CHARACTERIZATION OF CELLULAR-RESPONSE TO SILICONE IMPLANTS IN RATS - IMPLICATIONS FOR FOREIGN-BODY CARCINOGENESIS

Foreign-body (FB) carcinogenesis is a classic model of multistage tumo ur development in rodents. Previous studies have demonstrated that the physical characteristics of the implant, and not the chemical composi tion, are the critical determinants of tumour development. The recent controversy over silicone breast implants has raised questions regardi ng the potential carcinogenicity of lifetime tissue exposure to silico ne products. The present study was designed to determine whether the i nflammatory and fibrotic reactions associated with silicone implants a re due to a non-specific foreign-body reaction or whether these respon ses reflect the unique chemical composition of silicone. F344 rats wer e implanted subcutaneously with one of three biomaterials: silicone el astomer (Group 1), impermeable cellulose acetate filters (Group 2, pos itive control); or porous cellulose acetate filters (Group 3, negative control). The silicone and cellulose implants of Groups 1 and 2 have been previously shown to induce fibrosarcomas in rodents, whereas the porous cellulose acetate implants of Group 3 have been shown to be non -carcinogenic. One week and two months after implantation, the pericap sular tissues were evaluated using histopathological and in situ immun ohistochemical analyses. Endpoints included expression of leucocyte an tigens CD4 (T helper/inducer), CD8 (T suppressor/cytotoxic) and CD11 b /c (macrophage), proliferating cell nuclear antigen (PCNA) as an indic ator of proliferation, and in situ end-labelling (ISEL) of 3' OH DNA s trand breaks as an indicator of DNA damage and apoptosis. The results indicated that the acute and chronic cellular responses to silicone (G roup 1) were not different from impermeable cellulose filters (Group 2 ) of identical size and shape, suggesting that these responses were no t unique to silicone. The inflammatory response to the carcinogenic ce llulose and silicone implants (Groups 1 and 2) was attenuated and asso ciated with the formation of a thick fibrotic capsule. In contrast, th e porous cellulose filters (Group 3) induced a markedly different cell ular response in which the inflammatory reaction was more extensive, p rolonged and associated with minimal fibrosis. Within the fibrotic cap sule surrounding the tumorigenic implants, but not the non-tumorigenic implants, cell proliferation and apoptotic cell death were increased and associated with persistent DNA strand breaks. Taken together, the results suggest that the micrometre-scale surface morphology of the im plant determines the nature of the subsequent cellular response which may predispose to tumour development Further, these studies serve to e mphasize the critical importance of appropriate physical controls in s tudies designed to evaluate carcinogenic or autoimmune manifestations associated with silicone implants in order to rule out the contributio n of the chronic foreign-body reaction. Published by Elsevier Science Limited.