Development of a physiological cardiac microtissue platform for drug development

药物对心脏的不良疗效和不可预测的毒性是导致药物从市场上下架的主要原因。许多药物在患者身上的作用是不可预测的，因为它们是在实验室使用塑料培养皿中培养的细胞和模拟人类很差的动物进行测试的。经过改进的心脏组织模型可以在药物发现过程的早期识别和消除有毒和无效的药物。为了满足这一需求，我们开发了一个微流体平台，可以比标准细胞培养模型更好地模拟体内组织的特征，如血流和三维组织排列。该平台将被改装成伸展和电刺激心脏微组织，以更好地模拟人体心脏生理。我们还开发了一种新的超声成像技术，可以从平台外部快速评估心脏微组织的搏动和收缩。我们建议将这些技术结合起来，开发一种新的、改进的心脏模型，以快速、容易地评估心脏微组织的功能。该模型在与标准实验室设备和中高通量工作流程的兼容性方面将是独一无二的，确保以最少的时间和精力轻松实施。我们将优化新的心脏模型，以实现比目前可能的更类似于天然人类心脏组织的功能，使用患者来源的心脏细胞来模拟正常和患病的心脏组织。在项目完成时，我们将提供一种新的同类最佳的人体心脏组织模型，通过在药物开发过程中比目前的方法更早地识别无效和有毒药物，预计将减少与药物开发相关的时间和成本。该项目将产生的技术将由我们的合作伙伴公司和具有跨学科专业知识的学员进行商业化准备，以引领加拿大生物技术、生物医学和卫生部门的下一代创新。

Poor efficacy and unpredictable toxic effects of drugs on the heart are leading causes ofremoval of a drug from the market. Many drugs act unpredictably in patients because they aretested in labs using cells grown in plastic dishes and in animals that poorly mimic humans.Improved heart tissue models could identify and eliminate toxic and ineffective drugs earlier inthe drug discovery process.To meet this need, we have developed a microfluidic platform that can model features oftissues in the body, like blood flow and three-dimensional tissue arrangement, better than canbe done with standard cell culture models. This platform will be adapted to stretch andelectrically stimulate heart microtissues to better simulate human heart physiology. We havealso developed a new ultrasound imaging technique that can rapidly assess heart microtissuebeating and contraction from outside the platform. We propose to combine these techniquesto develop a new and improved heart model to rapidly and easily assess the function of heartmicrotissues. This model will be unique in its compatibility with standard laboratory equipmentand medium- to high-throughput workflow, ensuring ease of implementation with minimal timeand effort.We will optimize the new heart model to achieve functionality more similar to native humanheart tissue than currently possible, using patient-derived heart cells to model normal anddiseased heart tissue. At project completion, we will deliver a new best-in-class model ofhuman heart tissue that is expected to decrease the time and cost associated with drugdevelopment by identifying ineffective and toxic drugs much earlier in the drug developmentprocess than is possible with current methods.This project will produce technologies that are primed for commercialization by our partnercompanies and trainees with interdisciplinary expertise to lead the next generation ofinnovations in the Canadian biotechnology, biomedicine, and health sectors.