Multiscale Anisotropic Scaffolds Enable a Biomimetic Electro-Mechanical Myocardial Platform for Drug Discovery and Heart Repair

Abstract

The core challenge in engineering functional cardiac tissue in vitro is the lack of an integrated platform that simultaneously provides multiscale anisotropic topography and conductive signaling, leading to poor cellular alignment, weak electromechanical coupling, and asynchronous contraction. Herein, this study developed a multiscale anisotropic conductive fiber scaffold featuring integrated nano-and micro-scale characteristics to mimic the hierarchical topological structure and electrochemical microenvironment of native myocardial tissue, thereby providing a biomimetic platform for cardiac tissue engineering. The engineered cardiac microtissues derived from this platform exhibit more ordered sarcomeres, a 5.45-fold increase in Cx43 expression, a 117.6% enhancement in contraction amplitude, and a 96.4% improvement in contraction frequency. Notably, the model demonstrates high sensitivity, responding accurately to drug concentrations as low as 1 nM-an order of magnitude improvement over conventional models. In addition, we developed a label-free CardioFlow analysis tool based on optical flow algorithms, enabling rapid extraction and visualization of the spatiotemporal beating patterns of cardiac microtissues. After implantation into MI rats, the microtissues promote angiogenesis, polarize macrophages toward the M2 phenotype, and inhibit fibrosis and ventricular remodeling, thereby improving cardiac function. This engineered cardiac microtissue platform with multi-level anisotropic architecture provides a universal platform and theoretical foundation for drug cardiotoxicity evaluation and clinical myocardial regeneration.