Immunocompatibility and non-thrombogenicity of gelatin-based hydrogels

Article type: Research Article

Authors: Krüger-Genge, A.^a | Tondera, C.^{b; c} | Hauser, S.^b | Braune, S.^a | Görs, J.^a | Roch, T.^{a; e; **} | Klopfleisch, R.^d | Neffe, A.T.^{a; e} | Lendlein, A.^{a; e; f; *} | Pietzsch, J.^{b; c} | Jung, F.^{a; e; *}

Affiliations: [a] Institute of Biomaterial Science and Berlin-Brandenburg Centre for Regenerative Therapies (BCRT), Helmholtz Zentrum Geesthacht, Teltow, Germany | [b] Department of Radiopharmaceutical and Chemical Biology, Institute of Radiopharmaceutical Cancer Research, Helmholtz-Zentrum Dresden-Rossendorf, Dresden, Germany | [c] School of Science, Faculty of Chemistry and Food Chemistry, Technical University Dresden, Dresden, Germany | [d] Institute of Veterinary Pathology, Freie Universität Berlin, Berlin, Germany | [e] Helmholtz Virtual Institute – Multifunctional Biomaterials for Medicine, Teltow and Berlin, Germany | [f] Institute of Chemistry, University of Potsdam, Potsdam, Germany

Correspondence: [*] Corresponding authors: A. Lendlein, E-mails: andreas.lendlein@hzg.de; F. Jung, E-mail: friedrich.jung@hzg.de.

Note: [**] Present address: BIH Center for Regenerative Therapies, Charité - Universitätsmedizin Berlin, Germany and Center for Translational Medicine, Marien Hospital Herne, Ruhr-University Bochum, Herne, Germany.

Abstract: Immunocompatibility and non-thrombogenicity are important requirements for biomedical applications such as vascular grafts. Here, gelatin-based hydrogels formed by reaction of porcine gelatin with increasing amounts of lysine diisocyanate ethyl ester were investigated in vitro in this regard. In addition, potential adverse effects of the hydrogels were determined using the “Hen’s egg test on chorioallantoic membrane” (HET-CAM) test and a mouse model. The study revealed that the hydrogels were immunocompatible, since complement activation was absent and a substantial induction of reactive oxygen species generating monocytes and neutrophils could not be observed in whole human blood. The density as well as the activation state of adherent thrombocytes was comparable to medical grade polydimethylsiloxane, which was used as reference material. The HET-CAM test confirmed the compatibility of the hydrogels with vessel functionality since no bleedings, thrombotic events, or vessel destructions were observed. Only for the samples synthesized with the highest LDI amount the number of growing blood vessels in the CAM was comparable to controls and significantly higher than for the softer materials. Implantation into mice showed the absence of adverse or toxic effects in spleen, liver, or kidney, and only a mild lymphocytic activation in the form of a follicular hyperplasia in draining lymph nodes (slightly increased after the implantation of the material prepared with the lowest LDI content). These results imply that candidate materials prepared with mid to high amounts of LDI are suitable for the coating of the blood contacting surface of cardiovascular implants.

Keywords: Gelatin-based hydrogels, immune cells, platelets, in vitro testing, mouse model

DOI: 10.3233/CH-201028

Journal: Clinical Hemorheology and Microcirculation, vol. 77, no. 3, pp. 335-350, 2021