Nonthrombogenic treatments and Strategies

Sung Wan Kim overview for the design of nonthrombogenic surfaces

The initial event after a foreign material is exposed to the blood is protein adsorption onto the surface, followed by a complicated sequences of events, including activation of the intrinsic clotting system (Chapter 4.5), activation of platelets (Chapter 4.5), thrombolysis (Chapter 4.5), and activation of the complement system (Chapter 4.3). This chapter describes strategies to modify the surface of polymeric prosthetic devices (such as vascular grafts and artificial hearts) to minimize surface-induced thrombosis and device failure.

Over the years, a substantial amount of research has been performed to improve the biocompatibility of polymeric materials in contact with blood. However, the precise relationship between the nature of the surface, blood compatibility, and the mechanism of surface-induced thrombosis has not yet been completely elucidated.

Major factors influencing blood interaction at polymer interfaces are determined by the composition of the surface and the physical and chemical properties that the surface may encounter within the biological environment. One approach taken by many groups is to synthesize nonthrombogenic polymers with surfaces tailored to minimize specific blood interactions, such as thrombus formation and platelet interactions. General methods of surface modification are described in Chapter 2.9, while specific examples of surface modification using pharmacologically active compounds are summarized in this chapter and also in Chapter 2.11.

it is generally accepted that a hydrophilic environment at the blood—polymer interface is beneficial in reducing platelet adhesion and thrombus formation. Modification of surface hydrophilicity was attempted using albumin and poly(etbylene oxide) by different research groups. Polymer surfaces were designed by Mason et al. (1971) with selective affinity toward albumin. They confirmed that platelets showed little adherence to albumin-coated surfaces, while fibrinogen- or gamma globulin-coated surfaces exhibited an increased number of adhering platelets. Kim et al. (1974) and Lee and Kim (1979) studied the interactions of adsorbed plasma proteins with platelets and postulated mechanisms of cell adhesion involving glycoprotein terminal sugar groups. Munro etal. (1981) coupled alkyl chains of 16- and 18-carbon residues (C16, C18) to polymers to enhance albumin binding to the surface and thereby improve blood compatibility. They demonstrated that albumin binding was significantly enhanced with C16 and C18 alkylation, while fibrinogen adsorption was inhibited by C18 alkylation. Plate and Matrosovich (1976) also confirmed that C16- and C18-alkvlated surfaces increased albumin binding, thereby improving blood compatibility.

Polyiethylene oxide) (PEO) has also received much attention for applications as a biomaterial interface. Detailed studies utilizing PEO can be found in Chapters 2.3 and 2.4 and in a reference by Harris (1992). The main benefits of PEO are its unlimited solubility in water, favorable chain conformation in water that allows for high mobility, and large excluded volume to repel protein and cell interactions. Furthermore, the simple chemical structure of PEO allows for sophisticated and quantitative end-group coupling to enhance the chemical reactivity for surface immobilization (Harris, 1992). These properties of PEO, especially the dynamic motion and excluded volume, were studied as surface-grafted polymers. Nagaoka et al. (1982) immobilized PEO on hydrophobic surfaces and demonstrated that the water content, surface mobility, and volume restriction of the hydrophilic interface are critical factors influencing blood interaction. Gregonis et al. (1984) showed that PEO covalently bounded to a quartz interface decreased protein adsorption as a function of molecular weight.

In addition to the benefits of increased surface hydrophilicity documented with PEO, many groups have incorporated anticoagulant drugs, such as heparin, directly into or upon the polymer surface. These drugs interact directly with the coagulation cascade and prevent fibrin formation. Furthermore, the drug is concentrated directly at the site that initiates thrombus generation: the polymer surface in contact with blood. A more in-depth discussion of blood hemostasis can be found in Chapter 4.5.

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