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.
The protein adsorption and immuno-compatibility of hydrogels largely influence the clinical outcome in biomedical application scenarios. In this study photo-crosslinked 2-isocyanate ethyl methacrylate-functionalized oligo(ethylene glycol)-oligo(propylene glycol)-oligo(ethylene glycol) (IEMA-OEG-OPG-OEG-IEMA)-based polymer hydrogel films were explored with respect to endotoxin contaminations, intrinsic immuno-modulatory features, and protein adsorption of human fibronectin as well as serum albumin. Therefore three different hydrogel films were prepared from aqueous solutions of dimethacrylated OEG-OPG-OEG triblock copolymers (M n = 12,700 g mol À1 , 70 mol% OEG content) with varying wt% of the macromonomer (10 to 30%) resulting in polymeric networks, which differ in their crosslinking density and accordingly their physical properties. It could be shown that all three hydrogel film compositions do not cause complement and immune cell activation. The films were protein repellent, but reversible protein diffusion in and out of the hydrogel network, depending on the mesh size of the network, could be observed. In conclusion, the hydrogels can be considered as immuno-compatible, which qualifies them for biomedical applications such as drug release systems.
Summary: Biomaterials are of increasing importance in regenerative medicine and entail delivery systems in somatic cell therapies, matrices for tissue engineering or tissue regeneration. The evaluation of biomaterial induced biological effects remains a key issue in clinical application. Cell-based assays for potential cytotoxic and immunological responses have been developed but are often inadequate to address cell-type specific responses to biomaterials. To quantitatively monitor attachment, survival, proliferation and fusion-controlled differentiation of osteoclasts (bone resorbing cells), a High Content Screening (HCS) assay has been developed based on osteoclast differentiation of the murine monocytic cell line RAW 264.7. This assay was applied to investigate the influence of degradation products of polymers from gelatin and lysine diisocyanate, which display tailorable mechanical properties and have potential as biomaterials. The data show that the degradation products inhibit formation of multinuclear osteoclasts and suggest a potential support of bone regeneration by suppression of bone resorption.
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