Deployment of drug-eluting stents instead of bare-metal stents has dramatically reduced restenosis rates, but rates of very late stent thrombosis (>1 year postimplantation) have increased. Vascular ...endothelial cells normally provide an efficient barrier against thrombosis, lipid uptake, and inflammation. However, endothelium that has regenerated after percutaneous coronary intervention is incompetent in terms of its integrity and function, with poorly formed cell junctions, reduced expression of antithrombotic molecules, and decreased nitric oxide production. Delayed arterial healing, characterized by poor endothelialization, is the primary cause of late (1 month-1 year postimplantation) and very late stent thrombosis following implantation of drug-eluting stents. Impairment of vasorelaxation in nonstented proximal and distal segments of stented coronary arteries is more severe with drug-eluting stents than bare-metal stents, and stent-induced flow disturbances resulting in complex spatiotemporal shear stress can also contribute to increased thrombogenicity and inflammation. The incompetent endothelium leads to late stent thrombosis and the development of in-stent neoatherosclerosis. The process of neoatherosclerosis occurs more rapidly, and more frequently, following deployment of drug-eluting stents than bare-metal stents. Improved understanding of vascular biology is crucial for all cardiologists, and particularly interventional cardiologists, as maintenance of a competently functioning endothelium is critical for long-term vascular health.
Abstract To avoid complications of prosthetic vascular grafts, engineered vascular constructs have been investigated as an alternative for vascular reconstruction. The scaffolds for vascular tissue ...engineering remain a cornerstone of these efforts and yet many currently available options are limited by issues of inconsistency, poor adherence of vascular cells, or inadequate biomechanical properties. In this study, we investigated whether PCL/collagen scaffolds could support cell growth and withstand physiologic conditions while maintaining patency in a rabbit aortoiliac bypass model. Our results indicate that electrospun scaffolds support adherence and growth of vascular cells under physiologic conditions and that endothelialized grafts resisted adherence of platelets when exposed to blood. When implanted in vivo , these scaffolds were able to retain their structural integrity over 1 month of implantation as demonstrated by serial ultrasonography. Further, at retrieval, these scaffolds continued to maintain biomechanical strength that was comparable to native artery. This study suggests that electrospun scaffolds combined with vascular cells may become an alternative to prosthetic vascular grafts for vascular reconstruction.
Perfusion catheters have recently emerged as a novel approach to deliver liquid anti-proliferative agents into flow obstructed arterial segments. The purpose of this study was to determine the impact ...of luminal delivery pressure on liquid drug penetration into the vessel wall. An ex vivo model using harvested porcine carotid arteries and a two-dimensional computational model were utilized to determine the impact of delivery pressure of liquid therapy into the arterial wall. A pig peripheral injury model determined the impact of intra-luminal delivery pressure on drug retention. Ex vivo results demonstrated that depth of fluid penetration varies from 6.93 ± 1.90% at 0 atm to 27.75 ± 6.61% penetration of the medial layer at 0.4 atm. Computational results had similar outcomes, as penetration varied between 4.4% and 22.84%. The in vivo results demonstrated significant increase in drug delivery to the arterial tissue at 0.4 atm versus 0.1 atm at 1 h (23.43 ± 13.59 ng/mg vs. 2.49 ± 1.81 ng/mg, p = 0.026) and 7 days (0.50 ± 0.39 ng/mg vs. 0.018 ± 0.023 ng/mg, p = 0.0496). The result of this study provides an innovative strategic and technical approach to enable targeted liquid therapy.
Abstract Objectives This study sought to evaluate whether the permanent fluoropolymer-coated Xience Xpedition everolimus-eluting stent (Xience-EES) exhibits lower acute thrombogenicity compared with ...contemporary drug-eluting stents (DES) with biodegradable polymer coatings in an acute swine shunt model. Background Previous pre-clinical and clinical experience suggests that several factors may influence the predisposition for acute thrombus formation of polymer-coated DES, including stent design and the polymer coating technology. It remains unclear whether relevant differences exist with respect to acute thrombogenicity, particularly between current commercial stent designs using permanent polymers and those using biodegradable polymers. Methods An ex vivo carotid to jugular arteriovenous porcine shunt model involving a test circuit of 3 in-line stents, was used to test acute thrombogenicity, where Xience-EES (n = 24) was compared with 4 CE-marked DES with biodegradable polymer coatings (BioMatrix Flex, Synergy, Nobori, and Orsiro n = 6 each). After 1 h of circulation, platelet aggregation in whole mount stents was evaluated by confocal microscopy with immunofluorescent staining against dual platelet markers (CD61/CD42b) along with scanning electron microscopy. Results Xience-EES showed the least percentage of thrombus-occupied area as compared with the biodegradable polymer-coated DES, with a significant difference compared with BioMatrix Flex and Synergy (mean differences: BioMatrix Flex: 15.54, 95% confidence interval CI: 11.34 to 19.75, p < 0.001; Synergy: 8.64, 95% CI: 4.43 to 12.84, p < 0.001; Nobori: 4.22, 95% CI: -0.06 to 8.49, p = 0.055; Orsiro: 2.95, 95% CI: -1.26 to 7.15, p = 0.286). The number of cell nuclei on strut surfaces was also the least in Xience-EES, with a significant difference relative to BioMatrix Flex, Nobori, and Orsiro (mean ratios: BioMatrix Flex: 4.73, 95% CI: 2.46 to 9.08, p < 0.001; Synergy: 1.44, 95% CI: 0.75 to 2.76, p = 0.51; Nobori: 5.97, 95% CI: 3.11 to 11.44, p < 0.001; Orsiro: 5.16, 95% CI: 2.69 to 9.91, p < 0.001). Conclusions Xience-EES’s overall design confers acute thromboresistance relative to contemporary DES with biodegradable coatings, with less platelet aggregation versus BioMatrix Flex and Synergy, and less inflammatory cell attachment versus BioMatrix Flex, Nobori, and Orsiro, in an ex vivo swine shunt model, which lends support to reported clinical findings of lower early stent thrombosis.
Simulations of the temperature field in silicon-on-insulator (SOI) and strained-Si transistors can benefit from experimental data and modeling of the thin silicon layer thermal conductivity at high ...temperatures. This paper develops algebraic expressions to account for the reduction in thermal conductivity due to the phonon-boundary scattering for pure and doped silicon layers and presents the experimental data for 50-nm-thick single-crystal silicon layers at high temperatures. The model applies to the temperature range of 300-1000 K for silicon layer thicknesses from 10 nm to 1 mum (and even bulk), which agrees well with the experimental data. In addition, the algebraic model has an excellent agreement with both the experimental data and predictions of thin-film thermal conductivity based on thermal conductivity integral and Boltzmann transport equation. The analytical thermal modeling and ISE-TCAD electrothermal simulations confirm that both the electrical and thermal performances of SOI transistor can be largely affected if the reduced thermal conductivity of the silicon due to phonon boundary scattering is not properly taken into consideration
The local delivery of antiproliferative agents to inhibit neointimal growth is not specific to vascular smooth muscle cells (VSMC) and delays reendothelialization and vascular healing. This ...investigation was intended to evaluate the effect of luminal delivery of a VSMC-specific aptamer on endothelial healing. The impact of an RNA aptamer (Apt 14) was first examined on the migration and proliferation of primary cultured porcine aortic endothelial cells (ECs) in response to in vitro scratch wound injury. We further evaluated the impact of Apt 14 on reendothelialization when delivered locally in a swine iliofemoral injury model. Although Apt 14 did not affect EC migration and proliferation, in vitro results confirmed that paclitaxel significantly inhibited EC migration and proliferation. En face scanning electron microscopy demonstrated confluent endothelium with elongated EC morphology in Apt 14-treated arteries 14 and 28 days post-treatment. In contrast, vessels treated with paclitaxel-coated balloons displayed a cobblestone morphology and significant platelet and fibrin attachment at cell junctions. These results provide the first evidence of the efficacy of a cell-targeted RNA aptamer to facilitate endothelial healing in a clinically relevant large animal model.
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An RNA aptamer (Apt14) specifically selected to target vascular smooth muscle cells (VSMCs) had no impact on endothelial cell (EC) migration or proliferation in culture. Intravascular delivery of Apt 14 to the iliofemoral artery accelerated vascular healing and reendothelialization in a large animal model of peripheral vascular disease.
Drug-coated balloons (DCBs), which deliver anti-proliferative drugs with the aid of excipients, have emerged as a new endovascular therapy for the treatment of peripheral arterial disease. In this ...study, we evaluated the use of keratose (KOS) as a novel DCB-coating excipient to deliver and retain paclitaxel.
A custom coating method was developed to deposit KOS and paclitaxel on uncoated angioplasty balloons. The retention of the KOS-paclitaxel coating, in comparison to a commercially available DCB, was evaluated using a novel vascular-motion simulating
flow model at 1 h and 3 days. Additionally, the locoregional biological response of the KOS-paclitaxel coating was evaluated in a rabbit ilio-femoral injury model at 14 days.
The KOS coating exhibited greater retention of the paclitaxel at 3 days under pulsatile conditions with vascular motion as compared to the commercially available DCB (14.89 ± 4.12 ng/mg vs. 0.60 ± 0.26 ng/mg,
= 0.018). Histological analysis of the KOS-paclitaxel-treated arteries demonstrated a significant reduction in neointimal thickness as compared to the uncoated balloons, KOS-only balloon and paclitaxel-only balloon.
The ability to enhance drug delivery and retention in targeted arterial segments can ultimately improve clinical peripheral endovascular outcomes.
First generation drug-eluting stents (DES) have significantly improved the treatment options for patients with symptomatic coronary artery disease by decreasing rates of acute vessel closure and ...restenosis after percutaneous coronary revascularization procedures. However, early enthusiasm was temperd by reports of late stent thrombosis (LST), which raised concerns about safety. Since millions of DES have been implanted in patients worldwide, it is imperative to understand the pathology of DES in man. Autopsy studies from the CVPath DES registry documented that delayed arterial healing is accompanied by poor endothelialization of stent struts which is the single best predictor of late stent thrombosis. Arterial healing of DES is highly heterogeneous and is dependent on underlying plaque morphology as well as on the stent location. We identified several anatomical and pathological changes in man, which were associated with LST; these include hypersensitivity reaction to polymer, plaque rupture, bifurcation sites, malapposition and stent fracture. DES was also associated with premature atherosclerotic changes versus BMS.
Objectives This study sought to examine the capability of optical frequency domain imaging (OFDI) to characterize various morphological and histological responses to stents implanted in human ...coronary arteries. Background A precise assessment of vascular responses to stents may help stratify the risk of future adverse events in patients who have been treated with coronary stents. Methods Fourteen human stented coronary segments with implant duration ≥1 month from 10 hearts acquired at autopsy were interrogated ex vivo by OFDI and intravascular ultrasound (IVUS). Comparison with histology was assessed in 134 pairs of images where the endpoints were to investigate: 1) accuracy of morphological measurements; 2) detection of uncovered struts; and 3) characterization of neointima. Results Although both OFDI and IVUS provided a good correlation of neointimal area with histology, the correlation of minimum neointimal thickness was inferior in IVUS (R2 = 0.39) as compared with OFDI (R2 = 0.67). Similarly, IVUS showed a weak correlation of the ratio of uncovered to total stent struts per section (RUTSS) (R2 = 0.24), whereas OFDI maintained superiority (R2 = 0.66). In a more detailed analysis by OFDI, identification of individual uncovered struts demonstrated a sensitivity of 77.9% and specificity of 96.4%. Other important morphological features such as fibrin accumulation, excessive inflammation (hypersensitivity), and in-stent atherosclerosis were characterized by OFDI; however, the similarly dark appearance of these tissues did not allow for direct visual discrimination. The quantitative analysis of OFDI signal reflections from various in-stent tissues demonstrated distinct features of organized thrombus and accumulation of foamy macrophages. Conclusions The results of the present study reinforce the potential of OFDI to detect vascular responses that may be important for the understanding of long-term stent performance, and indicate the capability of this technology to serve as a diagnostic indicator of clinical success.
Drug coated balloons (DCB) are continually improving due to advances in coating techniques and more effective excipients. Paclitaxel, the current drug choice of DCB, is a microtubule-stabilizing ...chemotherapeutic agent that inhibits smooth muscle cell proliferation. Excipients work to promote coating stability and facilitate paclitaxel transfer and retention at the target lesion, although current excipients lack sustained, long-term paclitaxel retention. Keratose, a naturally derived protein, has exhibited unique properties allowing for tuned release of various therapeutic agents. However, little is known regarding its ability to support delivery of anti-proliferative agents such as paclitaxel. The goal of this project was to thus demonstrate the feasibility of keratose as a DCB-coating excipient to promote the release and delivery of paclitaxel.
Keratose was combined with paclitaxel
and the release kinetics of paclitaxel and keratose were evaluated through high performance liquid chromatograph-mass spectroscopy (HPLC-MS) and spectrophotometry, respectively. A custom coating method was developed to deposit keratose and paclitaxel on commercially available angioplasty balloons via an air spraying method. Coatings were then visualized under scanning electron microscopy and drug load quantified by HPLC-MS. Acute arterial transfer of paclitaxel at 1 h was assessed using a novel
model and further evaluated
in a porcine ilio-femoral injury model.
Keratose demonstrated tunable release of paclitaxel as a function of keratose concentration
. DCB coated via air spraying yielded consistent drug loading of 4.0 ± 0.70 μg/mm
. Under scanning electron microscopy, the keratose-paclitaxel DCB showed uniform coverage with a consistent, textured appearance. The acute drug transfer of the keratose-paclitaxel DCB was 43.60 ± 14.8 ng/mg at 1 h
. These measurements were further confirmed
as the acute 1 h arterial paclitaxel levels were 56.60 ± 66.4 ng/mg.
The keratose-paclitaxel coated DCB exhibited paclitaxel uptake and achieved acute therapeutic arterial tissue levels, confirming the feasibility of keratose as a novel excipient for DCB.
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