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

影响呼吸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挽救生命的选择。理想情况下，我们需要获得现成的替代移植物，以减少对捐献器官的依赖、等待时间和死亡风险。在肺中，器官再生是通过使用部分合成或天然支架的生物杂交设备实现的。利用先进的生物反应器在优化的生理条件下运行，以重新填充新的细胞，其中的驻留细胞已被移除，并用于受损组织的功能性替换的方法。虽然再生的全肺移植是一个遥远的目标，但我们开发了更简单的气管系统，我们拥有广泛的专业知识，同时解决了将为未来全肺移植的临床应用奠定基础的关键问题。在资助期结束时，我们预计将开始临床翻译一种功能性气管生物移植物，分别用于解决小气道和较大的气管健康缺陷。开发的优化的气管生物反应器可以通过向现有的肺部生物技术公司授权或通过专注于增强型器官特定生物反应器的公司创建合资企业来产生商业产品。此外，利用血管(和呼吸道)网络的计算机化几何模型开发流体流动的计算模型，将使电子实验程序能够探索靶向细胞输送的策略。这里开发的模型在肺组织工程中具有显著的潜力，并可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战略，有可能挽救生命，并极大地改善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 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.