Dae Sung Park

Thromboresistant and endothelialization effects of dopamine-mediated heparin coating on a stent material surface

Heparinization of surfaces has proven a successful strategy to prevent thrombus formation. Inspired by the composition of adhesive proteins in mussels, the authors used dopamine to immobilize heparin on a stent surface. This study aimed to assess the thromboresistant and endothelialization effects of dopamine-mediated heparin (HPM) coating on a stent material surface. The HPM was synthesized by bonding dopamine and heparin chemically. Cobalt–chromium (Co–Cr) alloy disks were first placed in the HPM solution and applied to surface stability then underwent thromboresistant tests and human umbilical vein endothelial cells (HUVEC) cytotoxicity assays. The results showed not only thromboresistant activity and a stable state of heparin on the surfaces after investigation with toluidine blue and thrombin activation assay but also proliferation of HUVEC in vitro. Studies on animals showed that the HPM-coated stent has no obvious inflammation response and increasing of restenosis rate compared to the bare metal stent (BMS) indicating good biocompatibility as well as safety in its in vivo application. Moreover, improving the endothelial cell (EC) proliferation resulted in a higher strut-covering rate (i.e., endothelialization) with shuttle-shaped EC in the HPM-coated stent group compared to that of the BMS group. These results suggest that this facile coating approach could significantly promote endothelialization and offer greater safety than the BMS for its much improved thromboresistant property. Moreover, it may offer a platform for conjugating secondary drugs such as anti-proliferative drugs.

Mechanical and Histopathological Comparison between Commercialized and Newly Designed Coronary Bare Metal Stents in a Porcine Coronary Restenosis Model.

The aim of this study was to compare the stent designed by Chonnam National University Hospital (designated as CNUH) with commercial cobalt-chromium coronary stent in a porcine coronary overstretch restenosis model. CNUH stent was subjected to mechanical performance tests. Pigs were randomized into two groups in which the coronary arteries (10 pigs, 10 coronaries in each group) had either CNUH stent or control commercial bare metal stent. Histopathologic analysis was assessed at 28 days after stenting. In mechanical performance tests, CNUH stent showed 2.65N, 35.1N, 0.52N, 1.94%, 4.29% in the flat plate radial compression, radial force, 3 point bending, Foreshortening and recoil test, respectively. There was no significant difference in the injury score, internal elastic lamina (IEL), lumen area, neointima area, percent area stenosis, inflammation score and fibrin score between the two groups (1.2±0.35, 4.1±0.41 mm2, 2.7±0.56 mm2, 1.6±0.47 mm2, 36.7±11.2%, 1.2±0.62, 0.2±0.34 in CNUH stent group vs. 1.2±0.38, 3.7±0.64 mm2, 2.5±0.49 mm2, 1.5±0.61 mm2, 36.3±12.17%, 1.1±0.12, 0.4±0.46 in commercial stent group, respectively). In the mechanical performance test, CNUH stent showed the moderated performance under the guideline of FDA. CNUH stent demonstrated similar histological reactions compared with commercial cobalt-chromium stent in a porcine coronary overstretch restenosis model.

Effect of a novel peptide, WKYMVm- and sirolimus-coated stent on re-endothelialization and anti-restenosis

The drug-eluting stent still has limitations such as thrombosis and inflammation. These limitations often occur in the absence of endothelialization. This study investigated the effects of WKYMVm- and sirolimus-coated stents on re-endothelialization and anti-restenosis. The WKYMVm peptide, specially synthesized for homing endothelial colony-forming cells, was coated onto a bare-metal stent with hyaluronic acid through a simple dip-coating method (designated HA-Pep). Thereafter, sirolimus was consecutively coated to onto the HA-Pep (designated Pep/SRL). The cellular response to stents by human umbilical-vein endothelial cells and vascular smooth-muscle cells was examined by XTT assay. Stents were implanted into rabbit iliac arteries, isolated 6xa0weeks post-implantation, and then subjected to histological analysis. The peptide was well attached to the surface of the stents and the sirolimus coating made the surface smooth. The release pattern for sirolimus was similar to that of commercial sirolimus-coated stents (57.2xa0% within 7xa0days, with further release for up to 28xa0days). Endothelial-cell proliferation was enhanced in the HA-Pep group after 7xa0days of culture (38.2xa0±xa07.62xa0%, compared with controls). On the other hand, the proliferation of smooth-muscle cells was inhibited in the Pep/SRL group after 7xa0days of culture (40.7xa0±xa06.71xa0%, compared with controls). In an animal study, the restenosis rates for the Pep/SRL group (13.5xa0±xa04.50xa0%) and commercial drug-eluting stents (Xience Prime™; 9.2xa0±xa07.20xa0%) were lower than those for bare-metal stents (25.2xa0±xa04.52xa0%) and HA-Pep stents (26.9xa0±xa03.88xa0%). CD31 staining was incomplete for the bare-metal and Xience Prime™ groups. On the other hand, CD31 staining showed a consecutive linear pattern in the HA-Pep and Pep/SRL groups, suggesting that WKYMVm promotes endothelialization. These results indicate that the WKYMVm coating could promote endothelial healing, and consecutive coatings of WKYMVm and sirolimus onto bare-metal stents have a potential role in re-endothelialization and neointimal suppression.

The impact of triple anti-platelet therapy for endothelialization and inflammatory response at overlapping bioabsorbable polymer coated drug-eluting stents in a porcine coronary model

BACKGROUNDnThis study was conducted to evaluate the endothelialization and the inflammatory responses depending on the administration duration of triple anti-platelet therapy at overlapping bioabsorbable polymer coated biolimus-eluting stents (BESs) in a porcine coronary model.nnnMETHODSnWe successfully deployed 36 overlapping BESs for the left anterior descending coronary and left circumflex artery or right coronary artery in 18 non-injured pigs. Total pigs were divided into 3 groups (12 overlapping stents of 6 pigs in each group) as follows: group I received aspirin 100mg and clopidogrel 75 mg daily for 8 weeks, group II received aspirin 100mg and clopidogrel 75 mg daily for 8 weeks and cilostazol 200mg daily for initial 4 weeks, and group III received aspirin 100mg, clopidogrel 75 mg, and cilostazol 200mg daily for 8 weeks. Follow-up coronary angiograms and histomorphometric and histopahtologic analyses at overlapping and non-overlapping segments were performed respectively.nnnRESULTSnInflammation score was similar between overlapping and non-overlapping segments in all pigs (1.2 ± 0.33 vs. 1.1 ± 0.17, p=0.117). The neointima area (NA) and percent area stenosis (%AS) at overlapping segments were not significantly different among the 3 groups. However, at non-overlapping segments, NA and %AS in group III were significantly smaller than those in group I (2.3 ± 0.50mm(2) vs. 1.8 ± 0.43 mm(2), p=0.037; 48.9 ± 12.85% vs. 37.7 ± 9.08%, p=0.031).nnnCONCLUSIONSnOur study shows that BES appears to be reliable on the inflammatory response at overlapping segments as well as non-overlapping segments. Long-term administration of cilostazol is more effective in reducing neointimal formation at non-overlapping segments of BESs in a porcine coronary model.

Comparison of dextran‐based sirolimus‐eluting stents and PLA‐based sirolimus‐eluting stents in vitro and in vivo

The aim of this study was to compare dextran and Poly(l-lactide) (PLLA) polymer stent coatings as mediators for sirolimus (SRL) drug elution in a porcine coronary model. The bare metal stent (BMS) surface was first coated with a layer of SRL and then either dextran (DSS, a natural polymer) or PLA (PSS, a synthetic polymer). The release velocity of SRL was slightly faster in DSS than PSS over the first 7 days (78.5% and 62.3%, respectively, nu2009=u200910, pu2009<u20090.05) and continued to 28 days in both groups. The contact angle was dramatically decreased in DSS (38.7°u2009±u20091.24) compared to BMS and PSS groups (72.7°u2009±u20095.32 and 81.1ºu2009±u20091.70, respectively, nu2009=u200910, pu2009<u20090.05). Smooth muscle cell migration was arrested in both the DSS and PSS-treated groups compared to that in the nontreated group (4.2%u2009±u20090.31, 5.8%u2009±u20090.60, 80.0%u2009±u20094.4, respectively, nu2009=u200910, pu2009<u20090.05). In the animal study, there were no significant differences in the injury score, the internal elastic lamina, and the lumen area among the groups. However, percent area stenosis was significantly decreased in the SRL-containing group (27.5%u2009±u20092.52 in DSS and 27.9%u2009±u20093.30 in PSS) compared to BMS (35.9%u2009±u20093.51, pu2009<u20090.05). The fibrin score was higher in the PSS (2.9u2009±u20090.31) than BMS (2.1u2009±u20090.12) and DSS (2.5u2009±u20090.66). The inflammation score in the DSS (0.7u2009±u20090.21) was similar to that in the BMS (0.7u2009±u20090.12), which was dramatically lower than that PSS (1.5u2009±u20090.18, pu2009<u20090.005). Immunofluorescence analysis revealed that endothelialization was increased and inflammation prevented in the DSS. These results suggest that dextran may be useful for the fabrication of drug eluting stent as an alternative existing synthetic polymer.

Prednisolone- and sirolimus-eluting stent: Anti-inflammatory approach for inhibiting in-stent restenosis.

Glucocorticoids are powerful anti-inflammatory, immunosuppressive, and anti-proliferative agents. The aim of this study was to evaluate the effectiveness of a prednisolone- (PDScs) and sirolimus-coated stent (SRLcs) in preventing artery vessel neointimal hyperplasia and inflammatory reactions in vitro and in vivo. PDS, a synthetic glucocorticoid, is a derivative of cortisol, which is used to treat a variety of inflammatory and autoimmune conditions. The stents were fabricated with PDS, SRL, or both agents using a layer-by-layer coating system (designated as PDScs, SRLcs, and PDSRLcs, respectively). The surface morphology of the PDScs showed an evenly dispersed and roughened shape, which was smoothened by the SRL coating. Half of the total drug amounts were released within seven days, followed by an additional release, which continued for up to 28 days. The proliferation of smooth muscle cells was inhibited in the SRLcs group (31.5u2009±u20094.08%), and this effect was enhanced by PDS addition (PDSRLcs, 46.8u2009±u20098.11%). Consistently, in the animal study, the restenosis rate was inhibited by the SRLcs and PDSRLcs (18.5u2009±u20096.23% and 14.5u2009±u20093.55%, respectively). Especially, fibrin expression and inflammation were suppressed in the PDS-containing group (PDScs, 0.6u2009±u20090.12 and 1.4u2009±u20090.33; PDSRLcs, 0.7u2009±u20090.48 and 1.7u2009±u20090.12, respectively) compared to PDS non-containing groups (BMS, 1.1u2009±u20090.12, and 1.8u2009±u20090.55; SRLcs, 1.6u2009±u20090.32 and 2.0u2009±u20090.62, respectively). Moreover, re-endothelialization was enhanced in the PDScs group as determined using immunohistochemistry with a cluster of differentiation (CD)-31 antibodies. These results suggest that the inhibitory effect of SRLcs on anti-restenosis can be accelerated by additional coating with PDS, which has promising properties as a bioactive compound with useful anti-inflammatory effects.

Sirolimus coating on heparinized stents prevents restenosis and thrombosis

The aim of this study was to evaluate the inhibitory effect of sirolimus coating on the occurrence of restenosis and thrombosis with heparinized stents. Heparin and dopamine were conjugated by chemical bonding and anchored on the stent surface by a mussel-inspired adhesion mechanism. Subsequently, sirolimus was coated with poly lactic-glycolic acid on the heparinized stent surface. The heparin was well attached to the surface, and the surface was smooth after sirolimus coating. The smoothness of the surface was maintained after expansion of the stent. The amount of sirolimus released from the stent was 67.3%u2009±u20094.55% within 7 days, followed by continual release up to day 28. The proliferation of smooth muscle cells was successfully arrested (51.3%u2009±u20092.25% at 7 days of culture) by sirolimus released from the stent. Platelet adhesion was clearly prevented in the heparin-coated group (78.0u2009±u20098.00/1.8u2009cm2) compared to that in the heparin noncoated group (5.0u2009±u20091.00/1.8u2009cm2). Animal studies showed that the heparin and sirolimus-coated stent group had no obvious inflammatory response and no change in the fibrin score compared to those in the other groups. However, restenosis clearly decreased in the heparin and sirolimus-coated group (12.3%u2009±u20093.54%) compared to the bare-metal stent group (27.5%u2009±u20098.52%) and the heparin-coated group (25.3%u2009±u200911.79%). These results suggest that heparinized surface-based sirolimus coating may be a useful approach for the prevention of restenosis and stent thrombosis.

Tacrolimus-eluting stent with biodegradable polymer is more effective than sirolimus- and everolimus-eluting stent in rabbit iliac artery restenosis model

Drug-eluting stents, which are widely used in percutaneous coronary intervention, are fabricated with various considerations, such as drugs, design, polymers, and coating techniques. The aim of this study was to compare tacrolimus-eluting stents (TES), sirolimus-eluting stents (SES) and everolimus-eluting stents (EES) under identical conditions. Poly(lactic-co-glycolic acid) (PLGA) biodegradable polymer was used to coat bare metal stents (Chonnam National University Hospital Stent, CNUH Stent) with the drugs in all fabricating procedures with an ultrasonic stent-coating machine. Surface morphologies of the stents were investigated by scanning electron microscopy. The effect of drugs released from stents on rat smooth muscle and human umbilical vein endothelial cells was examined by MTT assay. The stents were implanted in rabbit iliac arteries randomly, with either TES (n=10), SES (n=10), or EES (n=10). After six weeks of implantation, the stents were isolated and subjected to histopathological analysis. Cell viability decreased in a dose-dependent manner. The surface morphologies of the stents showed a smooth and uniform shape. The release patterns of the stents showed similar profiles over 30 days. There were no significant differences in the injury score, internal elastic lamina, lumenal area, neointimal area, percent area stenosis, and inflammation score among the three groups. However, there was a significant difference in the fibrin score (0.6±0.44 in the TES, vs. 0.8±0.48 in the SES, vs. 0.8±0.61 in the EES, n=10, p<0.05). This study showed that tacrolimus was not inferior to sirolimus (SRL) and everolimus (EVL). Moreover, tacrolimus (TCL) is more effective in decreasing the fibrin score. Therefore, tacrolimus can be a useful alternative drug for fabricating drug-eluting stents.

The Control of Drug Release and Vascular Endothelialization after Hyaluronic Acid-Coated Paclitaxel Multi-Layer Coating Stent Implantation in Porcine Coronary Restenosis Model

Background and Objectives Hyaluronic acid (HA) is highly biocompatible with cells and the extracellular matrix. In contrast to degradation products of a synthetic polymer, degradation products of HA do not acidify the local environment. The aim of this study was to fabricate an HA-coated paclitaxel (PTX)-eluting stent via simple ionic interactions and to evaluate its effects in vitro and in vivo. Materials and Methods HA and catechol were conjugated by means of an activation agent, and then the stent was immersed in this solution (resulting in a HA-coated stent). After that, PTX was immobilized on the HA-coated stent (resulting in a hyaluronic acid-coated paclitaxel-eluting stent [H-PTX stent]). Study groups were divided into 4 groups: bare metal stent (BMS), HA, H-PTX, and poly (L-lactide)-coated paclitaxel-eluting stent (P-PTX). Stents were randomly implanted in a porcine coronary artery. After 4 weeks, vessels surrounding the stents were isolated and subjected to various analyses. Results Smoothness of the surface was maintained after expansion of the stent. In contrast to a previous study on a PTX-eluting stent, in this study, the PTX was effectively released up to 14 days (a half amount of PTX in 4 days). The proliferation of smooth muscle cells was successfully inhibited (by 80.5±12.11% at 7 days of culture as compared to the control) by PTX released from the stent. Animal experiments showed that the H-PTX stent does not induce an obvious inflammatory response. Nevertheless, restenosis was clearly decreased in the H-PTX stent group (9.8±3.25%) compared to the bare-metal stent group (29.7±8.11%). Conclusion A stent was stably coated with PTX via simple ionic interactions with HA. Restenosis was decreased in the H-PTX group. These results suggest that HA, a natural polymer, is suitable for fabrication of drug-eluting stents (without inflammation) as an alternative to a synthetic polymer.

888 CARDIOPROTECTIVE BENEFIT OF NEW ANGIOTENSIN RECEPTOR BLOCKER, FIMASARTAN, IN A PORCINE MODEL OF ACUTE MYOCARDIAL INFARCTION

Background: We evaluated the cardioprotective effect of fimasartan, a new angiotensin receptor blocker (ARB), in a porcine model of acute MI. Methods: Twenty-five pigs were allocated to group 1 (sham operation, n = 5), group 2 (no medication post-MI, n = 5), group 3 (perindopril 2 mg daily, n = 5), group 4 (valsartan 40 mg daily, n = 5), or group 5 (fimasartan 30 mg daily, n = 5). Acute MI was induced by occlusion of the left anterior descending artery with a balloon catheter for 50 min. Two-dimensional echocardiography, myocardial perfusion single photon emission computed tomography (SPECT) with technetium-99m sestamibi and F-18 fluorodeoxyglucose (FDG) cardiac positron emission tomography (PET) were performed at baseline, 1 week, and 4 weeks and iodine-123 meta-iodobenzylguanidine (MIBG) scan at 6 weeks for visualization of cardiac sympathetic activity. Results: Baseline LV ejection fraction (EF), infarct size, and viable myocardium size were similar between the 5 groups. LVEF and the number of segments matched and mismatched between SPECT and FDG PET at 4 weeks were not different in groups 2 to 5. The heart/mediastinum count ratios on MIBG images were—although not statistically significantly—lower in group 2 (17.4 ± 4.1), but similar in group 1, 3, 4, and 5 (20.4 ± 3.6, 21.9 ± 5.6, 20.0 ± 5.6, 20.2 ± 4.0, respectively), indicating restored sympathetic nerve activity induced by use of ACEI or ARB. Conclusions: Fimasartan, a new ARB, used post-MI improved cardiac sympathetic nerve activity and this benefit was comparable to that of other ACEI or ARB.