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.
Clinical Relevance: Inflammatory reactions have been described in
association with the use of hyaluronic acid compounds. These clinical
reactions may be explained by the immune responses to the various hyaluronic
compounds demonstrated in this study.