2018 Theses Doctoral

Human Tissue Engineered Model of Myocardial Ischemia-Reperfusion Injury

Chen, Timothy Han

Timely reperfusion after a myocardial infarction is necessary to salvage the ischemic region; however, reperfusion itself is a major contributor to the final tissue damage. Currently, there is no clinically relevant therapy available to reduce ischemia-reperfusion injury. While many drugs have shown promise in reducing ischemia-reperfusion injury in preclinical studies, none of these drugs have demonstrated benefit in large clinical trials. Part of the failure to translate therapies can be attributed to the reliance on small animal models for preclinical studies. While animal models encapsulate the complexity of the systemic in vivo environment, they do not fully recapitulate human cardiac physiology.
In this thesis, we utilized cardiac tissue engineering methods in conjunction with cardiomyocytes derived from human induced pluripotent stem cells, to establish a biomimetic human tissue-engineered model of ischemia-reperfusion injury. The resulting cardiac constructs were subjected to simulated ischemia or ischemia-reperfusion injury in vitro. We demonstrated that the presence of reperfusion injury can be detected and distinguished from ischemic injury. Furthermore, we demonstrated that we were able to detect changes in reperfusion injury in our model following ischemic preconditioning, modification of reperfusion conditions, and addition of cardioprotective therapeutics. This work establishes the utility of the human tissue model in studying ischemia-reperfusion injury and the potential of the human tissue platform to help translate therapeutic strategies into the clinical setting.