Tzafriri AR. “Immunofluorescence and Computational Methods for Tracking Tissue Distribution of Drugs in Support of Stent Coating Innovations”
Summary: Drug eluting stents (DES) have revolutionized the treatment of atherosclerosis in coronary vasculature. The key has been to identify biological agents that can counter hyperplastic tissue responses to stent expansion/implantation and to develop effective and safe local delivery strategies that can maintain efficacious drug levels across the artery wall over the course of device effects. Though DES designs abound, most approved devices are surprisingly similar, releasing sirolimus analogs from conformal coatings and differing mostly in coating composition, geometry, and strut design. This is true for polymer-coated DES that sustain drug elution via diffusion-limitation as well as for polymer free stents that sustain drug release via a dissolution limitation. Until now we have not adequately utilized tools to determine how changes in coating design will impact local drug delivery kinetics and reaction with local receptors.
To fill this void, CBSET has developed Immunofluorescent (IF) methods to visualize drug (sirolimus and its analogs) and binding proteins and used these methods, supported by mechanistic computational models, to distinguish one form of stent-based drug delivery from another. To test this, we contrasted a clinically used durable coating to a deployable absorbable coating. The former is a paradigmatic strut-based release system where drug diffusion through tissue in concert with tissue binding determines overall spatial distribution and tissue content. Diffusion-based computational models predict high drug distribution gradients, with sharp peristrut peaks and interstrut valleys. High strut-based concentrations are required to drive drug any distance from the strut especially as binding proteins, upregulated by the local reaction to the embedded device, will maintain drug locally. The data show that a deployable coating that flows from the struts can carry its drug load into the tissue, thereby spatially extend drug release, and reducing vicissitudes in tissue concentrations with lower peaks and higher troughs.
This and similar studies may now enable us to define local drug delivery on a more refined scale than ever before.
Presented at Biointerface Symposium, 2018 October 1-3, Boulder, Colorado.