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.

抽象的 目前尚无对长段气管狭窄的成功治疗，最常见的是 长时间插管或气管切开术。可用的治疗选择不足以预防再狭窄 并且通常需要连续的手术。组织工程气管有可能满足这种需求。一个 功能性气管更换必须（1）具有径向刚度，（2）是血管化的或鼓励 血管形成和（3）含有呼吸道上皮，以恢复露天道，同时避免再狭窄， 细菌感染和缺血性坏死。该建议旨在通过 这些功能要求通过将组织环融合到由多个细胞组成的复合组织管中 具有受控，局部生长因子表现的类型，并评估其充当的能力 体内兔气道缺陷模型中的气管置换。这项工作的假设是多 细胞类型，无脚手架的Neotrachea可以通过重要的细胞组织和关键 通过以时空控制方式传递生物活性因子到模块化组织单位的功能 由自组装的人类细胞组成。通过使用自定义装配系统，我们将集成 组织环单元进入复合管状气管构建体。具体而言，该提案旨在（1）工程师 具有定义尺寸和必要机械性能的软骨环和管状结构 高密度HMSC培养物可作为Neotrachea中的径向支持，（2）工程师血管过血管 具有交替软骨和血管生成环的复合管状构建体支持血管 在新刹车中的形成，（3）工程师在软骨管上的腔内上皮衬里进行接口 在外部环境和（4）测试工程气管恢复气道的能力 动物缺陷模型中的功能。这项工作旨在通过使用 植入体内时支持血管化和上皮化的径向刚性。这个自下而上的自我 带有局部生物活性因子表示的组装高细胞密度策略是一种新型的模块化方法 为患有患者 大且目前无法治疗的气管缺陷。该平台技术也有可能成为 用于再生体内其他复杂的组织和器官。