For over forty years a number of medical devices which contact the blood or blood products of living persons or animals have been developed, manufactured and used clinically. A partial list of such articles would include pacemakers, arterial grafts, heart valves, artificial hearts, heart pumps, hip protheses, heart lung machines, catheters and kidney dialysis equipment.
A major problem with such articles is that their working surfaces, (i.e., surfaces which contact blood or blood products, including, serum, plasma and other fluids and solids derived from blood), are foreign to blood and blood products and tend to initiate, among other things, red cell destruction and coagulation of blood to form clots (thrombogenesis).
Normal intact endothelium is nonthrombogenic due partly to the synthesis of heparan sulfate. Heparan sulfate tends to remain bound to the surface of endothelial cells accelerating the inactivation of thrombin, the enzyme responsible for the polymerization of fibrinogen to fibrin in clot formation, by antithrombin III (ATIII). Heparan sulfate is a very powerful anticoagulant in the natural vasculature. Consequently, it has been of great interest to physicians and the medical industry to devise blood-contacting polymeric surfaces that possess characteristics of heparan sulfate, specifically by coating surfaces with heparin. For example, in U.S. Pat. No. 3,826,678 to Hoffman et al., biologically active molecules are chemically bonded to polymers and copolymers which previously have been radiation-grafted to inert polymeric substrates such as a polyurethane and polyethylene. The grafted polymer is preferably a hydrophilic hydrogel (e.g. HEMA) and may include heparin bonded to the hydrogel.
Another major problem with such articles is their susceptibility to post-implant infection. Staph. epidermidis, which exists on human skin and Staph. aureus, sometimes found in hospital environments, are the two most frequent pathogens encountered in implant and similar situations. They both have the ability to enter the body through the surgical opening and attack the implant site. This problem has been addressed, for example, in U.S. Pat. No. 4,442,133 to Greco et al. in which a PTFE or Dacron graft is soaked in TDMAC (tridodecyl methyl ammonium chloride) dissolved in ethanol. The TDMAC is absorbed to form a coating and then incubated in a solution of antibiotic e.g. penicillin or cefoxitin. Also, for example, in U.S. Pat. No. 4,612,337 to Fox, Jr., et al., a polymeric material such as (PTFE) is soaked in antibiotic solutions with an organic solvent, then soaked in an organic solvent with a metal salt followed by a resoak in the antibiotic/organic solvent solution.
There is therefore a clear need for new and improved thromboresistant and infection resistant articles. This need can be met by providing such articles with antimicrobial agents which can result in bactericidal activity of that polymer or with anticoagulant agents to impart thromboresistance. It is also sometimes desirable to include bioactive agents other than antimicrobials and anticoagulants in such articles. This invention is directed to those ends.
USPTO Backgrounds
USPTO Backgrounds