醫(yī)用抗凝血聚氨酯材料的制備與表征
發(fā)布時(shí)間：2018-07-14 19:35
【摘要】：從醫(yī)用導(dǎo)管到人工心臟,聚氨酯(PU)在醫(yī)療器械中具有廣泛的應(yīng)用。但是,當(dāng)PU與血液接觸時(shí)其凝血問題仍需解決。目前主要有兩種改性方法用于改進(jìn)這一問題：物理方法和化學(xué)方法。其中因?yàn)槲锢砉不焖幬锔男院蟮腜U只具有中短期抗凝血性；而其他的改性方法主要是針對(duì)PU表面的改性,而材料表面的性能在復(fù)雜的血液環(huán)境中的影響并不確定。因此,本項(xiàng)研究中的PU不僅在表面也在本體內(nèi)接枝上抗凝血藥物肝素,希望改性后的PU可以同時(shí)具有持續(xù)的抗凝血性。同時(shí)這種改性方法制備的聚氨酯抗凝血材料可以制備成任意形狀,或作為其他生物醫(yī)用材料的表面涂層。 本項(xiàng)研究采用一種新的方法將肝素共價(jià)接枝到聚醚型聚氨酯上以制備醫(yī)用抗凝血聚氨酯。首先,由異佛爾酮二異氰酸酯、雙羥甲基丙二酸二乙酯(DBM)、聚乙二醇、1,6-己二醇合成具有二個(gè)脂基側(cè)鏈的PU。二個(gè)脂基是由擴(kuò)鏈劑DBM引入。為了比較DBM含量不同對(duì)肝素接枝量的影響,本研究合成的兩種PU,其一為PU-3DBM:DBM占總單體摩爾分?jǐn)?shù)為12.5at%；另一為PU-6BDM:DBM占總單體摩爾分?jǐn)?shù)為25at%。然后,通過將PU-3DBM和PU-6DBM分別分散于水中,進(jìn)行水解和羧基化,最后分別接枝了0.49wt.%和0.93wt.%肝素。其中,將水解時(shí)間定為30min是為了在保證PU的機(jī)械性能沒有很大損失的情況下,將二個(gè)脂基充分水解。本研究用羅丹明6G法測定了水解和羧基化后PU中羧基的濃度,并用于解釋DBM對(duì)肝素接枝量的影響。 本文還采用傅里葉變換紅外光譜和核磁共振氫譜確定肝素的成功接枝；采用化學(xué)元素分析分析接枝肝素后的PU的化學(xué)組成,結(jié)果顯示：接枝了肝素的PU-6DBM (PU-6DBM-Hep)中硫元素的含量是接枝了肝素的PU-3DBM (PU-3DBM-Hep)的兩倍；化學(xué)分析電子能譜顯示PU-3DBM-Hep薄膜表面的硫元素含量要高于其本體中硫元素的含量；水接觸角測試結(jié)果顯示接枝有肝素的PU薄膜表面的親水性能顯著提高。在體外肝素釋放試驗(yàn)中,本文合成的接枝有肝素的PU可以在生理鹽水中持續(xù)釋放肝素90小時(shí)。另外,通過體外血液相容性實(shí)驗(yàn)(溶血率和血小板粘附實(shí)驗(yàn))表明,通過本方法合成的接枝有肝素的抗凝血聚氨酯在體外具有很好的血液相容性。但是,將制備的抗凝PU作為血管支架涂層應(yīng)用于動(dòng)物體內(nèi)實(shí)驗(yàn)后結(jié)果顯示,具有涂層的血管支架相對(duì)于裸支架,置入動(dòng)物血管內(nèi)一個(gè)月后會(huì)使血管損傷和炎癥程度增加,血管壁增生加重。因此,初步認(rèn)為本項(xiàng)研究制備的抗凝血聚氨酯可作為體外血液接觸材料。
[Abstract]:Polyurethane (pu) is widely used in medical instruments from medical catheter to artificial heart. However, the coagulation problem of pu still needs to be solved when it is in contact with blood. At present, there are two main modification methods to improve this problem: physical method and chemical method. The modified pu has only medium and short term anticoagulant effect, while other modification methods are mainly aimed at the surface modification of pu, and the effect of the material surface on the complex blood environment is uncertain. Therefore, the pu in this study not only grafted on the surface but also on the body of anticoagulant drug heparin, it is hoped that the modified pu can also have continuous anticoagulant. At the same time, the polyurethane anticoagulant material prepared by the modified method can be prepared into arbitrary shape or be used as the surface coating of other biomedical materials. In this study, heparin was covalently grafted onto polyether polyurethane to prepare medical anticoagulant polyurethane. Firstly, two aliphatic side chains were synthesized from isophorone diisocyanate, diethyl dimethylol malonate (DBM) and poly (ethylene glycol) 1-hexanediol. Two lipids were introduced by the chain extender DBM. In order to compare the effect of DBM content on the graft capacity of heparin, two kinds of PUM were synthesized, one was that the molar fraction of PU-3DBM: DBM to the total monomer was 12.5 atand the other was PU-6BDM: DBM, the molar fraction of PU-3DBM: DBM was 25atlay. Then, PU-3DBM and PU-6DBM were dispersed in water for hydrolysis and carboxylation respectively. Finally, 0.49wt.% and 0.93wt.% heparin were grafted with PU-3DBM and PU-6DBM, respectively. The hydrolysis time was chosen as 30min in order to fully hydrolyze the two lipids without great loss of the mechanical properties of pu. In this study, the concentration of carboxyl groups in pu after hydrolysis and carboxylation was determined by Rhodamine 6G method, and the effect of DBM on the graft capacity of heparin was explained. The successful grafted heparin was determined by Fourier transform infrared spectroscopy (FTIR) and nuclear magnetic resonance (NMR), and the chemical composition of pu grafted with heparin was analyzed by chemical elements. The results show that the content of sulfur in the grafted PU-6DBM (PU-6DBM-Hep) is twice as much as that in the grafted heparin PU-3DBM (PU-3DBM-Hep), and the content of sulfur on the surface of the PU-3DBM-Hep film is higher than that of the PU-3DBM-Hep film. The results of water contact angle test showed that the surface hydrophilicity of pu films grafted with heparin was improved significantly. In vitro heparin release test, the grafted pu grafted with heparin can continuously release heparin in normal saline for 90 hours. In addition, the in vitro blood compatibility test (hemolysis rate and platelet adhesion test) showed that the anticoagulant polyurethane grafted with heparin had good blood compatibility in vitro. However, the application of the prepared anticoagulant pu as a vascular stent coating in vivo showed that compared with the bare stent, the vascular stent with the coating could increase the degree of vascular injury and inflammation one month after the stent was placed in the blood vessel of the animal. The proliferation of vascular wall was aggravated. Therefore, the anticoagulant polyurethane prepared in this study can be used as in vitro blood contact material.
【學(xué)位授予單位】：復(fù)旦大學(xué)
【學(xué)位級(jí)別】：碩士
【學(xué)位授予年份】：2012
【分類號(hào)】：R318.08
本文編號(hào)：2122727
[Abstract]:Polyurethane (pu) is widely used in medical instruments from medical catheter to artificial heart. However, the coagulation problem of pu still needs to be solved when it is in contact with blood. At present, there are two main modification methods to improve this problem: physical method and chemical method. The modified pu has only medium and short term anticoagulant effect, while other modification methods are mainly aimed at the surface modification of pu, and the effect of the material surface on the complex blood environment is uncertain. Therefore, the pu in this study not only grafted on the surface but also on the body of anticoagulant drug heparin, it is hoped that the modified pu can also have continuous anticoagulant. At the same time, the polyurethane anticoagulant material prepared by the modified method can be prepared into arbitrary shape or be used as the surface coating of other biomedical materials. In this study, heparin was covalently grafted onto polyether polyurethane to prepare medical anticoagulant polyurethane. Firstly, two aliphatic side chains were synthesized from isophorone diisocyanate, diethyl dimethylol malonate (DBM) and poly (ethylene glycol) 1-hexanediol. Two lipids were introduced by the chain extender DBM. In order to compare the effect of DBM content on the graft capacity of heparin, two kinds of PUM were synthesized, one was that the molar fraction of PU-3DBM: DBM to the total monomer was 12.5 atand the other was PU-6BDM: DBM, the molar fraction of PU-3DBM: DBM was 25atlay. Then, PU-3DBM and PU-6DBM were dispersed in water for hydrolysis and carboxylation respectively. Finally, 0.49wt.% and 0.93wt.% heparin were grafted with PU-3DBM and PU-6DBM, respectively. The hydrolysis time was chosen as 30min in order to fully hydrolyze the two lipids without great loss of the mechanical properties of pu. In this study, the concentration of carboxyl groups in pu after hydrolysis and carboxylation was determined by Rhodamine 6G method, and the effect of DBM on the graft capacity of heparin was explained. The successful grafted heparin was determined by Fourier transform infrared spectroscopy (FTIR) and nuclear magnetic resonance (NMR), and the chemical composition of pu grafted with heparin was analyzed by chemical elements. The results show that the content of sulfur in the grafted PU-6DBM (PU-6DBM-Hep) is twice as much as that in the grafted heparin PU-3DBM (PU-3DBM-Hep), and the content of sulfur on the surface of the PU-3DBM-Hep film is higher than that of the PU-3DBM-Hep film. The results of water contact angle test showed that the surface hydrophilicity of pu films grafted with heparin was improved significantly. In vitro heparin release test, the grafted pu grafted with heparin can continuously release heparin in normal saline for 90 hours. In addition, the in vitro blood compatibility test (hemolysis rate and platelet adhesion test) showed that the anticoagulant polyurethane grafted with heparin had good blood compatibility in vitro. However, the application of the prepared anticoagulant pu as a vascular stent coating in vivo showed that compared with the bare stent, the vascular stent with the coating could increase the degree of vascular injury and inflammation one month after the stent was placed in the blood vessel of the animal. The proliferation of vascular wall was aggravated. Therefore, the anticoagulant polyurethane prepared in this study can be used as in vitro blood contact material.
【學(xué)位授予單位】：復(fù)旦大學(xué)
【學(xué)位級(jí)別】：碩士
【學(xué)位授予年份】：2012
【分類號(hào)】：R318.08
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