In Vitro Models of Ischemia-Reperfusion Injury

Timely reperfusion after a myocardial infarction is necessary to salvage the ischemic region; however, reperfusion itself is also a major contributor to the final tissue damage. Currently, there is no clinically relevant therapy available to reduce ischemia-reperfusion injury (IRI). While many drugs have shown promise in reducing IRI in preclinical studies, none of these drugs have demonstrated benefit in large clinical trials. Part of this 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. Furthermore, it is difficult to uncouple the various interacting pathways in vivo. In contrast, in vitro models using isolated cardiomyocytes allow studies of the direct effect of therapeutics on cardiomyocytes. External factors can be controlled in simulated ischemia-reperfusion to allow for better understanding of the mechanisms that drive IRI. In addition, the availability of cardiomyocytes derived from human-induced pluripotent stem cells (hiPS-CMs) offers the opportunity to recapitulate human physiology in vitro. Unfortunately, hiPS-CMs are relatively fetal in phenotype and are more resistant to hypoxia than the mature cells. Tissue engineering platforms can promote cardiomyocyte maturation for a more predictive physiologic response. These platforms can further be improved upon to account for the heterogenous patient populations seen in the clinical settings and facilitate the translation of therapies. Thereby, the current preclinical studies can be further developed using currently available tools to achieve better predictive drug testing and understanding of IRI. In this article, we discuss the state of the art of in vitro modeling of IRI, propose the roles for tissue engineering in studying IRI and testing the new therapeutic modalities, and how the human tissue models can facilitate translation into the clinic. Heart attacks are treated by unblocking the occluded blood vessel; however, the restoration of blood flow to the damaged area causes additional injury, termed ischemia-reperfusion injury (IRI). Many treatments have successfully decreased IRI in animals, but none have shown the same success in humans. This failure may be because animal hearts have important functional differences compared to human hearts. Human engineered tissue models are important tools to overcome this hurdle because they utilize human cells in a highly controllable environment. In this article, we discuss models of IRI and how they can facilitate the development of treatments for patient use.