The design of cellulosic based membranes that do not activate complement.

Complement is a principal mediator of the acute inflammatory response that works by nonspecific recognition mechanisms to eliminate foreign substances from the body. Because of the non-selective nature of complement, extracorporeal therapies employing hydrophilic cellulosic based materials can result in significant complement activation and systemic exposure to large amounts of C5a which in turn may lead to a variety of pathological sequelae. Several approaches have been identified to produce materials with a limited potential to activate complement. Activation proceeds on a material following the covalent attachment of C3b to surface nucleophiles which leads to the formation of C3 and C5 convertase enzymes. Interference with these enzymes may be achieved at several levels. Surfaces that contain fewer nucleophilic sites bind less C3b and thus generate lower levels of convertase activity. This is exemplified by the Cellulose Triacetate membrane that is produced by exhaustive acetylation of surface hydroxyl groups. This membrane binds only a third of the amount of C3b that a cuprophan membrane will bind. An alternative means of affecting convertase activity can occur by facilitating the regulatory activity of Factors H and I. Evidence is presented here that suggests that Hemophan appears to limit activation by augmenting regulation of bound-C3b. Finally we have begun studies on a new type of modification using dicarboxylic acid anhydrides that produce materials with a very limited potential to activate complement.