Patrick W. Kelly

Preparation, characterization, in vitro drug release, and cellular interactions of tailored paclitaxel releasing polyethylene oxide films for drug-coated balloons.

UNLABELLED Drug-coated balloons (DCBs) are used to treat various cardiovascular diseases. Currently available DCBs carry drug on the balloon surface either solely or using different carriers. Several studies have shown that a significant amount of drug is lost in the blood stream during balloon tracking to deliver only a sub-therapeutic level of drug at the treatment site. This research is focused on developing paclitaxel (PAT) loaded polyethylene oxide (PEO) films (PAT-PEO) as a controlled drug delivery carrier for DCBs. An array of PAT-PEO films were developed in this study to provide tailored release of >90% of drug only at specific time intervals, which is the time frame required for carrying out balloon-based therapy. The characterizations of PAT-PEO films using SEM, FTIR, and DSC showed that the films developed were homogenous and the PAT was molecularly dispersed in the PEO matrix. Mechanical tests showed that most PAT-PEO films developed were flexible and ductile, with yield and tensile strengths not affected after PAT incorporation. The viability, proliferation, morphology, and phenotype of smooth muscle cells (SMCs) interacted with control-PEO and PAT-PEO films were investigated. All control-PEO and PAT-PEO films showed a significant inhibitory effect on the growth of SMCs, with the degree of inhibition strongly dependent on the w/v% of the polymer used. The PAT-PEO coating was produced on the balloons. The integrity of PAT-PEO coating was well maintained without any mechanical defects occurring during balloon inflation or deflation. The drug release studies showed that only 15% of the total PAT loaded was released from the balloons within the initial 1min (typical balloon tracking time), whereas 80% of the PAT was released between 1min and 4min (typical balloon treatment time). Thus, this study demonstrated the use of PEO as an alternate drug delivery system for the balloons. STATEMENT OF SIGNIFICANCE Atherosclerosis is primarily responsible for cardiovascular diseases (CVDs) in millions of patients every year. Drug-coated balloons (DCBs) are commonly used to treat various CVDs. However, in several currently used DCBs, a significant amount of drug is lost in the blood stream during balloon tracking to deliver only a sub-therapeutic level of drug at the treatment site. In this study, paclitaxel containing polyethylene oxide (PEO) films were developed to provide unique advantages including drug release profiles specifically tailored for balloon-based therapy, homogeneous films with molecularly dispersed drug, flexible and ductile films, and exhibits significant inhibitory effect on smooth muscle cell growth. Thus, this study demonstrated the use of PEO as an alternate drug delivery platform for DCBs to improve its efficacy.

Responses of Endothelial Cells, Smooth Muscle Cells, and Platelets Dependent on the Surface Topography of Polytetrafluoroethylene

In this study, the effect of different structures (flat, expanded, and electrospun) of polytetrafluoroethylene (PTFE) on the interactions of endothelial cells (ECs), smooth muscle cells (SMCs), and platelets was investigated. In addition, the mechanisms that govern the interactions between ECs, SMCs, and platelets with different structures of PTFE were discussed. The surface characterizations showed that the different structures of PTFE have the same surface chemistry, similar surface wettability and zeta potential, but uniquely different surface topography. The viability, proliferation, morphology, and phenotype of ECs and SMCs interacted with different structures of PTFE were investigated. Expanded PTFE (ePTFE) provided a relatively better surface for the growth of ECs. In case of SMC interactions, although all the different structures of PTFE inhibited SMC growth, a maximum inhibitory effect was observed for ePTFE. In case of platelet interactions, the electrospun PTFE provided a better surface for preventing the adhesion and activation of platelets. Thus, this study demonstrated that the responses of ECs, SMCs, and platelets strongly dependent on the surface topography of the PTFE.

Safety and efficacy of ultrasound-accelerated catheter-directed lytic therapy in acute pulmonary embolism with and without hemodynamic instability

OBJECTIVE The objective of this study was to evaluate the safety and effectiveness of ultrasound-accelerated thrombolysis in acute pulmonary embolism. METHODS A retrospective study of 45 patients was performed to evaluate treatment of acute pulmonary embolism at a single center from January 2011 to December 2013. All patients were diagnosed with computed tomography or ventilation-perfusion scan and had hemodynamic instability (systolic blood pressure <100 mm Hg) or right-sided heart strain evidenced by right ventricular dilation, septal deviation, or hypokinesis by echocardiography or computed tomography. EkoSonic catheters (EKOS Corporation, Bothell, Wash) were placed into the affected pulmonary arteries, and recombinant tissue plasminogen activator was infused through the catheters at 0.5 to 1.0 mg/h per catheter. RESULTS Hypotension (systolic blood pressure <100 mm Hg) was present in 12 patients, with 100% resolution by treatment completion. Tachycardia (heart rate >100 beats/minute) was present in 26 patients and resolved in 92% by treatment completion; the average heart rate for all patients decreased from 109 to 77 beats/minute during the treatment period. Direct pulmonary artery pressure measurement showed average decrease of 21.5 mm Hg, representing a 40.2% reduction. Postprocedure echocardiography demonstrated complete resolution of cardiac dysfunction in 64%. Patients received a total dose of 30.5 mg (range, 14-66 mg) recombinant tissue plasminogen activator during an infusion time of 14.2 hours (range, 8-21 hours). There were no deaths through 90 days of follow-up and no major periprocedural bleeding events. CONCLUSIONS This retrospective study demonstrates the safety and efficacy of current ultrasound-accelerated thrombolysis methods to treat acute pulmonary embolism.

Dextran sulfate as a drug delivery platform for drug‐coated balloons: Preparation, characterization, in vitro drug elution, and smooth muscle cell response

Abstract Drug‐coated balloons (DCBs) have now emerged as a promising approach to treat peripheral artery disease. However, a significant amount of drug from the balloon surface is lost during balloon tracking and results in delivering only a subtherapeutic dose of drug at the diseased site. Hence, in this study, the use of dextran sulfate (DS) polymer was investigated as a platform to control the drug release from balloons. An antiproliferative drug, paclitaxel (PAT), was incorporated into DS films (PAT‐DS). The characterizations using SEM, FT‐IR, and DSC showed that the films prepared were smooth and homogenous with PAT molecularly dispersed in the bulk of DS matrix in amorphous form. An investigation on the interaction of smooth muscle cells (SMCs) with control‐DS and PAT‐DS films showed that both films inhibited SMC growth, with a superior inhibitory effect observed for PAT‐DS films. PAT‐DS coatings were then produced on balloon catheters. The integrity of coatings was well‐maintained when the balloons were either deflated or inflated. In this study, up to 2.2 µg/mm2 of PAT was loaded on the balloons using the DS platform. Drug elution studies showed that only 10 to 20% of the total PAT loaded was released from the PAT‐DS coated balloons during the typical time period of balloon tracking (1 min) and then ∼80% of the total PAT loaded was released during the typical time period of balloon inflation and treatment (from 1 min to 4 min). Thus, this study demonstrated the use of DS as a platform to control drug delivery from balloons.

In vitro and in vivo evaluation of effect of excipients in local delivery of paclitaxel using microporous infusion balloon catheters

Drug-infusion balloons are one of the currently used local drug delivery devices for preventing restenosis after endovascular treatments. An antiproliferative drug (paclitaxel, PAT) is infused through the balloon using a cremophor-based formulation to control restenosis. However, the major limitations of this approach are poor in vivo drug uptake and a limit in the amount of PAT delivered because of cremophor toxicity. In this study, we have investigated the use of different excipients for effectively infusing PAT out of the balloon for improved drug uptake in the tissue. The excipients include nanoparticle albumin-bound PAT (nab-PAT, a nanobiomaterial used in cancer therapy), urea (a hydrophilic agent used for faster drug transfer), iodixanol (a contrast agent used for coronary angiography), and cremophor-PAT (the most commonly used PAT formulation). An in vitro drug release, smooth muscle cell (SMC) response, endothelial cell (EC) response, and in vivo drug uptake were investigated for all the different excipients of PAT infused through the balloon. The nab-PAT was as effective as cremophor in infusing out of the balloon and inhibiting SMC growth. Also, nab-PAT showed a significantly greater amount of in vivo PAT uptake than that of cremophor-PAT. Urea and iodixanol were not effective in delivering a clinically relevant dose of PAT due to the poor solubility of PAT in these excipients. Urea eradicated all the SMCs and ECs, suggesting a toxic effect, which impedes its use in balloon-based therapy. Thus, this study demonstrated that nab-PAT is an effective formulation to locally deliver PAT through infusion balloons.

Polytetrafluoroethylene topographies determine the adhesion, activation, and foreign body giant cell formation of macrophages

Polytetrafluoroethylene (PTFE) is one of the commonly used materials in making various cardiovascular implants. However, the success rates of these implants in several occasions are hindered by unwanted immune responses from immune cells, such as macrophages. In this study, we investigated the response of macrophages with different structures (flat, expanded, and electrospun) of PTFE having varied surface topographies: smooth planar surface (flat PTFE), node-fibrils (ePTFE), and randomly oriented microfibers (electrospun PTFE). The electrospun PTFE showed the least adhesion of macrophages. Also, the morphology of macrophages adhered on electrospun PTFE exhibited minimal activation. The macrophage pro-inflammatory cytokine secretions showed that the lowest level of TNF-α was produced on electrospun PTFE whereas IP-10 was produced in lowest levels on expanded PTFE (ePTFE). The production of IL-6 and MCP-1 cytokines was also dependent on the structure of PTFE that the macrophages interacted with, but in a time-dependent manner. Confocal microscopy images taken at 7, 14, and 21 days showed that the electrospun PTFE resulted in the lowest percentage of macrophage fusion, thus indicating the least possible chance of foreign body giant cell (FBGC) formation. Therefore, this study showed that electrospun PTFE with randomly oriented microfibers can provide reduced adhesion, activation, and FBGC formation of macrophages compared to the smooth and planar surface of flat PTFE and node-fibril structured surface of ePTFE.

Examination of near-wall hemodynamic parameters in the renal bridging stent of various stent graft configurations for repairing visceral branched aortic aneurysms

OBJECTIVE This study examined the flow behavior of four stent graft configurations for endovascular repair of complex aneurysms of the descending aorta. METHODS Computational fluid dynamics models with transient boundary conditions and rigid wall simplifying assumptions were developed and used with four distinct geometries to compare various near-wall hemodynamic parameters. RESULTS Graphic plots for time-averaged wall shear stress, oscillating shear index, and relative residence time were presented and compared among the four stent graft configurations of interest. CONCLUSIONS Abrupt 90° and 180° changes in stent geometry (particularly in the side branches) cause a high momentum change and thus increased flow separation and mixing, which has significant implications in blood flow characteristics near the wall. By comparison, longer bridging stents provide more gradual changes in momentum, thus allowing blood flow to develop before reaching the target vessel.

Description of a new technique for repairing chronic type B dissections that involve visceral branches being fed by both true and false lumen by using both lumens as conduits

Here we present three cases performed using a novel technique where aortic flow is compartmentalized proximal to the target vessels through a physician-modified endograft. The visceral segment is then further compartmentalized by the use of another physician modified endograft. By compartmentalizing the flow proximal to the visceral segment, both the true lumen and false lumen can be used as conduits for coextensive bridging stent grafts. Overall, patients have tolerated this procedure extremely well, and while further study and follow-up must be conducted, this procedure could offer a reasonable long-term solution to thoracoabdominal aortic aneurysms complicated by dissection.

Shear accumulation as a means for evaluating risk of thromboembolic events in novel endovascular stent graft designs

Objective: This study proposes to establish a simulation‐based technique for evaluating shear accumulation in stent grafts and to use the technique to assess the performance of a novel branched stent graft system. Methods: Computational fluid dynamics models, with transient boundary conditions, particle injection, and rigid walls, simplifying assumptions were developed and used to evaluate the shear accumulation in various stent graft configurations with a healthy aorta as comparison. Results: Shear streamlines are presented for the various configurations. Shear accumulation was also calculated for each configuration. The number of particles with shear accumulations >3.5 Pa‐s for each configuration was compared with the shear accumulation values of commercially available mechanical aortic valves from the literature. Conclusions: The stent graft configuration with the diaphragm does have particles with shear accumulation >3.5 Pa‐s. However, the percentage of particles with shear accumulation above 3.5 Pa‐s is less than the two commercially available mechanical aortic valves, and more surprisingly, is smaller than in the healthy aorta. Clinical Relevance: This study includes some advanced computational fluid dynamic analysis. Shear accumulation, as discussed in this report, is an important predictor of thromboembolic events with mechanical valves; thus, the parameter is of interest to the United States Food and Drug Administration. To date we believe this analysis has not been performed on stent grafts and published in a peer reviewed journal. With stent graft designs becoming more complex and the anatomic variations of patients with complex aneurysms increasing, we determined it was an important method to introduce to the community of vascular surgeons.

In vitro particulate and in vivo drug retention study of a novel polyethylene oxide formulation for drug-coated balloons

Objective: The purpose of this study was to investigate the newly developed drug‐coated balloon (DCB) using polyethylene oxide (PEO) as a platform and to compare it directly with a commercially available DCB in a preclinical experimental setting. Methods: The PEO balloon was characterized for coating morphology and degree of paclitaxel (PAT) crystallinity. PAT tissue levels were then measured up to 30 days in a healthy porcine model (10 swine, 20 vessels) after treatment with either a PEO balloon or a commercially available DCB. An in vitro bench‐top model was used to compare the particulates released from the PEO balloon and commercially available DCB. Results: The coating on the PEO balloon was smooth and homogeneous with PAT in its amorphous state. From the porcine survival study, the PAT tissue levels were comparable between PEO balloon and commercially available DCB after 7 days of treatment. Both the PEO balloon and the commercially available DCB retained therapeutic drug up to 30 days. During the simulated in vitro model, the PEO balloon shed significantly fewer particulates that were smaller than those of the commercially available DCB. Most important, the PEO balloon shed 25 times fewer large particulates than the commercially available DCB. Conclusions: The amorphous PAT in the PEO balloon provided comparable drug tissue retention levels to those of the commercially available DCB and fewer particulates. Thus prepared PEO balloon proved to be safe and effective in the preclinical experimental setting. The clinical outcomes of these findings need further investigation. Clinical Relevance: Drug‐coated balloons (DCBs) have not been indicated for use in lesions below the knee (BTK). Although it is not fully understood why DCBs have failed BTK, the latest literature has indicated that a DCB that retains drug in the tissues for an extended time while also limiting particulate formation may be beneficial BTK. The polyethylene oxide balloon developed in this study had comparable drug retention to a commercially available DCB and fewer particulates. Therefore, the polyethylene oxide balloon should be investigated further for clinical importance in a porcine model using BTK lesions.