Evaluating and improving biocompatibility of conductive polymers for cardiac tissue engineering

Conductive polymers (CPs) have gained increasing attention in cardiac tissue engineering (CTE) due to their ability to restore electrical conductivity, enhance cardiomyocyte (CM) function, and support tissue regeneration. Despite significant progress in the field, challenges related to variability in biocompatibility testing, including dopant-dependent cytotoxicity, poor reporting of biodegradability, unpredictable long-term stability, and regulatory uncertainty of CPs continue to hinder their applications. To address this, we reviewed the properties, applications, and biocompatibility of the three most studied CPs: polypyrrole (PPy), poly(3,4-ethylenedioxythiophene) (PEDOT), and polyaniline (PANI) in CTE, and contrast their advantages and safety challenges with inorganic electrodes and carbon-based materials. We critically assessed current methods for evaluating the biocompatibility of CPs, highlighting limitations in traditional in vitro and in vivo approaches. Our analysis revealed a significant gap in chronic implantation data beyond six months and provided dopant-centered assessment and toxicity risks across different CP platforms. A comprehensive roadmap was further suggested to guide the evaluation of the biocompatibility of CPs, including material characterization, in vitro cytotoxicity testing with particular emphasis on in vitro 3D human heart model testing platforms of human pluripotent stem cell (hPSC)-derived engineered heart tissues and cardiac organoids, and in vivo evaluation. Additionally, we discussed recent advances in improving the biocompatibility of CPs through hybrid scaffold development, molecular engineering, surface chemistry modifications, and the development of stimuli-responsive and targeted CP constructs. By establishing this standardized framework and highlighting critical regulatory requirements, this review aims to overcome current biocompatibility barriers and facilitate the improved implementation of CPs in CTE applications.