Advanced Bioreactors for Evaluation and Systematic Optimization of Decellularization and Recellularization of the Lung and Trachea

影响气道的疾病是一个重要的临床问题，对于大多数终末期疾病患者来说，肺和/或气管移植已成为唯一的救命选择。理想情况下，我们需要获得现成的替代移植物，减少对供体器官的依赖，减少等待时间和死亡风险。在肺部，器官再生是通过使用部分合成或天然支架的生物混合装置来实现的。该方法**是利用先进的生物反应器在优化的生理条件下运行，以**重新填充新细胞，移除原有细胞的支架，并使用**对受损组织进行功能性替换。虽然再生的全肺移植是一个遥远的目标，但我们利用更简单的气管系统，在解决关键问题的同时，我们拥有广泛的专业知识，这将为未来全肺移植的临床应用奠定基础。在资助期结束时，我们预计将开始功能性气管生物移植物的临床翻译，分别用于解决小气道和大气管缺陷。开发的优化气管生物反应器可以通过授权给现有的肺生物技术公司或通过专注于增强器官特异性生物反应器的公司创建企业来产生商业产品。此外，利用血管（和气道）网络的计算机化几何模型开发的流体流动计算模型将允许在硅实验程序中探索靶向细胞递送的策略。这里开发的模型有可能在肺组织工程中产生重大影响，并且可以应用于专注于其他器官的研究小组。这项工作的完成将启动一项治疗策略，有可能挽救生命，并大大提高加拿大终末期肺病患者的生活质量。

Diseases affecting the airways are an important clinical problem and for the majority of**patients with end-stage disease, transplantation of lung and/or trachea has become the only**life-saving option. Ideally we need access to off-the-shelf replacement grafts reducing the**dependency on donor organs, wait-time and risk of death. In the lung, organ regeneration is**achieved by using biohybrid devices with partially synthetic or natural scaffolds. The approach**is to utilize advanced bioreactors operating under optimized physiological conditions to**repopulate with new cells, scaffolds in which the resident cells have been removed, and use**for functional replacement of damaged tissue. While transplantation of regenerated whole**lungs is a far-off goal, we exploit the simpler system of the trachea with which we have**extensive expertise while addressing key issues that will set the foundation for future clinical**application of whole lung grafts. At the end of the funding period, we expect to begin clinical**translation of a functional tracheal biograft used to address small airway and larger tracheal**defects, respectively. The optimized tracheal bioreactors developed can result in commercial**products via licensing to already existing lung biotech companies or through company**creation ventures with focus on enhanced organ-specific bioreactors. In addition, the**development of a computational model of fluid flow using a computerized geometrical models**of vascular (and airway) networks will allow in silico experimental programs to explore**strategies for targeted cell delivery. Models developed here have the potential for significant**impact in lung tissue engineering, and can be applied to research groups focused on other**organs. Completion of this work will set in motion a therapeutic strategy with the potential to**save lives and vastly improve the quality of life of Canadians suffering from end-stage lung**disease.