Inflammatory and immunological responses to hyaluronan preparations. Study of a murine biocompatibility model.
BACKGROUND
Intra-articular injection of hyaluronan preparations is a popular treatment for osteoarthritis of the knee. Recently, clinical reports have described acute inflammatory reactions in joints following these injections. The purpose of this study was to use a murine pouch model to study the local inflammatory and possibly immunological effects of three commercially available hyaluronan-derived products.


METHODS
Each of three different hyaluronan products (Synvisc, Hyalgan, and Supartz) was injected into air pouches established in groups of BALB/c mice. A positive control group (with particle-induced inflammation) and a negative control group (injected with saline solution) were also included. After fourteen days, the mice were killed and the air pouches were explanted and prepared for histological evaluation of the local inflammatory reaction. The antibody response was measured with use of ELISA (enzyme-linked immunosorbent assay) of serum samples obtained after the mice were killed.


RESULTS
Histological analysis revealed a significant increase in total membrane cellularity (p < 0.001 to p < 0.03) after the use of all hyaluronan preparations. The increased cellularity was attributed to an inflammatory cell influx, rather than accumulation of fibroblasts, and elevated lymphocyte counts were observed in membranes stimulated by Synvisc (hylan G-F 20). The ELISA data revealed an antibody response to the Synvisc preparation. This immunological response was directed against a non-hyaluronan portion of the product, as indicated by the lack of cross-reactivity with the other hyaluronan products.


CONCLUSIONS
These findings demonstrate that all three hyaluronan preparations, as currently manufactured, can cause an inflammatory soft-tissue reaction, but only the non-hyaluronan portion of the Synvisc product created an immunological response. It appears likely that this component may be the target of adverse responses in patients.
Ottaviani
Robert A
RA
Department of Orthopaedic Surgery, Wayne State University School of Medicine, Detroit, MI 48201, USA.
Wooley
Paul
P
Song
Zheng
Z
Markel
David C
DC
D000276:Adjuvants, Immunologic / Q000008:administration & dosage / Q000009:adverse effects*; D000818:Animals; D000906:Antibodies / Q000097:blood; D001672:Biocompatible Materials / Q000008:administration & dosage / Q000009:adverse effects*; D004195:Disease Models, Animal; D006820:Hyaluronic Acid / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000276:immunology*; D007249:Inflammation / Q000209:etiology*; D007270:Injections, Intra-Articular; D051379:Mice; D008807:Mice, Inbred BALB C; D012867:Skin / Q000187:drug effects* / Q000473:pathology
D000276:Adjuvants, Immunologic; D000906:Antibodies; D001672:Biocompatible Materials; C049816:hylan; D006820:Hyaluronic Acid