Modelli bioelettronici umani innovativi come alternativa alla validazione animale per una più efficace predizione del rischio cardiotossico e per la salvaguardia della biodiversità

The increasing need for effective drug safety evaluation preventing cardiotoxicity highlights the importance of developing physiologically relevant models. This study presents a novel concept of tissue-engineered myocardium, specifically conceived for in vitro cardiotoxicity risk prediction and generated with decellularized extracellular matrix (dECM) hydrogel scaffold derived from porcine ventricular myocardium and cardiomyocytes derived from the differentiation of human induced pluripotent stem cells (hiPSC-CMs). Optimized decellularization protocols, including automation, were designed to obtain acellular myocardial scaffolds, whose structural and biochemical components were preserved and supported subsequent hydrogel formation. This dECM hydrogel was shown to provide a cytocompatible 3D microenvironment for human bone marrow-derived mesenchymal stem cells, as demonstrated by cell proliferation over 10 days. These hosting properties were also demonstrated in combination with hiPSC-CM spheroids, allowing the manufacture of viable 3D engineered cardiac tissues. Thanks to a Multi-Electrode Array (MEA) platform, these engineered cardiac tissues were demonstrated to possess electrophysiological functionality and detectability, including stable field potential durations and conduction profiles. These findings emphasize the potential of this bioelectronic system to detect drug-induced arrhythmogenic risks and provide a reliable platform for cardiotoxicity testing, addressing critical gaps in preclinical drug development. In addition, compared to traditional 2D and animal models, this in vitro 3D myocardial modeling concept offers a scalable, reproducible, and ethically superior alternative, reducing reliance on animal testing. By mimicking the native cardiac microenvironment and enabling high-throughput electrophysiological assessments, it represents a transformative tool for advancing cardiac drug safety evaluation and regenerative medicine. Future directions include further optimization for cardiomyocyte applications and clinical translation of its therapeutic potential, paving the way for its broader adoption in clinical and industrial settings.