Multiscale Experimental and Computational Modeling Approaches to Characterize Therapy Delivery to the Heart from an Implantable Epicardial Biomaterial Reservoir

Abstract

Delivery of therapeutic-laden biomaterials to the epicardial surface of the heart presents a promising method of treating a variety of diseased conditions by offering targeted, localized release with limited systemic recirculation and enhanced myocardial tissue uptake. A vast range of biomaterials and therapeutic agents using this approach have been investigated.However, the fundamental factors that govern transport of the drug molecules from the biomaterials to the tissue are not well understood. Here, the transport of a drug analog from a biomaterial reservoir to the epicardial surface is characterized using experimental techniques and microscale modeling. Using the experimentally determined parameters, a multiscale This article is protected by copyright. All rights reserved. model of transport is developed. The model is then used 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.

Sustained subcutaneous delivery of secretome of human cardiac stem cells promotes cardiac repair following myocardial infarction

“…The idea of harnessing the stem cell secretome in a sustained manner for cardiac repair has also recently been explored by other groups using different innovative devices. These include the epicardial devices 17,18 and catheter-based intravascular bioreactors 19 that are capable of protecting the encapsulated cells from host immune attack while allowing sustained released of paracrine factors. However, these devices entailed invasive implantation methods that will limit their clinical applicability.…”

“…The epicardial devices required open chest surgery to access the implantation site and the foreign body responses toward these devices on the epicardial surface could aggravate adverse remodelling of the infarcted myocardium post-MI. 17,18 Although delivery of the intravascular bioreactors to the vasculature 19 can be achieved using the minimally invasive percutaneous surgical technique, the high risk of thrombosis as a result of direct contact between the device and blood flow will limit the translatability of this approach in patients.…”

Tunable biomaterials for myocardial tissue regeneration: promising new strategies for advanced biointerface control and improved therapeutic outcomes

“…Recently, microscale modelling used to investigate the transport of therapeutic agents released from scaffolds into the cardiac tissue revealed the importance of design parameters such as loading conditions, biomaterial geometry, and orientation relative to the cardiac fibers on drug delivery to the myocardium. 213 Cardiac fiber anisotropy was determined to be a governing factor of drug distribution on the epicardial surface and a limiting factor for drug infiltration into the myocardium.…”

Inverse Mechanistic Modeling of Transdermal Drug Delivery for Fast Identification of Optimal Model Parameters

“…Mechanistic, physics-based modeling and simulation is increasingly used in healthcare for device engineering and design ( FDA, 2016 ; Caccavo et al, 2017 ; Shirazi et al, 2019 ). A typical example is the transdermal drug delivery systems (TDDS).…”