First-in-Human Evaluation of a Polymer-Free Everolimus-Eluting Stent Using a Titanium Dioxide Film.

BACKGROUND: In patients with coronary artery disease treated with permanent polymer-coated drug-eluting stents (DES), the persistent presence of a less biocompatible polymer might delay arterial healing. Thin strut polymer-free DES have the potential to improve clinical outcomes and reduce the duration of dual antiplatelet therapy (DAPT). The purpose of this first-in-human study was to assess the safety and effectiveness of a novel polymer-free DES in patients with de novo coronary lesions. The TIGERevolutioN® stent (CG Bio Co., Ltd., Seoul, Korea) consists of a cobalt chromium platform with a strut thickness of 70 µm and a surface treated with titanium dioxide onto which everolimus-eluting stent (EES) is applied abluminally (6 µg/mm of stent length) without utilization of a polymer. METHODS: A total of 20 patients were enrolled, with de novo coronary lesions (stable or unstable angina) and > 50% diameter stenosis in a vessel 2.25 to 4.00 mm in diameter and ≤ 40 mm in length for angiographic, optical coherence tomography (OCT), and clinical assessment at 8 months. All patients received DAPT after stent implantation. The primary endpoint was angiographic in-stent late lumen loss (LLL) at 8 months. RESULTS: Twenty patients with 20 lesions were treated with TIGERevolutioN®. At 8 months, in-stent LLL was 0.7 ± 0.4 mm. On OCT, percent area stenosis was 29.2 ± 9.4% and stent strut coverage was complete in all lesions. No adverse cardiovascular event occurred at 8 months. CONCLUSION: The new polymer-free EES was safe and effective with low LLL and excellent strut coverage at 8 months of follow-up. TRIAL REGISTRATION: Trial Registration: Clinical Research Information Service Identifier: KCT0005699.

Preclinical Evaluation of a Novel Polymer-free Everolimus-eluting Stent in a Mid-term Porcine Coronary Restenosis Model.

BACKGROUND: Titanium dioxide films exhibit good biocompatibility and may be effective as drug-binding matrices for drug-eluting stents. We conducted a mid-term evaluation of a novel polymer-free everolimus-eluting stent using nitrogen-doped titanium dioxide film deposition (TIGEREVOLUTION®) in comparison with a commercial durable polymer everolimus-eluting stent (XIENCE Alpine®) in a porcine coronary restenosis model. METHODS: Twenty-eight coronary arteries from 14 mini-pigs were randomly allocated to TIGEREVOLUTION® stent and XIENCE Alpine® stent groups. The stents were implanted in the coronary artery at a 1.1-1.2:1 stent-to-artery ratio. Eleven stented coronary arteries in each group were finally analyzed using coronary angiography, optical coherence tomography, and histopathologic evaluation 6 months after stenting. RESULTS: Quantitative coronary analysis showed no significant differences in the pre-procedural, post-procedural, and 6-month lumen diameters between the groups. In the volumetric analysis of optical coherence tomography at 6 months, no significant differences were observed in stent volume, lumen volume, and percent area stenosis between the groups. There were no significant differences in injury score, inflammation score, or fibrin score between the groups, although the fibrin score was zero in the TIGEREVOLUTION® stent group (0 vs. 0.07 ± 0.11, P = 0.180). CONCLUSION: Preclinical evaluation, including optical coherence tomographic findings 6 months after stenting, demonstrated that the TIGEREVOLUTION® stent exhibited efficacy and safety comparable with the XIENCE Alpine® stent, supporting the need for further clinical studies on the TIGEREVOLUTION® stent.

Identifying genetic variants underlying medication-induced osteonecrosis of the jaw in cancer and osteoporosis: a case control study.

BACKGROUND: Bisphosphonate-induced osteonecrosis of the jaw (BRONJ) presents with a typical pattern of jaw necrosis in patients who have been prescribed bisphosphonates (BPs) and other antiangiogenetic drugs to treat osteoporosis or bone-related complications of cancer. METHODS: This study divided 38 patients with BRONJ into two groups according to the prescribing causes: cancer (n = 13) and osteoporosis (n = 25), and underwent whole exome sequencing and compared them with normal controls (n = 90). To identify candidate genes and variants, we conducted three analyses: a traditional genetic model, gene-wise variant score burden, and rare-variant analysis methods. RESULTS: The stop-gain mutation (rs117889746) of the PZP gene in the BRONJ cancer group was significantly identified in the additive trend model analysis. In the cancer group, ARIDS, HEBP1, LTBP1, and PLVAP were identified as candidate genes. In the osteoporosis group, VEGFA, DFFA, and FAM193A genes showed a significant association. No significant genes were identified in the rare-variant analysis pipeline. Biologically accountable functions related to BRONJ occurrence-angiogenesis-related signaling (VEGFA and PLVAP genes), TGF-ß signaling (LTBP1 and PZP genes), heme toxicity (HEBP1) and osteoblast maturation (ARIDS)-were shown in candidate genes. CONCLUSION: This study showed that the candidate causative genes contributing to the development of BRONJ differ according to the BP dose and background disease.

Analysis of intradiscal cement leakage during percutaneous vertebroplasty: multivariate study of risk factors emphasizing preoperative MR findings.

OBJECTIVE: Previous reports have shown that intradiscal cement leakage during percutaneous vertebroplasty (PVP) is related to several risk factors. The purpose of this study was to evaluate preoperative MRI scans for such risk factors. METHODS: The study retrospectively analyzed 136 patients (aged 43-93 years; 234 vertebral bodies) with osteoporotic compression fractures. All patients underwent both MRI and PVP. There were 28 men (20.59%) and 108 women (79.41%). Age, gender, bone mineral density (BMD) score, endplate cortical disruption, abnormal T2-weighted hyperintensity in adjacent discs, presence of Kümmell's disease, linear body fracture with extension to endplate, level of treated vertebral body and injected cement volume were considered risk factors for intradiscal cement leakage. RESULTS: Of the 234 vertebral bodies, 55 bodies from 42 patients with no endplate cortical disruption showed no adjacent intradiscal cement leakage. Of 179 bodies from 95 patients with endplate cortical disruption, 54 (30.17%) showed intradiscal cement leakage. Of the other possible risk factors, abnormal T2 hyperintensity in adjacent discs was significantly related to intradiscal cement leakage (P = 0.016). The other possible factors (age, gender, BMD score, Kümmell's disease, linear body fracture extending to the endplate, level of treated vertebral body and injected cement volume) were not related to intradiscal cement leakage. CONCLUSION: There was no adjacent intradiscal cement leakage without endplate cortical disruption. Abnormal T2 hyperintensity in adjacent discs may be related to intradiscal cement leakage, but only in the presence of endplate cortical disruption. Also, not having Kümmell's disease did not prevent intradiscal cement leakage. Thus, given these circumstances, careful cement injection is needed to reduce intradiscal cement leakage.

Data Communication Based on MQTT in a Polymer Extrusion Process.

This work aims at building a flexible data communication structure for a polymer processing machine by employing a publisher-subscriber based protocol called Message Queuing Telemetry Transport (MQTT), which is operated over TCP/IP. Even when using conventional equipment, processing data can be measured and recorded by various devices anywhere through an Internet communication. A message-based protocol allows flexible communication that overcomes the shortcomings of the existing server-client protocol. Multiple devices can subscribe to the processing data published by source devices. The proposed method facilitates data communication between multiple publishers and subscribers. This work has implemented a system that publishes data from the equipment and additional sensors to a message broker. The subscribers can monitor and store the process data relayed by the broker. The system has been deployed and run for a film extrusion line to demonstrate the effectiveness.

Successful implantation of a novel polymer-free everolimus-eluting stent using nitrogen-doped titanium dioxide film with good patency on follow-up angiography: A case report.

RATIONALE: Despite technological advances in interventional cardiology during the last decades, many concerns remain regarding the narrowing and occlusion of the in-stent area. Particularly, polymer materials pose several problems, including chronic arterial inflammation, impaired arterial healing, and stent thrombosis. To avoid these complications, we invented the TIGEREVOLUTION stent with a cobalt-chromium alloy-based stent platform deposited with N-TiO2 film, which has demonstrated good biocompatibility. As this stent is not coated with polymer, it is expected to have decreased risk of stent thrombosis. PATIENT CONCERNS: A 62-year-old Korean man visited our department because of angina. We commenced coronary angiography (CAG). DIAGNOSIS: CAG revealed critical stenosis in the mid-portion of the right coronary artery, with a minimum lumen area of 1.08mm2 on optical coherence tomography (OCT). INTERVENTION: Percutaneous coronary intervention was performed with implantation of a novel 3.5 × 26-mm polymer-free everolimus-eluting stent using nitrogen-doped titanium dioxide film (TIGEREVOLUTION® stent). Post-percutaneous coronary intervention OCT showed good stent expansion and apposition, and the patient was discharged successfully and uneventfully. OUTCOMES: Eight months later, follow-up coronary angiography demonstrated good stent patency with no definitive evidence of in-stent restenosis, with thin stent strut coverage demonstrated on OCT. LESSONS: We report the first case of TIGEREVOLUTION stent implantation with follow-up OCT at 8 months.

South Korean geriatrics on Beers Criteria medications at risk of adverse drug events.

BACKGROUND: The Beers Criteria released by the American Geriatrics Society includes a list of drugs to avoid in the geriatric population and is frequently used as a safety resource in geriatric pharmacotherapy. OBJECTIVE: To evaluate the exposure of South Korean geriatrics to potentially inappropriate medications according to the Beers Criteria and the risk of adverse events from these medications. METHODS: This study included medications recommended to be avoided in patients 65 years or older regardless of concomitant drug therapy or disease. The exposure of South Korean geriatrics to each of the study medications were examined using health claims data of 2011. The number of South Korean geriatrics at risk of experiencing adverse drug events from the study medications were estimated by multiplying the number of patients exposed to the medication in 2011 and the incident rate of the event obtained from literature sources. RESULTS: This study examined 166,822 geriatrics for Beers Criteria medication exposure and adverse drug event risk. The most prevalent Beers Criteria medication prescribed in South Korean geriatrics >1 day was chlorpheniramine (53.9%) and the adverse drug event with the highest number of this geriatric population at risk of was amitriptyline related dry mouth (4.9%). The proportion of South Korean geriatrics on chronic Beers Criteria medications >1 day at risk of adverse drug events from these medications was significantly higher than in US geriatrics (0.005 vs. 0.001, 2-way ANOVA post hoc pairwise t-test P<0.0001). CONCLUSIONS: In 2011, over half of South Korean geriatrics was exposed to medications recommended to be avoided in geriatrics and their adverse drug event risk warrants close monitoring of their occurrence.

Hydrophilic surface modification of coronary stent using an atmospheric pressure plasma jet for endothelialization.

The first two authors contributed equally to this study. Bioactivity and cell adhesion properties are major factors for fabricating medical devices such as coronary stents. The aim of this study was to evaluate the advantages of atmospheric-pressure plasma jet in enhancing the biocompatibility and endothelial cell-favorites. The experimental objects were divided into before and after atmospheric-pressure plasma jet treatment with the ratio of nitrogen:argon = 3:1, which is similar to air. The treated surfaces were basically characterized by means of a contact angle analyzer for the activation property on their surfaces. The effect of atmospheric-pressure plasma jet on cellular response was examined by endothelial cell adhesion and XTT analysis. It was difficult to detect any changeable morphology after atmospheric-pressure plasma jet treatment on the surface. The roughness was increased after atmospheric-pressure plasma jet treatment compared to nonatmospheric-pressure plasma jet treatment (86.781 and 7.964 nm, respectively). The X-ray photoelectron spectroscopy results showed that the surface concentration of the C-O groups increased slightly from 6% to 8% after plasma activation. The contact angle dramatically decreased in the atmospheric-pressure plasma jet treated group (22.6 ± 15.26°) compared to the nonatmospheric-pressure plasma jet treated group (72.4 ± 15.26°) ( n = 10, p < 0.05). The effect of the increment in hydrophilicity due to the atmospheric-pressure plasma jet on endothelial cell migration and proliferation was 85.2% ± 12.01% and 34.2% ± 2.68%, respectively, at 7 days, compared to the nonatmospheric-pressure plasma jet treated group (58.2% ± 11.44% in migration, n = 10, p < 0.05). Taken together, the stent surface could easily obtain a hydrophilic property by the atmospheric-pressure plasma jet method. Moreover, the atmospheric-pressure plasma jet might affect re-endothelialization after stenting.

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% ± 4.55% within 7 days, followed by continual release up to day 28. The proliferation of smooth muscle cells was successfully arrested (51.3% ± 2.25% at 7 days of culture) by sirolimus released from the stent. Platelet adhesion was clearly prevented in the heparin-coated group (78.0 ± 8.00/1.8 cm2) compared to that in the heparin noncoated group (5.0 ± 1.00/1.8 cm2). 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% ± 3.54%) compared to the bare-metal stent group (27.5% ± 8.52%) and the heparin-coated group (25.3% ± 11.79%). These results suggest that heparinized surface-based sirolimus coating may be a useful approach for the prevention of restenosis and stent thrombosis.

A novel polymer-free drug-eluting stent coated with everolimus using nitrogen-doped titanium dioxide film deposition in a porcine coronary restenosis model.

BACKGROUND: Titanium dioxide (TiO2) films have superior biocompatibility and may be effective as drug-binding matrices for drug-eluting stents (DESs). We sought to evaluate efficacy of a polymer-free DES coated with everolimus using nitrogen-doped TiO2 film deposition in a porcine coronary restenosis model. METHODS: Forty coronary arteries in 20 pigs were randomly allocated to group 1 (bare-metal stents (BMSs), 3.0×18mm, n=10), group 2 (BMSs with nitrogen-doped TiO2 film deposition, 3.0×18mm, n=10), group 3 [commercial everolimus-eluting stent, 3.0×18mm, n=10], and group 4 (polymer-free everolimus-eluting stent using nitrogen-doped TiO2 film deposition, 3.0×18mm, n=10). Stents were randomly implanted in the left anterior descending coronary artery and left circumflex artery with stent:artery ratio of 1.3. Four weeks later, pigs underwent follow-up coronary angiography and were sacrificed for histopathologic analysis. RESULTS: Percent area stenosis was greater in group 1 compared to groups 3 and 4 (46.4±13.8% vs. 30.2±11.7% vs. 29.2±8.9%, respectively, p=0.005). Fibrin score was lower in groups 1 and 2, compared to groups 3 and 4: 0.87±0.67 vs. 0.76±0.61 vs. 2.27±0.24 vs. 1.75±0.31, respectively, p<0.001). Injury score and inflammation score were not different. Comparison between DES showed a higher fibrin score in group 3 than group 4 (2.27±0.24 vs. 1.75±0.31, p=0.023). CONCLUSIONS: In a porcine model of coronary restenosis, a novel polymer-free DES using nitrogen-doped TiO2 film deposition shows higher biocompatibility and compares favorably with a commercial DES.

Comparison of phytoncide with sirolimus as a novel drug candidate for drug-eluting stent.

A drug-eluting stent (DES) is one of the commonly used treatment techniques in percutaneous coronary intervention (PCI). Sirolimus (SRL) has been widely used for DES as a drug for suppressing neointimal hyperplasia causing restenosis. Phytoncides (PTC) are compounds released from trees and plants, and their solutions contain monoterpenoids such as α-pinene, careen, and myrceen. Some studies have reported that these components exhibit antioxidant, antimicrobial, and anti-inflammatory activities. We hypothesized that PTC may become an alternative drug to SRL for DES, exhibiting alleviated side effects as compared to SRL. A PTC-incorporated stent was compared with an SRL-incorporated stent in terms of physicochemical, pharmacokinetic, and biological properties. In in vitro studies, the effects of each drug on cells were investigated. The results showed that both drugs exhibited similar cytotoxicity, anti-inflammation, and antiproliferation effects. However, these effects resulted from different mechanisms associated with cells, as seen in the immunofluorescence result. An in vivo assay showed that the lumen area was significantly larger and the neointimal area was significantly smaller in SRL- and PTC-loaded stents compared to a drug-unloaded stent. These results suggest that phytoncide can be a feasible alternative drug to SRL for advanced DES although more studies are needed.

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.

BACKGROUND: This 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. METHODS: We 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. RESULTS: Inflammation 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). CONCLUSIONS: Our 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.

Impact of postprocedure minimum stent area on long-term results following abciximab-coated stent implantation: an intravascular ultrasound analysis.

BACKGROUND: Smaller postprocedural minimum stent areas (MSA) measured by intravascular ultrasound (IVUS) have been associated with higher restenosis rates. METHODS: This was a single-center, prospective, randomized trial and we assessed the predictive value of MSA for long-term patency and the incidence and extent of incomplete stent apposition (ISA) following abciximab-coated stent (n=69) compared to bare metal stent (BMS) implantation (n=69). All patients underwent IVUS follow-up at 6 months. RESULTS: At follow-up coronary angiogram, the restenosis rate and late loss were 12%, 0.30+/-0.24 mm in abciximab-coated stent group and 29%, 0.68+/-0.36 mm in BMS group (p=0.011, 0.010, respectively). At follow-up IVUS, intrastent lumen area was significantly larger and intrastent neointimal hyperplasia area was significantly smaller in abciximab-coated stent group than those in BMS group (5.9+/-1.6 mm(2) vs. 4.5+/-1.7 mm(2), p=0.001, and 1.9+/-1.5 mm(2) vs. 3.3+/-1.9 mm(2), p<0.001, respectively). Target lesion revascularization occurred in 9%, 0%, and 0% in abciximab-coated stent group and 19%, 4%, and 1% in BMS group in lesions with a MSA <6.0 mm(2), from 6 to 7.5 mm(2), and >7.5 mm(2), respectively. Late-acquired ISA at follow-up was observed in 7 patients and there was no difference in the incidence of ISA between both groups [abciximab-coated stent: n=3 (4%) vs. BMS: n=4 (6%), p=0.698]. CONCLUSION: Abciximab-coated stent reduced restenosis and had a considerably lower optimal MSA threshold compared to BMS and showed lower incidence of late-acquired ISA.

Effects of beta-radiation using a holmium-166 coated balloon on neointimal hyperplasia in a porcine coronary stent restenosis model.

Brachytherapy is a promising method of preventing and treating coronary stent restenosis. The present study was designed to observe the therapeutic effects of a radioactive balloon loaded with Holmium-166 ((166)Ho) in a porcine coronary stent restenosis model. A radioisotope of (166)Ho was coated onto the balloon surface using polyurethane (20 Gy at 0.5 mm depth). Stent overdilation injuries were induced in 2 coronary arteries in each pig (n=8). Four weeks after the injury, control balloon dilation was performed in one coronary artery (Group I) and radiation therapy using the (166)Ho coated balloon in the other coronary artery (Group II) in each pig. Follow-up coronary angiography and histopathologic assessment were performed at 4 weeks after the radiation therapy or the control balloon dilations. With regard to complete blood cell counts, liver function tests, lipid profiles and coagulation tests, there were no differences between the baseline and after radiation. On quantitative coronary angiographic analysis, reference and target artery diameter showed no differences between the 2 groups before, or 4 and 8 weeks after stenting. On histopathologic analysis of groups I and II, the injury score was 1.34+/-0.09 and 1.32+/-0.10, the area of internal elastic lamina was 4.99+/-0.17 mm(2) and 4.82+/-0.20 mm(2), and the luminal area was 3.20+/-0.10 mm(2) and 3.45+/-0.14 mm(2), respectively (p=NS). The neointimal area was 1.78+/-0.11 mm(2) in group I and 1.36+/-0.12 mm(2) in group II (p=0.017), and the histopathologic area of stenosis was 35.1+/-1.6% in group I and 27.6+/-1.9% in group II (p=0.005). In conclusion, beta-radiation of the stented porcine coronary artery using a radioactive (166)Ho coated balloon inhibited stent restenosis without any side effects.

The long-term clinical results of a platelet glycoprotein IIb/IIIa receptor blocker (Abciximab: Reopro) coated stent in patients with coronary artery disease.

BACKGROUND: Previously, the inhibition of coronary restenosis with Abciximab (ReoPro)-coated stent in a porcine model was reported. ReoPro inhibits platelet aggregation, the proliferation of vascular smooth muscle cells and the inflammatory reaction. METHODS: A prospective randomized trial was performed to compare two types of stent for revascularization in the native coronary artery. The primary effective end points were major adverse coronary events (MACE): cardiac death, acute myocardial infarction, target vessel revascularization (TVR) and restenosis at the 6-month clinical and angiographic follow-ups. RESULTS: One hundred and fifty-five patients were enrolled between August 2001 and June 2003. The mean ages (56.0 +/- 10.0 vs. 56.9 +/- 10.8 years), baseline diameter of stenosis and minimal luminal diameter were no different between the two groups. There was one myocardial infarction and revascularization during the hospital stay in control stent group. During the clinical follow-up there were two myocardial infarctions in control group. Follow-up coronary angiograms were performed in 62.3% (48/77) and 65.4% (51/78) of the coated and control groups, respectively. The diameter of stenosis and late loss were significantly less in the ReoPro-coated stent group compared with the controls (16.4 +/- 5.8% vs. 34.3 +/- 6.1%, p = 0.009; and 0.33 +/- 0.28 mm vs. 0.88 +/- 0.41 mm; p = 0.002). The restenosis and TVR rates of the ReoPro-coated stent were relatively lower compared with the control stent [14.6% (7/48) vs. 29.4% (15/51), p = 0.062; and 9.2% (7/76) vs. 14.7% (11/75); p = 0.327]. CONCLUSION: A ReoPro-coated stent is safe, and may be effective in the prevention of coronary restenosis.