Abstract
In-stent restenosis (ISR) often occurs after applying drug eluting stents to the blood vessels suffering from atherosclerosis or thrombosis. For treatment of ISR, drug eluting balloons (DEB) have been developed to deliver anti-proliferative drugs to the lesions with ISR. However, there are still limitations of DEB such as low drug delivery efficiency and drug loss to blood flow. Although most researches have focused on alteration of drug formulation for more efficient drug delivery, there are few studies that have attempted to understand and utilize the contact modality of DEB drug delivery. Here, we developed a linear micro-patterned DEB (LMDEB) that applied higher contact pressure to enhance drug stamping to vascular tissue. Ex vivo and in vivo studies confirmed that higher contact pressure from micro-patterns increased the amount of drug delivered to the deeper regions of vessel. Finite element method simulation also showed significant increase of contact pressure between endothelium and micro-patterns. Quantitative analysis by high performance liquid chromatography indicated that LMDEBs delivered 2.3 times higher amount of drug to vascular tissue in vivo than conventional DEBs. Finally, efficacy studies using both atherosclerotic and ISR models demonstrated superior patency of diseased vessels treated with LMDEB compared to those treated with DEB.
Highlights
Coating of polymeric matrix containing anti-proliferative drug on the surface of DES significantly reduces ISR occurrence
linearly micro-patterned drug eluting balloon (LMDEB) were fabricated by the following process; thin cylinder tubes made of polyether block amide elastomer (PEBAX) were blow-molded in a micro-machined balloon forming mold
The micro-machined mold was fabricated by an electric discharge machining (EDM) wire-cut process to have a linear array of intaglio linear micro-patterns (LMs) on the inner surface of the mold
Summary
Since more than 200% higher amount of residual PTX was measured in LMDEB-treated tissue samples (Fig. 6D), the contribution of the increased surface area to the enhanced drug delivery is relatively small compared to the contribution of the increased contact pressure. The outcomes from our in vivo studies indicated that LMDEBs had enhanced delivery efficiency and therapeutic efficacy than DEBs, and this can be ascribed to deeper drug delivery by higher contact pressure as well as more uniform and reliable contacts even with ISR tissue. In vivo studies with fluorescent and LC/MS analyses confirmed significantly higher drug delivery efficiency of LMDEBs than DEBs. in vivo efficacy tests were performed using atherosclerotic rabbit and ISR minipig models, and demonstrated statistically-significant therapeutic efficacy of LMDEBs compared to conventional DEB of LMDEBs
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