Molecular basis of biomaterial-mediated foreign body reactions

Abstract

Despite being inert and nontoxic, implanted biomaterials often trigger adverse foreign body reactions such as inflammation, fibrosis, infection, and thrombosis. With regard to the inflammatory responses to biomaterial implants, it was previously found that a crucial precedent event was the spontaneous adsorption and denaturation of fibrinogen on implant surfaces. It was further found that interactions between the phagocyte integrin Mac-1 (CD11b/CD18) 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 soluble 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, the 13 amino acid P1 sequence was found to be hidden. However, the adsorption and denaturation of fibrinogen on the surfaces of commonly used biomaterials 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 protein. The extent of biomaterial-mediated P1 and P2 exposure appears directly related to the severity of inflammatory responses to a test panel of biomaterials. Finally, thrombin-mediated conversion of fibrinogen to fibrin also exposes both P1 and P2 epitopes. These observations may help explain both the inflammation caused by many types of implanted biomaterials and that which occurs naturally following thrombotic events. (Blood. 2001;98:1231-1238)

Species and Density of Implant Surface Chemistry Affect the Extent of Foreign Body Reactions

“…It is well established that the numbers of CD11b+ cells reflect the extent of inflammatory responses. 15,43,71,82 The strong correlation between capsule thickness and inflammatory cell accumulation suggests that biomaterial-mediated inflammatory responses dictate the subsequent fibrotic tissue formation surrounding biomaterial implants. This suggestion is supported by observations from studies that showed the presence of a large number of inflammatory cells around untreated PET disks implanted in rabbits.…”

“…9 However, many of these medical devices fail to produce long term therapeutic effect raising serious concerns over the efficiency of these implants. [10][11][12][13][14][15][16][17] For example, the chemotherapeutic doxorubicin delivering millirods has been reported to lose efficacy 8 days post subcutaneous implantation. 8 .…”

Inflammasome components Asc and caspase-1 mediate biomaterial-induced inflammation and foreign body response

“…Our current understanding of this process involves surface adsorption of proteins present in edematous interstitial fluid, such as fibrinogen, which causes their denaturation and renders them adhesive for inflammatory cells (4). For example, exposure of the cryptic integrin-specific epitopes P1 and P2 in fibrinogen has been shown to influence the accumulation of inflammatory cells in short-term in vivo studies (5). In addition, surface-induced activation of complement has been shown to occur and enhance biomaterialinflammatory cell interactions (6,7).…”

In Vitro Method for Real-Time, Direct Observation of Cell–Vascular Graft Interactions under Simulated Blood Flow

“…Platelet adhesion/aggregation onto vascular grafts is directly related to their propensity to adsorb plasma proteins, which is dependent on surface hydrophilicity, electric charge, and chain mobility. 26 It is the combination of these factors that determines the thrombogenicity of a material and makes its in vivo performance difficult to predict. Previously, it was shown that the dHUV scaffold is resistant to platelet adhesion, though comparatively favorable for attachment of EC under static conditions.…”