Abstract
When designing innovative biomaterials, biocompatibility is regarded as a prerequisite for safe clinical use in humans. In this study, the biological safety of KiOmedine® CM-chitosan, which is a non-animal carboxymethyl chitosan biomaterial, was evaluated using a large panel of both <i>in vitro</i> and <i>in vivo</i> biocompatibility tests in accordance with the ISO 10993 series. KiOmedine® CM-chitosan was non-cytotoxic and non-genotoxic <i>in vitro</i>. The biomaterial was neither found to be haemolytic nor was it able to potentiate the activation of the central complement component C5a or the inflammatory mediators IL-1β and IL-8 in the presence of human whole blood. Furthermore, no evidence of any significant irritation, sensitization, pyrogenicity, and organ toxicity was detected in specific animal studies conducted with KiOmedine® CM-chitosan, and only minimal local tissue effects were observed after the intra-articular or intra-dermal injection of KiOmedine® CM-chitosan in the rabbit model. KiOmedine® CM-chitosan had minimal potential to induce immunotoxic reactions in the mouse air pouch model. Its biodegradation process was appropriately characterized at the histological level. In summary, our study represents an unprecedented body of work supporting the biological safety evaluation of KiOmedine® CM-chitosan, allowing its use in injectable medical devices.
Highlights
Over the last two decades, chitosan and its chemical derivatives has become a biomaterial of growing interest in regenerative medicine research and biomedical applications [1, 2]
KiOmedine® CM-chitosan was found to be non-genotoxic to S. typhimurium tester strains TA98, TA100, TA1535, and TA1537, and to the E. coli WP2uvrA tester strain in the Bacterial Reverse Mutation Assay in the presence or absence of metabolic activation and did not cause any significant increase in the mean mutant frequency of the L5178Y/TK+/cell line greater than the mutant frequency of the negative control in the Mouse Lymphoma Assay either in the presence or absence of metabolic activation
After 18 hours of incubation, KiOmedine® CM-chitosan did not induce any secretion of IL1β as compared to LPS used as the positive control, whereas slight IL1β release was observed with Hylan (B)
Summary
Over the last two decades, chitosan and its chemical derivatives has become a biomaterial of growing interest in regenerative medicine research and biomedical applications [1, 2]. Chitosan is a linear polysaccharide that consists of N-acetyl-D-glucosamine (GlcNAc) and D-glucosamine units (GlcN) linked by β(1-4)-bonds. Chitosan is obtained by deacetylation of chitin, a naturally occurring carbohydrate polymer that is widely distributed in nature in crustacean shells, insects, and mollusks, as well as fungal cell walls. The degree of acetylation (DA) is known to influence the solubility of chitosan and its rheological properties. Whereas chitin is considered to have DA >90%, chitosan has typically low DA < 35-40% [3, 4]. From their chemical structure, chitin and chitosan have a limited solubility in physiological aqueous systems
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