Immobilization of heparin on polylactide for application to degradable biomaterials in contact with blood

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Abstract
The poly-(D, L-lactide) RESOMER® R208 (Boehringer-Ingelheim, Germany) was modified with heparin to improve the blood contacting properties of the material. The immobilization of herapin was carried out by covalent binding with glutaraldehyde as the coupling agent. The reaction conditions, such as temperature and time, were varied to optimize the binding of herapin. The efficiency of the immobilization was monitored with respect to the total amount of coupled herapin with a toluidine blue assay and the anticoagulant activity of immobilized heparin with a factor Xa assay. The hemocompatibility of the modified polylactide was estimated after blood-material contact by the activation of platelets measured with an enzyme immuno assay for GMP140. Immobilization at ambient temperature and a reaction time of 2 h resulted in maximal heparin binding, high anticoagulant activity, and low thrombogenicity. Since the remaining unsaturated aldehyde groups of the coupling agent may cause a low hemocompatibility of the material, washing of the heparinized polylactide was carried out with ethanol. However, it was shown that washing diminished the anticoagulant activity of heparin and increased the thrombogenicity. The prolonged storage of heparinized polylactide in phosphate buffered saline for 8 days demonstrated that small quantities of herapin were released but the hemocompatibility was further improved, indicated by an increasing anticoagulant potential and a decrease in platelet activiation with incubation time. A comparison of polylactide, heparinized polylactide, polypropylene, and Pellethane® with respect to platelet activation by GMP140 assay and scanning electron microscopy, revealed that the heparinization of polylactide substantially improved the hemocompatibility of RESOMER® R208, making the material comparable to Pellethane®.