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，并用于功能性替代受损组织。虽然再生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，我们拥有丰富的专业知识，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，我们期望开始功能性气管生物移植物的临床转化，分别用于解决小气道和大气道缺陷。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公司创建的专注于增强器官特异性生物反应器的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的流体流动计算模型的发展将允许在硅实验程序中探索靶向细胞递送的策略。这里开发的模型在肺组织工程中具有重要的潜力，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，并大大提高患有终末期肺病的加拿大人的生活质量。

Diseases affecting the airways are an important clinical problem and for the majority ofpatients with end-stage disease, transplantation of lung and/or trachea has become the onlylife-saving option. Ideally we need access to off-the-shelf replacement grafts reducing thedependency on donor organs, wait-time and risk of death. In the lung, organ regeneration isachieved by using biohybrid devices with partially synthetic or natural scaffolds. The approachis to utilize advanced bioreactors operating under optimized physiological conditions torepopulate with new cells, scaffolds in which the resident cells have been removed, and usefor functional replacement of damaged tissue. While transplantation of regenerated wholelungs is a far-off goal, we exploit the simpler system of the trachea with which we haveextensive expertise while addressing key issues that will set the foundation for future clinicalapplication of whole lung grafts. At the end of the funding period, we expect to begin clinicaltranslation of a functional tracheal biograft used to address small airway and larger trachealdefects, respectively. The optimized tracheal bioreactors developed can result in commercialproducts via licensing to already existing lung biotech companies or through companycreation ventures with focus on enhanced organ-specific bioreactors. In addition, thedevelopment of a computational model of fluid flow using a computerized geometrical modelsof vascular (and airway) networks will allow in silico experimental programs to explorestrategies for targeted cell delivery. Models developed here have the potential for significantimpact in lung tissue engineering, and can be applied to research groups focused on otherorgans. Completion of this work will set in motion a therapeutic strategy with the potential tosave lives and vastly improve the quality of life of Canadians suffering from end-stage lungdisease.