【作者】 方建林；

【导师】 冯敢生；

【作者基本信息】 华中科技大学 ， 影像医学与核医学， 2009， 博士

【摘要】 第一部分温敏纳米凝胶相关特性研究目的研究新型栓塞剂温敏型聚(N—异丙基丙烯酰胺—co—甲基丙烯酸丁酯)纳米凝胶(简称温敏纳米凝胶)的相关特性及其作为血管栓塞剂的有效性、安全性。材料与方法对温敏纳米凝胶进行一系列有关特性的鉴定，并分别进行体外模拟实验及10只家兔肝动脉栓塞实验，另10只用生理盐水注入肝动脉作对照。结果温敏纳米凝胶为温度敏感性栓塞材料，常温下流动性好，呈液体状态，37℃时完全凝固，失去流动性，且具有高触变性，易经导管注射；具有良好的血液相容性和组织相容性，无致热原性及毒性作用；栓塞部位主要是末梢小动脉；经光镜观察其对正常肝组织损伤轻微，仅出现栓塞部位的肝细胞变性和坏死。结论温敏纳米凝胶使用方便、安全，是一种较理想的末梢型血管栓塞剂。可用于进一步动物实验。第二部分温敏纳米凝胶栓塞正常家兔肾动脉的栓塞实验研究目的应用温敏纳米凝胶栓塞家兔的肾动脉及肝动脉，探讨温敏纳米凝胶作为血管栓塞剂的可行性。材料与方法60只新西兰大白兔，分别用温敏纳米凝胶栓塞右肾动脉及肝动脉，并用PVA栓塞右肾动脉作对照，术后观查家兔一般情况、存活时间、肝功能及病理改变。结果温敏纳米凝胶为温度敏感性栓塞材料，易经介入导管注射，栓塞后家兔精神、饮食正常，肾功能14天可恢复正常；凝胶可根据需要栓塞各级动脉，栓塞末梢血管牢固，时间达两月以上；栓塞后家兔无明显毒副反应；病理检查右肾动脉栓塞后3天即出现梗死，肝组织14天后出现坏死；35天后被凝胶栓塞的肝组织及肾组织均出现弥漫性坏死。结论温敏纳米凝胶使用方便、安全，栓塞血管效果好，是一种较理想的血管栓塞剂。第三部分温敏纳米凝胶对兔VX2移植性肝癌栓塞效果的实验研究实验一用于介入栓塞剂研究的肝癌模型的建立目的建立兔VX2移植性肝癌模型、探讨其影像学及病理学特点。材料与方法将50只新西兰大白兔采用移植法建立兔VX2移植性肝癌模型，于移植术后13天行DSA、MRI、CT及病理检查。结果有48只兔接种成功，其影像学及病理学表现均类似于人类原发性肝癌。结论兔VX2移植性肝癌模型可用于血管栓塞剂温敏纳米凝胶的实验研究。实验二温敏纳米凝胶介入栓塞治疗兔VX2移植性肝癌的疗效目的评价温敏纳米凝胶介入栓塞治疗兔VX2移植性肝癌的疗效。材料和方法将45只新西兰大白兔采用移植法建立移植性肝癌模型，于移植术后13天后行MRI检查，测量肿瘤体积(V1)，再随机分成3组，A组：经肝动脉注入温敏纳米凝胶0.6ml；B组：经肝动脉灌注超液态碘油0.6ml+0.25mg明胶海绵粉；C组：经肝动脉灌注生理盐水1ml。14天后再行磁共振检查以确定肿瘤体积(V2)，对三组间肿瘤生长率(V2／V1)进行比较。先进行大体标本观察，包括肿瘤大小、坏死、出血情况。镜下组织学观察肿瘤细胞排列方式、坏死及肝内转移等。结果A、B、C三组间肿瘤生长速率不完全相同，肿瘤大小术前分别为0.068±0.11cm~3，0.071±0.23 cm~3，0.069±0.19 cm~3；术后14天分别为0.289±0.18cm~3，1.018±0.21cm~3，4.290±0.67cm~3，术后三组间肿瘤体积有显著性差异(p＜0.01)，两两比较各组间均有显著性差异(p＜0.01)；各组间肝表面转移灶及显微镜下瘤周1cm肝组织转移灶不完全相同，两两比较示A组与B组、A组与C组均存在显著性差异(p＜0.01)，而B、C两组无统计学差异(p＞0.05)。结论温敏纳米凝胶的栓塞治疗对兔VX2移植性肝癌具有显著的生长抑制作用，是一种较理想的肝癌栓塞物质更多还原

【Abstract】 Part oneStudy on the Characteristics of Thermosensitve Poly NanogelObjective To study the correlation properties of thermosensitve poly (N-isopropylacrylamide- co-butyl methacrylate) nanogel and the efficacy, safety andcorrelative characteristics as a vascular embolization agent.Materials and methods Related characteristics of thermosensitve poly nanogel werestudied. Extra corporeal simulation experiments and hepatic arterial embolization of 10rabbits were performed with thermosensitve poly nanogel respectively, others 10 rabbitsembolized with Normal saline as a control.Results Thermosensitve poly nanogel is a thermosensitive embolic material in liquid statewith fine fluidity at room temperatrue, fully solidifies at 37℃and loses fluidity, having ahigh thixotropy and being easily injected through all sorts of interventional catheters andthe embolization agent has hemo-compatibility and good histocompat- ibility, withoutpyrogenetic response and toxicity. Thermosensitve poly nanogel mainly embolized theperipheral arteries. Slight injuries of normal hepatic tissues with hepatic cytonecrosisandendochyloma focal necrosis were found through electronic microscopy.Conclusion Thermosensitve poly nanogel is a safe and effective peripheral embolizationagent in experimental application and a and may be confirmed in further animalexperiments. Part twoThe Animal experimental study On the Vascular Embolization Agent ofThermosensitve Poly Nanogelobjective To emblazc the right renal artery and the hepatic arterial of rabbits withthermosensitve poly nanogel and investigate its feasibility as a vascular embolization agent.Materials and methods To emblize the right renal artery the hepatic arterial of 60 rabbitswith thermosensitvc poly nanogel, PVA as a control. General condition, survival time,hepatic and renal function and pathological changes of the rabbits treated byThermosensitve poly nanogel were performed. Follow-up angiography was performed forembolic efficacy.Results Thermosensitve poly nanogel which easily injected through all sorts ofinterventional catheters is a thermosensitive embolic material. The spirit, drink, eating,hepatic function were normal after embolization and renal function could get normal after14 days. Thermosensitve poly nanogel could emblize arteries at all levels according toexperimental need and could emblaze the periphcral arteries firmly with maintainingocclusion for over one month without pyrogenetic response and toxicity. Pathologically,infarction of renal tissuc was found 3 days after the right renal were embolized,whilehepatic tissue necrosis was found 14days after the hepatic were embolized and diffusenecrosis of renal and hepatic tissue was found 35 days after operation.Conclusion Thermosensitve poly nanogel is a safe and convincnt embolization agentwith good angiocmbolic function and is an ideal vascular embolization agent. Part threeTreatment effect of Thermosensitve Poly Nanogel for Rabbit VX2transplanted hepatocarcinoma modelTest 1 Establishing Rrabbit transplanted VX2 hepatocarcinoma modelfor study of Vascular embolization agentObjective To establish the rabbit VX2 hepatocarcinoma model and study the features ofimaging and pathology examination.Materials and methods Fifty Newzealand rabbits hepatocarcinoma model wereestablished by VX2 tumor implantation, Digital subtraction angiography(DSA), magneticresonance imaging(MRI), computed tomography(CT) scanning and Pathology wereperformed 13 days after implantation.Result Succecssful implantation was obtained in 38 rabbits by the examination ofMRI.The imagology and pathology are all similar with human hepatocarcinoma.Conclusion Rabbit VX2 heptocarcinoma model is suitable for interventional experimentstudy of the vascular embolization agent of thermosensitve poly nanogel onhepatocarcinoma.Test 2 Treatment effect of Thermosensitve Poly Nanogel for Rabbit VX2transplanted hepatocarcinoma modelobjective To observe the inhibiting effect of thermosensitve poly nanogel on rabbit VX2transplanted hepatocarcinoma model through emblazing hepatic artery. Materials and methods 45 rabbits hepatoma model were established by VX2 tumorimplantation.The tumor volume (V1) was measured by magnetic resonance imaging 13days after implantation, then the rabbits were splited randomly into three group(n=15).Andafter 14 days thermosensitve poly nanogel 0.6ml,ultrofluid lipiodol 0.6ml and 0.25mggelfoam spong, Normal saline 1 ml were infused though hepatic artery respectively. Afteranother 14days MRI were performed once again to determine the tumor volume and Thetumor growth rates of three groups were compared. Gross specimen were performedfirstly, including tumor size, necrosis, hemorrhage and liver surface metastases and thearrangement of tumor cells, necrosis and intrahepatic metastasis were observed throughhistological observation under a microscope.Results Average tumor volume of the three groups before operation were0.068±0.11cm~3, 0.071±0.23 cm~3, 0.069±0.19 cm~3, while after operation, average tumorvolume of the three group were 0.289±0.18cm~3, 1.018±0.21cm~3, 4.290±0.67cm~3, Significantdifference existed in growth rates among 3 groups (p＜0.01) and between eithergroups(p＜0.01); Significant difference existed in metastasis of livers 1cm around tumoramong 3 groups (p＜0.01), but not between B and C (p＞0.05).Conclusion Arterial Embolization of thermosensitve poly nanogel had markedinhibitory effect on rabbit VX2 transplanted hepatocarcinoma, and is an ideal embolizationagent for hepatocarcinoma.更多还原