An optogenetic tissue-engineered cardiac pacemaker: demonstration of principle in an isolated rat heart

Background: Heart rhythm disturbances remain a serious problem in modern cardiology. Traditional pacemakers have certain limitations including invasiveness, risk of infection, mechanical complications, and a limited service life. Advances in bioengineering and optogenetics technologies offers new prospects for the production of minimally invasive, biocompatible, and controllable cardiac pacing systems. The combination of cell therapy and optogenetics enables to create a photo-controlled biological pacemaker, free from the key drawbacks of traditional devices. Objective: The aim of this study was to produce photosensitive cellular patches and to further investigate their functionality as an optogenetic tissue-engineered pacemaker in an ex vivo rat heart model. Methods: We engineered a cell-based construct using either human cardiomyocytes derived from induced pluripotent stem cells or neonatal rat cardiomyocytes expressing channelrhodopsin-2. These cells were seeded onto fibrous scaffolds made of poly-L-lactic acid and collagen, coated with fibronectin. The testing model was an isolated, temporarily maintained ex vivo rat heart. Optical mapping of calcium activity was used to record cardiac electrophysiology. Results: Functional coupling between the implanted patch and the host myocardium was observed 35 minutes after implantation. Photostimulation reliably increased the heart rate, which was confirmed by stochastic dominance analysis. The experiments in vitro on cell cultures demonstrated the operational capacity of channelrhodopsin-2 upon illumination with 470 nm light. Conclusion: This study successfully demonstrates a complete technology cycle, from the genetic modification of cells to the control of contractions in a whole organ. It represents a significant step towards developing targeted and safe methods for future temporary cardiac pacing. Our results confirm the fundamental feasibility of a hybrid optogenetic approach and lay the groundwork for further research into creating safe, controllable, and biocompatible next-generation pacemaker systems.