Molecular determinants of acute inflammatory responses to biomaterials.

Abstract

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 ␥ 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-proteinphagocyte interactions may permit the future development of more biocompatible implantable materials. ( J. Clin. Invest. 1996. 97:1329-1334.)

Surface-related triggering of the neutrophil respiratory burst. Characterization of the response induced by IgG adsorbed to hydrophilic and hydrophobic glass surfaces

“…accessibility of the Fc parts of the molecules on the surface to the corresponding neutrophil receptors FcgRs), or simply the ligand density on the surface, which is determined by the physicochemical property of the supporting surface. Our results on the effect of surface-adsorbed albumin are in agreement with earlier observations [13][14][15][34][35][36]. With respect to fibrinogen adsorption, it has been shown that this protein predominates on most…”

“…Liu et al surfaces [37]. Owing to the fact that fibrinogen has been suggested to be of great importance in the acute inflammatory response, reflected by the accumulation of neutrophils on implanted fibrinogen-coated surfaces [21,34,35], we expected some cellular activation during neutrophil interaction with such a surface. However, fibrinogen coating on our glass surfaces failed to activate the neutrophils to any detectable degree.…”

Controlling Protein Adsorption through Nanostructured Polymeric Surfaces

“…Molecular dynamic simulation studies by Dragneva et al suggested that the "end-on" orientation of fibrinogen, in particular, strongly affects the secondary structure content of the D-domain, with consequent exposure of the previously occult recognition sites (e.g., residues 190-202 of the fibrinogen γ-chain) involved in the immune response. [49,50] Recent observations [11,51] that protein adsorption configuration can be guided by surface topographical features allow us to postulate that a reasonable starting point for a healthcare material-implant design would be to eliminate/tune surface topographical features in a way to inhibit protein "end-on" orientation.…”

Mice that lack the angiogenesis inhibitor, thrombospondin 2, mount an altered foreign body reaction characterized by increased vascularity

“…The question of why materials with diverse surface properties elicit the same FBR has troubled investigators for more than two decades (3)(4)(5). It is believed that implants acquire a protein coat immediately after implantation, which serves as a stimulus for the development of the FBR (6)(7)(8)(9)(10), and it has been suggested that fibrinogen is a critical component of this protein coat (10,11). Adsorption of proteins can be influenced by the surface properties of the material and may lead to modification of the FBR (3,(12)(13)(14)(15).…”