Kyung Seob Lim

Suppression of post-angioplasty restenosis with an Akt1 siRNA-embedded coronary stent in a rabbit model.

Restenosis is the formation of blockages occurring at the site of angioplasty or stent placement. In order to avoid such blockages, the suppression of smooth muscle cells near the implanted stent is required. The Akt1 protein is known to be responsible for cellular proliferation, and specific inhibition of Akt1 gene expression results in the retardation of cell growth. To take advantage of these benefits, we developed a new delivery technique for Akt1 siRNA nanoparticles from a hyaluronic acid (HA)-coated stent surface. For this purpose, the disulfide cross-linked low molecular polyethyleneimine (PEI) (ssPEI) was used as a gene delivery carrier because disulfide bonds are stable in an oxidative extracellular environment but degrade rapidly in reductive intracellular environments. In this study, Akt1 siRNA showed efficient ionic interaction with the ssPEI carrier, which was confirmed by polyacrylamide gel electrophoresis. Akt1 siRNA/ssPEI nanoparticles (ASNs) were immobilized on the HA-coated stent surface and exhibited stable binding and localization, followed by time-dependent sustained release for intracellular uptake. Cellular viability on the nanoparticle-immobilized surface was assessed using A10 vascular smooth muscle cells, and the results revealed that immobilized ASNs exhibited negligible cytotoxicity against the adhering A10 cells. Transfection efficiency was quantified using a luciferase assay; the transgene expression of Akt1 suppression through the delivered Akt1 siRNA was measured using RT-PCR and western blot, demonstrating higher gene silencing efficiency when compared to other carriers. ASN coated on HA stents were deployed in the balloon-injured external iliac artery in rabbits in vivo. It was shown that the Akt1 released from the stent suppressed the growth of the smooth muscle at the peri-stent implantation area, resulting in the prevention of restenosis in the post-implantation phase.

Piceatannol attenuates cardiac hypertrophy in an animal model through regulation of the expression and binding of the transcription factor GATA binding factor 6.

GATA6 physically interacts with GATA4 by anti V5 tag coimmunoprecipitation (View interaction)

Histopathological Comparison among Biolimus, Zotarolimus and Everolimus-Eluting Stents in Porcine Coronary Restenosis Model.

Background and Objectives The aim of this study was to examine the histolopathogical effects among the biolimus, zotarolimus, and everolimus eluting stent (EES) in the porcine coronary restenosis model. Subjects and Methods Pigs were randomized into three groups in which the coronary arteries (15 pigs, 10 coronaries in each group) had either a biolimus A9 eluting stent (BES, n=10), zotarolimus eluting stent (ZES, n=10) or an EES (n=10). Histopathologic analysis was performed at 28 days after stenting. Results There were no significant differences in the injury score among the three groups. There was a significant difference in the internal elastic lamina, lumen area, neointima area, percent area stenosis, and the fibrin and inflammation score among the three groups (4.3±0.53 mm2, 2.5±0.93 mm2, 1.8±1.03 mm2, 40.7±20.80%, 1.7±0.41, 1.4±0.72 in the BES group vs. 5.1±0.55 mm2, 2.3±1.14 mm2, 2.8±1.00 mm2, 55.4±21.23%, 2.0±0.39, 1.6±0.76 in the ZES group vs. 4.4±0.53 mm2, 1.7±1.22 mm2, 2.8±1.23 mm2, 64.0±26.00%, 1.8±0.76, 2.1±0.90 in the EES group, respectively). BES is more effective in inhibiting neointimal hyperplasia compared to ZES and EES (p<0.0001). According to the fibrin and inflammation score, BES and EES are more effective in decreasing the fibrin deposition compared to ZES (p<0.001). Moreover, BES and ZES are more effective in reducing the inflammatory reaction compared to EES (p<0.001). Conclusion The result demonstrates that BES shows better histopathological characteristics than ZES and EES at one month after stenting in the porcine coronary restenosis model.

Nitric Oxide Releasing Coronary Stent: A New Approach Using Layer-by-Layer Coating and Liposomal Encapsulation.

The sustained or controlled release of nitric oxide (NO) can be the most promising approach for the suppression or prevention of restenosis and thrombosis caused by stent implantation. The aim of this study is to investigate the feasibility in the potential use of layer-by-layer (LBL) coating with a NO donor-containing liposomes to control the release rate of NO from a metallic stent. Microscopic observation and surface characterizations of LBL-modified stents demonstrate successful LBL coating with liposomes on a stent. Release profiles of NO show that the release rate is sustained up to 5 d. In vitro cell study demonstrates that NO release significantly enhances endothelial cell proliferation, whereas it markedly inhibits smooth muscle cell proliferation. Finally, in vivo study conducted with a porcine coronary injury model proves the therapeutic efficacy of the NO-releasing stents coated by liposomal LBL technique, supported by improved results in luminal healing, inflammation, and neointimal thickening except thrombo-resistant effect. As a result, all these results demonstrate that highly optimized release rate and therapeutic dose of NO can be achieved by LBL coating and liposomal encapsulation, followed by significantly efficacious outcome in vivo.

Effects of ticagrelor on neointimal hyperplasia and endothelial function, compared with clopidogrel and prasugrel, in a porcine coronary stent restenosis model

BACKGROUND Several investigations have been conducted to evaluate the off-target effects of ticagrelor. The aim of the present study was to evaluate the off-target effects of ticagrelor such as neointimal formation and endothelial function after drug-eluting stent implantation in a porcine restenosis model. METHODS A total of 30 pigs were randomly allocated based on the following P2Y12 inhibitor: (1) clopidogrel 300mg loading plus 75mg maintenance (n=10); (2) prasugrel 60mg loading plus 10mg maintenance (n=10); (3) ticagrelor 180mg loading plus 180mg maintenance (n=10). In each group, zotarolimus-eluting stents were implanted in the proximal portion of the left anterior descending artery and left circumflex artery. One month after stenting, the animals underwent follow-up angiography, endothelial function assessment, optical coherence tomography (OCT) and histopathological analysis. RESULTS Regarding vasomotor responses to acetylcholine infusion, there were significant vasoconstrictions to maximal acetylcholine infusion in the clopidogrel and prasugrel group compared with those in the ticagrelor group. The mean neointimal area were significantly lower in the ticagrelor group (1.0±0.3 by OCT, 0.9±0.3 by histology), than in the clopidogrel (1.8±0.7, p=0.003, 1.6±0.8, p=0.030) and prasugrel (1.8±0.5, p=0.001, 1.5±0.5, p=0.019) groups. Percentages of moderate to dense peri-strut inflammatory cell infiltration were significantly lower in the ticagrelor group (9.0%) compared with the clopidogrel (17.3%, p<0.001) and prasugrel groups (15.7%, p=0.002). There were no significant differences in all findings between clopidogrel and prasugrel groups. CONCLUSIONS Compared to clopidogrel and prasugrel, ticagrelor reduced neointimal formation, endothelial dysfunction, and peri-strut inflammation.

Comparison of sirolimus loaded PLGA-PEG Co-polymer coronary stent and bare metal stent in a porcine coronary restenosis model

The aim of this study was to compare the effect of the sirolimus loaded PLGA-PEG co-polymer coronary stent with that of the bare metal stent in a porcine coronary restenosis model. Pigs were randomized into two groups (10 pigs, 10 coronary arteries in each group), in which either the sirolimus loaded PLGA-PEG copolymer stent (SPPS, n=10) or the bare metal stent (BMS, n=10) was implanted in the coronary arteries. Histopathologic analysis was performed at 28 days after stenting. There were no significant differences in the injury score, internal elastic lamina (IEL) area, and inflammation score between the two groups. There were significant differences in the lumen area (3.6±0.42 mm2 in the SPPS group vs. 2.5±0.89 mm2 in the BMS group, p<0.001), in the neointimal area (1.2±0.34 mm2 in the SPPS group vs. 2.5±0.99 mm2 in the BMS group, p<0.001), in the percent area stenosis (26.0±6.58% in the SPPS group vs. 48.6±16.95% in the BMS group, p<0.001) and in the fibrin score (1.2±0.41 in the SPPS group vs. 0.5±0.26 in the BMS group, p<0.001). These results demonstrate that SPPS had a superior effect on suppression of neointimal hyperplasia than BMS at one month after stenting in a porcine coronary restenosis model.

Effect of polymer-free TiO2 stent coated with abciximab or alpha lipoic acid in porcine coronary restenosis model.

BACKGROUND Polymer-free drug-eluting stents (DES) may overcome the shortcomings of polymer-based DES. The aim of this study was to examine the effect of the polymer-free TiO2 film-coated stent with abciximab or alpha lipoic acid in a porcine coronary overstretch restenosis model. METHODS Pigs were randomized into four groups in which the coronary arteries (24 pigs, 48 coronaries in each group) had TiO2 film-coated stent with abciximab (TCA, n = 12), TiO2 film-coated stent with alpha lipoic acid (TCALA, n = 12), biolimus A9-eluting stents with biodegradable polymer (BES, n = 12), and TiO2 film-coated stent (TCstent, n = 12). Histopathologic analysis was performed at 28 days after stenting. RESULTS There was no significant difference in the injury score and internal elastic lamina (IEL) among the four groups. There were significant differences in the lumen area, neointima area, percent area stenosis, fibrin score, and inflammation score among the four groups [2.7 ± 1.0mm(2), 2.6 ± 0.94 mm(2), 48.9 ± 16.25%, 1.0 (range 0.0-3.0), 1.0 (range 0.0-2.0) in TCA stent group vs. 2.7 ± 1.24 mm(2), 2.9 ± 0.83 mm(2), 53.5 ± 17.19%, 1.0 (range 0.0-2.0), 1.0 (range 0.0-2.0) in TCALA stent group vs. 2.7 ± 1.30 mm(2), 2.6 ± 1.06 mm(2), 50.1 ± 23.20%, 2.0 (range 1.0-3.0), 2.0 (range 1.0-3.0) in BES group vs. 1.7 ± 0.63 mm(2), 3.3 ± 0.58 mm(2), 60.2 ± 10.12%, 0.5 (range 0.0-2.0), 1.0 (range 0.0-2.0) in TC stent group, respectively]. CONCLUSION TCA and TCALA are more effective to reduce neointimal hyperplasia compared to TC. Moreover, fibrin and inflammation scores are significantly lower in TCA and TCALA than BES in porcine coronary restenosis model.

Novel abciximab-Kruppel-like factor 4-plasmid dual-delivery titanium dioxide-coated coronary stent

a Department of Cardiology, Chonnam National University Hospital, Gwangju, Republic of Korea b Heart Research Center, Chonnam National University Hospital, Gwangju, Republic of Korea c Department of Molecular Medicine and Advanced Chemical & Engineering, Chonnam National University Graduate School, Gwangju, Republic of Korea d Center for Functional Nano Fine Chemicals & School of Applied Chemical Engineering, Chonnam National University, Gwangju, Republic of Korea e Institute of Interventional Medicine, M.I. Tech Co., Ltd., Pyeongtaek, Republic of Korea

Penetration of an artificial arterial thromboembolism in a live animal using an intravascular therapeutic microrobot system

The biomedical applications of wireless robots are an active area of study. In addition to moving to a target lesion, wireless locomotive robots can deliver a therapeutic drug for a specific disease. Thus, they hold great potential as therapeutic devices in blood vessel diseases, such as thrombi and occlusions, and in other diseases, such as cancer and inflammation. During a percutaneous coronary intervention (PCI), surgeons wear a heavy shielding cloth. However, they cannot escape severe radiation exposure owing to unstable shielding. They may also suffer from joint pains because of the weight of the shielding cloth. In addition, the catheters in PCIs are controlled by the surgeons hand. Thus, they lack steering ability. A new intravascular therapeutic system is needed to address these problems in conventional PCIs. We developed an intravascular therapeutic microrobot system (ITMS) using an electromagnetic actuation (EMA) system with bi-plane X-ray devices that can remotely control a robot in blood vessels. Using this proposed ITMS, we demonstrated the locomotion of the robot in abdominal and iliac arteries of a live pig by the master-slave method. After producing an arterial thromboembolism in a live pig in a partial iliac artery, the robot moved to the target lesion and penetrated by specific motions (twisting and hammering) of the robot using the proposed ITMS. The results reveal that the proposed ITMS can realize stable locomotion (alignment and propulsion) of a robot in abdominal and iliac arteries of a live pig. This can be considered the first preclinical trial of the treatment of an artificial arterial thromboembolism by penetration of a blood clot.

Stent linker effect in a porcine coronary restenosis model.

In this study, we aimed to evaluate the mechanical effects of different stent linker designs on in-stent restenosis in porcine coronary arteries. We fabricated stents with an open-cell structure composed of nine main cells and three linker structures in model 1 (I-type), model 2 (S-types) and model 3 (U-types)) as well as Model 4, which is similar to a commercial bare metal stent design. The stent cells were 70 mm thick and wide, with a common symmetrical wave pattern. As the radial force increased, the number of main cells increased and the length of linker decreased. Radial force was higher in model 1, with a linear I-linker, than in models with S- or U-linkers. The flexibility measured by three-point bending showed a force of 1.09 N in model 1, 0.35 N in model 2, 0.19 N in model 3, and 0.31 N in model 4. The recoil results were similar in all models except model 4 and were related to the shape of the main cells. The foreshortening results were related to linker shape, with the lowest foreshortening observed in model 3 (U-linker). Restenosis areas in the porcine restenosis model 4 weeks after implantation were 35.4 ± 8.39% (model 1), 30.4 ± 7.56% (model 2), 40.6 ± 9.87% (model 3) and 45.1 ± 12.33% (model 4). In-stent restenosis rates measured by intravascular ultrasound (IVUS) and micro-computed tomography (micro-CT) showed similar trends as percent area stenosis measured by micro-CT. Model 2, with optimized flexibility and radial force due to its S-linker, showed significantly reduced restenosis in the animal model compared to stents with different linker designs. These results suggest that the optimal stent structure has a minimum radial force for vascular support and maximum flexibility for vascular conformability. The importance of the effects of these differences in stent design and their potential relationship with restenosis remains to be determined.