3D Bioprinting of Cardiac Tissues

心力衰竭等慢性心血管疾病正在上升到流行水平，每5个加拿大人中就有一个受到影响。左心室没有明显的再生能力，心肌梗死后残留的存活组织通常不足以维持足够的心输出量。心脏移植通常不是一个可用的或合适的选择。因此，迫切需要进行替代干预。这项研究计划的长期目标是开发和利用先进的生物制造技术，结合发育生物学的见解，建立用于预测药物发现的工程化3D体外模型，并创建用于再生的功能性组织工程植入物。成年心肌细胞的增殖能力有限，因此必须使用干细胞作为其来源。从人类诱导的多能干细胞生成心血管血统的能力和3D生物打印的最新进展，为建立人类心血管疾病的体外模型(即单芯片心脏模型)以及开发自体左心室替代提供了前所未有的机会。3D生物打印可以精确地逐层定位生物材料(即生物墨水)和活细胞，并对功能部件的放置进行空间控制，以制造具有与天然组织非常相似的结构、生物学和机械特性的3D功能活心脏组织。这项研究计划的5年目标是：1)使用3D生物打印技术制造和表征3D血管化左心室；以及2)制造和表征3D生物打印的单芯片心脏平台。因此，我们将开发和表征一种3D生物打印：1)片状血管化人工左心室以促进再生；2)环形结构作为3D体外模型用于药物发现和筛选应用。3D生物打印的人工血管左心室(片状结构)最终将能够对电刺激做出同步收缩。在更短的时间内，3D生物打印的环状结构将为药物发现和测试提供高保真模型。由于该模型忠实地模拟了人类生理学的特征，因此有可能更精确和高效地测试心脏毒性。鉴于心脏毒性是将新药推向市场的主要障碍，我们的体外模型可以改变药物开发过程。此外，我们的体外模型与精密医学兼容，可以在更个性化的环境中测试药物，并揭示潜在的分子机制。总体而言，可以预见，这一研究计划的结果将构成为提供用于再生和体外建模的人类功能组织的重要步骤。

Chronic cardiovascular diseases such as heart failure is increasing to epidemic levels, affecting 1 in 5 Canadians. The left ventricle has no significant ability to regenerate and the viable tissue remaining after myocardial infarction is often insufficient to maintain adequate cardiac output. Heart transplant is very often not an available or appropriate option. Thus, there is a pressing need for alternative intervention. The long-term goal of this research program is to develop and utilize advanced biofabrication techniques integrated with insights from developmental biology to build engineered 3D in vitro models for predictive drug discovery and to create functional tissue-engineered implants for regeneration. Adult cardiomyocytes have a limited ability to proliferate, thus stem cells must be used as their source. The ability to generate cardiovascular lineages from human induced pluripotent stem cells and recent advances in 3D bioprinting, provide an unprecedented opportunity to establish human in vitro models of cardiovascular diseases (i.e. heart-on-a-chip models) as well as to develop autologous replacement left ventricle. 3D bioprinting allows precise layer-by-layer positioning of biomaterials (i.e. bioinks) and living cells, with spatial control of the placement of functional components to fabricate 3D functional living cardiac tissues with structural, biological, and mechanical properties that are very similar to those of native tissues. The 5-year goals of this research program are to: 1) fabricate and characterize 3D vascularized left ventricle using 3D bioprinting technology; and 2) fabricate and characterize 3D bioprinted heart-on-a-chip platforms. Therefore, we will develop and characterize a 3D bioprinted:1) sheet-like vascularized artificial left ventricle to accelerate regeneration; 2) ring-like structure as a 3D in vitro model for drug discovery and screening applications. The 3D bioprinted artificial vascularized left ventricle (sheet-like structures) will eventually be capable of synchronous contraction in response to electrical stimulation. In a more immediate term, the 3D bioprinted ring-like structures will provide high fidelity models for drug discovery and testing. This model has the potential to test cardiac toxicity with more precision and efficiency, due to the faithfully mimicking the hallmarks of human physiology. Given that cardiac toxicity is a major hurdle to bring novel drugs to market, our in vitro model can transform the drug development process. Furthermore, our in vitro model is compatible with precision medicine to test drugs in a more personalized environment and shed light to the underlying molecular mechanisms. Overall, it is foreseen that the outcome of this research program will constitute important steps towards providing human functional tissues for regeneration and in vitro modelling.