Biodegradable three-dimensional networks of poly(dimethylamino ethyl methacrylate). Synthesis, characterization and in vitro studies of structural degradation and cytotoxicity

Abstract

In ophthalmology, there is a need for novel degradable biomaterials for e.g. controlled drug release in the vitreous body. These degradable materials should feature both excellent biocompatibility, and well-defined kinetics of degradation. In most cases, poly(D,L-lactic acid), or poly(lactic-co-glycolic acid) are used. These materials, however, suffer from some serious drawbacks, since the degradation kinetics are difficult to control, especially since the so-called 'burst-degradation' occurs. Here, we describe a set of novel polymeric networks which largely consist of poly(dimethylamino ethyl methacrylate) (poly(DMAEMA)); these materials are crosslinked via a dimethacrylate molecule that contains two carbonate groups. This system is susceptible to hydrolytic scission. The degradation products do not exert a catalytic effect on the ongoing degradation reaction (i.e. there is no burst effect). We describe the synthesis of three of these materials, which differ merely with regard to the crosslinker content. These materials were characterized through DMTA, 1H NMR and FT-IR spectroscopy, and scanning electron microscopy. The reaction DMAEMA + 2-hydroxyethyl methacrylate (HEMA) was studied in detail, using 1H NMR spectroscopy, and these experiments revealed that the reaction of DMAEMA and HEMA produces a random (Bernouillian-type) copolymer. From this, we contend that the new materials have more or less uniform distribution of the crosslinks throughout their volume. Structural degradation of the three materials was studied in vitro, at pH 7.4, 9.1 and 12.0. It is found that the materials exhibit smooth hydrolysis, which can be controlled via the crosslink density and the pH, as was expected a priori. It should be noted that degradation of these materials produces non-hydrolysable, but water-soluble, oligo(DMAEMA) and poly(DMAEMA) molecules. We subsequently performed in vitro studies on the biocompatibility of these materials. The MTT cytotoxicity assay revealed that the materials were cytotoxic to chondrosarcoma cells. This is most probably due to local increase of the pH due to the basic character of the pending dimethylamino groups. Cytotoxicity remained virtually unchanged after extended washing with water. This indicates that the cytotoxicity is an intrinsic property of the material and was not caused by remnants of free monomer. Cytotoxicity was also seen in cell cultures (human fibroblasts isolated from donor corneas) which were grown in contact with the materials. It is concluded that the new materials have attractive degradation characteristics, but their cytotoxicity makes them unsuitable for applications in ophthalmology.