Design of a new type of coating for the controlled release of heparin

Thrombus formation at the surface of blood contacting devices can be prevented by local release of heparin. Preferably, the release rate should be constant for prolonged periods of time. The minimum heparin release rate to achieve thromboresistance will be different for various applications and should therefore be adjustable. In this study a new type of heparin release system is presented which may be applied as a coating for blood contacting devices. The system is based on the covalent immobilization of heparin onto porous structures via hydrolysable bonds. This approach was evaluated by the immobilization of heparin onto a porous cellulosic substrate via ester bonds. Cuprophan was used as a model substrate and N,N'-carbonyldiimidazole as a coupling agent. Heparinized Cuprophan incubated in phosphate buffered saline showed a release of heparin due to the hydrolysis of the ester bonds between heparin and Cuprophan. The release rate could be easily adjusted by varying the amount of coupling agent used during immobilization. Cuprophan with a rather stable heparin coating (release rate: 6.1 mU/cm2 ̇ h) and Cuprophan which shows a substantial release of heparin (release rate up to 23.0 mU/cm2 ̇ h) could be prepared. Except when the release was relatively high, release rates were constant for at least 1 week. Storage of the release system at ambient conditions up to 6 months or sterilization by means of steam, ethylene oxide exposure, or gamma irradiation did not affect the release properties. It was concluded that this concept for a heparin release system is highly promising to prepare thromboresistant surfaces for various blood contacting devices.