Abstract
Introduction: Creation of 3-D tissue model similar to a biological tissue using tissue engineering method are expected as an alternative approach to 2-D culture or animal test in a research for developing a new medicine. We have already developed functional 3-D heart tissue with perfusable blood vessels in vitro using cell sheet based tissue engineering approach. Present study assessed the possibility as 3-D tissue model by performing drug evaluation in the engineered heart tissues. Methods: Firefly luciferase positive cardiac cells co-cultured with endothelial cells were harvested as cell sheets from temperature-responsive culture dishes. Triple-layer cell sheets were overlaid on the vascular bed with an artery and a vein in vitro. Layered cardiac cell sheets were maintained in custom made bioreactor system with perfusion medium. After neovascularization within the first triple-layer tissue, the second triple-layer cardiac cells sheets were overlaid on the first graft after cultivation for 3 days and then the whole construct was further perfused for an additional 3 days. After 6-day perfusion culture, isoproterenol or doxorubicin were administrated to the engineered heart tissues from artery side. The sympathetic and toxic effects were measured by in vitro bioluminescence imaging, electrical potential, and blood pressure. Results: In case of isoproterenol administration, bioluminescence imaging (BLI) demonstrated that adenosine triphosphate (ATP) of the heart tissue improved. In addition, electrograms demonstrated increasing beating rate and amplitude. Moreover, sphygmomanometer showed decreasing arterial pressure. In case of doxorubicin administration, BLI showed that the ATP of the heart tissue worsened after 24 hours. It is now possible to analyze the pharmacological effects such as metabolism and the blood pressure as well as action potential by using our vascularized heart tissue model. Conclusions: We believe that our 3-D heart tissue model offers a new possibilities for evaluation of drug efficacy.
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