Implantation of silicon elastomer biopolymers is associated with the formation of a fibrous capsule surrounding the implant, which has been reported to occur in as high as 74% of patients receiving silicone implants. The formation of fibrous capsule and the subsequent contracture of the implant can result in a wide range of symptoms ranging from relatively mild reactions such as pain, discomfort and implant displacement to such severe reactions as the development of connective tissue diseases including scleroderma, rheumatoid arthritis and lupus erythematosus. Although there have been numerous studies documenting the development of fibrous encapsulation following implantation of silicone elastomer biopolymers, the mechanisms underlying host responses to these foreign materials remain unclear. It is our Hypothesis that soluble mediators and cell surface molecules produced by tissue fixed cells at the local site of implantation and infiltrating leukocytes and lymphocytes regulate the host response to silicone biopolymers. Previous studies in our laboratory used a novel in vivo air pouch model to characterize the host response to biomaterials which are implanted for replacement or reconstructive purposes. In this model, an air pouch is formed by subcutaneous injection of air beneath the dorsal skin of rabbits or rats and biomaterials are then placed in the pouch. This model provides a means to examine tissue alterations induced by implantation of biopolymers and also allows characterization of the types and states of activation of cells which infiltrate into the pouch in the presence of silicon elastomer. Furthermore, this model allows the cells which adhere to the biopolymer itself to be characterized. Using this in vivo model, implantation of silica free polydimethylsiloxane (PDMS) was found to stimulate an early (1-2d), rapid infiltration of neutrophils and macrophages into the local area of biomaterial implantation, which was followed at d 7-14 by infiltration of lymphocytes. Within 2-7 d, the PDMS implant became covered by fibroblastic-like cells. Fluid isolated from the local site was found to be highly chemotactic for monocytes and lymphocytes and contained significant levels of Interleukin-1 biological activity. Infiltrating nonadherent cells within the site of implantation produced enhanced levels of both hydroperoxide and superoxide anion. A hallmark of the host response to biomaterials is the localization of leukocytes to the site of implantation and adherence of fibroblasts to silicone biomaterials. One of the mechanisms by which localization and retention of leukocytes and fibroblasts occurs is via cytokine-induced expression/upregulation of cell surface receptor-ligand pairs, such as intercellular adhesion molecule (ICAM-1; CD54) and the integrin molecule lymphocyte function associated antigen (LFA-1, CD11a/CD18). In the proposed studies, in situ hybridization and reverse transcriptase polymerase chain reaction studies will be performed to evaluate the production of cytokines such as Interleukin-1 (IL-1), tumor necrosis factor-alpha (TNF-alpha), and lymphokines such as interferon-gamma and Interleukin-2 produced by tissue fixed cells and infiltrating leukocytes. The temporal sequence of production of other growth factors, such as basic fibroblast growth factor (bFGF), which induces fibroblast proliferation, will also be examined. Recent studies in our laboratory indicate that in vivo injection of antibodies directed against IL-1 inhibit proliferation of cells such as fibroblasts, while antibodies directed against integrin/adhesion molecules inhibit leukocyte migration to a local site of inflammation. These approaches, as well as the use of a protein kinase C inhibitor, staurosporine, and the use of IL-1 receptor antagonist, will be used to provide insight into pathways which can be used to diminish or abrogate the host response to silicone biopolymer implantation.
