Complex coacervate tissue adhesives: effect of polycation chemistry and ionic strength on cytocompatibility

Tissue adhesives are regularly used for wound healing, bleeding control and sealing internal organ leakages. However, currently available tissue adhesives are often cytotoxic. Polycations containing primary amines are generally known to induce cytotoxicity. Complex coacervates, composed of oppositely charged polyelectrolytes, may offer a biocompatible alternative. In this study, primary amines of polyallylamine hydrochloride (pAH) were reacted with glycidyltrimethylammonium chloride (GTMAC) following an epoxide ring nucleophilic substitution to obtain pAH with quaternary ammonium pendant groups (q-pAH). These polycations were combined with negatively charged polysulfopropyl methacrylate (pSPMA) to form complex coacervates. The biocompatibility of the individual polyelectrolytes and resulting complex coacervates was studied using A549 cells through Live/Dead, MTS (3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium) and LDH (lactate dehydrogenase) assays. Additionally, adhesion to porcine tissues was evaluated. Quaternization of pAH strongly reduced the critical salt concentration (CSC) of the coacervate system, while remaining easy to process and injectable. The cytocompatibility of q-pAH/pSPMA was increased compared to pAH/pSPMA, mainly caused by the reduction of the required salt concentration. Nevertheless, quaternization did not reduce the cytotoxicity of the polycation itself. Complexation with pSPMA effectively reduced cytotoxicity through charge neutralization. Upon direct contact of A549 cells with q-pAH/pSPMA coacervates improved biocompatibility was observed compared to pAH/pSPMA, which could not be fully attributed to effects of reduced salt levels. Both coacervates formed stable, gel-like patches upon the salt switch and these adhered to various tissues. Reduction of complex coacervate cytotoxicity by polycation quaternization can be included in future designs of medical adhesives.