【作者】 田维明；

【导师】 李恒德； 崔福斋；

【作者基本信息】 清华大学 ， 材料科学与工程， 2005， 博士

【摘要】 中枢神经(CNS)的再生是一个世界性的难题。与皮肤、肌肉、肝组织和外周神经(PNS)相比,成熟的CNS组织的再生能力十分有限。组织工程是一种促进CNS再生的很有希望的途径之一。本课题模拟CNS组织的细胞外基质的基本成分和结构,首次详细研究了以透明质酸为基础的水凝胶作为CNS组织工程框架材料的可行性。由于纯的透明质酸凝胶缺乏细胞黏附性能不利于细胞贴附和生长,为了模拟CNS细胞外基质的结构和成分,通过化学接枝的手段,分别用层粘连蛋白(laminin,LN)和多聚赖氨酸(PDL)分别对透明质酸进行改性,以增强HA的神经细胞贴附性能和神经相容性。这一将该材料植入成年缺损大鼠的大脑皮层后,该材料具有良好的神经相容性,能够抑制胶质瘢痕的形成,并能诱导神经胶质细胞的迁移进入材料,为轴突的再生提供良好的生物为环境,促进神经轴突长入将改性后的水凝胶。该材料具有促进血管再生的功能。采用化学接枝的方法将Nogo-66受体的抗体接枝到HA分子上,制备了pH值敏感的抗体疏松系统,研究结果表明接枝抗体在酸性环境中,以较高的速率释放,在中性和碱性的环境下,抗体释放的速度较低。由于损伤后的脑组织的pH值会降低,并且随着组织的修复pH值逐渐恢复到正常的生理值,抗体的释放速度由快逐渐减慢,因此抗体的释放速率就会受到损伤的脑组织不断变化的pH值的调控。同时还系统检测了该抗体输送系统的诱导神经纤维再生的特点,在体外与神经细胞共培养时能够诱导轴突向着材料的方向生长。本研究选用了阻断单侧大脑中动脉的局部灶性缺血大鼠模型作为CNS的损伤模型,将抗体释放系统植入大鼠的脑梗塞区域,能够促进梗塞区脑组织再生及功能重建,并在植入的凝胶内部了发现了β-tublin-Ш阳性的神经细胞。更多还原

【Abstract】 The regeneration of central nervous system (CNS) is world wide puzzle.Compared with skin, muscle, liver and peripheral nervous system, CNS haslimited ability to restore itself. Tissue engineering is one of promisingstrategies to promote the regeneration of CNS. By mimicing the structure andcomponents of the extracellular matrix (ECM) of the central nervous system,hyaluronic acid based hydrogel was studied as the tissue engineering scaffoldfor CNS. Because previous work showed that pure HA was ineffective assubstrate for nerve fiber growth because of a lack of cell adherence, lamininand poly-d-lysine (PDL) were immobilized on the backbone of the hydrogels.The in vitro cell culture study showed that 3D hydrogel could promote celladhesion and to support cell growth and to retain the differentiated function.After implantation into the injure brain of rat model, the polymer hydrogelcould correctly bridge the tissue defects, form a permissive interface with thehost tissue to favour cell ingrowth and angisgenesis.A new antibody (IgG) releasing system has been developed by covalently attachingIgG to the biodegradable hyaluronic acid (HA) hydrogel via the hydrolyticallyunstable hydrazone linkage, aiming to deliver the antibody of CNS regenerationinhibitors to the injured brain. Furthermore, pH sensitive linkage-hydrozone has beenformed between hydrogel and antibody. At low pH, the antibodies released quite fast.However, the antibodies released much slower in neutral and alkaline environment.Clinical and laboratory investigations have suggested that traumatic brain injury canproduce metabolic acidosis and reductions in cellular pH. Acidosis of the brain istypically transient, the pH recovers to physiological levels in hours. Therefore, releaserate of the antibody in this delivery system can be regulated with the changing pH oftraumatic brain tissue environment.The antibody delivery system administered to neuron cell adherence andsurvival. Furthermore it could release antibody and induce neurite outgrowth invitro. After implanting to the adult rat model of middle cerebral arteryocclusion, the antibody delivery system promoted the regeneration andimproved functional recovery dramatically in adult rat model. The β-tublin-Шpositive neurons were found in the hydrogel implanted into the brain.更多还原