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Research Article

Molecular determinants of acute inflammatory responses to biomaterials.

L Tang, T P Ugarova, E F Plow and J W Eaton

Division of Experimental Pathology, Albany Medical College, New York 12208, USA.

Published March 1, 1996

The frequent inflammatory responses to implanted medical devices are puzzling in view of the inert and nontoxic nature of most biomaterials. Because implant surfaces spontaneously adsorb host proteins, this proteinaceous film is probably important in the subsequent attraction of phagocytes. In fact, earlier we found that acute inflammatory responses to experimental polyethylene terephthalate implants in mice require the precedent adsorption of one particular host protein, fibrinogen. The present investigations were aimed at defining the molecular determinants of fibrinogen-mediated acute inflammatory responses to implanted biomaterials. We find: (a) plasmin degradation of purified fibrinogen into defined domains reveals that the proinflammatory activity resides within the D fragment, which contains neither the fibrin cross-linking sites nor RGD sequences; (b) the major (and, perhaps, exclusive) proinflammatory sequence appears to be fibrinogen gamma 190-202, previously shown to interact with CD11b/CD18 (Mac-1). The chemically synthesized peptide, cross-linked to albumin (which itself does not promote inflammatory responses), mimics the proinflammatory effect of adsorbed native fibrinogen; and (c) this sequence probably promotes inflammatory responses through interactions with Mac-1 because phagocyte accumulation on experimental implants is almost completely abrogated by administration of recombinant neutrophil inhibitory factor (which blocks CD11b-fibrin(ogen) interaction). We conclude that improved knowledge of such surface-protein-phagocyte interactions may permit the future development of more biocompatible implantable materials.

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