Effect of composition of interpenetrating polymer network hydrogels based on poly(acrylic acid) and gelatin on tissue response: A quantitative in vivo study

The local tissue response of the biomaterial is the most important criteria for determination of its biocompatibility. In the present study, full and semi-interpenetrating polymer networks (IPN) based on polyacrylic acid (AAc) and gelatin (Ge) crosslinked with 0.5 mol % N,N'-methylene bisacrylamide (BAm) and 4% glutaraldehyde (GA), respectively, were evaluated for tissue response in rats. IPNs with varying ratios of AAc and Ge were implanted subcutaneously in rats. Gentamicin sulfate (GS)-loaded IPN samples were also studied to evaluate the possible therapeutic use of these polymers. The site of implantation was biopsied and processed for light microscopy (LM) with image analysis for assessment of tissue reaction at 2-, 6-, and 12-week intervals. The tissue reaction was evaluated as a function of composition and time. The degree of neutrophil, lymphocyte and macrophage infiltration, fibrosis, granuloma formation, integration with extracellular matrix, vascular proliferation, and damage of adjacent structures were assessed. Polymers with >66% crosslinked Ge (Gx) showed persistence of acute inflammatory reaction till 3 months, with marked tissue injury and fibrosis. On the other hand, high crosslinked AAc (Ax) content showed chronic inflammatory reaction with high macrophage infiltration. Macrophages took active part in phagocytosis, degradation, and removal of polymers without granuloma formation or significant giant cell reaction. The IPNs with acrylic acid and gelatin in the ratio of 1:1 showed least tissue reaction and thus appeared to be most biocompatible. The majority of the polymers showed integration with extracellular matrix and growth of capillaries in and around the polymer. The heamogram, liver and renal function tests, and histology of vital organs were all normal. GS loading showed no additional local or systemic reaction suggesting the potential usefulness of the hydrogels as carrier for drugs such as GS.