Jennifer McGregor

In vivo delivery and long-term tissue retention of nano-encapsulated sirolimus using a novel porous balloon angioplasty system.

AIMS Among antirestenotic compounds, sirolimus displays a superior safety profile compared to paclitaxel, but its pharmacokinetic properties make it a challenging therapeutic candidate for single-time delivery. Herein we evaluate the feasibility of delivery, long-term retention and vascular effects of sirolimus nanoparticles delivered through a novel porous angioplasty balloon in normal porcine arteries and in a swine model of in-stent restenosis (ISR). METHODS AND RESULTS Sirolimus nanoparticle formulation was delivered via porous balloon angioplasty to 753 coronary artery segments for pharmacokinetic studies and 26 segments for biological effect of sirolimus delivery in different clinical scenarios (de novo [n=8], ISR [n=6] and following stent implantation [n=12]). Sirolimus coronary artery concentrations were above the target therapeutic level of 1 ng/mg after 26 days, and were >100-fold higher in coronary artery treatment sites than in distal myocardium and remote tissues at all time points. At 28 days, reduction in percent stenosis in formulation-treated sites compared to balloon angioplasty treatment was noted in all three clinical scenarios, with the largest effect seen in the de novo study. CONCLUSIONS Local coronary delivery of sirolimus nanoparticles in the porcine model using a novel porous balloon delivery system achieved therapeutic long-term intra-arterial drug levels without significant systemic residual exposure.

Paclitaxel-iopromide coated balloon followed by "bail-out" bare metal stent in porcine iliofemoral arteries: first report on biological effects in peripheral circulation.

AIMS Despite recent abundance of data on drug-coated balloon technology, the biological effects of paclitaxel coated balloon (PCB) treatment followed by bare metal stent (BMS) implantation in peripheral arteries (simulating bail-out stenting, a common clinical scenario), have not been published. METHODS AND RESULTS PCB technology containing a paclitaxel-iopromide coating and identical iopromide-coated controls (without paclitaxel) were used in 16 porcine ilio-femoral arteries. The biological effects of inflating one (PCBx1) or two sequential (PCBx2) paclitaxel coated balloons before BMS implantation were compared to the single application of a control balloon (CCBx1; contrast coated balloons). At 30 days PCBx2 displayed significantly reduced late lumen loss by angiography (58% reduction vs. CCBx1; p=0.04) and neointimal area by histomorphometry (35% reduction vs. CCBx1 and 30% vs. PCBx1; p=0.02). Similarly, percent area stenosis in the PCBx2 group was reduced by 45% as compared to CCBx1 and PCBx1 (p=0.04). At this time, all parameters of vessel wall healing (including injury score, inflammation, and endothelialisation) following drug coated balloon treatment were comparable to the control group. CONCLUSIONS Paclitaxel delivery to porcine ilio-femorals using PCB followed by BMS implantation effectively decreased neointimal proliferation. More extensive and prolonged proliferative response of the vessel after stenting (necessitating higher drug dose) could potentially explain the undetectable effect of PEBx1 relative to CCBx1 in this pilot study. Histological analysis confirmed the safety and biocompatibility of PCB technology.

In vivo intravascular ultrasound analysis of the absorption rate of the Angio-Seal™ vascular closure device in the porcine femoral artery

AIMS Device-based arterial closure is currently used to achieve haemostasis following percutaneous intervention. Little is known about the in vivo patterns of device absorption. We aimed to characterise the absorption dynamics following implantation of the Angio-Seal VIP closure device (AVCD) (St. Jude Medical, St. Paul, MN, USA) by using serial intravascular ultrasound (IVUS) and histology. METHODS AND RESULTS Eleven AVCD were implanted following 6 Fr femoral arterial sheath in six pigs. Using carotid access, angiograms and IVUS were performed at baseline, 3, 5, 7, 14, 30 and 42 days following deployment. At termination, arteries were processed for histology at 14 (n=3), 30(n=4) and 42 days (n=4). By IVUS, following implantation the intravascular component (IC) area remained unchanged up to 14 days and decreased by 50% at 30 days and 95% by 42 days. By histology, there was a progressive decline in the IC area at 14 days and decrease by 30% at 30 days and 77% by 42 days. Histology demonstrated almost complete absorption of the IC and no signs of severe chronic granulomatous inflammation. CONCLUSIONS IVUS serial imaging demonstrated almost complete absorption of the IC by 42 days in normal porcine femoral arteries. There was no evidence of severe chronic granulomatous vascular inflammation demonstrated by histology.

VERY LONG-TERM (1 AND 2-YEAR) COMPARISON OF BIORESORBABLE VS. PERMANENT POLYMER LIMUS-ELUTING STENTS IN A PORCINE CORONARY ARTERY MODEL

A Biolimus A9 self-expandable nitinol stent (BA9SES) stent was engineered with a permanent primer layer consisting of parylene and a bioabsorbable abluminal layer of polylactic acid (PLA) and Biolimus A9 (∼22 μg/mm of stent length), in contrast to the permanent polymer-based, sirolimus-

DRUG RELEASE PROFILE OF A NOVEL SIROLIMUS ELUTING BIORESORBABLE SCAFFOLD: IMPLICATION ON NEOINTIMAL FORMATION AND HEALING

The first-in-class Absorb (Abbott Vascular, Santa Clara, CA) bioresorbable scaffold (BRS) is eluting everolimus, but a number of other scaffolds are in development with sirolimus as the antirestenotic agent. In this study, we set out to correlate the pharmacokinetic data with antirestenotic efficacy

Two-year longitudinal evaluation of a second-generation thin-strut sirolimus-eluting bioresorbable coronary scaffold with hybrid cell design in porcine coronary arteries

BACKGROUND The first commercially available bioresorbable scaffold (BRS) had a strut thickness of 156 microns. As such, it had the potential for delivery challenges and higher thrombogenicity. The aim herein, is to evaluate biomechanical performance, pharmacokinetics and vascular healing of a novel thin strut (100 µm) sirolimus eluting BRS (MeRes-100, Meril Life Sciences, Gujarat, India) against the once clinically used BRS (Absorb BVS, Abbott, Santa Clara, CA) in porcine coronary arteries. METHODS Following device implantation, angiographic and optical coherence tomography (OCT) evaluation were performed at 45, 90, 180 days, 1 year and 2 years. Histological evaluation was performed at 30, 90 and 180 days. RESULTS At 2 years, both lumen (MeRes-100 7.07 ± 1.82 mm² vs. Absorb BVS 7.57 ± 1.39 mm², p = NS) and scaffold areas (MeRes-100 9.73 ± 1.80 mm² vs. Absorb BVS 9.67 ± 1.25 mm², p = NS) were comparable between tested and control scaffolds. Also, the late lumen area gain at 2 years was similar in both groups tested (MeRes-100 1.03 ± 1.98 mm² vs. Absorb BVS 0.85 ± 1.56 mm², p = NS). Histologic examination up to 6 months showed comparable healing and inflammation profiles for both devices. CONCLUSIONS The novel sirolimus-eluting BRS with thinner struts and hybrid cell design showed similar biomechanical durability and equivalent inhibition of neointimal proliferation when compared to the first-ever Absorb BVS up to 2 years in normal porcine coronary arteries.

ACCURACY AND REPRODUCIBILITY OF A NOVEL IN VIVO AUTOMATIC BORDER DETECTION SOFTWARE FOR THE ANALYSIS OF STENT NEOINTIMAL RESPONSE COMPARED TO HISTOLOGY IN A FAMILIAL HYPERCHOLESTEROLEMIC SWINE MODEL

Results: 26 OCT frames were analyzed per operator. Lumen area showed high correlation (r=0.96, p < 0.001) and no signiicant difference between automatic (A; 4.93±2 mm2) manual (M; 4.94±2 mm2) or histological assessment (H; 5.27±2.4 mm2, p 0.58). Similar results were obtained on neointimal thickness (A=0.5±0.2mm; M=0.5±0.2mm and H=0.6±0.3mm, p=0.39). The OCT-histology correlation for neointimal thickness was also very high (r=0.95, p<0.001). Stent area show no statistical difference between both OCT techniques (A=9.3±1.4 mm2 vs M=9.3±1.3 mm2, p=0.99). However, the OCT-histology correlation for stent area was lower (OCT= 9.3±1.3 mm2 vs histology= 10.6±1.3mm2, r=0.89, p < 0.001) than seen in the other analyzed variables. Conclusions: The morphometric evaluation of neointimal response using a novel in-vivo automatic border detection software highly correlated with the data obtained by histology. Although still high, the evaluation of stent areas by OCT appears to have a lower degree of correlation in comparison to the other analyzed variables.