A comparative biocompatibility study of micropheres based on crosslinked dextran or poly(lactic-co-glycolic)acid after subcutaneous injection in rats

Microspheres based on methacrylated dextran (dex-MA), dextran derivatized w ith lactate-hydroxyethyl methacrylate (dex-lactate-HEMA) or derivatized wit h HEMA (dex-HEMA) were prepared. The microspheres were injected subcutaneou sly in rats and the effect of the particle size and network characteristics [initial water content and degree of methacrylate substitution (DS)] on th e tissue reaction was investigated for 6 weeks. As a control, poly(lactic-c o-glycolic)acid (PLGA) microspheres with varying sizes (unsized, smaller th an 10 mum, smaller and larger than 20 mum) were injected as well. A mild ti ssue reaction to the PLGA microspheres was observed, characterized by infil tration of macrophages (M circle divides) and some granulocytes. Six weeks postinjection, the PLGA microspheres were still present. However, their siz e was decreased indicating degradation and many spheres had been phagocytos ed. The tissue reaction was hardly affected by size differences, except for particles smaller than 10 mum, which induced an extensive tissue reaction. The initial tissue reaction to nondegradable dex-MA microspheres was stron ger than towards the PLGA microspheres, but at day 10 the tissue reactions were comparable for both groups. Six weeks postinjection, the dex-MA micros pheres were completely phagocytosed, and no signs of degradation were obser ved. The size and initial water content of dex-MA microspheres hardly affec ted the tissue response, although less granulocytes were observed for micro spheres with higher DS. Slowly degrading dextran microspheres composed of d ex-(lactate(1)-)HEMA induced a tissue reaction comparable to the PLGA micro spheres. However, degradation of the dex-(lactate(1,3)-)HEMA microspheres w as associated with An increased number of M circle divide 's and giant cell s, both phagocytosing the microspheres and their degradation products. Simi lar to PLGA, no adverse reactions were observed for the nondegradable dex-M A and degradable dextran microspheres. This study shows that both nondegrad able and degradable dextran-based microspheres are well tolerated after sub cutaneous injection in rats, which make them interesting candidates as cont rolled drug delivery systems. (C) 2001 John Wiley & Sons, Inc.