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Hemocompatibility of All-trans Retinoic Acid–Loaded Citrate Polymer Coatings for Vascular Stents

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Abstract

Purpose

Current strategies implementing drug-eluting polymer stent coatings fail to fully address the lasting effects of endothelial suppression which ultimately result in delayed reendothelialization and thrombogenic complications. The present study investigates the in vitro hemocompatibility of all-trans retinoic acid–loaded poly(1,8-octanediol-co-citrate) coatings (AtRA-POC coatings) for advanced intravascular stent technology. The ability of these materials to support endothelial restoration via migration and proliferation while inhibiting smooth muscle cell growth is also explored.

Methods

Using in vitro models, the hemocompatibility of AtRA-loaded POC-coated cobalt chromium (CoCr) vascular stents was evaluated in terms of platelet and inflammatory activity. Platelet activity was quantified by platelet adhesion and platelet activation, further supported by SEM visualization. Inflammatory activity was quantified by the production of proinflammatory cytokines by THP1 monocytes. Lastly, in vitro wound healing and 5-ethynyl-2′-deoxyuridine (EdU) and PicoGreen DNA assays were used in quantitating endothelial and smooth muscle cell migration and proliferation.

Results

Experimental examinations of platelet adhesion and activation demonstrate significant reductions in the platelet response to POC-coated AtRA-loaded stents when compared to bare CoCr stents. Such findings reveal AtRA-POC coatings to have significantly improved hemocompatibility compared to that of bare metal stents and at least as good as that of POC alone. Similarly, in reference to LPS-stimulated controls, human monocyte-like THP1 cells in culture with AtRA-POC-CoCr stents for 24 h showed reduced detection of proinflammatory cytokines, comparable to that of bare CoCr and untreated controls. This result supports AtRA-POC coatings as possessing limited immunological potential. Observations from in vitro endothelial and smooth muscle cell investigations demonstrate the ability of the drug AtRA to allow cell processes involved in restoration of the endothelium while inhibiting smooth muscle cell processes.

Conclusion

This study demonstrates AtRA-loaded POC coatings are hemocompatible and noninflammatory, and provide a promising strategy in enhancing vascular stent techniques and clinical integration. Possessing hemocompatibility and immunological compatibility that is at least as good as bare metal stents as clinical standards supports the use of AtRA-POC coatings for vascular applications. Additionally, selectively reducing smooth muscle cell proliferation while supporting endothelial cell proliferation and migration further demonstrates the potential of these materials in significantly improving the state of vascular stent technology in the area of stent thrombosis and neointimal hyperplasia.

Lay Summary

Hemocompatibility and support of endothelial cell functions are essential for advancing drug-eluting stent technology. Since vascular stents will be directly in contact with blood, the materials used for these devices must be compatible with blood components and associated cells to prevent clotting and proinflammatory events. Additionally, ideal strategies must support the restoration of surrounding vascular tissue which becomes damaged during stent implantation and is at the crux of addressing the current challenges of drug-eluting stent approaches. Thus, the present study investigates the in vitro hemocompatibility and effects on endothelial healing of all-trans retinoic acid–loaded poly(1,8-octanediol-co-citrate) coatings for advanced intravascular stent technology.

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Data availability

Data available upon request.

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Funding

This work was funded by the National Institutes of Health R01, grant number R01HL130493.

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Authors and Affiliations

  1. Department of Materials Science and Engineering, University of Florida, Gainesville, FL, USA

    Heather Ursino, Bisheng Zhang, Antonio Webb & Josephine B. Allen

  2. J. Crayton Pruitt Family Department of Biomedical Engineering, University of Florida, Gainesville, FL, USA

    Christopher Ludtka & Josephine B. Allen

Authors
  1. Heather Ursino
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  2. Bisheng Zhang
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  3. Christopher Ludtka
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  4. Antonio Webb
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Contributions

Project conceptualization: Antonio Webb and Josephine Allen; formal analysis and investigation: Heather Ursino, Bisheng Zhang, and Christopher Ludtka; writing—original draft preparation: Heather Ursino and Josephine Allen; writing—review and editing: all authors; funding acquisitions: Antonio Webb and Josephine Allen; supervision: Antonio Webb and Josephine Allen.

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Correspondence to Josephine B. Allen.

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Ethics Approval

The study includes experimentation with porcine whole-blood components. All animal procedures to collect whole blood were performed in accordance with the Institutional Animal Care and Use Committee (IACUC) and the University of Florida’s Animal Care Services (ACS) and policies.

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Conflict of Interest

Author Josephine Allen holds a position on the editorial board of the Regenerative Engineering and Translational Medicine journal. The other authors have no relevant financial or nonfinancial interests to disclose.

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Future Works

Future studies may incorporate flow parameters and signals of relevant surrounding cell types to better replicate in situ conditions for improved translatability to clinical applications. Other variables like injury severity, drug dosage, and further stent surface characterization may also be explored due to known complexities involving these parameters.

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Ursino, H., Zhang, B., Ludtka, C. et al. Hemocompatibility of All-trans Retinoic Acid–Loaded Citrate Polymer Coatings for Vascular Stents. Regen. Eng. Transl. Med. 8, 579–592 (2022). https://doi.org/10.1007/s40883-022-00257-y

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