【作者】 饶华新；

【导师】 张子勇；

【作者基本信息】 暨南大学 ， 生物医学工程， 2008， 博士

【摘要】 人工肺，也称氧合器，具有调节血液内O₂和CO₂含量的功能，是治疗急性呼吸疾病和等待肺移植阶段必需的医疗设备，也是心血管手术的辅助医疗设备。作为当前已经临床应用和商业化的体外膜式人工肺，由于O₂和CO₂使用同一种通道，主要存在气体交换能力差、血液传输效率不足、使用时间短等问题。目前国内临床应用的人工肺使用的膜组件几乎全部依靠进口。为此，本论文设计和研究了一种O₂和CO₂分别具有各自通道的新型双通道中空纤维膜式人工肺。为了提高涂覆中空纤维的液晶／硅橡胶膜的透氧性、生物相容性和抗凝血性，采用高效酰化法和酰氯化法分别合成了丙烯酸胆甾醇酯、丁烯酸胆甾醇酯、戊烯酸胆甾醇酯、己烯酸胆甾醇酯和十一烯酸胆甾醇酯5种胆甾醇酯衍生物，并对其化学结构和液晶性能进行了表征。高效酰化催化剂法能明显提高产品的产率与纯度、简化操作、降低反应毒性。除丙烯酸胆甾醇酯外，其余4个胆甾醇酯样品均具有液晶性。使用硅橡胶、含氢硅油和胆甾醇酯液晶，首次制备了胆甾醇酯液晶／硅橡胶交联膜。研究了各种因素（压差、温度、取代基、交联时间、液晶含量、物理性能等）对交联膜的透气性能和分离性能的影响。结果表明，该膜具有良好的成膜性能、透气性能和分离性能。例如，在0．1 MPa压差和40℃下，透氧系数和氧氮分离系数分别高达为789 Barrer和3．40，其渗透性能明显优于普通改性的硅橡胶膜材料，可用作膜式人工肺中空纤维的涂覆膜。通过磺化、中和和络合反应制备了含钴离聚体膜。在测试中发现，处于低压侧的CO₂自发地透过离聚体膜向N₂或空气的高压侧反向渗透。这种CO₂反向渗透的现象，是一种新的气体渗透行为，至今未见有类似现象的报道。研究了离聚体膜的气体正向渗透性能和CO₂反向渗透行为，发现离聚体膜具有优越的CO₂渗透性能和相对较差的O₂渗透性能。例如，在25℃和0．1 MPa压差下，CO₂和O₂渗透系数分别为170 Barrer和28 Barrer。利用这一性能，可将其应用于通过壳体材料排除CO₂的新型膜式人工肺内表面的涂敷膜材料。通过动态凝血、溶血、血小板粘附和接触角等实验研究了液晶／硅橡胶交联膜和离聚体膜的生物相容性。作为对照，按照肝素化的离子键结合方式，制备了肝素化液晶／硅橡胶交联膜和离聚体膜。结果表明，硅橡胶交联膜、离聚体膜和肝素化膜都具有良好的生物相容性，能够满足膜式人工肺膜材料的基本要求。改进目前工业上中空纤维单组分涂敷工艺，设计了中空纤维双组分涂敷工艺。优化了涂敷工艺条件：液晶／硅橡胶溶液的浓度为5．0％，交联时间为10 min，固化温度在60℃以下。按照中空纤维双组份涂敷工艺，在中空纤维的外表面涂敷具有O₂促进输送的液晶／硅橡胶交联膜。将具有优越的CO₂渗透性能和较差的O₂渗透性能的离聚体膜涂敷于梯度陶瓷管的内壁。按照双组份涂敷工艺将具有O₂促进输送的液晶／硅橡胶交联膜涂覆于中空纤维的外表面，以梯度陶瓷管作为外壳材料、中空纤维膜为基质材料，首次设计了一种O₂和CO₂分别具有各自通道的新型双通道中空纤维膜式人工肺，未见国内外相关文献报道。作为对比，同时也设计了一种O₂和CO₂使用同一种通道的中空纤维膜式人工肺。以生理盐水和去离子水代替血液，测试了单通道中空纤维膜式人工肺组件的体外性能。实验结果表明，单通道中空纤维膜式人工肺具有具有较好的氧合效果。例如，当生理盐水的流速为450 ml／min时，氧气传输速率和压力降分别为48．3 ml／（min·m²）和21．6 mmHg，其氧合效果接近于国际上通用优良膜式人工肺的性能。与单通道中空纤维膜式人工肺相比，双通道膜式人工肺的氧气传输速率更大，压力降更低，使用寿命更长。表明液晶／硅橡胶交联膜和离聚体膜有利于提高膜式人工肺的氧合效果。可以展望，双通道中空纤维膜式人工肺将具有很好的研究前景和应用价值。更多还原

【Abstract】 Artificial lung, also called as oxygenator, which is to provide cardiopulmonary bypass during open-heart surgery, performs a function of exchanging O₂ and removing CO₂ from blood. It also serves as a bridge to lung transplant and a needed appliance for treatment patients with acute respiratory failure. Due to O₂ and CO₂ permeating through one-channel, the extracorporeal membrane oxygenators used in clinical and commercial application at present have still some disadvantages, such as lower gas exchange capability, more inadequate blood transport efficiency; shorter service time. In addition, membrane parts of oxygenators used in clinical application in China almost rely on importation. Therefore, the paper will design and study a novel two-channel hollow-fiber membrane oxygenator with different permeation channels for O₂ and CO₂.To improve permeability for O₂, biocompatibility and anticoagulation of hollow fibers coated liquid crystal/silicone rubber membrane, five kinds of olefine acid cholesteryl ester derivatives （such as acrylic acid cholesterol ester, vinylacetic acid cholesterol ester, pentenoic acid cholesterol ester, hexenoic acid cholesterol ester and 11-alkenoic acid cholesterol ester） were synthesized respectively by 2n acylation method and a super esterification method. Their chemical structures and liquid crystal behaviors were characterized by using FTIR, DSC and polarized microscopy with a hot stage. The research results showed that the super acylation catalyst method could improve obviously yield and purity, low toxicity and simplify operation process. Apart from crylic acid cholesterol ester, the other cholesterol esters showed cholesteryl liquid crystal behavior. Liquid crystal/silicone rubber crosslinked membranes were prepared firstly by using silicone rubber, silicone oil containing hydrogen and cholesterol ester liquid crystal as matrix materials. Some influential factors （such as difference pressure, testing temperature, substituent group, vulcanizing time, liquid crystal content, mechanics property） on permeability and permselectivity for the crosslinked membranes were studied. The results showed that the crosslinked membranes had better membrane-forming, permeability and permselectivity, especially better permeability for oxygen than normal modified silicon rubber membranes. For example, at pressure difference of 0.1 MPa and testing temperature of 40℃, the permeability coefficient and separation factor of the crosslinked membrane were up to 789 Barrer and 3.40, respectively. So, the crosslinked membrane can be used as coating membrane material of hollow fiber for membrane artificial lung.An ionomer membrane containing cobalt was prepared by sulfonated reaction, neutralization reaction and complex reaction. We discovered a peculiar behavior of gas permeation that CO₂ could permeate spontaneously through the membrane from the downstream side toward the upstream side of N₂ gas or air. The CO₂ reverse permeation behavior is a novel gas permeation behavior and has not been reported so far. The permeability and CO₂ reverse permeation behavior of the ionomer membrane were investigated. The results showed the ionomer membrane had better permeability for CO₂ and relatively poorer permeability for O₂. For example, at 25℃and the pressure difference of 0.1 MPa, the permeability coefficients for CO₂ and O₂ were 170 Barrer and 28 Barrer, respectively. Based on these properties, the ionomer membrane can be used as coating membrane material for a novel membrane artificial lung, which can exclude CO₂ from blood by a shell material.The biocompatibility of the crosslinked membrane and the ionomer membrane were studied by measurement of the haemolysis ratio, the dynamic blood clotting test and the platelet adhesion test. By contrast, the heparinized crosslinked membrane and ionomer membrane were prepared by an ionic linkage method. The results showed that these membranes exhibited better biocompatibility to satisfy the needs of membrane materials of membrane artificial lung.A self-assembled dip-coating technology using double-components was designed firstly to improve currently industrialized dip-coating technology using one-component for hollow fiber. The dip-coating conditions of the double-components technology were optimized: the concentration of liquid crystal/silicone rubber solution was 5.0%; the vulcanizing time was 10 minutes; curing temperature was under 60℃.According to the double-components dip-coating technology, the liquid crystal/silicone rubber crosslinked membranes with facilitated transportation for O₂ were coated on the surface of hollow fiber. And the ionomer membranes with better permeability for CO₂ and relatively poorer permeability for O₂ were coated on the wall of gradient ceramic. By using the gradient ceramic as an out-housing material and the hollow fiber membrane as a matrix material, a novel two-channel hollow-fiber membrane oxygenator with different permeation channels for O₂ and CO₂ was designed firstly. The membrane oxygenator has not been reported in the world. In contrast, a one-channel hollow-fiber membrane oxygenator with one permeation channel for O₂ and CO₂ was assembled. The properties of the one-channel membrane oxygenator in vitro were measured by using normal saline and deionized water as a substitute for blood. The results showed the one-channel membrane oxygenator had better oxygenation performance which was close to that of commercial membrane oxygenator in the world. For example, when the flow rate of normal saline was 450 ml/min, O₂ transfer rate and pressure drop were 48.3 ml/（min·m²） and 21.6 mmHg, respectively.By comparison of the one-channel membrane oxygenator, the two-channel hollow-fiber membrane oxygenator had higher O₂ transfer rate, lower pressure drop and longer service time. These suggested that the liquid crystal/silicone rubber crosslinked membrane and the ionomer membrane were benefit to improve oxygenation performance of membrane artificial lung. Therefore, it is speculated that the two-channel hollow-fiber membrane oxygenator will posses better research prospect and greater value in application.更多还原