The use of synthetic biomaterials to sustain, augment or completely replace diseased human organs has increased tremendously over the past thirty years. Synthetic implants have cardiovascular applications such as vascular grafts, heart valves, and ventricular assist devices; extracorporeal systems; and a wide range of invasive treatment and diagnostic systems. Unfortunately, existing biomaterials suffer from well-known problems associated with surface-induced thrombosis or clot formation such as thrombotic occlusion and thromboemboli, and infection. Synthetic vascular grafts having a diameter less than 6 mm are currently impracticable, because of potential thrombotic occlusion, and the artificial heart has been plagued with problems of thromboemboli and infection. Advances in the development of artificial organs and artificial vascular grafts have resulted in the need for nonthrombogenic materials.
Thrombosis is initiated by the deposition of a plasma protein layer on the surface of the implanted biomaterial. Thereafter, platelets, fibrin, and possibly leukocytes, adhere to the deposited protein. The interactions between the plasma proteins and the surface of the implant determine the adhesion, the activation and the spreading of platelets, the activation of coagulation, cell attachment and protein deposition. However, at the molecular level, the fundamental forces and interactions of plasma proteins with implants is not well understood.
There have been several attempts to create nonthrombogenic surfaces on polymer implants thereby increasing the blood-biocompatibility of implants.
Early attempts included precoating the implants with proteins not involved in thrombosis, such as albumin, to mask the thrombogenic surface of the implant. However, such implants loose their nonthrombogenic properties within a short time. Attempts have been made to mask the thrombogenic surface by coating gelatin onto implants such as ventricular assist devices. While the gelatin coating reduced the thrombus formation, it did not adhere to the implant and it did not prevent thromboemboli and infection.
Attempts have been made to render implants nonthrombogenic by coating the surface of the implant with polyethylene oxide to mask the thrombogenic surface of the implant; it was discovered that such a coating at times also reduced protein adsorption. While this reduced thrombogenesis, the coupling of polyethylene oxide to the surface of the implant involves very complex procedures, and the coated implants do not consistently exhibit protein resistance.
There have been many attempts to prepare nonthrombogenic surfaces by attaching heparin to biomaterials, because of heparin's potent anticoagulant properties. However, each method requires that the implant surface be first modified by attachment of a coupling molecule before heparin can be attached. For example, the positively charged coupling agent tridodecylmethylammonium chloride, is coated onto an implant, which provides a positively charged surface and allows heparin which has a high negative charge density, to be attached. However, the heparin slowly dissociates from the surface, to expose the positively charged, TDMAC surface which is particularly thrombogenic. The TDMAC attracts platelets and other cells; cells surfaces have a high negative charge density. Thus the TDMAC heparin coated implant is successful only for short term implants such as catheters.
Implants coated with heparin coupled to coupling molecules typically have limited anti-thrombogenic effectiveness because commercial heparin preparations contain the protein core and because many heparin molecules which having no anticoagulant activity. As a result, the surfaces soon become covered by adsorbing protein on exposure to blood, thus neutralizing the anticoagulant activity of the active heparin molecule.
It is desirable to have implants which resist plasma protein deposition, and to have a simple procedure for modifying the surface of implants. Nonthrombogenic implants would reduce the need for aggressive anticoagulant therapy, improve the performance of implants, particularly cardiovascular prosthetic devices, and encourage the development of devices not currently feasible.