Engineering improvements for epicardial drug delivery systems

Abstract

Cardiovascular diseases continue have a large disease burden despite advancements in technology, therapeutic modalities, and prevention efforts. For various cardiovascular pathologies, epicardial drug delivery systems have shown promise. Our group has developed a replenishable epicardial drug delivery device called Therepi that allows for repeat administrations of therapeutics without necessitating multiple invasive surgeries. The purpose of this thesis is to improve upon the Therepi device and utilize the platform to study the effects of specific therapeutics on cardiac function in a preclinical small animal myocardial infarction (MI) model. I first show that the fibrous capsule that forms around the polycarbonate membrane interface of the first iteration Therepi device post-implantation can impede transport of therapeutics from the device to the heart.

Then, I utilize a modified version of Therepi without the polycarbonate membrane to study the effects of repeat administrations of FSTL1, a promising protein with great therapeutic potential, on cardiac function post-MI. Results from this study indicate that removal of the polycarbonate membrane reduces the formation of a fibrous capsule and that repeat administrations of FSTL1 improve cardiac function after MI. Following this, I utilize a computational macroscale model of Therepi to study the effect of important design parameters such as loading conditions, biomaterial geometry and orientation relative to the cardiac fibers on drug delivery to the myocardium. The simulations highlight the significance of the cardiac fiber anisotropy as a crucial factor in governing drug distribution on the epicardial surface and limiting factor for penetration into the myocardium.

The multiscale model can be useful for rapid iteration of different device concepts and determination which designs for epicardial drug delivery may be optimal and most promising for the ultimate therapeutic goal. In the future, the findings from this thesis will be further investigated to develop an improved version of Therepi that allows for better device-tissue adhesion, conformability, and transport. The effects of repeat administrations of FSTL1 from the Therepi device will be elucidated further to mechanistically understand how cardiac function is improved through this strategy.