In Vivo Safety Evaluation of Granules and Dressing Hemostatic Agents from Radiation Processed Polymeric Materials

Abstract

Granules and dressing hemostatic agents were developed from radiation-crosslinked carboxymethyl cellulose (CMC) and the combination of kappa-carrageenan (KC) and polyethylene oxide (PEO), respectively. Bioburden and sterility studies showed that 25 kGy irradiation dose was sufficient to achieve sterility in ten out of ten samples that were tested. The safety and biocompatibility of both granules and dressing hemostats revealed very promising results that support their suitability as medical devices for bleeding control. Extracts from CMC granules (CMC-G) and KC/PEO dressing (KP-D) hemostats injected into female and male Sprague-Dawley rats did not produce any systemic toxic signs like reduction in feed and water consumption and body weight. During the 14-d testing period, no rats in any of the treatment groups manifested behavioral, respiratory, and neurologic changes indicative of systemic toxicity. Hematology tests resulted in mean values within the published normal range. Blood chemistry assays gave normal alanine amino transferase, creatine, and blood urea nitrogen levels – indicating that the extracts were neither hepatotoxic nor nephrotoxic. Microscopic examination of the kidneys and liver revealed intact and normal structures with no inflammatory cells, fibrosis, or necrosis. No mortality occurred in all male and female test rats regardless of the treatment given; thus, the LD50 for all treatment groups is zero (0). The skin irritation evaluation via intracutaneous injection of hemostat extracts generally did not induce erythema in four out of five rabbits, while edema was absent in all rabbits per treatment group throughout the 14-d test period. Both hemostat extracts had zero irritation score and is therefore classified as a non-irritant. The Guinea Pig Maximization Test (GPMT) of the Magnusson and Kligman method for skin sensitization potential classified both granules and dressing hemostats as weak sensitizers.