Molecular basis of biomaterial-mediated foreign body reactions

Despite being inert and nontoxic, implanted biomaterials often trigger adve rse foreign body reactions such as inflammation, fibrosis, infection, and t hrombosis. With regard to the inflammatory responses to biomaterial implant s, it was previously found that a crucial precedent event was the spontaneo us adsorption and denaturation of fibrinogen on implant surfaces. It was fu rther found that interactions between the phagocyte integrin Mac-1 (CD11b/C D18) and one short sequence within the fibrinogen D domain (gamma 190-202; P1) at least partially explained phagocyte accumulation on implant surfaces . However, the reason that adsorbed fibrinogen is proinflammatory-while sol uble fibrinogen clearly is not-remained obscure. In this study, therefore, the question of how fibrinogen is converted to a proinflammatory state when adsorbed to biomaterial surfaces is investigated. In soluble fibrinogen, t he 13 amino acid P1 sequence was found to be hidden. However, the adsorptio n and denaturation of fibrinogen on the surfaces of commonly used biomateri als lead to the exposure of P1 and a second neo-epitope, gamma 377-395 (P2) , which also interacts with Mac-1 and is similarly occult in the soluble pr otein. The extent of biomaterial-mediated PI and P2 exposure appears direct ly related to the severity of inflammatory responses to a test panel of bio materials. Finally, thrombin-mediated conversion of fibrinogen to fibrin al so exposes both P1 and P2 epitopes. These observations may help explain bot h the inflammation caused by many types of implanted biomaterials and that which occurs naturally following thrombotic events.