The Development of an ex vivo Flow System to Assess Acute Arterial Drug Retention of Cardiovascular Intravascular Devices.

Kathryn Cooper,Uwe Christians,Marzieh Atigh,Claire V Cawthon,Saami K Yazdani,Emily Goel

doi:10.3389/fmedt.2021.675188

Abstract

Purpose: The goal of this study was to develop an ex vivo system capable of rapidly evaluating arterial drug levels in living, isolated porcine carotid arteries.Methods: A vascular bioreactor system was developed that housed a native porcine carotid artery under physiological flow conditions. The ex vivo bioreactor system was designed to quantify the acute drug transfer of catheter-based drug delivery devices into explanted carotid arteries. To evaluate our ex vivo system, a paclitaxel-coated balloon and a perfusion catheter device delivering liquid paclitaxel were utilized. At 1-h post-drug delivery, arteries were removed, and paclitaxel drug levels measured using liquid chromatography-tandem mass spectrometry (LC-MS/MS). Parallel experiments were performed in a pig model to validate ex vivo measurements.Results: LC-MS/MS analysis demonstrated arterial paclitaxel levels of the drug-coated balloon-treated arteries to be 48.49 ± 24.09 ng/mg and the perfusion catheter-treated arteries to be 25.42 ± 9.74 ng/mg at 1 h in the ex vivo system. Similar results were measured in vivo, as arterial paclitaxel concentrations were measured at 59.23 ± 41.27 ng/mg for the drug-coated balloon-treated arteries and 23.43 ± 20.23 ng/mg for the perfusion catheter-treated arteries. Overall, no significant differences were observed between paclitaxel measurements of arteries treated ex vivo vs. in vivo.Conclusion: This system represents the first validated ex vivo pulsatile system to determine pharmacokinetics in a native blood vessel. This work provides proof-of-concept of a quick, inexpensive, preclinical tool to study acute drug tissue concentration kinetics of drug-releasing interventional vascular devices.

Highlights

Patients and primary care physicians have acknowledged the clinical burden of peripheral artery disease (PAD) and coronary artery disease (CAD) for over many decades [1, 2]
The results demonstrate that paclitaxel can be delivered successfully to native porcine arteries within our bioreactor system using a drug-coated balloons (DCBs) and a perfusion catheter
These results demonstrate a viable platform for evaluating drug release kinetics of interventional vascular devices in an ex vivo setting

Summary

Introduction

Patients and primary care physicians have acknowledged the clinical burden of peripheral artery disease (PAD) and coronary artery disease (CAD) for over many decades [1, 2] Both PAD and CAD are caused by atherosclerosis, a buildup of cholesterol plaques in the inner vessel wall [3]. The use of drug-eluting stents (DES) was a major breakthrough in reducing the risk of restenosis following stent-induced injury [4, 5]. This injury induces the inflammatory response that in turn activates the restenotic cascade; amidst this cascade, neointimal proliferation, extracellular matrix production, and reendothelization occur [6, 7]. To combat the unwanted growth, DES utilize the stent scaffold to deliver antiproliferative drugs over several weeks to months [8]

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