Blood compatibility of heparin-modified acyclic polyurethane elastomers☆

Abstract

AIM：To improve the technique of covalently grafting of heparin (Hep) onto the surfaces of acyclic polyurethane (PU) elastomers and to investigate the blood compatibility of Hep-modified PU obtained.

METHODS： This experiment was conducted in the laboratory of School of Materials Science and Engineering, Tongji University from August 2005 to August 2006. Material preparation: ①Acyclic PU was synthesized by "one-step" method, using hexamethylene diisocyanate (HMDI) or isophorone diisocyanate (IPDI) and chain extender, 1,4-butanediol, as hard segments, while polytetrahydrofuran as soft segment. HMDI-PU and IPDI-PU were obtained, respectively.②Hep was immobilized on the surface of PU elastomers by covalent bond grafting to obtain PU-Hep, PU-polyvinyl alcohol (PVA)-Hep, PU-polyethylene glycol (PEO)-Hep and PU-PVA-PEO-Hep. Experimental evaluation: ①The amount of heparin immobilized on PU surface was determined by toluidine blue colorimetric method and the release rate of heparin was determined by spectrophotometry.②The blood compatibility of heparin immobilized surface was assayed by hemolysis test and platelet adhesion test.

RESULT:①The amounts of heparin grafted on IPDI-PU-PVA-PEO and HMDI-PU-PVA-PEO surfaces were 64.8 mg/m2 and 51.0 mg/m2, respectively.②The Hep amount decreased to 51.7 mg/m2 (released by 20.2%) for IPDI-PU-PVA-PEO-Hep and to 39.1 mg/m2 (released by 23.3%) for HMDI-PU-PVA-PEO-Hep after 20-day soaking. The release rate of Hep from the heparinized PU became stable after soaked for 7 days and was about 0.6×10－8 g/(m2·min). ③The rate of hemolysis decreased (IPDI-PU from 2.40% to 1.94%, HMDI-PU from 3.20% to 2.36%) when Hep was immobilized on PU surface. All the rates of hemolysis observed were less than 5%, indicating that the materials prepared met the hemolysis standard of biomedical materials. The blood compatibility of IPDI-PU was better than that of HMDI-PU.④Platelet adhesion test: The number of adhesive platelet was higher on IPDI-PU than on HMDI-PU, and the ability of inhibiting thrombosis was better. After Hep grafting, the blood compatibility of PU-PVA-PEO-Hep was also superior to that of PU-PVA-Hep and PU-PEO-Hep.

CONCLUSION: PU surfaces heparinized by covalent bond grafting exhibit good blood compatibility and low release rate of heparin. Such heparin-modified PU can be used as materials for fabricating artificial heart valve.

Xu QW, Xiao SY.Blood compatibility of heparin?鄄modified acyclic polyurethane elastomers.Zhongguo Zuzhi Gongcheng Yanjiu yu Linchuang Kangfu 2007;11(13):2415-2419(China) [www.zglckf.com/zglckf/ejournal/upfiles/07-13/13k-2415(ps).pdf]

摘要
目的：改进脂肪族聚氨酯（polyurethane，PU）弹性体表面接枝肝素（heparin，Hep）的工艺过程，观察共价键合法接枝肝素后其血液相容性。
方法：实验于2005－08/2006－08于同济大学材料科学与工程学院实验室完成。材料制备：①脂肪族聚氨酯的合成：采用一步法合成以4,4'－甲烷二苯基二异氰酸酯(HMDI)或异氟尔酮二异氰酸醑(IPDI)、扩链剂1,4－丁二醇为硬段，聚四氢呋喃醚为软段的脂肪族聚氨酯，分别生成IPDI型聚氨酯和HMDI型聚氨酯。②共价键合法聚氨酯表面接枝肝素：形成PU-Hep，PU－聚乙烯醇(polyvinyl alcohol,PVA)-Hep,PU－聚乙二醇（polyethylene glycol，PEO）-Hep，PU-PVA-PEO-Hep中间产物。实验评估：①接枝肝素含量的测定：甲苯胺蓝显色法测定聚氨酯表面的肝素含量；甲苯胺蓝分光光度法测定肝素释放速率。②肝素接枝表面的血液相容性测定：通过溶血实验和血小板黏附实验测定。
结果：①聚氨酯表面的肝素含量：IPDI型聚氨酯和HMDI型聚氨酯表面肝素（PU-PVA-PEO-Hep）接枝量分别达到64.8，51.0 mg/m2。②肝素释放速率：浸泡20 d后，IPDI型聚氨酯肝素化表面（PU-PVA-PEO-R-NHCO-Hep）的肝素含量从64.8 mg/m2下降到51.7 mg/m2（脱落20.2%），HMDI型聚氨酯肝素化表面（PU-PVA-PEO-Hep）的肝素含量从51.0 mg/m2下降到39.1 mg/m2（脱落23.3%）。肝素的释放速率在浸泡7 d后达到稳定，约为0.6×10－8 g/（m2·min）。③聚氨酯表面接枝肝素后溶血率：溶血率有一定降低（IPDI型从2.40%降低至1.94%、HMDI型从3.20%降低至2.36%），溶血率均小于5%，符合生物医用材料的溶血性要求，其中IPDI型聚氨酯血液相容性好于HMDI型。④血小板黏附情况：表面改性之前，IPDI型聚氨酯表面黏附的血小板数目多于HMDI型。IPDI型聚氨酯抑制血小板形成血栓的能力好于HMDI型。表面接枝肝素后，PU-PVA-PEO-Hep的血液相容性优于PU-PVA-Hep和PU-PEO-Hep。
结论：表面共价键合法接枝肝素的脂肪族聚氨酯有良好的血液相容性，且肝素释放速率慢，基本满足人工心脏瓣膜材料的要求。
关键词：脂肪族聚氨酯；肝素；共价结合；血液相容性；生物材料

许乾慰，肖世英.脂肪族聚氨酯弹性体肝素化的血液相容性[J].中国组织工程研究与临床康复，2007，11(13):2415-2419
[www.zglckf.com/zglckf/ejournal/upfiles/07-13/13k-2415(ps).pdf]