THEREPI: A therapeutic epicardial reservoir for the treatment of cardiac disease

Abstract

The clinical translation of regenerative therapy for the diseased heart, whether in the form of cells, macromolecules or small molecules, is hampered by several factors: the poor retention and short biological half-life of the therapeutic agent, the adverse side effects from systemic delivery, and difficulties with the administration of multiple doses. Here, we report the development, manufacturing processes and pre-clinical application of a therapeutic epicardial device that enables sustained and repeated administration of small molecules, macromolecules and cells directly to the epicardium via a biomaterial-based reservoir connected to a subcutaneous port. In a myocardial infarct rodent model, we show that repeated administration of cells over a four-week period using the epicardial reservoir provided functional benefits in ejection fraction, fractional shortening and stroke work, compared to a single injection of cells and to no treatment. Finally, in pursuit of a multimodal delivery system that that can deliver biological therapy with precise spatial and temporal control, we couple the therapeutic reservoir with a pneumatic soft robotic actuator. Using this approach, we demonstrate controlled drug release by altering the compressive stimulus and the biomaterial/cargo interaction. This work has important practical and translational implications; preclinical use of the system as a research model may elucidate new insights into regenerative cardiac therapy, highlight the synergistic benefits of a holistic multi-modal approach and ultimately progress experimental therapies towards clinical use and improve patient outcomes.