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Inflammatory and Immunological Responses to Hyaluronan PreparationsStudy of a Murine Biocompatibility Model
Robert A. Ottaviani, MD1; Paul Wooley, PhD1; Zheng Song, MS1; David C. Markel, MD2
1 Department of Orthopaedic Surgery, Wayne State University School of Medicine, Detroit, MI 48201
2 Department of Orthopaedic Surgery and Biomedical Research, Providence Hospital, 22250 Providence Drive, Southfield, MI 48075. E-mail address: dmarkel@providence-hospital.org
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Disclosure: The authors did not receive grants or outside funding in support of their research for or preparation of this manuscript. They did not receive payments or other benefits or a commitment or agreement to provide such benefits from a commercial entity. No commercial entity paid or directed, or agreed to pay or direct, any benefits to any research fund, foundation, educational institution, or other charitable or nonprofit organization with which the authors are affiliated or associated.
Investigation performed at Wayne State University School of Medicine, Detroit, Michigan

The Journal of Bone and Joint Surgery, Incorporated
J Bone Joint Surg Am, 2007 Jan 01;89(1):148-157. doi: 10.2106/JBJS.E.01135
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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.

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    Accreditation Statement
    These activities have been planned and implemented in accordance with the Essential Areas and policies of the Accreditation Council for Continuing Medical Education (ACCME) through the joint sponsorship of the American Academy of Orthopaedic Surgeons and The Journal of Bone and Joint Surgery, Inc. The American Academy of Orthopaedic Surgeons is accredited by the ACCME to provide continuing medical education for physicians.
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