氧化鈦材料與血漿界面反應(yīng)的分子機(jī)制探究
發(fā)布時(shí)間：2018-11-08 10:55
【摘要】：心腦血管疾病是當(dāng)今嚴(yán)重威脅人類生命和健康的常見疾病之一。凝血、栓塞與抗凝并發(fā)癥仍然是臨床心血管生物材料就治過程中面臨的常見問題,嚴(yán)重制約了此類材料的臨床應(yīng)用。深入研究材料與血液的界面反應(yīng)過程(特別是材料-蛋白界面作用)；探討材料介導(dǎo)血栓形成的關(guān)鍵環(huán)節(jié)和關(guān)鍵因素；從分子學(xué)水平揭示材料的抗凝血機(jī)理；這些將是新一代具有操控性血液接觸類生物材料發(fā)展的要求。本課題組在十多年對(duì)于鈦氧薄膜抗凝血材料的改良應(yīng)用研究中,積累了豐富的理論和實(shí)踐研究經(jīng)驗(yàn),相應(yīng)產(chǎn)品已應(yīng)用臨床中。本研究在此基礎(chǔ)上,選取具有典型代表意義的高溫退火及表面電化學(xué)摻雜氧化鈦材料,結(jié)合先進(jìn)精密的界面反應(yīng)手段,原位探討其材料-血液界面的反應(yīng)機(jī)制,以期實(shí)現(xiàn)對(duì)其抗凝血機(jī)理的深入全面認(rèn)識(shí)。論文主要內(nèi)容如下：(1)模型氧化鈦材料的選取及血液相容性評(píng)價(jià)：選取兩種在實(shí)踐加工中具有操作簡(jiǎn)單、對(duì)材料表面性質(zhì)影響較為單一的高溫退火及表面電化學(xué)n型摻雜處理方法：獲得具有不同抗凝血性能的系列氧化鈦薄膜及粉末材料；對(duì)薄膜和粉末材料的表面物理化學(xué)及凝血性能進(jìn)行了全面表征。結(jié)果發(fā)現(xiàn)高溫退火能導(dǎo)致薄膜表面氧空位的產(chǎn)生,其中尤以800度高溫退火最為顯著,氧空位的產(chǎn)生(或增加)使得薄膜表面羥基含量增加,堿性羥基的比例同期增加,薄膜的親水及負(fù)電性能增強(qiáng)。對(duì)于表面電化學(xué)n型摻雜的氧化鈦材料也可以通過表面電子的轉(zhuǎn)移,電子的注入能中和材料表面的路易斯酸和質(zhì)子酸位,使得材料表面的酸性羥基減少,堿性羥基比例增多,材料表面整體的負(fù)電性能增加。系列血液相容性評(píng)價(jià)試驗(yàn)證實(shí)800度高溫退火及n型摻雜氧化鈦材料的血液相容性都較優(yōu)異。(2)材料血液界面反應(yīng)的動(dòng)態(tài)原位的監(jiān)控與探索性研究：利用QCM技術(shù)分別研究了表面電化學(xué)n型摻雜前后氧化鈦材料與血漿各組分(纖維蛋白原、凝血因四十二、貧板血漿及富板血漿)階段性及全局性的原位作用過程。重點(diǎn)研究了參與凝血行為的重要蛋白質(zhì)的吸附行為及與血栓形成的關(guān)系。發(fā)現(xiàn)在熱力學(xué)驅(qū)動(dòng)下,纖維蛋白原在高濃度下傾向于end-on的可逆吸附行為,而在低濃度下side-on的吸附方式增多。低濃度下,材料與纖維蛋白原的界面作用越明顯,在具有更強(qiáng)負(fù)電性能的n型摻雜氧化鈦表面其吸附方式呈二相吸附,其構(gòu)象變化中參與凝血的關(guān)鍵位點(diǎn)(激活血小板結(jié)合位點(diǎn)、凝血酶作用位點(diǎn))暴露較少。n型摻雜氧化鈦表面更能促進(jìn)凝血因子十二的激活,能更早的促進(jìn)凝血的啟動(dòng),但血栓形成的質(zhì)量和強(qiáng)度還是主要由纖維蛋白原的吸附狀態(tài)決定。(3)模型材料與凝血關(guān)鍵蛋白纖維蛋白原的分子作用機(jī)制解析：采用精密的界面表征手段(AFM, CD,Microdsc,FCM,免疫化學(xué))結(jié)合納米技術(shù),將模型氧化鈦材料與蛋白質(zhì)的界面反應(yīng)效應(yīng)放大,從表面形貌、免疫化學(xué)功能、熱力學(xué)方面解析吸附纖維蛋白原的分子構(gòu)象。結(jié)果顯示：在帶有更多負(fù)電荷及堿性羥基的高溫退火及電子轉(zhuǎn)移氧化鈦表面,纖維蛋白原更傾向于通過帶有正電的αC端形成side-on的方式與材料結(jié)合,這種結(jié)合可以形成空間位阻,維持D結(jié)構(gòu)域完整,二級(jí)結(jié)構(gòu)中α螺旋和β折疊改變較少,避免D結(jié)構(gòu)域中γ鏈C端血小板結(jié)合位點(diǎn)及α鏈中凝血酶位點(diǎn)的更多暴露,從而降低血栓形成的幾率。綜上所述。本研究認(rèn)為提高氧化鈦材料的抗凝血性能,可以通過提高其表面的負(fù)電性能,調(diào)控纖維蛋白原更多的通過其帶正電的αC端與材料表面形成side-on的吸附方式,減少血小板結(jié)合位點(diǎn)及凝血酶位點(diǎn)的更多的暴露,從而降低血栓形成的幾率。本文為鈦氧類材料的抗凝血機(jī)理的完善提供了數(shù)據(jù)支持,也為血液接觸材料的表面設(shè)計(jì)提供了新思路。
[Abstract]:Cardiovascular and cerebrovascular diseases are one of the most serious diseases that seriously threaten human life and health. Coagulation, embolization and anti-coagulation complications are still common problems in the treatment of clinical cardiovascular and biological materials, which severely restrict the clinical application of such materials. In-depth study of the interface reaction between materials and blood (especially the role of the material-protein interface), the key and key factors in the formation of material-mediated thrombosis, and the anti-coagulation mechanism of the material from the level of molecular chemistry; These will be a new generation of requirements for the development of blood-contacting biological materials. The research group has accumulated rich theoretical and practical experience in the study of the modified application of the titanium-oxygen thin-film anticoagulant materials for more than a decade, and the corresponding products have been applied in clinical practice. On the basis of this study, the high-temperature annealing and the surface electrochemical-doped titanium oxide material with typical representative meaning are selected, and the reaction mechanism of its material-blood interface is discussed in-situ with the advanced and sophisticated interface reaction means, with a view to realizing an in-depth and comprehensive understanding of its anticoagulant mechanism. The main contents of this paper are as follows: (1) the selection of the model titanium oxide and the evaluation of the compatibility of the blood: two kinds of high-temperature annealing and surface electrochemical n-type doping treatment method with simple operation and single effect on the surface properties of the materials are selected. A series of titanium oxide films and powder materials with different anticoagulant properties were obtained, and the physical and chemical properties and the coagulation properties of the films and the powder materials were comprehensively characterized. The results show that the high-temperature annealing can lead to the generation of oxygen vacancies on the surface of the film, in which the high-temperature annealing of the film is most significant, and the generation (or increase) of the oxygen vacancies causes the hydroxyl content of the surface of the film to increase, the proportion of the basic hydroxyl groups is increased in the same period, and the hydrophilic and electronegative properties of the film are enhanced. The titanium oxide material doped with the surface electrochemical n-type can also be transferred by the surface electrons, the injection energy of the electrons can neutralize the Lewis acid and the proton acid position on the surface of the material, so that the acid hydroxyl group on the surface of the material is reduced, the proportion of the basic hydroxyl groups is increased, and the negative potential of the whole surface of the material is increased. The series of blood compatibility evaluation tests show that the blood compatibility of the 800-degree high-temperature annealing and the n-type doped titanium oxide material is excellent. (2) The dynamic in-situ monitoring and exploratory study of the reaction of the blood interface of the material: The surface electrochemical n-type pre-and post-doping titanium oxide material and the plasma components (fibrinogen and coagulation factor) were studied by using the QCM technique, respectively. The phase and global in-situ action process of the plasma of the lean plate and the plasma rich in the plate. The adsorption behavior of important proteins involved in blood coagulation and its relationship with thrombosis were studied. It was found that in the thermodynamic drive, the fibrinogen tends to be reversible adsorption behavior of end-on at high concentration, while the adsorption of side-on at low concentration is increased. under the low concentration, the more obvious the interface between the material and the fibrinogen, the adsorption mode of the n-type doped titanium oxide surface with the stronger electronegative property is two-phase adsorption, and the conformational change of the n-type doped titanium oxide is involved in the key sites of blood coagulation (activating the platelet binding site, the thrombin action site) is less exposed. The n-type doped titanium oxide surface can promote the activation of the blood coagulation factor 12, and can promote the activation of the blood coagulation earlier, but the quality and the intensity of the thrombus formation are mainly determined by the adsorption state of the fibrinogen. (3) the molecular action mechanism of the model material and the thromboplastin fibrinogen is analyzed, a precise interface characterization method (AFM, CD, Microdsc, FCM, immunochemistry) is adopted to combine the nano technology, the interface reaction effect of the model titanium oxide material and the protein is amplified, and the surface morphology is obtained, the molecular conformation of the adsorbed fibrinogen is analyzed by the immunochemical function and the thermodynamics. The results show that in high temperature annealing with more negative and basic hydroxyl groups and the surface of the electron transfer titanium oxide, the fibrinogen is more likely to be combined with the material through a side-on with the positive C-terminal, which can form a steric hindrance and maintain the integrity of the D domain. in that secondary structure, the change of the spiral and the fold fold is small, so that more exposure of the platelet-binding site in the C-terminal of the C-terminal in the D domain and the thrombin point in the crotch chain can be avoided, so that the probability of the thrombosis is reduced. To sum up. According to the research, the anti-coagulation property of the titanium oxide material can be improved, and more exposure of the platelet binding site and the thrombin site can be reduced by regulating the electronegative property of the surface of the titanium oxide material, regulating the adsorption mode of the fibrinogen more by the side-on with the surface of the material, reducing the binding site of the platelets and the thrombin site, so as to reduce the probability of thrombus formation. The paper provides the data support for the improvement of the anticoagulant mechanism of the titanium-oxygen-based material, and also provides a new way for the surface design of the blood-contacting material.
【學(xué)位授予單位】：西南交通大學(xué)
【學(xué)位級(jí)別】：博士
【學(xué)位授予年份】：2015
【分類號(hào)】：R318.08
[Abstract]:Cardiovascular and cerebrovascular diseases are one of the most serious diseases that seriously threaten human life and health. Coagulation, embolization and anti-coagulation complications are still common problems in the treatment of clinical cardiovascular and biological materials, which severely restrict the clinical application of such materials. In-depth study of the interface reaction between materials and blood (especially the role of the material-protein interface), the key and key factors in the formation of material-mediated thrombosis, and the anti-coagulation mechanism of the material from the level of molecular chemistry; These will be a new generation of requirements for the development of blood-contacting biological materials. The research group has accumulated rich theoretical and practical experience in the study of the modified application of the titanium-oxygen thin-film anticoagulant materials for more than a decade, and the corresponding products have been applied in clinical practice. On the basis of this study, the high-temperature annealing and the surface electrochemical-doped titanium oxide material with typical representative meaning are selected, and the reaction mechanism of its material-blood interface is discussed in-situ with the advanced and sophisticated interface reaction means, with a view to realizing an in-depth and comprehensive understanding of its anticoagulant mechanism. The main contents of this paper are as follows: (1) the selection of the model titanium oxide and the evaluation of the compatibility of the blood: two kinds of high-temperature annealing and surface electrochemical n-type doping treatment method with simple operation and single effect on the surface properties of the materials are selected. A series of titanium oxide films and powder materials with different anticoagulant properties were obtained, and the physical and chemical properties and the coagulation properties of the films and the powder materials were comprehensively characterized. The results show that the high-temperature annealing can lead to the generation of oxygen vacancies on the surface of the film, in which the high-temperature annealing of the film is most significant, and the generation (or increase) of the oxygen vacancies causes the hydroxyl content of the surface of the film to increase, the proportion of the basic hydroxyl groups is increased in the same period, and the hydrophilic and electronegative properties of the film are enhanced. The titanium oxide material doped with the surface electrochemical n-type can also be transferred by the surface electrons, the injection energy of the electrons can neutralize the Lewis acid and the proton acid position on the surface of the material, so that the acid hydroxyl group on the surface of the material is reduced, the proportion of the basic hydroxyl groups is increased, and the negative potential of the whole surface of the material is increased. The series of blood compatibility evaluation tests show that the blood compatibility of the 800-degree high-temperature annealing and the n-type doped titanium oxide material is excellent. (2) The dynamic in-situ monitoring and exploratory study of the reaction of the blood interface of the material: The surface electrochemical n-type pre-and post-doping titanium oxide material and the plasma components (fibrinogen and coagulation factor) were studied by using the QCM technique, respectively. The phase and global in-situ action process of the plasma of the lean plate and the plasma rich in the plate. The adsorption behavior of important proteins involved in blood coagulation and its relationship with thrombosis were studied. It was found that in the thermodynamic drive, the fibrinogen tends to be reversible adsorption behavior of end-on at high concentration, while the adsorption of side-on at low concentration is increased. under the low concentration, the more obvious the interface between the material and the fibrinogen, the adsorption mode of the n-type doped titanium oxide surface with the stronger electronegative property is two-phase adsorption, and the conformational change of the n-type doped titanium oxide is involved in the key sites of blood coagulation (activating the platelet binding site, the thrombin action site) is less exposed. The n-type doped titanium oxide surface can promote the activation of the blood coagulation factor 12, and can promote the activation of the blood coagulation earlier, but the quality and the intensity of the thrombus formation are mainly determined by the adsorption state of the fibrinogen. (3) the molecular action mechanism of the model material and the thromboplastin fibrinogen is analyzed, a precise interface characterization method (AFM, CD, Microdsc, FCM, immunochemistry) is adopted to combine the nano technology, the interface reaction effect of the model titanium oxide material and the protein is amplified, and the surface morphology is obtained, the molecular conformation of the adsorbed fibrinogen is analyzed by the immunochemical function and the thermodynamics. The results show that in high temperature annealing with more negative and basic hydroxyl groups and the surface of the electron transfer titanium oxide, the fibrinogen is more likely to be combined with the material through a side-on with the positive C-terminal, which can form a steric hindrance and maintain the integrity of the D domain. in that secondary structure, the change of the spiral and the fold fold is small, so that more exposure of the platelet-binding site in the C-terminal of the C-terminal in the D domain and the thrombin point in the crotch chain can be avoided, so that the probability of the thrombosis is reduced. To sum up. According to the research, the anti-coagulation property of the titanium oxide material can be improved, and more exposure of the platelet binding site and the thrombin site can be reduced by regulating the electronegative property of the surface of the titanium oxide material, regulating the adsorption mode of the fibrinogen more by the side-on with the surface of the material, reducing the binding site of the platelets and the thrombin site, so as to reduce the probability of thrombus formation. The paper provides the data support for the improvement of the anticoagulant mechanism of the titanium-oxygen-based material, and also provides a new way for the surface design of the blood-contacting material.
【學(xué)位授予單位】：西南交通大學(xué)
【學(xué)位級(jí)別】：博士
【學(xué)位授予年份】：2015
【分類號(hào)】：R318.08
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