Native hyaluronan produces less hypersensitivity than cross-linked hyaluronan.

Hyaluronan has been used in patients with osteoarthritis to relieve the painful symptoms associated with this condition. The native form of hyaluronan and artificially cross-linked forms of hyaluronan (such as Hylan G-F 20) are widely used brands that are approved by the Food and Drug Administration for use in patients with osteoarthritis. Clinical evidence suggests that some of these hyaluronan products may induce an antigenic reaction in some patients. Therefore, it was critical to do controlled studies on the potential antigenic reaction induced by these substances. The purpose of this study was to assess the immunologic reactions resulting from the native or cross-linked forms of hyaluronan products in guinea pigs after subcutaneous injection. Guinea pigs were sensitized to hyaluronan via three subcutaneous injections. Active cutaneous or delayed-type hypersensitivity to hyaluronan was studied. The elicitation of antihyaluronan antibodies also was studied by indirect competitive ELISAs. Our results showed that Synvisc induced delayed-type hypersensitivity in guinea pigs, however, no hypersensitivity to the native hyaluronan was observed. This delayed-type hypersensitivity reaction to the cross-linked form of hyaluronan was confirmed by our finding that sera from guinea pigs sensitized to the cross-linked form showed increased antihyaluronan-specific antibodies in competitive ELISAs. In a direct comparison, the native form of hyaluronan produced significantly less hypersensitivity than an artificially cross-linked form of high molecular weight hyaluronan. The hypersensitivity to the cross-linked form of hyaluronan can be explained in part by its elicitation of ant-hyaluronan immunoglobulins in sensitized animals.