Distinct Effects of Heparin and Interleukin-4 Functionalization on Macrophage Polarization and In Situ Arterial Tissue Regeneration Using Resorbable Supramolecular Vascular Grafts in Rats
Bonito, Valentina; Koch, Suzanne E; Krebber, Merle M; Carvajal-Berrio, Daniel A; Marzi, Julia; Duijvelshoff, Renee; Lurier, Emily B; Buscone, Serena; Dekker, Sylvia; de Jong, Simone M J; Mes, Tristan; Vaessen, Koen R D; Brauchle, Eva M; Bosman, Anton W; Schenke-Layland, Katja; Verhaar, Marianne C; Dankers, Patricia Y W; Smits, Anthal I P M; Bouten, Carlijn V C
(2021) Advanced Healthcare Materials, volume 10, issue 21, pp. 1 - 19
(Article)
Abstract
Two of the greatest challenges for successful application of small-diameter in situ tissue-engineered vascular grafts are 1) preventing thrombus formation and 2) harnessing the inflammatory response to the graft to guide functional tissue regeneration. This study evaluates the in vivo performance of electrospun resorbable elastomeric vascular grafts, dual-functionalized with anti-thrombogenic
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heparin (hep) and anti-inflammatory interleukin 4 (IL-4) using a supramolecular approach. The regenerative capacity of IL-4/hep, hep-only, and bare grafts is investigated as interposition graft in the rat abdominal aorta, with follow-up at key timepoints in the healing cascade (1, 3, 7 days, and 3 months). Routine analyses are augmented with Raman microspectroscopy, in order to acquire the local molecular fingerprints of the resorbing scaffold and developing tissue. Thrombosis is found not to be a confounding factor in any of the groups. Hep-only-functionalized grafts resulted in adverse tissue remodeling, with cases of local intimal hyperplasia. This is negated with the addition of IL-4, which promoted M2 macrophage polarization and more mature neotissue formation. This study shows that with bioactive functionalization, the early inflammatory response can be modulated and affect the composition of neotissue. Nevertheless, variability between graft outcomes is observed within each group, warranting further evaluation in light of clinical translation.
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Keywords: biodegradable polymers, cardiovascular, immunomodulatory biomaterials, in situ tissue engineering, Raman microspectroscopy, supramolecular chemistry, tissue-engineered vascular graft (TEVG), Biomedical Engineering, Biomaterials, Pharmaceutical Science, Journal Article
ISSN: 2192-2640
Publisher: John Wiley & Sons Inc.
Note: Funding Information: V.B., S.K., A.S., and C.B. contributed equally to this work. The authors gratefully acknowledge Josephine Hermans, Agnes Barentsen, Harry Blom, Anja van der Sar, Rika Kramer, and Esmée Bouma of the Central Lab Animal Research Facility of the University of Utrecht, for facilitating and conducting the animal surgeries. Rogier Veltrop is gratefully acknowledged for his help with the collection of the explants, Bente de Kort for the elastin biochemical assays, Eline van Haaften, Marjan Hagelaars and Rob Driessen for their help with the analysis of the uniaxial tensile tests, Annick Meeuwsen for her help with the immunofluorescent imaging, and Krista den Ouden and Melanie Nieuwenhuijzen‐van de Kaa for their expert technical assistance on the immunohistochemical stainings and analyses. The authors thank the ICMS animation studio for the schematic representation of the supramolecular polymers. This research is part of the ImaValve Project, which received funding from the European Union's Seventh Framework Programme (604514) and the InSiTeVx project (436001003), financially supported by ZonMw within the LSH 2Treat Programme and the Dutch Kidney Foundation. The collaboration between Eindhoven University of Technology and the University of Tübingen for the Raman spectroscopy analysis was facilitated by a Short‐Term Fellowship (8169) of the European Molecular Biology Organization (EMBO) to Anthal Smits. The authors gratefully acknowledge the Gravitation Program “Materials Driven Regeneration,” funded by the Netherlands Organization for Scientific Research (024.003.013). Funding Information: V.B., S.K., A.S., and C.B. contributed equally to this work. The authors gratefully acknowledge Josephine Hermans, Agnes Barentsen, Harry Blom, Anja van der Sar, Rika Kramer, and Esm?e Bouma of the Central Lab Animal Research Facility of the University of Utrecht, for facilitating and conducting the animal surgeries. Rogier Veltrop is gratefully acknowledged for his help with the collection of the explants, Bente de Kort for the elastin biochemical assays, Eline van Haaften, Marjan Hagelaars and Rob Driessen for their help with the analysis of the uniaxial tensile tests, Annick Meeuwsen for her help with the immunofluorescent imaging, and Krista den Ouden and Melanie Nieuwenhuijzen-van de Kaa for their expert technical assistance on the immunohistochemical stainings and analyses. The authors thank the ICMS animation studio for the schematic representation of the supramolecular polymers. This research is part of the ImaValve Project, which received funding from the European Union's Seventh Framework Programme (604514) and the InSiTeVx project (436001003), financially supported by ZonMw within the LSH 2Treat Programme and the Dutch Kidney Foundation. The collaboration between Eindhoven University of Technology and the University of T?bingen for the Raman spectroscopy analysis was facilitated by a Short-Term Fellowship (8169) of the European Molecular Biology Organization (EMBO) to Anthal Smits. The authors gratefully acknowledge the Gravitation Program ?Materials Driven Regeneration,? funded by the Netherlands Organization for Scientific Research (024.003.013). Publisher Copyright: © 2021 The Authors. Advanced Healthcare Materials published by Wiley-VCH GmbH
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