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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., Competing Interests: The authors have no potential conflicts of interest to disclose., (© 2024 The Korean Academy of Medical Sciences.)

Background: Current polymer-based drug-eluting stents (DESs) have fundamental issues about inflammation and delayed re-endothelializaton of the vessel wall. Substance-P (SP), which plays an important role in inflammation and endothelial cells, has not yet been applied to coronary stents. Therefore, this study compares poly lactic-co-glycolic acid (PLGA)-based everolimus-eluting stents (PLGA-EESs) versus 2-methacryloyloxyethyl phosphorylcholine (MPC)-based SP-eluting stents (MPC-SPs) in in-vitro and in-vivo models., Methods: The morphology of the stent surface and peptide/drug release kinetics from stents were evaluated. The in-vitro proliferative effect of SP released from MPC-SP is evaluated using human umbilical vein endothelial cell. Finally, the safety and efficacy of the stent are evaluated after inserting it into a pig's coronary artery., Results: Similar to PLGA-EES, MPC-SP had a uniform surface morphology with very thin coating layer thickness (2.074 μm). MPC-SP showed sustained drug release of SP for over 2 weeks. Endothelial cell proliferation was significantly increased in groups treated with SP (n = 3) compared with the control (n = 3) and those with everolimus (n = 3) (SP: 118.9 ± 7.61% vs. everolimus: 64.3 ± 12.37% vs. the control: 100 ± 6.64%, p < 0.05). In the animal study, the percent stenosis was higher in MPC-SP group (n = 7) compared to PLGA-EES group (n = 7) (MPC-SP: 28.6 ± 10.7% vs. PLGA-EES: 16.7 ± 6.3%, p < 0.05). MPC-SP group showed, however, lower inflammation (MPC-SP: 0.3 ± 0.26 vs. PLGA-EES: 1.2 ± 0.48, p < 0.05) and fibrin deposition (MPC-SP: 1.0 ± 0.73 vs. PLGA-EES: 1.5 ± 0.59, p < 0.05) around the stent strut. MPC-SP showed more increased expression of cluster of differentiation 31, suggesting enhanced re-endothelialization., Conclusion: Compared to PLGA-EES, MPC-SP demonstrated more decreased inflammation of the vascular wall and enhanced re-endothelialization and stent coverage. Hence, MPC-SP has the potential therapeutic benefits for the treatment of coronary artery disease by solving limitations of currently available DESs., (© 2023. Korean Tissue Engineering and Regenerative Medicine Society.)

Background: Biodegradable poly (l-lactic acid) (PLLA), a bio safe polymer with a large elastic modulus, is widely used in biodegradable medical devices. However, because of its poor mechanical properties, a PLLA strut must be made twice as thick as a metal strut for adequate blood vessel support. Therefore, the mechanical properties of a drug-eluting metal-based stents (MBS) and a bioresorbable vascular scaffolds (BVS) were evaluated and their safety and efficacy were examined via a long-term rabbit iliac artery model., Methods: The surface morphologies of the MBSs and BVSs were investigated via optical and scanning electron microscopy. An everolimus-eluting (EE) BVS or an EE-MBS was implanted into rabbit iliac arteries at a 1.1:1 stent-to-artery ratio. Twelve months afterward, stented iliac arteries from each group were analyzed via X-ray angiography, optical coherence tomography (OCT), and histopathologic evaluation., Results: Surface morphology analysis of the EE coating on the MBS confirmed that it was uniform and very thin (4.7 μm). Comparison of the mechanical properties of the EE-MBS and EE-BVS showed that the latter outperformed the former in all aspects (radial force (2.75 vs. 0.162 N/mm), foreshortening (0.24% vs. 1.9%), flexibility (0.52 vs. 0.19 N), and recoil (3.2% vs. 6.3%). At all time points, the percent area restenosis was increased in the EE-BVS group compared to the EE-MBS group. The OCT and histopathological analyses indicate no significant changes in strut thickness., Conclusion: BVSs with thinner struts and shorter resorption times should be developed. A comparable long-term safety/efficacy evaluation after complete absorption of BVSs should be conducted., (© 2023. Korean Tissue Engineering and Regenerative Medicine Society.)

The purpose of this study was to evaluate the performance of biodegradable polymer sirolimus and ascorbic acid eluting stent systems with four commercially available drug-eluting stents (DES). We investigated the characterization of mechanical properties by dimension, foreshortening, recoil, radial force, crossing profile, folding shape, trackability, and dislodgement force. Additionally, we identify the safety and efficacy evaluation through registry experiments. Each foreshortening and recoil of D + Storm® DES is 1.3 and 3.70%, which has better performance than other products. A post-marketing clinical study to evaluate the performance and safety of D + Storm® DES is ongoing in real-world clinical settings. Two hundred one patients were enrolled in this study and have now completed follow-up for up to 1 month. No major adverse cardiovascular event (MACE) occurred in any subjects, confirming the safety of D + Storm® DES in the clinical setting. An additional approximately 100 subjects will be enrolled in the study and the final safety profile will be assessed in 300 patients. In conclusion, this study reported the objective evaluation of DES performance and compared the mechanical responses of four types of DES available in the market. There is little difference between the four cardiovascular stents in terms of mechanical features, and it can help choose the most suitable stent in a specific clinical situation if those features are understood. Graphical abstract., (© 2022. The Author(s).)

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., Competing Interests: The authors have no potential conflicts of interest to disclose., (© 2021 The Korean Academy of Medical Sciences.)

Inflammation and thrombosis are linked to the use of polymer-based drug-eluting stents (DES). The aim of this study was to develop a polymer-free everolimus (EVL)-eluting stent using nitrogen-doped titanium dioxide (N-TiO 2 ) and verify its efficacy by in vitro and in vivo assessment in a porcine coronary model. Various analytical approaches such as scanning electron microscopy and atomic force microscopy, electron spectroscopy, Fourier transform infrared spectrometry and contact angle measurement were employed for the characterization. As a part of biocompatibility assessment, platelet adhesion and smooth muscle cell (SMC) proliferation were examined. Bare metal stent (BMS), N-TiO 2 stent, everolimus-eluting N-TiO 2 (N-TiO 2 -EVL) stent, and commercialized EVL-eluting stent (EES) were randomly placed in forty coronary arteries in twenty pigs. After four weeks of implantation, the stents were subjected to histological and quantitative analysis. The N-TiO 2 film used in this study was well coated without any cracks or peeling. Surface hydrophilicity (88.8% of angle decrement) could be associated with the decrease in surface roughness post N-TiO 2 deposition (37.0%). The platelet adhesion on the N-TiO 2 surfaces was less than that on the BMS surface. The proliferation of SMC was suppressed in the N-TiO 2 -EVL group (30.2%) but not in the BMS group. In the animal study, the percent area restenosis was significantly decreased in the N-TiO 2 -EVL group compared to that in the BMS group. The results (BMS; 47.0 ± 11.00%, N-TiO 2 -EVL; 31.7 ± 10.50%, and EES; 29.1 ± 11.21%, n = 10, p < 0.05) were almost at par with those of the commercialized EVL-eluting stent. The introduction of N-TiO 2 deposition during fabrication of polymer-free DES may be an efficient accessorial process for preventing in-stent restenosis and thrombosis., (Copyright © 2018 Elsevier B.V. All rights reserved.)

The aim of this study was to fabricate a novel polymer-free everolimus-eluting stent with nanostructure using a femtosecond laser (FSL). The stent were coated with everolimus (EVL) using FSL and electrospinning processes. The surface was rendered hydrophobic, which negatively affected both platelet adhesion (82.1%) and smooth muscle cell response. Animal study was performed using a porcine coronary restenosis model. The study groups were divided into 1) bare metal stent (BMS), 2) poly(L-lactide) (PLA)-based EVL drug eluting stent (DES), 3) commercial EVL-eluting DES, and 4) FSL-EVL-DES. After four weeks of stent implantation, various analyses were performed. Quantitative analysis showed that the amount of in-stent restenosis was higher in the BMS group (BMS; 27.8 ± 2.68%, PLA-based DES; 12.2 ± 0.57%, commercial DES; 9.8 ± 0.28%, and FSL-DES; 9.3 ± 0.25%, n = 10, p < 0.05). Specifically, the inflammation score was reduced in the FSL-DES group (1.9 ± 0.39, n = 10, p < 0.05). The increment in re-endothelialization in the FSL-DES group was confirmed by immunofluorescence analysis. Taken together, the novel polymer-free EVL-eluting stent fabricated using FSL can be an innovative DES with reduced risk of ISR, thrombosis, and inflammation.

The aim of this study was to evaluate the effects of bilirubin- and/or everolimus (EVL)-coated stents to prevent arterial neointimal hyperplasia and inflammation in vitro and in vivo. The stents were prepared by spray coating bare metal stents (BMS) with bilirubin and/or EVL. Study groups were divided into (1) BMS, (2) bilirubin-coated stents (BES), (3) commercialized stents (Synergy™; EES), and (4) bilirubin/EVL-coated stents (B-EES). The coating thickness and drug release rates were comparable to previous reports (i.e., <4 µm thickness and 50% drug release in 7 days). Smooth muscle cell migration was inhibited in both EVL-containing groups (20.5 ± 3.80% in EES and 18.4 ± 2.55% in B-EES) compared to the non-EVL-containing groups (78.0 ± 6.41% in BMS and 76.1 ± 4.88% in BES) (n = 10, p < 0.05). Stents were randomly implanted to 40 coronary arteries in 20 pigs and subjected to various analyses after 4 weeks of implantation. As results, the inflammation score was dramatically increased in the EES group (2.1 ± 0.42) compared to that of the other groups (1.5 ± 0.55, 1.3 ± 0.23, and 1.5 ± 0.27 for BMS, BES, and B-EES, respectively, n = 10, p < 0.05). Immunofluorescence analysis revealed that inflammation was prevented in the bilirubin-containing groups (BES and B-EES). However, the percent area of restenosis was decreased in the EVL-containing groups (20.5 ± 4.11% for EES and 18.4 ± 3.61% for B-EES) compared to the non-EVL-containing groups (32.3 ± 6.41% for BMS and 29.6 ± 5.95% for BES, n = 10, p < 0.05). The percent areas of restenosis determined by histopathology, optical coherence tomography, and micro-computed tomography were consistent. In addition, the stent was barely covered in the EES and B-EES groups at 4 weeks postimplantation. These dual drug-coated stents may be especially beneficial to patients who have an increased risk of inflammation. These stents have great potential for use in cardiovascular applications. © 2017 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 106B: 1486-1495, 2018., (© 2017 Wiley Periodicals, Inc.)

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 cm 2 ) compared to that in the heparin noncoated group (5.0 ± 1.00/1.8 cm 2 ). 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.

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, n = 10, p < 0.05) and continued to 28 days in both groups. The contact angle was dramatically decreased in DSS (38.7° ± 1.24) compared to BMS and PSS groups (72.7° ± 5.32 and 81.1º ± 1.70, respectively, n = 10, p < 0.05). Smooth muscle cell migration was arrested in both the DSS and PSS-treated groups compared to that in the nontreated group (4.2% ± 0.31, 5.8% ± 0.60, 80.0% ± 4.4, respectively, n = 10, p < 0.05). 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% ± 2.52 in DSS and 27.9% ± 3.30 in PSS) compared to BMS (35.9% ± 3.51, p < 0.05). The fibrin score was higher in the PSS (2.9 ± 0.31) than BMS (2.1 ± 0.12) and DSS (2.5 ± 0.66). The inflammation score in the DSS (0.7 ± 0.21) was similar to that in the BMS (0.7 ± 0.12), which was dramatically lower than that PSS (1.5 ± 0.18, p < 0.005). 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. © 2016 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 105A: 301-310, 2017., (© 2016 Wiley Periodicals, Inc.)

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 (31.5 ± 4.08%), and this effect was enhanced by PDS addition (PDSRLcs, 46.8 ± 8.11%). Consistently, in the animal study, the restenosis rate was inhibited by the SRLcs and PDSRLcs (18.5 ± 6.23% and 14.5 ± 3.55%, respectively). Especially, fibrin expression and inflammation were suppressed in the PDS-containing group (PDScs, 0.6 ± 0.12 and 1.4 ± 0.33; PDSRLcs, 0.7 ± 0.48 and 1.7 ± 0.12, respectively) compared to PDS non-containing groups (BMS, 1.1 ± 0.12, and 1.8 ± 0.55; SRLcs, 1.6 ± 0.32 and 2.0 ± 0.62, 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., (© The Author(s) 2016.)

The aim of this study was to evaluate antiproliferative sirolimus- and antioxidative alpha-lipoic acid (ALA)-eluting stents using biodegradable polymer [poly-L-lactic acid (PLA)] in a porcine coronary overstretch restenosis model. Forty coronary arteries of 20 pigs were randomized into four groups in which the coronary arteries had a bare metal stent (BMS, n = 10), ALA-eluting stent with PLA (AES, n = 10), sirolimus-eluting stent with PLA (SES, n = 10), or sirolimus- and ALA-eluting stent with PLA (SAS, n = 10). A histopathological analysis was performed 28 days after the stenting. The ALA and sirolimus released slowly over 30 days. There were no significant differences between groups in the injury or inflammation score; however, there were significant differences in the percent area of stenosis (56.2 ± 11.78% in BMS vs. 51.5 ± 12.20% in AES vs. 34.7 ± 7.23% in SES vs. 28.7 ± 7.30% in SAS, P < 0.0001) and fibrin score [1.0 (range 1.0-1.0) in BMS vs. 1.0 (range 1.0-1.0) in AES vs. 2.0 (range 2.0-2.0) in SES vs. 2.0 (range 2.0-2.0) in SAS, P < 0.0001] between the four groups. The percent area of stenosis based on micro-computed tomography corresponded with the restenosis rates based on histopathological stenosis in different proportions in the four groups (54.8 ± 7.88% in BMS vs. 50.4 ± 14.87% in AES vs. 34.5 ± 7.22% in SES vs. 28.9 ± 7.22% in SAS, P < 0.05). SAS showed a better neointimal inhibitory effect than BMS, AES, and SES at 1 month after stenting in a porcine coronary restenosis model. Therefore, SAS with PLA can be a useful drug combination for coronary stent coating to suppress neointimal hyperplasia.

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 6 weeks 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 (57.2% within 7 days, with further release for up to 28 days). Endothelial-cell proliferation was enhanced in the HA-Pep group after 7 days of culture (38.2 ± 7.62%, compared with controls). On the other hand, the proliferation of smooth-muscle cells was inhibited in the Pep/SRL group after 7 days of culture (40.7 ± 6.71%, compared with controls). In an animal study, the restenosis rates for the Pep/SRL group (13.5 ± 4.50%) and commercial drug-eluting stents (Xience Prime™; 9.2 ± 7.20%) were lower than those for bare-metal stents (25.2 ± 4.52%) and HA-Pep stents (26.9 ± 3.88%). 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.

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., (Copyright © 2014. Published by Elsevier Ltd.)