Multiscale Anisotropic Scaffold Integrating 3D Printing and Electrospinning Techniques as a Heart-on-a-chip Platform for Evaluating Drug-induced Cardiotoxicity.

Cardiac safety assessments are significant in drug discovery, as drug-induced cardiotoxicity is the primary cause of drug attrition. Despite heart-on-a-chip technology having become an increasingly popular tool for evaluating drug-induced cardiotoxicity, its development remains a challenge owing to the anisotropic cardiac structure of the native myocardium. Herein, we present an anisotropic multiscale cardiac scaffold via a hybrid biofabrication method by combining 3D printing with electrospinning technology, where the 3D-printed micrometer-scale scaffold frames enable mimicking the interwoven myocardium anatomical structure and the branched-aligned electrospun nanofibers network was able to directionally guide cellular arrangements. The in vitro 3D bioengineered cardiac tissues were then fabricated by encapsulating three-layer multiscale scaffolds within a photocurable methacrylated gelatin hydrogel shell. It was demonstrated that such anisotropic multiscale structure could contribute to enhancing cardiomyocyte maturation and synchronous beating behavior. More attractively, with the integration of 3D bioengineered cardiac tissues and a self-designed microfluidic perfusion system, a 3D anisotropic heart-on-a-chip platform was established for evaluating drug-induced cardiotoxicity and cardioprotective efficacy. Collectively, these results indicated that our heart-on-a-chip model developed by integrating the 3D bioengineered cardiac tissues could effectively recapitulate the clinical manifestations, thereby highlighting their efficacy as a valuable preclinical platform for testing drug efficacy and cardiotoxicity. This article is protected by copyright. All rights reserved.