Cross-linked poly(alkylene citrates) with l-glutathione for vascular tissue engineering: structure–property relationships and cell-type dependent response to oxidative stress†

Abstract

Cross-linked poly(alkylene citates) (cPAC) based on 1,6-hexanediol (cPHC) and 1,8-octanediol (cPOC) and modified with 0.4, 0.8 and 1.6% w/w L-glutathione (GSH) were synthesized as potential materials for vascular tissue engineering. The materials prepared at a citric acid : diol molar ratio of 2 : 3 exhibited superior mechanical strength and reduced acidity in comparison to the 1 : 1 materials. All materials exhibited blue fluorescence, which intensity was enhanced with increasing GSH concentration. Conversely, the latter demonstrated marginally enhanced antioxidant properties. The preliminary cell culture tests of the 2 : 3 materials with human adipose tissue stem cells (ASCs) revealed that cPOC did not provide an appropriate environment for cell colonization due to its higher acidity than cPHC. In contrast, cPHC promoted the growth of ASCs and other cell types, including fibroblasts (NHDFs), endothelial cells (HUVECs), and smooth muscle cells (SMCs), at all GSH concentrations, with minimal negative effect on HUVEC and SMC proliferation. The induction of oxidative stress by menadione demonstrated a notable decline in the metabolic activity of both ASCs and NHDFs on cPHCs across all GSH concentrations. However, an incremental protective effect on the cells was observed with increasing GSH concentrations. In contrast, HUVECs and SMCs demonstrated increased metabolic activity, without the protective effect of GSH being observed. Therefore, the findings demonstrate that cell type-specific differences exist in cell response to oxidative stress. Consequently, the addition of antioxidants to the polymer should be guided by the intended cell type for use in vascular reconstruction. Our results also suggest an intrinsic antioxidant activity of cPHC materials and their good hemocompatibility with human blood in vitro.