MOLECULAR DETERMINANTS OF ACUTE INFLAMMATORY RESPONSES TO BIOMATERIALS

The frequent inflammatory responses to implanted medical devices are p uzzling in view of the inert and nontoxic nature of most biomaterials. Because implant surfaces spontaneously adsorb host proteins, this pro teinaceous film is probably important in the subsequent attraction of phagocytes. In fact, earlier we found that acute inflammatory response s to experimental polyethylene terephthalate implants in mice require the precedent adsorption of one particular host protein, fibrinogen. T he present investigations were aimed at defining the molecular determi nants 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 reside s within the D fragment, which contains neither the fibrin cross-linki ng sites nor RGD sequences; (b) the major (and, perhaps, exclusive) pr oinflammatory sequence appears to be fibrinogen gamma 190-202, previou sly shown to interact with CD11b/CD18 (Mac-1). The chemically synthesi zed peptide, cross-linked to albumin (which itself does not promote in flammatory responses), mimics the proinflammatory effect of adsorbed n ative fibrinogen; and (c) this sequence probably promotes inflammatory responses through interactions with Mac-1 because phagocyte accumulat ion on experimental implants is almost completely abrogated by adminis tration of recombinant neutrophil inhibitory factor (which blocks CD11 b-fibrin(ogen) interaction). We conclude that improved knowledge of su ch surface-protein-phagocyte interactions may permit the future develo pment of more biocompatible implantable materials.