; Organ; Oryctolagus cuniculus; Oxygen; Patients; Performance; Production; Proteins; Radial; Respiratory System; Role; Seeds; Stenosis; Structure; Structure of respiratory epithelium; Surface; System; TGFB1 gene; Technology; Testing; Tissue Engineering; Tissues; Trachea; Tracheal Epithelium; Tracheal Stenosis; Tracheostomy procedure; Tube; Tubular formation; Umbilical vein; Vascularization; Work; airway epithelium; base; blood vessel development; cartilaginous; cell type; density; effective therapy; functional restoration; healing; improved; in vivo; in vivo Model; innovation; mechanical properties; neovascularization; novel; novel strategies; prevent; reconstruction; respiratory; restenosis; scaffold; self assembly; spatiotemporal

Abstract There is currently no successful treatment for long-segment tracheal stenosis, most commonly a result of prolonged intubation or tracheostomy. Available treatment options are inadequate in preventing restenosis and often require successive surgeries. A tissue engineered trachea has the potential to fill this need. A functional tracheal replacement must (1) have radial rigidity, (2) be vascularized or encourage vascularization and (3) contain respiratory epithelium to restore an open airway while avoiding restenosis, bacterial infections and ischemic necrosis. This proposal seeks to develop a tracheal replacement with these functional requirements by fusing tissue rings into a composite tissue tube comprised of multiple cell types with controlled, localized growth factor presentation, and to evaluate its ability to serve as a tracheal replacement in a rabbit airway defect model in vivo. The hypothesis of this work is that a multi- cell type, scaffold-free neotrachea can be engineered with vital cellular organization and critical functionality by delivering bioactive factors in a spatiotemporally controlled manner to modular tissue units comprised of self-assembled human cells. By utilizing a custom assembly system, we will integrate the tissue ring units into a composite tubular tracheal construct. Specifically, the proposal aims to (1) engineer cartilaginous ring and tubular structures with defined dimensions and requisite mechanical properties using high-density hMSC culture to serve as radial support in the neotrachea, (2) engineer cartilage-prevascular composite tubular constructs with alternating cartilage and vascular tissue rings to support blood vessel formation in the neotrachea, (3) engineer a luminal epithelial lining on cartilaginous tubes for interfacing with the external environment and (4) test the capacity of the engineered tracheas to restore airway functionality in an animal defect model. This work seeks to engineer a replacement human trachea with radial rigidity that supports vascularization and epithelialization when implanted in vivo. This bottom-up, self- assembled high-cell density strategy with localized bioactive factor presentation is a novel, modular approach to engineer a multi-tissue, function-restoring organ of the respiratory system for patients suffering from large and currently untreatable tracheal defects. This platform technology also has the potential to be employed to regenerate other complex tissues and organs in the body.

摘要 目前还没有成功的治疗长段气管狭窄，最常见的结果是 延长插管或气管切开术。可用的治疗方案不足以预防再狭窄 并且经常需要连续的手术。组织工程气管有可能满足这一需求。一 功能性气管置换必须（1）具有径向刚度，（2）血管化或促进 血管化和（3）包含呼吸上皮以恢复开放的气道同时避免再狭窄， 细菌感染和缺血性坏死。该提案旨在开发一种气管替代品， 通过将组织环融合成由多个细胞组成的复合组织管 类型与控制，局部生长因子的介绍，并评估其能力，作为一个 在体兔气道缺损模型的气管替代。这项工作的假设是，一个多- 细胞类型，无支架的新气管可以被工程化为具有重要的细胞组织和关键的 通过以时空受控的方式将生物活性因子递送到模块化组织单元 由自我组装的人体细胞组成。通过使用定制装配系统，我们将集成 组织环单元到复合管状气管构造中。具体而言，该提案旨在（1）工程师 软骨环和管状结构，具有确定的尺寸和必要的机械性能， 高密度hMSC培养作为新生气管的放射状支持，（2）工程化软骨-血管前 具有交替的软骨和血管组织环以支撑血管的复合管状结构 在新气管中形成，（3）在软骨管上工程化管腔上皮衬里，用于接口 与外部环境的关系;（4）测试工程化气管恢复气道的能力 在动物缺陷模型中的功能。这项工作旨在设计一个替代人类气管， 当植入体内时支持血管形成和上皮形成的径向刚度。这种自下而上的自我-- 具有局部生物活性因子呈递的组装高细胞密度策略是一种新颖的模块化方法 为患有呼吸系统疾病的患者设计一个多组织、恢复功能的呼吸系统器官 目前无法治愈的大气管缺损该平台技术也有潜力成为 用于再生体内其他复杂的组织和器官。