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Preliminary Investigation on Efficacy and Safety of Substance P-Coated Stent for Promoting Re-Endothelialization: A Porcine Coronary Artery Restenosis Model

  • Original Article
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Tissue Engineering and Regenerative Medicine Aims and scope

Abstract

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.

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Data availability statement

The datasets used and/or analyzed during the present study are available from the corresponding author on reasonable request.

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Acknowledgements

This work was supported by the Korea Medical Device Development Fund grant funded by the Korea government (the Ministry of Science and ICT, the Ministry of Trade, Industry and Energy, the Ministry of Health & Welfare, the Ministry of Food and Drug Safety) (1711138916, KMDF_PR_20200901_0280 & 1711137864, KMDF_PR_20200901_0005). This research was supported by Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education (NRF-2020R1I1A3A04036675). We wish to thank YOOYOUNG Pharm. Co., Ltd. (33 Yongso 2-gil, Gwanghyewon-myeon, jincheon-gun, Chungcheongbuk-do, Korea) for support with the experiments (2018-3231). Korea Medical Device Development Fund, 1711138916, Myung Ho Jeong, KMDF_PR_20200901_0280, Myung Ho Jeong, 1711137864, Myung Ho Jeong, KMDF_PR_20200901_0005, Myung Ho Jeong, YOOYOUNG Pharm (KR), 2018-3231, Myung Ho Jeong.

Author information

Author notes

  1. Doo Sun Sim and Myung Ho Jeong have equally contributed to this work of research as the co-corresponding authors.

Authors and Affiliations

  1. The Korea Cardiovascular Stent Research Institute, Chonnam National University, Gwangju, Korea

    Dae Sung Park, Seok Oh, Yu Jeong Jin, Mi Hyang Na, Munki Kim, Jeong Ha Kim, Dae Young Hyun, Kyung Hoon Cho, Young Joon Hong, Ju Han Kim, Youngkeun Ahn, Doo Sun Sim & Myung Ho Jeong

  2. The Cardiovascular Convergence Research Center of Chonnam National University Hospital Designated by Korea Ministry of Health and Welfare, Gwangju, Korea

    Dae Sung Park, Seok Oh, Munki Kim, Jeong Ha Kim, Dae Young Hyun, Kyung Hoon Cho, Young Joon Hong, Ju Han Kim, Youngkeun Ahn, Doo Sun Sim & Myung Ho Jeong

  3. The Research Institute of Medical Sciences, Chonnam National University, Gwangju, Korea

    Dae Sung Park

  4. Department of Cardiovascular Medicine, Chonnam National University Hospital, Gwangju, Korea

    Seok Oh, Dae Young Hyun, Kyung Hoon Cho, Young Joon Hong, Ju Han Kim, Youngkeun Ahn, Doo Sun Sim & Myung Ho Jeong

  5. Department of Cardiovascular Medicine, Chonnam National University Medical School, Gwangju, Republic of Korea

    Kyung Hoon Cho, Young Joon Hong, Ju Han Kim, Youngkeun Ahn, Doo Sun Sim & Myung Ho Jeong

  6. Instituto de Investigación Biomédica de A Coruña (INIBIC), Universidade da Coruña (UDC), A Coruña, Spain

    Manuel Hermida-Prieto & José Manuel Vázquez-Rodríguez

  7. Servicio de Cardiología, Complexo Hospitalario Universitario de A Coruña, A Coruña, Spain

    José Manuel Vázquez-Rodríguez

  8. Bundeswehrzentralkrankenhaus (Federal Army Central Military Hospital), Koblenz, Germany

    Juan Luis Gutiérrez-Chico

  9. Facultad de Ciencias de La Salud, Universidad Internacional de Valencia (VIU), Valencia, Spain

    Luis Mariñas-Pardo

  10. Futuristic Animal Resource & Research Center, Korea Research Institute of Bioscience and Biotechnology, Ochang, Korea

    Kyung Seob Lim

  11. CGBio Co. Ltd., Seoul, Korea

    Jun-Kyu Park & Dae-Heung Byeon

  12. Department of Clinical Laboratory Medicine, Chonnam National University Hospital, Gwangju, Korea

    Young-Nan Cho & Seung-Jung Kee

  13. Universidad Alfonso X el Sabio, Madrid, Spain

    Juan Luis Gutiérrez-Chico

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  1. Dae Sung Park
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Contributions

Conceptualization: SDS, JMH. Data curation: PDS, OS, JYJ, NMH, KM, KJH, HDY, CKH, LKS, PJK, BDH. Formal analysis: PDS, OS, HYJ, KJH, AY, H-PM, VRJM, G-CJL, MPL. Funding acquisition: JMH. Investigation: PDS, OS, JYJ, NMH, KM, KJH, HDY, CKH, CYN, KSJ, LKS, PJK, BDH. Methodology: PDS, OS, H-PM, VRJM, G-CJL, MPL. Software: PDS, OS, JYJ, NMH, KM. Supervision: SDS, JMH. Visualization: PDS, OS, JYJ, NMH, KM, KJH Writing—original draft: PDS and OS. Writing—review and editing: HYJ, KJH, AY, PMH, RJMV, CJLG, PLM, SDS, JMH.

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Correspondence to Doo Sun Sim or Myung Ho Jeong.

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The animal studies were performed after receiving approval of the Institutional Animal Care and Use Committee (IACUC) in Chonnam National University Hospital (IACUC approval No. CNUHIACUC-20019).

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13770_2023_608_MOESM1_ESM.tif

Schematic diagrams of the stent fabrication. A Coronary artery anatomy and stents. B Bare metal stent. C Drug-eluting stent. D Substance P-coated stent.

13770_2023_608_MOESM2_ESM.tif

Example of measurements by QCA. A CAG pre-implantation. B–C CAG during implantation. D CAG post-implantation. E–H CAG at 4-week follow-up. CAG, coronary angiogram; QCA, quantitative coronary analysis.

13770_2023_608_MOESM3_ESM.tif

Histopathological analysis of the porcine coronary restenosis model at 4-week follow-up. BMS, bare-metal stent; IEL, internal elastic lamina; MPC-SP, 2-methacryloyloxyethyl phosphorylcholine-based substance P-eluting stent; PLGA-EES, poly lactic-co-glycolic acid-based everolimus-eluting stent.

13770_2023_608_MOESM4_ESM.tif

In-vitro whole blood platelet aggregation test of PLGA-EES and MPC-SP. A–D In-vitro circulation equipment for mimicking the body’s circulation system. E, F Whole blood platelet aggregation test. G, HSEM images of surfaces of PLGA-EES and MPC-SP after anti-platelet aggregation test. MPC-SP, 2-methacryloyloxyethyl phosphorylcholine-based substance P-eluting stent; PLGA-EES, poly lactic-co-glycolic acid-based everolimus-eluting stent

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Park, D.S., Oh, S., Jin, Y.J. et al. Preliminary Investigation on Efficacy and Safety of Substance P-Coated Stent for Promoting Re-Endothelialization: A Porcine Coronary Artery Restenosis Model. Tissue Eng Regen Med 21, 53–64 (2024). https://doi.org/10.1007/s13770-023-00608-y

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