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Background: Paclitaxel-containing devices (PTXDs) significantly reduce reintervention in patients with symptomatic femoropopliteal peripheral artery disease. A recent aggregate-data meta-analysis reported increased late mortality in patients with peripheral artery disease treated with PTXDs. We performed an individual patient data meta-analysis to evaluate mortality. Methods: Manufacturers of US Food and Drug Administration–approved and commercially available devices in the United States provided deidentified individual patient data for independent analysis. Cox proportional hazards 1-stage meta-analysis models using intention-to-treat methods were used for the primary analysis. A secondary analysis of recovered missing vital status data was performed. The impact of control crossover to PTXDs, cause-specific mortality, and drug dose mortality were assessed. Results: A total of 2185 subjects and 386 deaths from 8 PTXD trials with 4-year median follow-up were identified. The primary analysis indicated a 38% (95% CI, 6% to 80%) increased relative mortality risk, corresponding to 4.6% absolute increase, at 5 years associated with PTXD use. Control and treatment arm loss to follow-up and withdrawal were 24% and 23%, respectively. With inclusion of recovered vital status data, the excess relative mortality risk was 27% (95% CI, 3%–58%). This observation was consistent across various scenarios, including as-treated analyses, with no evidence of increased risk over time with PTXDs. Mortality risk tended to be increased for all major causes of death. There were no subgroup differences. No drug dose–mortality association was identified. Conclusions: This individual patient data meta-analysis, based on the most complete available data set of mortality events from PTXD randomized controlled trials, identified an absolute 4.6% increased mortality risk associated with PTXD use.

Hydrophilic polymer coatings on intravascular devices lower friction between the device and vasculature, thereby reducing trauma during interventional procedures. Polymer coating embolism-the detachment and downstream embolism of polymer particles-has been reported as an iatrogenic complication of coated interventional devices affecting the vasculature and various organs. The Food and Drug Administration (FDA) acknowledges this complication and continues to work with stakeholders to close gaps in performance testing and standards related to polymer coating integrity. Recent innovations within interventional technologies have led to development of new hydrophilic-coated devices with expanded indications for use. The 2018 FDA draft guidance for intravascular guidewires expands the application of particulate generation testing to most devices and recommends labeling changes to increase industry awareness. This article highlights current procedural trends where the phenomenon of polymer coating embolism may be more prevalent. It describes the mechanisms of polymer separation, reported clinical sequelae, and risk factors for relevant indications. These procedural trends and associated risk factors articulate the need for particulate testing and support the FDA's draft guidance recommendations for performance testing of applied coatings. If standardized, particulate assessments may allow characterization and comparisons of coating integrity among devices from various manufacturers, and are an important foundation for setting particulate limits. As hydrophilic coatings enable endovascular treatment for a range of patient populations, setting particulate limits or finding alternative solutions without compromise to device function may be essential. Particulate testing is relevant to physicians, regulators, and manufacturers for the purposes of product development and quality improvement of interventional devices.

This study sought to evaluate perisplenic artery nerve distribution and the feasibility of splenic artery denervation (SDN). The NEXION radiofrequency catheter was used to perform SDN in healthy and inflammatory arthritis pigs. Splenic artery anatomy, nerve distribution, and splenic norepinephrine (NEPI) levels were evaluated before and after SDN. Perisplenic artery nerves were primarily distributed within 2.5 mm of the arterial lumen and were largely sympathetic on the basis of tyrosine hydroxylase expression. The pancreas, tended to be circumferentially positioned around the proximal splenic artery, typically >2.5 mm from the lumen, ensuring that most of the nerves could be targeted without affecting this sensitive organ. The mid segment of the splenic artery was relatively free of contact with the adjacent pancreas. Splenic NEPI levels and nerve abundance followed a decreasing gradient from the proximal to distal splenic artery. SDN resulted in significant reductions in splenic NEPI levels at day 14 (60.7%, P = 0.024) in naive pigs and day 45 (100%, P = 0.001) in inflammatory arthritis pigs. There was no significant effect of SDN on joint soft tissue injury or circulating inflammatory markers in the inflammatory arthritis model. The majority of perisplenic arterial nerves are within close proximity of the lumen and are primarily sympathetic efferent fibers. Nerves in the mid-segment may be the preferred SDN target given their proximity to the artery and paucity of periarterial off-target organs. SDN appears safe and effective at reducing splenic NEPI levels.

© 2019 Elsevier B.V. Paclitaxel coated balloons (PCBs) are a promising non-implantable alternative to drug-eluting stents, whereby drug is delivered to the arterial wall in solid form as a semi-continuous solid coating or as micro drug depots. To date, it has been impossible to predict or even infer local tissue dosing levels and persistence, making it difficult to compare in vivo performance of different devices in healthy animals or to extrapolate such data to diseased human arteries. Here we derive and analyze a coupled reaction diffusion model that accounts for coating dissolution and tissue distribution, and predicts the concentration of dissolved drug in the tissue during and post dissolution. Time scale analysis and numerical simulations based on estimated diffusion coefficients in healthy animal and diseased human arteries both imply that dissolution of crystalline paclitaxel coating is mass transfer coefficient-limited, and can therefore be solved for independently of the tissue transport equations. Specifically, coating retention is predicted to follow piecewise linear kinetics, reflecting the differential and faster dissolution of lumenal versus tissue-embedded coating owing to a disparity in convective forces. This prediction is consistent with published data on a range of PCBs and allowed for the estimation of the associated dissolution rate-constants and the maximal soluble drug concentration in the tissue during coating dissolution. Maximal soluble drug concentration in the tissue scales as the product of the solubility and ratio of the dissolution and diffusion rate-constants. Thus, coatings characterized by micromolar solubilities give rise to nanomolar soluble concentrations in healthy animal arteries and ~0.1 micromolar in calcified atherosclerotic arteries owing to slower tissue diffusion. During dissolution, retention in porcine iliofemoral arteries is predicted to be dominated by solid coating, whereas post dissolution it is dominated by receptor-bound drug (3.7 ng receptors/g tissue). Paclitaxel coating dissolution and dosing kinetics can now be modeled based upon accepted principles of surface dissolution and tissue transport to provide insights into the dependence of clinical efficacy on device properties and the interplay of lesion complexity and procedural parameters.

Paclitaxel coated balloon catheters (PCB) were developed as a polymer-free non-implantable alternative to drug eluting stents, delivering similar drug payloads in a matter of minutes. While PCB have shown efficacy in treating peripheral arterial disease in certain patient groups, restenosis rates remain high and there is no class effect. To help further optimize these devices, we developed a scanning electron microscopy (SEM) imaging technique and computational modeling approach that provide insights into the coating micromorphology dependence of in vivo drug transfer and retention. PCBs coated with amorphous/flaky or microneedle coatings were inflated for 60 sec in porcine femoral arteries. Animals were euthanized at 0.5, 24 and 72 h and treated arteries processed for SEM to image endoluminal coating distribution followed by paclitaxel quantification by mass spectrometry (MS). Endoluminal surfaces exhibited sparse coating patches at 0.5 h, predominantly protruding (13.71 vs 0.59%, P 0.001), with similar micro-morphologies to nominal PCB surfaces. Microneedle coating covered a 1.5-fold endoluminal area (16.1 vs 10.7%, P = 0.0035) owing to higher proximal and distal delivery, and achieved 1.5-fold tissue concentrations by MS (1933 vs 1298 μg/g, P = 0.1745) compared to amorphous/flaky coating. Acute longitudinal coating distribution tracked computationally predicted microindentation pressure gradients (r = 0.9, P 0.001), with superior transfer of the microneedle coatings attributed to their amplification of angioplasty contact pressures. By 24 h, paclitaxel concentration and coated tissue areas both declined by93% even as nonprotruding coating levels were stable between 0.5 and 72 h, and 2.7-fold higher for microneedle vs flaky coating (0.64 vs 0.24%, P = 0.0195). Tissue retained paclitaxel concentrations at 24-72 h trended 1.7-fold higher post treatment with microneedle coating compared to the amorphous/flaky coating (69.9 vs 39.9 μg/g, P = 0.066). Thus, balloon based drug delivery is critically dependent on coating micromorphologies, with superior performance exhibited by micromorphologies that amplify angioplasty pressures.

Background/purpose: Catheter-based renal sympathetic denervation (RDN) has been introduced to lower blood pressure (BP) and sympathetic activity in patients with uncontrolled hypertension with at best equivocal results. It has been postulated that anatomic and procedural elements introduce unaccounted variability and yet little is known of the impact of renal anatomy and procedural parameters on BP response to RDN. Methods/materials: Anatomical parameters such as length and diameter were analyzed by quantitative vascular analysis and the prevalence of accessory renal arteries and renal artery disease were documented in 150 patients with resistant hypertension undergoing bilateral RDN using a mono-electrode radiofrequency catheter (Symplicity Flex, Medtronic). Results: Accessory renal arteries and renal artery disease were present in 56 (37%) and 14 patients (9%), respectively. At 6-months, 24 h-ambulatory BP was reduced by 11/6 mm Hg (p < 0.001 for both). Change of systolic blood pressure (SBP) was not related to the presence of accessory renal arteries (p = 0.543) or renal artery disease (p = 0.598). Patients with at least one main renal artery diameter ≤ 4 mm had a more pronounced reduction of 24 h-ambulatory SBP compared to patients where both arteries were >4 mm (−19 vs. −10 mmHg; p = 0.038). Neither the length of the renal artery nor the number of RF ablations influenced 24 h-ambulatory BP reduction at 6 months. Conclusions: 24 h-ambulatory BP lowering was most pronounced in patients with smaller renal artery diameter but not related to renal artery length, accessory arteries or renal artery disease. Further, there was no dose-response relationship observed with increasing number of ablations. Condensed abstract: Because little is known of the impact of renal anatomy and procedural parameters on blood pressure (BP) response to renal denervation (RDN), anatomical and procedural data were analyzed in 150 patients undergoing bilateral RDN. BP lowering was most pronounced in patients with smaller renal artery diameter but not related to renal artery length, the presence of renal artery disease or accessory renal arteries. Further, there was no dose-response relationship observed with increasing number of ablations., National Institutes of Health (Grant R01-GM49039)

AIMS: Simple surface modifications can enhance coronary stent performance. Ultra-hydrophilic surface (UHS) treatment of contemporary bare metal stents (BMS) was assessed in vivo to verify whether such stents can provide long-term efficacy comparable to second-generation drug-eluting stents (DES) while promoting healing comparably to BMS. METHODS AND RESULTS: UHS-treated BMS, untreated BMS and corresponding DES were tested for three commercial platforms. A thirty-day and a 90-day porcine coronary model were used to characterise late tissue response. Three-day porcine coronary and seven-day rabbit iliac models were used for early healing assessment. In porcine coronary arteries, hydrophilic treatment reduced intimai hyperplasia relative to the BMS and corresponding DES platforms (1.5-fold to threefold reduction in 30-day angiographic and histological stenosis; p

We evaluated the preclinical safety of a novel paclitaxel-coated balloon catheter (PCB) with a nitinol constraining structure positioned over it, designed to improve acute treatment of stenotic and occluded arteries. PCBs (TriReme Medical, Singapore) with 5.53mg PTX and (3μg/mm2, 6×80 mm) and a

Computational modeling is revolutionizing device design and evaluation. While great progress has been made in virtual stent angioplasty and computational hemodynamics, drug-delivery modeling in patient-specific geometries remains a challenge owing to its inherently-dynamic nature. We developed a

Radiofrequency renal denervation (RDN) is under investigation for treatment of hypertension with variable success. We developed preclinical models to examine the dependence of ablation biomarkers on RDN treatment parameters and anatomical variables. 129 porcine renal arteries were denervated with an irrigated RF catheter with multiple helically arrayed electrodes. Nerve effects and ablation geometries at 7d were characterized histomorphometrically and correlated with associated renal norepinephrine (NEPI) levels. NEPI exhibited a threshold dependence on the percentage of affected nerves (%AN) across the range of treatment durations (30–60sec) and power set-points (6–20W). For 15W/30sec treatments, NEPI reduction and %AN tracked with number of electrode treatments, confirming additive effects of helically staggered ablations. Threshold effects were only attained when ≥four electrodes were powered. Histomorphometry and computational modeling both illustrated that RF treatments directed at large neighboring veins resulted in sub-average ablation areas, and therefore contributed suboptimally to efficacy. Account for measured nerve distribution patterns and the annular geometry of the artery revealed that, regardless of treatment variables, total ablation area and circumferential coverage were the prime determinants of RDN efficacy, with increased efficacy at smaller diameters. SUMMARY: Large animal experiments supported by computational and statistical models that account for arterial microanatomy and nerve distribution explain the dependence of RDN efficacy on procedural parameters, e.g. number of electrode treatments, and anatomic parameters, e.g. arterial diameter and the proximity of veins to ablation sites.

Aims Pulmonary arterial hypertension is a devastating disease characterised by pulmonary vascular remodelling and right heart failure. Radio-frequency pulmonary artery denervation (PDN) has improved pulmonary haemodynamics in preclinical and early clinical studies; however, denervation depth is limited. High-frequency non-focused ultrasound can deliver energy to the vessel adventitia, sparing the intima and media. We therefore aimed to investigate the feasibility, safety and efficacy of ultrasound PDN. Methods and results Histological examination demonstrated that innervation of human pulmonary arteries is predominantly sympathetic (71%), with >40% of nerves at a depth of >4 mm. Finite element analysis of ultrasound energy distribution and ex vivo studies demonstrated generation of temperatures >47oC to a depth of 10 mm. In domestic swine, PDN reduced mean pulmonary artery pressure induced by thromboxane A2 in comparison to sham. No adverse events were observed up to 95 days. Histological examination identified structural and immunohistological changes of nerves in PDN-treated animals, with sparing of the intima and media and reduced tyrosine hydroxylase staining 95 days post procedure, indicating persistent alteration of the structure of sympathetic nerves. Conclusions Ultrasound PDN is safe and effective in the preclinical setting, with energy delivery to a depth that would permit targeting sympathetic nerves in humans.

Endovascular drug delivery continues to revolutionize the treatment of atherosclerosis in coronary and peripheral vasculature. The key has been to identify biologic agents that can counter the hyperplastic tissue responses to device expansion/implantation and to develop effective local delivery strategies that can maintain efficacious drug levels across the artery wall over the course of device effects. This article reviews the evolution of endovascular drug delivery technology, explains the mechanisms they use for drug release, and provides a quantitative mechanistic framework for relating drug release mode to arterial drug distribution and effect.

Pancreatic ductal adenocarcinoma (PDAC) is one of the most devastating and painful cancers. It is often highly resistant to therapy owing to inherent chemoresistance and the desmoplastic response that creates a barrier of fibrous tissue preventing transport of chemotherapeutics into the tumor. The growth of the tumor in pancreatic cancer often leads to invasion of other organs and partial or complete biliary obstruction, inducing intense pain for patients and necessitating tumor resection or repeated stenting. Here, we have developed a delivery device to provide enhanced palliative therapy for pancreatic cancer patients by providing high concentrations of chemotherapeutic compounds locally at the tumor site. This treatment could reduce the need for repeated procedures in advanced PDAC patients to debulk the tumor mass or stent the obstructed bile duct. To facilitate clinical translation, we created the device out of currently approved materials and drugs. We engineered an implantable poly(lactic-co-glycolic)-based biodegradable device that is able to linearly release high doses of chemotherapeutic drugs for up to 60 days. We created five patient-derived PDAC cell lines and tested their sensitivity to approved chemotherapeutic compounds. These in vitro experiments showed that paclitaxel was the most effective single agent across all cell lines. We compared the efficacy of systemic and local paclitaxel therapy on the patient-derived cell lines in an orthotopic xenograft model in mice (PDX). In this model, we found up to a 12-fold increase in suppression of tumor growth by local therapy in comparison to systemic administration and reduce retention into off-target organs. Herein, we highlight the efficacy of a local therapeutic approach to overcome PDAC chemoresistance and reduce the need for repeated interventions and biliary obstruction by preventing local tumor growth. Our results underscore the urgent need for an implantable drug-eluting platform to deliver cytotoxic agents directly within the tumor mass as a novel therapeutic strategy for patients with pancreatic cancer. Keywords: Pancreatic cancer; Chemoresistance; Local delivery; Patient-derived xenograft; Paclitaxel; Poly(lactic-co-glycolic acid), National Institutes of Health (U.S.) (Grant P30-CA14051)

Background: Innovations in drug eluting stent designs make it increasingly important to develop models for differentiating performance through spatial definition of drug, receptor binding and cell state. Methods: Two designs of sirolimus analog eluting stents were implanted into porcine coronary arteries for 28, 60 or 90 days (n = 9/time point), durable coating (Xience) and deployable absorbable coating (MiStent). Explanted arteries were evaluated for drug content (n = 3/time point) by LC-MS/MS and for drug and target protein (mTOR) distributions by immunofluorescence (IF, n = 6/time point). A computational model was developed to predict drug release and arterial distribution maps. Results: Both stents released the majority of drug load by 28 days, with different tissue retention efficiencies (91.4 ± 4.9% MiStent versus 21.5 ± 1.9% Xience, P < 0.001). Computational modeling of MiStent coating deployment and microcrystal dissolution recapitulated in vivo drug release and net tissue content and predicted that >98.5% of deployed drug remains crystalline through 90 days. Immunofluorescence and computational modeling showed peristrut drug localization for both stents, with similar peaks, but high interstrut levels only at sites of coating deployment from the absorbable coating. Co-localization of mTOR-IF with drug-IF for both devices showed persistent drug effects, though with differential drug–receptor pharmacokinetics. Conclusions: Immunofluorescence and computational modeling provide insights into drug distribution and binding status that can help differentiate drug delivery technologies. Herein we found that tissue deployment of slow dissolving crystalline drug particles results in temporally and spatially more uniform drug delivery to interstrut zones that might otherwise be under-dosed without excess peristrut drug., National Institutes of Health (Grant R01-GM-49039)

Background: Calcific atherosclerosis is a major challenge to intraluminal drug delivery in peripheral artery disease (PAD). Objectives: We evaluated the effects of orbital atherectomy on intraluminal paclitaxel delivery to human peripheral arteries with substantial calcified plaque. Methods: Diagnostic angiography and 3-D rotational imaging of five fresh human lower limbs revealed calcification in all main arteries. The proximal or distal segment of each artery was treated using an orbital atherectomy system (OAS) under simulated blood flow and fluoroscopy. Explanted arterial segments underwent either histomorphometric assessment of effect or tracking of [superscript 14]C-labeled or fluorescent–labeled paclitaxel. Radiolabeled drug quantified bulk delivery and fluorescent label established penetration of drug over finer spatial domain in serial microscopic sections. Results: were interpreted using a mathematical model of binding-diffusion mediated arterial drug distribution. Results Lesion composition affected paclitaxel absorption and distribution in cadaveric human peripheral arteries. Pretreatment imaging calcium scores in control femoropopliteal arterial segments correlated with a log-linear decline in the bulk absorption rate-constant of [superscript 14]C-labeled, declining 5.5-fold per calcified quadrant (p = 0.05, n = 7). Compared to controls, OAS-treated femoropopliteal segments exhibited 180 μm thinner intima (p < 0.001), 45% less plaque calcification, and 2 log orders higher paclitaxel bulk absorption rate-constants. Correspondingly, fluorescent paclitaxel penetrated deeper in OAS-treated femoropopliteal segments compared to controls, due to a 70% increase in diffusivity (p < 0.001). Conclusions These data illustrate that calcified plaque limited intravascular drug delivery, and controlled OAS treatment of calcific plaques resulted in greater drug permeability and improved adjunct drug delivery to diseased arteries.Peripheral artery disease Keywords: Drug coated balloons, Drug eluting stents, Atherectomy, Orbital atherectomy, calcified plaque, Paclitaxel, National Institute of Mental Health (U.S.) (Grant R01 GM-49039)

A recent meta-analysis of randomized controlled trials investigating paclitaxel-coated balloons and stents in the femoral and/or popliteal arteries reported an increased risk of death 2 to 5 years after treatment. Yet, no mechanisms for mortality have been offered, and preclinical experiments

The failure of the prospective, randomized, sham-controlled SYMPLICITY HTN-3 trial to show significant difference in reduction of systolic blood pressure (SBP) in patients with resistant hypertension 6 months after renal denervation (RDN) compared with control subjects was attributed in part to

Paclitaxel (PTX) drug-coated balloons (DCBs) are effective at reducing restenosis following endovascular arterial revascularization; however, their efficacy is limited in highly calcified/impermeable arteries. However, no in vivo tool exists to guide arterial lesion preparation prior to DCB to

Background—Drug-coated balloons are increasingly used for peripheral vascular disease, and, yet, mechanisms of tissue uptake and retention remain poorly characterized. Most systems to date have used paclitaxel, touting its propensity to associate with various excipients that can optimize its transfer and retention. We examined zotarolimus pharmacokinetics. Methods and Results—Animal studies, bench-top experiments, and computational modeling were integrated to quantify arterial distribution after zotarolimus-coated balloon use. Drug diffusivity and binding parameters for use in computational modeling were estimated from the kinetics of zotarolimus uptake into excised porcine femoral artery specimens immersed in radiolabeled drug solutions. Like paclitaxel, zotarolimus exhibited high partitioning into the arterial wall. Exposure of intimal tissue to drug revealed differential distribution patterns, with zotarolimus concentration decreasing with transmural depth as opposed to the multiple peaks displayed by paclitaxel. Drug release kinetics was measured by inflating zotarolimus-coated balloons in whole blood. In vivo drug uptake in swine arteries increased with inflation time but not with balloon size. Simulations coupling transmural diffusion and reversible binding to tissue proteins predicted arterial distribution that correlated with in vivo uptake. Diffusion governed drug distribution soon after balloon expansion, but binding determined drug retention. Conclusions—A large bolus of zotarolimus releases during balloon inflation, some of which pervades the tissue, and a fraction of the remaining drug adheres to the tissue–lumen interface. As a result, the duration of delivery modulates tissue uptake where diffusion and reversible binding to tissue proteins determine drug transport and retention, respectively., National Institutes of Health (U.S.) (Grant R01 GM-49039), Abbott Vascular

BACKGROUND/PURPOSE: Catheter-based renal sympathetic denervation (RDN) can reduce blood pressure (BP) and sympathetic activity in certain patients with uncontrolled hypertension. Less is known about the impact of renal anatomy and procedural parameters on subsequent BP response. METHODS/MATERIALS: A total of 564 patients with resistant hypertension underwent bilateral RDN in 9 centers in Europe and Australia using a mono-electrode radiofrequency catheter (Symplicity Flex, Medtronic). Anatomical criteria such as prevalence of accessory renal arteries (ARA), presence of renal artery disease (RAD), length, and diameter were analyzed blinded to patient's characteristics. RESULTS: ARA was present in 171 patients (30%), and RAD was documented in 71 patients (13%). On average 11±2.7 complete 120-s ablations were performed, equally distributed on both sides. After 6months, BP was reduced by 19/8mmHg (p4mm (-29 vs. -26 vs. -17mmHg; p

available in PMC 2016 March 23, Aims: We sought to evaluate the incidence of embolic material in porcine brains following vascular interventions using hydrophilic-coated sheaths. Methods and results: A new self-expanding stent and delivery system (SDS) was deployed through a hydrophilic-coated (Flexor® Ansel; Cook Medical, Bloomington, IN, USA) guiding sheath into the iliac and/or carotid arteries of 23 anaesthetised Yucatan mini swine. The animals were euthanised at three, 30, 90 and 180 days and their brains were removed for histological analysis. In an additional single control animal, the guiding sheath was advanced but no SDS was deployed. Advancement of the coated guiding sheath with or without the SDS was associated with frequent foreign material in the arterioles of the brain. The embolic material was amorphous, non-refractile, non-crystalline, non-birefringent and typically lightly basophilic with a slightly stippled appearance on haematoxylin and eosin (H&E) stain. Material was observed at all time points involving 54% of all study animals (i.e., test and control) and in vitro after incubation in 0.9% saline. Conclusions: The hydrophilic coating on a clinically used guiding sheath readily avulses and embolises to the brain during deployment in a porcine model. Further documentation of this effect and monitoring in clinical scenarios are warranted., National Institutes of Health (U.S.) (NIH (R01 GM 49039))

Current drug eluting stent (DES) technology is not optimized with regard to the pharmacokinetics of drug delivery. A novel, absorbable-coating sirolimus-eluting stent (AC-SES) was evaluated for its capacity to deliver drug more evenly within the intimal area rather than concentrating drug around the stent struts and for its ability to match coating erosion with drug release. The coating consisted of absorbable poly-lactide-co-glycolic acid (PLGA) and crystalline sirolimus deposited by a dry-powder electrostatic process. The AC-SES demonstrated enhanced drug stability under simulated use conditions and consistent drug delivery balanced with coating erosion in a porcine coronary implant model. The initial drug burst was eliminated and drug release was sustained after implantation. The coating was absorbed within 90 days. Following implantation into porcine coronary arteries the AC-SES coating is distributed in the surrounding intimal tissue over the course of several weeks. Computational modeling of drug delivery characteristics demonstrates how distributed coating optimizes the load of drug immediately around each stent strut and extends drug delivery between stent struts. The result was a highly efficient arterial uptake of drug with superior performance to a clinical bare metal stent (BMS). Neointimal thickness (0.17 ± 0.07 mm vs. 0.28 ± 0.11 mm) and area percent stenosis (22 ± 9% vs. 35 ± 12%) were significantly reduced (p < 0.05) by the AC-SES compared to the BMS 30 days after stent implantation in an overlap configuration in porcine coronary arteries. Inflammation was significantly reduced in the AC-SES compared to the BMS at both 30 and 90 days after implantation. Biocompatible, rapidly absorbable stent coatings enable the matching of drug release with coating erosion and provide for the controlled migration of coating material into tissue to reduce vicissitudes in drug tissue levels, optimizing efficacy and reducing potential toxicity., Micell Technologies, Inc., National Institutes of Health (U.S.) (R01 GM49039)

Periarterial lymph nodes and blood vessels can shield nerves from radiofrequency heating and limit the efficacy of catheter based renal denervation (RDN). We quantified the distributions of accessible and shielded nerves surrounding porcine renal arteries. Left and right renal arteries from 9 swine

The spleen plays an important role in the immune response to inflammatory conditions including cancer, myocardial infarction and atherosclerosis. Device-based neuromodulation of the spleen’s neural pathways is an emerging therapeutic approach to regulating the immune response in various

Polymer-free drug-coated stents (PF DCS) avoid the concern for inflammatory material responses, but pose challenges in providing controlled drug release and sustained tissue retention. We used immunofluorescence (IF) methods to contrast the arterial distribution of Sirolimus and the highly

Though stents are deployed in diseased arteries drug distribution has only been quantified in intact, non-diseased vessels. We correlated steady-state arterial drug distribution with tissue ultrastructure and composition in abdominal aortae from atherosclerotic human autopsy specimens and rabbits with lesions induced by dietary manipulation and controlled injury. Paclitaxel, everolimus, and sirolimus depositions in the human aortae were maximal in the media and scaled inversely with lipid content. Net tissue paclitaxel and everolimus levels were indistinguishable in mildly injured rabbit arteries independent of diet. Yet, serial sectioning of cryopreserved arterial segments demonstrated a differential transmural deposition pattern that was amplified with disease and correlated with the expression of their intracellular targets, tubulin and FKBP-12. Tubulin distribution and paclitaxel binding increased with vascular injury and macrophage infiltration, and were reduced with lipid content. Sirolimus analogs and their specific binding target FKBP-12 were less sensitive to alterations of diet in mildly injured arteries, presumably reflecting a faster transient response of FKBP-12 to injury. The data demonstrate that disease-induced changes in the distribution of drug-binding proteins and interstitial lipid alter the distribution of these drugs, forcing one to consider how disease might affect the evaluation and efficacy of the local release of these and like compounds.

Endovascular stents reside in a dynamic flow environment and yet the impact of flow on arterial drug deposition after stent-based delivery is only now emerging. We employed computational fluid dynamic modeling tools to investigate the influence of luminal flow patterns on arterial drug deposition and distribution. Flow imposes recirculation zones distal and proximal to the stent strut that extend the coverage of tissue absorption of eluted drug and induce asymmetry in tissue drug distribution. Our analysis now explains how the disparity in sizes of the two recirculation zones and the asymmetry in drug distribution are determined by a complex interplay of local flow and strut geometry. When temporal periodicity was introduced as a model of pulsatile flow, the net luminal flow served as an index of flow-mediated spatio-temporal tissue drug uptake. Dynamically changing luminal flow patterns are intrinsic to the coronary arterial tree. Coronary drug eluting stents should be appropriately considered where luminal flow, strut design and pulsatility have direct effects on tissue drug uptake after local delivery.

The long held assumption that sustained drug elution from stent coatings over weeks to months is imperative for clinical efficacy has limited the choice for stent coating materials. We developed and evaluated an omega-3 fatty acid (O3FA) based stent coating that is 85% absorbed and elutes 97% of its Sirolimus analog (Corolimus) load within 8d of implantation. O3FA coated stents sustained drug levels in porcine coronary arteries similarly to those achieved by slow-eluting durable coated Cypher Select Plus Stents and with significantly lower levels of granuloma formation and luminal stenosis. Computational modeling confirmed that diffusion and binding constants of Corolimus and Sirolimus are identical and explained that the sustained retention of Corolimus was facilitated by binding to high affinity intracellular receptors (FKBP12). First in man outcomes were positive—unlike Cypher stents where late lumen loss drops over 6 month, there was a stable effect without diminution in the presence of O3FA. These results speak to a new paradigm whereby the safety of drug eluting stents can be optimized through the use of resorbable biocompatible coating materials with resorption kinetics that coincide with the dissociation and tissue elimination of receptor-bound drug., National Institutes of Health (U.S.) (R01 GM-49039)

Background— The intricacies of stent design, local pharmacology, tissue biology, and rheology preclude an intuitive understanding of drug distribution and deposition from drug-eluting stents (DES). Methods and Results— A coupled computational fluid dynamics and mass transfer model was applied to predict drug deposition for single and overlapping DES. Drug deposition appeared not only beneath regions of arterial contact with the strut but surprisingly also beneath standing drug pools created by strut disruption of flow. These regions correlated with areas of drug-induced fibrin deposition surrounding DES struts in porcine coronary arteries. Fibrin deposition immediately distal to individual isolated drug-eluting struts was twice as great as in the proximal area and for the stent as a whole was greater in distal segments than proximal segments. Adjacent and overlapping stent struts increased computed arterial drug deposition by far less than the sum of their combined drug load. In addition, drug eluted from the abluminal stent strut surface accounted for only 11% of total deposition, whereas, remarkably, drug eluted from the adluminal surface accounted for 43% of total deposition. Thus, local blood flow alterations and location of drug elution on the strut were far more important in determining arterial wall drug deposition and distribution than were drug load or arterial wall contact with coated strut surfaces. Conclusions— Simulations that coupled strut configurations with flow dynamics correlated with in vivo effects and revealed that drug deposition occurs less via contact between drug coating and the arterial wall than via flow-mediated deposition of blood-solubilized drug.

The Briggs–Haldane approximation of the irreversible Michaelis–Menten scheme of enzyme kinetics is cited in virtually every biochemistry textbook and is widely considered the classic example of a quasi-steady-state approximation. Though of similar importance, the reversible Michaelis–Menten scheme is not as well characterized. This is a serious limitation since even enzymatic reactions that go to completion may be reversible. The current work derives a total quasi-steady-state approximation (tQSSA) for the reversible Michaelis–Menten and delineates its validity domain. The tQSSA allows the derivation of uniformly valid approximations for the limit of low enzyme concentrations, ET⪡ST+KM, and under certain more restrictive conditions also for high enzyme concentrations such that ST⪡ET+KM. Using these simple analytical approximations, a sequential experimental–theoretical method is suggested for unambiguously estimating all the kinetic parameters of the reversible Michaelis–Menten scheme.

Predicting the time course of in vivo biodegradation is a key issue in the design of an increasing number of biomedical applications such as sutures, tissue analogs and drug-delivery devices. The design of such biodegradable devices is hampered by the absence of quantitative models for the enzymatic erosion of solid protein matrices. In this work, we derive and simulate a reaction diffusion model for the enzymatic erosion of fibrillar gels that successfully reproduces the main qualitative features of this process. A key aspect of the proposed model is the incorporation of steric hindrance into the standard Michaelis–Menten scheme for enzyme kinetics. In the limit of instantaneous diffusion, the model equations are analogous to the standard equations for enzymatic degradation in solution. Invoking this analogy, the total quasi-steady-state approximation is used to derive approximate analytical solutions that are valid for a wide range of in vitro conditions. Using these analytical approximations, an experimental–theoretical method is derived to unambiguously estimate all the kinetic model parameters. Moreover, the analytical approximations correctly describe the characteristic hyperbolic dependence of the erosion rate on enzyme concentration and the zero-order erosion of thin fibers. For definiteness, the analysis of published experimental results of enzymatic degradation of fibrillar collagen is demonstrated, and the role of diffusion in these experiments is elucidated.

The release of active agent from a bulk degrading matrix is formulated as a linear reaction diffusion problem. Two pools of active agent are assumed to contribute to the release: a pool of mobile active agent which readily diffuses out of the matrix upon immersion in an aqueous medium and a pool of immobilized active agent which can diffuse only after matrix degradation. Due to the linearity of our model, the dynamics of the two pools of active agent can be considered separately, for any mode of bulk degradation kinetics. For definiteness, we consider the case of first order degradation kinetics and a rectangular parallelepiped shaped matrix. A closed form solution is obtained for the release under perfect sink conditions which is then used to describe the in vitro release of the PerioChip¿trade mark omitted¿. This solution can explain the bi-phasic release profile characteristic of many hydrolytically degradable matrices. The case of mass transfer boundary conditions is solved numerically using the finite element method (FEM). This analysis indicates that under ordinary mixing conditions the diffusion layer is not rate limiting and the release is very well approximated by the analytical result for perfect sink conditions.

Polymer-free controlled drug elution has proved challenging for surface-modified drug eluting stents. Drug-filled stents (DFS; Medtronic, Santa Rosa CA) however, are a novel platform for polymer-free drug delivery in which the drug is contained in a hollow stent and released through laser drilled

Clinical trials and meta-analyses demonstrate the low restenosis and stent thrombosis risks of next generation drug eluting stents (DES). Co-evolution of device, delivery technique, and drug-related factors all contribute, yet relative advantages are difficult to surmise. On a background of

Background Successful recanalization (TICI ≥ 2b) using mechanical thrombectomy (MT) with stent retriever devices is associated with good outcomes in the treatment of ischemic stroke. Preclinical TICI flow assessement is challenging due to the difficulty of consistently occluding selected blood vessels in vivo using lab-created thrombus. We describe the development of a discrete occlusive porcine clot model for predictable and repeatable assessment of TICI flow restoration and treatment effects on the vessels at the 3 day and 28 day timepoints and following MT. Methods Firm and soft thrombus were aged for 24–48 hours prior to injection into the peripheral arteries of eight Yorkshire pigs. Oversized clots were introduced to the target region through a guide catheter via a customized luer to minimize shear/fragmentation. Clots were allowed to stabilize in the vessel prior to treatment. Clot retrieval was performed with a novel Revascularization Device (Neuravi Ltd.) or Trevo® ProVue Retriever (Stryker Inc.) as a control. TICI flow was assessed following clot administration and after thrombectomy. Vascular response to the treatment was assessed histologically at 3 and 28 days. Results Complete occlusion was achieved in 92% (22/24) of the targeted arteries by insertion of one (20/22) or two (2/22) pre-measured clots. Of the occluded arteries treated, TICI 3 flow restoration was achieved in all cases (100%) with the Neuravi device and 90% cases with Trevo; single pass recanalization (TICI ≥ 2b) rates were 92% and 80% respectively. All vessels were patent at 3 and 28 days post treatment, and histologically the prototype Neuravi revascularization device was associated with favorable local and end organ tissue responses, and was comparable to the Trevo ProVue. Conclusions Novel methods were developed to provide consistent thrombus morphology enabling controlled delivery and adherence and facilitating comparative analysis of thrombectomy devices using angiographic (TICI) flow assessment in the preclinical swine model. Angiographic assessments and vessel response to treatment by Mechanical Thrombectomy were successfully completed following occlusion with firm and soft thrombus administration. Disclosures L. Bailey: 1; C; Neuravi Ltd. M. Gilvarry: 5; C; Neuravi Ltd. M. Holian: 5; C; Neuravi Ltd. A. Tzafriri: 1; C; Neuravi Ltd. J. Stanley: 1; C; Neuravi Ltd. E. Edelman: None.

Catheter-based renal sympathetic denervation (RDN) can reduce blood pressure (BP) and sympathetic activity in certain patients with uncontrolled hypertension. Less is known about the impact of renal anatomy and procedural parameters on subsequent BP response. A total of 564 patients with resistant

Drug release from spray coatings applied to cylindrical stents is difficult to customize due to intermixing of successively coated layers. Flat sheets of electropolished L-605 Cobalt Chromium alloy were spray coated with a solution of Ridaforolimus and two polymers, folded and welded into cylinders

Drug eluting stent designs abound and yet the dependence of efficacy on drug dose and elution duration remains unclear. We examined these issues within a mathematical framework of arterial drug distribution and receptor binding following stent elution. Model predictions that tissue content linearly tracks stent elution rate were validated in porcine coronary artery sirolimus-eluting stents implants. Arterial content varied for stent types, progressively declining from its Day 1 peak and tracking with rate-limiting drug elution — near zero-order release was three-fold more efficient at depositing drug in the stented lesion than near first-order release. In vivo data were consistent with an overabundance of non-specific sirolimus-binding sites relative to the specific receptors and to the delivered dose. The implication is that the persistence time of receptor saturation and effect is more sensitive to duration of elution than to eluted amount. Consequently, the eluted amount should be sufficiently high to saturate receptors at the target lesion, but dose escalation alone is an inefficient strategy for prolonging the duration of sirolimus deposition. Moreover, receptor saturating drug doses are predicted to be most efficacious when eluted from stents in a constant zero order fashion as this maximizes the duration of elution and receptor saturation., National Institutes of Health (U.S.) (RO1 GM-49039), Cordis Corporation

Stat5 signaling in erythroblasts can assume either a binary, low-intensity form, essential for basal erythropoiesis, or a graded, high-intensity response, restricted to early erythroblasts and to erythropoietic stress., Erythropoietin (Epo)-induced Stat5 phosphorylation (p-Stat5) is essential for both basal erythropoiesis and for its acceleration during hypoxic stress. A key challenge lies in understanding how Stat5 signaling elicits distinct functions during basal and stress erythropoiesis. Here we asked whether these distinct functions might be specified by the dynamic behavior of the Stat5 signal. We used flow cytometry to analyze Stat5 phosphorylation dynamics in primary erythropoietic tissue in vivo and in vitro, identifying two signaling modalities. In later (basophilic) erythroblasts, Epo stimulation triggers a low intensity but decisive, binary (digital) p-Stat5 signal. In early erythroblasts the binary signal is superseded by a high-intensity graded (analog) p-Stat5 response. We elucidated the biological functions of binary and graded Stat5 signaling using the EpoR-HM mice, which express a “knocked-in” EpoR mutant lacking cytoplasmic phosphotyrosines. Strikingly, EpoR-HM mice are restricted to the binary signaling mode, which rescues these mice from fatal perinatal anemia by promoting binary survival decisions in erythroblasts. However, the absence of the graded p-Stat5 response in the EpoR-HM mice prevents them from accelerating red cell production in response to stress, including a failure to upregulate the transferrin receptor, which we show is a novel stress target. We found that Stat5 protein levels decline with erythroblast differentiation, governing the transition from high-intensity graded signaling in early erythroblasts to low-intensity binary signaling in later erythroblasts. Thus, using exogenous Stat5, we converted later erythroblasts into high-intensity graded signal transducers capable of eliciting a downstream stress response. Unlike the Stat5 protein, EpoR expression in erythroblasts does not limit the Stat5 signaling response, a non-Michaelian paradigm with therapeutic implications in myeloproliferative disease. Our findings show how the binary and graded modalities combine to generate high-fidelity Stat5 signaling over the entire basal and stress Epo range. They suggest that dynamic behavior may encode information during STAT signal transduction., Author Summary Hormone signaling through the erythropoietin (Epo) pathway is required both for the continuous replacement of red blood cells (RBCs) that are lost through aging (a process known as "basal erythropoiesis") and to boost tissue oxygen when bleeding, in anemia or at high altitude ("stress erythropoiesis"). A key challenge lies in understanding how extracellular Epo concentration is translated into different intracellular signals that promote transcription of proteins that are specific to basal versus stress erythropoiesis. Binding of Epo to its receptor EpoR on the surface of an erythroblast (the precursors of RBCs) triggers the addition of phosphates to a target protein Stat5; the phosphorylated Stat5 becomes activated and induces transcription. We show that the dynamic properties of the Stat5 activation signal convey additional information that specifies either basal or stress responses. During basal conditions, the Stat5 signal is low and binary in nature—an on/off switch-like response. Stress, on the other hand, triggers a distinct Stat5 response consisting of a highintensity signal that increases in a graded fashion with rising Epo concentration. We found that a mouse bearing a truncated EpoR is restricted to the low-intensity binary Stat5 signal and correspondingly fails to initiate stress erythropoiesis. Ultimately, it is the Stat5 protein level in erythroblasts that determines their ability to generate the high-intensity graded Stat5 signal in response to high Epo. These findings have therapeutic potential: targeting Stat5's high-intensity graded signal may inhibit its aberrant function in blood cell cancers without affecting its important binary response in normal cells.

Peripheral vascular interventions frequently employ guiding sheaths with hydrophilic coatings raising the concern for the embolization of this material clinically as increasingly documented. A peripheral stent and delivery system (SDS) were deployed in the iliac and/or carotid arteries of 23

The total quasi-steady state approximation (tQSSA) for the irreversible Michaelis-Menten scheme is derived in a consistent manner. It is found that self-consistency of the initial transient guarantees the uniform validity of the tQSSA, but does not guarantee the validity of the linearization in the original derivation of Borghans et al. (1996, Bull. Math. Biol., 58, 43-63). Moreover, the present rederivation yielded the noteworthy result that the tQSSA is at least roughly valid for any substrate and enzyme concentrations. This reinforces and extends the original assertion that the parameter domain for which the tQSSA is valid overlaps the domain of validity of the standard quasi-steady state approximation and includes the limit of high enzyme concentrations. The criteria for the uniform validity of the original (linearized) tQSSA are corrected, and are used to derive approximate solutions that are uniformly valid in time. These approximations overlap and extend the domains of validity of the standard and reverse quasi-steady state approximations.

Kinetic models have played a pivotal role in the study of ligand-induced endocytosis. However, an analysis that suggests a systematic way to validate such models is lacking. The current work analyses the base model of ligand-induced endocytosis for three widely used experimental protocols. In protocol I cells initially devoid of ligand are incubated in ligand solution, whereas protocols II and III are desorption experiments in which an initial pool of surface or internalized ligand-receptor complexes, respectively, are released into an elution medium that is initially devoid of ligand. A short-time analysis of protocol I using successive substitutions yielded a corrected pre-factor for the In/Sur plot introduced by Wiley and Cunningham (Cell 25 (1981) 433). In contrast, neglecting the variation in receptor numbers yielded an approximation of protocol I that is valid for long times (e.g. tens of minutes). Similarly, the low cell-concentration limits of protocols II and III are derived by neglecting the concentration of free ligand. The simplicity of these approximations provides a simple and reliable method for estimating the parameters governing ligand kinetics, while their definitive nature implies that they can be used to verify the validity of the base model. This analysis also provides insight on the fast endocytosis and recycling limit of protocol III.