新型固体栓塞剂——可显影栓塞微球的研究
|
摘要
介入神经放射学（interventional neuroradiology）是研究在X线的
监视下，对中枢神经系统的某些疾病进行直接诊断、治疗的学科。血
管内栓塞技术的应用使得一些原本难度和危险性都很大的疾病得到了
更为安全的治疗，提高了疗效。这项新技术的应用和发展与血管内栓
塞材料以及导管、导丝技术的研制开发是密切相关的。现在应用于临
床的栓塞材料较多，大致可分为固体和液体两大类。目前使用的固体
栓塞剂分为可吸收固体栓塞剂和不可吸收性固体栓塞剂。可吸收性固
体栓塞剂如：自体血凝块、明胶海绵、氧化纤维素或醋酸纤维素等。
不可吸收性固体栓塞剂主要有聚乙烯醇、冷冻硬膜、硅塑胶球、丙烯
酸球、丝线、弹簧圈等。微球作为一种神经外科血管内治疗的固体栓
塞剂广泛地用于临床，在动静脉畸形、动静脉瘘、毛细血管瘤等的治
疗，以及血供丰富肿瘤的术前栓塞中具有重要意义。
目的：本课题的研究目的在于研制一种含有X-线显影材料的固体
栓塞剂，用于临床的介入栓塞。使这种固体栓塞剂在栓塞治疗的过程
中能够在X-线下实时显影，有利于操作者在治疗当中随时了解栓塞的
准确性，栓塞的范围，栓塞的致密程度以及是否发生误栓等，以便及
时采取相应的措施。
mW羊厂人学恤卜学位论义
材料与方法：我们所采用的栓塞剂骨架分别为明胶和聚乙烯醇制扮
的微球。所采用的显影材料分别为硫酸钡、泛影葡肮、袒粉、优鳅显
和戍化钠。所采角的方法有物理浪合包埋和化学交联反应。本Uf穴分
为三部分，第一部分为微球骨架的制备，分别制作用于包埋、挽卅故
影材料的明胶微球和聚乙烯醇微球（明胶微球的制作方法为乳化聚合
汝，聚乙烯醇微球的制作人法为醇醛缩合法结合乳化聚合法），仆对
它们的分散性、膨胀性、稳定性等理化性质进行初步的测定：第 洲S
分为各种显影材料的包埋实验，同时对含有显影剂的栓塞材料的拈影
件、显影则间及它们是否有细胞毒性进行测定；第二祁分为利物’史
验，在数宇减影下使川以上实验所制备的栓寒材料对家兔进行）’仙of！部
位动脉血管的选择性栓塞，＃。且于栓塞后第一、二、凹周后冉次进影
门处死动物，作病理切片，综合判断以上栓塞材料的各人山付能；的
后讨论介入栓塞治疗对于固体栓塞剂的理化性质要求。
结果：通过实验制备出分别含有泛影葡胆、硫酸钡、钉l粉和仇为！．J
的明胶和聚乙烯醇微球，动物实验证实微球在家兔的颅月·背景 l‘llJ以
显影，操作者能够以此判断微球在颅内的栓塞情况；实验所制备的微
球其分散性，稳定性和膨胀性均符合栓塞要求。
结论：用乳化聚合法制备的明胶微球和聚乙烯醇微球具有良好的分
敝件、膨胀忏和’卜物川容们，足较为到Z想的W体栓末材料；介制利竹
过程小加入泛影匍胺和（或）硫酸钡等造影剂，IIJ”使制得的微球 X－线
下显影，从而使操作者在治疗当中可以随时了解栓塞的准确性，栓塞
的范围，栓塞的致密程度以及是否发牛误栓等，以提高栓塞治疗的可
拧N一
The interventional neuroradiology is a subject that aimed at diagnosis and therapy of some diseases of neural system under the surveiI lance of X~ray. The development of this technology made the therapy of certain diseases that used to be dangerous and difficult easier. The development and application of this technology is tightly related with 1 he manufacture and exploitation of embolism material. Nowadays, there are many embolism materials applied in clinic, they could be classified into two types: solid materials and liquid materials. Currently the widely used liquid embolism materials include silicone, IBCA, HEMA, NBCA, grain alcohol, etc.
Objective: This study is to manufacture some kinds of solid embolism materials that could develop under the X-ray. By using these embolism for embolization, the handlers could know many details about the operation at real time, thus to make right decisions during the operation.
Methods: The materials we used for producing embolism are gelatin and polyvinyl alcohol (PVA). The contrast mediums being used here arc sulfate barium, diatrizoate, tantalum powder, etc. They are commixed into microspheres by physical and chemical method. The study contains 3 parts. Part 1: produce gelatin and polyvinyl alcohol microspheres by the method ol' emulsificat ion, then evaluate their physical and chemical characteristic. Part 2: embed contrast mediums into gelatin and polyvinyl alcohol microspheres respectively. Part \\: direct embol i /at ion ol' the carotid ol' rabbits with the microspheres that produced anteriorly, and put the tissues under pathological observing after 1,2 and 4 weeks respectively.
Results: The gelatin and polyvinyl alcohol microspheres that contain X-ray contrast mediums of one kind or two are visible under X-ray in rabbit's skull. And the handlers could know many details about the embolization in real time.
Conclusion: The gelatin and polyvinyl alcohol microspheres that produced by the method of emulsificat ion have appropriate dispersibi1ity, expanding coefficient and specific gravity. Commix contrast mediums such as diatrizoate, sulfate barium into the raw material could make the microspheres be visible under X-ray. Thus, the handler could be ware of more details about the emhol i /.a I ion at real time.
监视下，对中枢神经系统的某些疾病进行直接诊断、治疗的学科。血
管内栓塞技术的应用使得一些原本难度和危险性都很大的疾病得到了
更为安全的治疗，提高了疗效。这项新技术的应用和发展与血管内栓
塞材料以及导管、导丝技术的研制开发是密切相关的。现在应用于临
床的栓塞材料较多，大致可分为固体和液体两大类。目前使用的固体
栓塞剂分为可吸收固体栓塞剂和不可吸收性固体栓塞剂。可吸收性固
体栓塞剂如：自体血凝块、明胶海绵、氧化纤维素或醋酸纤维素等。
不可吸收性固体栓塞剂主要有聚乙烯醇、冷冻硬膜、硅塑胶球、丙烯
酸球、丝线、弹簧圈等。微球作为一种神经外科血管内治疗的固体栓
塞剂广泛地用于临床，在动静脉畸形、动静脉瘘、毛细血管瘤等的治
疗，以及血供丰富肿瘤的术前栓塞中具有重要意义。
目的：本课题的研究目的在于研制一种含有X-线显影材料的固体
栓塞剂，用于临床的介入栓塞。使这种固体栓塞剂在栓塞治疗的过程
中能够在X-线下实时显影，有利于操作者在治疗当中随时了解栓塞的
准确性，栓塞的范围，栓塞的致密程度以及是否发生误栓等，以便及
时采取相应的措施。
mW羊厂人学恤卜学位论义
材料与方法：我们所采用的栓塞剂骨架分别为明胶和聚乙烯醇制扮
的微球。所采用的显影材料分别为硫酸钡、泛影葡肮、袒粉、优鳅显
和戍化钠。所采角的方法有物理浪合包埋和化学交联反应。本Uf穴分
为三部分，第一部分为微球骨架的制备，分别制作用于包埋、挽卅故
影材料的明胶微球和聚乙烯醇微球（明胶微球的制作方法为乳化聚合
汝，聚乙烯醇微球的制作人法为醇醛缩合法结合乳化聚合法），仆对
它们的分散性、膨胀性、稳定性等理化性质进行初步的测定：第 洲S
分为各种显影材料的包埋实验，同时对含有显影剂的栓塞材料的拈影
件、显影则间及它们是否有细胞毒性进行测定；第二祁分为利物’史
验，在数宇减影下使川以上实验所制备的栓寒材料对家兔进行）’仙of！部
位动脉血管的选择性栓塞，＃。且于栓塞后第一、二、凹周后冉次进影
门处死动物，作病理切片，综合判断以上栓塞材料的各人山付能；的
后讨论介入栓塞治疗对于固体栓塞剂的理化性质要求。
结果：通过实验制备出分别含有泛影葡胆、硫酸钡、钉l粉和仇为！．J
的明胶和聚乙烯醇微球，动物实验证实微球在家兔的颅月·背景 l‘llJ以
显影，操作者能够以此判断微球在颅内的栓塞情况；实验所制备的微
球其分散性，稳定性和膨胀性均符合栓塞要求。
结论：用乳化聚合法制备的明胶微球和聚乙烯醇微球具有良好的分
敝件、膨胀忏和’卜物川容们，足较为到Z想的W体栓末材料；介制利竹
过程小加入泛影匍胺和（或）硫酸钡等造影剂，IIJ”使制得的微球 X－线
下显影，从而使操作者在治疗当中可以随时了解栓塞的准确性，栓塞
的范围，栓塞的致密程度以及是否发牛误栓等，以提高栓塞治疗的可
拧N一
The interventional neuroradiology is a subject that aimed at diagnosis and therapy of some diseases of neural system under the surveiI lance of X~ray. The development of this technology made the therapy of certain diseases that used to be dangerous and difficult easier. The development and application of this technology is tightly related with 1 he manufacture and exploitation of embolism material. Nowadays, there are many embolism materials applied in clinic, they could be classified into two types: solid materials and liquid materials. Currently the widely used liquid embolism materials include silicone, IBCA, HEMA, NBCA, grain alcohol, etc.
Objective: This study is to manufacture some kinds of solid embolism materials that could develop under the X-ray. By using these embolism for embolization, the handlers could know many details about the operation at real time, thus to make right decisions during the operation.
Methods: The materials we used for producing embolism are gelatin and polyvinyl alcohol (PVA). The contrast mediums being used here arc sulfate barium, diatrizoate, tantalum powder, etc. They are commixed into microspheres by physical and chemical method. The study contains 3 parts. Part 1: produce gelatin and polyvinyl alcohol microspheres by the method ol' emulsificat ion, then evaluate their physical and chemical characteristic. Part 2: embed contrast mediums into gelatin and polyvinyl alcohol microspheres respectively. Part \\: direct embol i /at ion ol' the carotid ol' rabbits with the microspheres that produced anteriorly, and put the tissues under pathological observing after 1,2 and 4 weeks respectively.
Results: The gelatin and polyvinyl alcohol microspheres that contain X-ray contrast mediums of one kind or two are visible under X-ray in rabbit's skull. And the handlers could know many details about the embolization in real time.
Conclusion: The gelatin and polyvinyl alcohol microspheres that produced by the method of emulsificat ion have appropriate dispersibi1ity, expanding coefficient and specific gravity. Commix contrast mediums such as diatrizoate, sulfate barium into the raw material could make the microspheres be visible under X-ray. Thus, the handler could be ware of more details about the emhol i /.a I ion at real time.
引文
1．凌锋，李铁林，刘树山．介入神经放射学．北京人民卫生出版社．见第四章，栓塞材料．1991，9 第一版，1-50
2．高国栋，易声禹．血管内栓塞剂的应用进展与评价．国外医学，神经外科分册．1992，19(5)：235-237
3. Bilateral traumatic carotid-cavernous fistulae. Surg Neurol. 1975 Feb; 3(2):105-7.
4. The role of transvenous embolization in the treatment of intracranial dural arteriovenous fistulas. Neurosurgery. 1997 Jun; 40(6): 1133-41
5. Cheng DX, Tang MZ. Preparation of magnetic albumin microspheres carrying adriamycin and its localization in rabbit lung [J]. Di-si Junyi Daxue Xuebao (J Fourth Mil Med Univ) 1996; 17(1): 39-41
6. Liang ZH, Wang ZM, Zhang HX, Qi LJ, Guo WP, Wang YQ, Ni DH, Guan Y, Li WX. Effect of interventional thermotherapy through hepatic artery on liver function in dog [J]. Di-si Junyi Daxue Xuebao (J Fourth Mil Med Univ) 2000; 21(4): 430-432
7. Zhang JL, Ning MF. Interventional separating operation to cure aneurysm of the main artery [J]. Di-si Junyi Daxue Xuebao (J Fourth Mil Med Univ) 1997:18 (supplement) : 108-110
8. Liu Yz, Ni FC, Zhu XL, Shao GL, Ding Y. The preoperative application of superselective external carotid artery branch embolization in craniofacial tumor [J]. Clinic radiology, 1999; 18(8): 491-493
9. Thornton J, Dovey Z, Alazzaz A, Misra M, Aletich VA, Debrun GM, Ausman JI, Charbel FT. Surgery following endovascular coiling of intracranial aneurysms. Surg Neurol. 2000 Nov; 54(5): 352-60.
10． Morris P. Detachable balloon embolization: safety balloon technique. AJNR Am J Neuroradiol. 2000 May; 21(5) : 984． No abstract available.
11． Rosso D, Hammond RR, Pelz DM. Cavernous aneurysm rupture with balloon occlusion of a direct carotid cavernous fistula: postmortem examination. AJNR Am J Neuroradiol. 1999 May; 20(5) : 771-3．
12． Mironov A. Selective transparenchymal venous embolisation for dural arteriovenous fistulae. Neuroradiology. 2000 May; 42(5) : 388．
13． Kaji T, Hama Y, Iwasaki Y, Kyoto Y, Kusano S. Preoperative embolization of meningiomas with pial supply: successful treatment of two cases. Surg Neurol. 1999 Sep; 52(3) :270-3．
14． Lylyk P, Vinuela F, Vinters HV, Dion J, Bentson J, Duckwiler G, Lin T. Use of a new mixture for embolization of intracranial vascular malformations. Preliminary experimental experience. Neuroradiology. 1990; 32(4) : 304-10．
15． Kinugasa K, Mandai S, Tsuchida S, Kamata I, Ohmoto T. Direct thrombosis of a pseudoaneurysm after obliteration of a carotid-cavernous fistula with cellulose acetate polymer: technical case report-Neurosurgery. 1994 Oct; 35(4) : 755-9: discussion 759-60．
16． Teng MM, Chen CC, Lirng JF, Chen SS, Lee LS, Chang T.N-butyl-2-cyanoacrylate for embolisation of carotid aneurysm. Neuroradiology. 1994: 36(2) : 144-7．
17． Kallmes DF, Evans AJ, Kaptain GJ, Mathis JM, Jensen ME, Jane JA, Dion JE. Hemorrhagic complications in embolization of a meningioma: case report and review of the literature. Neuroradiology. 1997 Dec: 39(12) : 877-80． Review.
18． Defraigne JO, Sakalihassan N, Antoine P, Thiry A, Limet R. Carotid chemodectomas. Experience with nine cases with reference to
preoperative embolization and malignancy. Acta Chir Belg. 1997 Oct: 97(5) : 220-8．
19． Higashida RT, Halbach VV, Barnwell SL, Dowd C, Dormandy B, Bell J, Hieshima GB. Treatment of intracranial aneurysms with preservation of the parent vessel: results of percutaneous balloon embolization in 84 patients. AJNR Am J Neuroradiol. 1990 Jul-Aug: 11(4) :633-40．
20． Raymond J, Venne D, Alias S, Roy D, Oliva VL, Denbow N, Salazkin I, Leclerc G. Healing mechanisms in experimental aneurysms. I. Vascular smooth muscle cells and neointima formation. J Neuroradiol. 1999 Mar: 26(1) :7-20．
21． Lanman TH, Martin NA, Vinters HV. The pathology of encephalic arteriovenous malformations treated by prior embolotherapy. Neuroradiology. 1988: 30(1) : 1-10．
22． Rao VR, Ravimandalam K, Jayakrishnan A, Thanoo BC, Radhakrishnan VV, Gupta AK, Kumar S, Joseph S, Unni M, Rao AS. Hydrolysed microspheres from cross-linked polymethyl methacrylate (Hydrogel). A new embolic material for interventional neuroradiology. J Neuroradiol. 1991: 18(1) : 61-9．
23． Flandroy P, Grandfils C, Collignon J, Thibaut A, Nihant N, Barbette S, Jerome R, Teyssie P. (D, L) polylactide microspheres as embolic agent. A preliminary study. Neuroradiology. 1990: 32(4) :311-5．
24． Bendszus M, Klein R, Burger R, Warmuth-Metz M, Hofmann E, Solymosi L. Efficacy of trisacryl gelatin microspheres versus polyvinyl alcohol particles in the preoperative embolization of meningiomas. AJNR Am J Neuroradiol. 2000 Feb: 21 (2) :255-61．
25. Spenlehauer G, et al. Formation and characterization of cisplatin loadcd poly(d, l-lactide) microspheres for chemoembolization, J pharm Sci 1986: 75:750.
26．吴功柱，魏如槐，熊国军．5-氟脲嘧啶明胶微球化学交联固化研究．J 中国药房：1998 9(4)：154-155．
27. Berenstein A. Flow-controlled silicone fluid embolization. AJR Am J Roentgenol. 1980 Jun: 134(6):1213-8.
28. Miyazawa T, Murayama C, Yamanaka T, Fritz-Zieroth B. Cerebral embolization in rats induced by red blood cells treated with hypertonic X-ray contrast medium. Invest Radiol. 1993 Sep: 28(9):831-7.
29. Trocherie S, Alaoui F, Idee JM, Santus R, Court L. Electrocorticographic evaluation of iobitridol, a nonionic contrast medium, during selective cerebral arteriography in rabbits. AJNR Am J Neuroradiol. 1995 Sep; 16(8): 1637-42.
30. Hekster RE, Morre HH, Cleyndert P, Zapletal J, Sinnige LF, Bolstad B. Keetlapper Y. Intra-arterial digital subtraction angiography with isotonic dimeric (iodixanol) and monomeric (iohexol) nonionic contrast media: radiographic, clinical and neurophysiological evaluation. Neuroradiology. 1995 Jan: 37(1):48-50.
31．王剑红，陆彬，胥佩菱．肺靶向米托葸醌明胶微球的研究．药学学报，1995，30：549
32．王鹏，王玉珠，沈建民．均匀设计及其在药学中的应用．沈阳药学学报，1989，6：297
34. Montgomery DC. Response surface methodology. In: Montgomery DC. ed. Design and Analysis of Experiments. 2nd edition. New York: John Wiley & Sons, 1984. 445-474
35． Abu-Izza KA, Garcia-Contreras L, Lu DR. Preparation and evaluation of sustained release ATZ-loaded microspheres: optimization of the release characteristics using response surface methodology. J Pharm Sci, 1996, 85: 144
36． Abu-Izza KA, Garcia-Contreras L, Lu DR. Preparation and evaluation of sustained release ATZ-loaded microspheres. 2． Optimization of multiple response variables. J Pharm Sci, 1996, 85: 572
37． Molpeceres J, Guzman M, Aberturas MR, et al. Application of central composite designs to the preparation of polycaprolactone nanoparticles by solvent displacement. J Pharm Sci. 1996, 85: 206
38． Lou Y, Groves MJ, Klegerman ME. In-vivo and in-vitro targeting of a murine sarcoma by gelatin microparticles loaded with a glycan (PS1) . J Pharm Pharmacol. 1994 Nov; 46(11) :863-6．
39． Ford CW, Hamel JC, Stapert D, Yancey RJ. Establishment of an experimental model of a Staphylococcus aureus abscess in mice by use of dextran and gelatin microcarriers. J Med Microbiol. 1989 Apr; 28(4) :259-66．
40． Leung TW, Lau WY, Ho SK, Ward SC, Chow JH, Chan MS, Metreweli C, Johnson PJ, Li AK. Radiation pneumonitis after selective internal radiation treatment with intraarterial 90yttrium-microspheres for inoperable hepatic tumors. Int J Radiat Oncol Biol Phys. 1995 Nov 1 : 33(4) :919-24．
41． Kallskog O, Lindbom LO, Ulfendahl HR, Wolgast M. Regional and single glomerular blood flow in the rat kidney prepared for micropuncture. A methodological study. Acta Physiol Scand. 1975 Jun: 94(2) : 145-53．
42. Li H, Wang C, Wen Y, Wu H. Treatment of squamous cell carcinoma of the tongue using arterial embolism with cisplatin-ioaded albumin microspheres: a microstructural and ultrastructural investigation. Chin J Dent Res. 1999 Feb: 2(1):61-6.
43. Ho S, Lau WY, Leung TW, Chan M, Johnson PJ, Li AK. Clinical evaluation of the partition model for estimating radiation doses from yttrium-90 microspheres in the treatment of hepatic cancer. Eur J Nucl Med. 1997 Mar: 24(3): 293-8.
44. Nishioka Y, Kyotani S, Okamura M, Ohnishi S, Yamamoto Y, Kawashima Y, Tanada S, Nakamura T. A study of embolizing materials for chemo-embolization therapy of hepatocellular carcinoma: effects of particle size and dose on chitin-containing cisdiamminedichloroplatinum(Ⅱ) albumin microsphere antitumor activity in VX2 hepatic tumor model rabbits. Biol Pharm Bull. 1994 Sep: 17(9): 1251-5.
45. Nishioka Y, Kyotani S, Okamura M, Ohnishi S, Yamamoto Y, Tanada S, Nakamura T. A study of embolizing materials for chemo-embolization therapy of hepatocellular carcinoma: effects of chitin concentration on cis-diamminedichloroplatinum(Ⅱ) albumin microsphere properties and antitumor effect in VX2 hepatocellular carcinoma model rabbits. Biol Pharm Bull. 1993 Nov; 16(11): 1136-9.
46．李艳利，史永旭，姜涌明，等．壳聚糖多孔珠的制备及其作为亲和吸附剂载体的研究．药物生物技术：1998，5(4)：241-244
47. Vorlop K D, Klein J. In: Mosbach K ed. Methods in Enzymology, Acacemic press, Orlando, 1987, 135:259
48. Zimmermann A, Schubiger PA, Mettler D, Geiger L, Triller J, Rosier H. Renal pathology after arterial yttrium-90 microsphere administration in
pigs. A model for superselective radioembolization therapy. Invest Radiol. 1995 Dec; 30(12) :716-23．
49． Wollner IS, Knutsen CA, Ullrich KA, Chrisp CE, Juni JE, Andrews JC, Tuscan MJ, Stetson PL, Ensminger WD. Effects of hepatic arterial yttrium-90 microsphere administration alone and combined with regional bromodeoxyuridine infusion in dogs. Cancer Res. 1987 Jun 15; 47(12) : 3285-90．
50． Kassab AC, Xu K, Denkbas EB, Dou Y, Zhao S, Piskin E. Rifampicin carrying polyhydroxybutyrate microspheres as a potential chemoembolization agent. J Biomater Sci Polym Ed. 1997; 8(12) : 947-61．
51． Stridbeck H, Lorelius LE, Reuter SR. Collateral circulation following repeated distal embolization of the hepatic artery in pigs. Invest Radiol. 1984 May-Jun; 19(3) : 179-83．
52． Wright KC, Anderson JH, Gianturco C, Wallace S, Chuang VP. Partial splenic embolization using polyvinyl alcohol foam, dextran, polystyrene, or silicone. An experimental study in dogs. Radiology. 1982 Feb; 142(2) : 351-4．
53． Berenstein A, Kricheff Ⅱ. Catheter and material selection for transarterial embolization: technical considerations. Ⅱ. Materials. Radiology. 1979 Sep; 132(3) : 631-9．
54． Savastano S, Miotto D, Casarrubea G, Teso S, Chiesura-Corona M, Feltrin GP. Transcatheter arterial chemoembolization for hepatocellular carcinoma in patients with Child's grade A or B cirrhosis: a multivariate analysis of prognostic factors. J Clin Gastroenterol. 1999 Jun; 28(4) : 334-40
55． Wright KC, Greff RJ, Price RE. Experimental evaluation of cellulose acetate NF and ethylene-vinyl alcohol copolymer for selective arterial embolization. J Vasc Interv Radiol. 1999 Oct: 10(9) : 1207-18．
56． Koda Y, Kan Z, Wallace S, Kaminou T, Nakamura K, Yamada R. Hepatic microcirculatory changes induced by hepatic artery embolization in rats: original investigation. Invest Radiol. 1999 Feb; 34(2) : 160-6．
57． Derdeyn CP, Graves VB, Salamat MS, Rappe A. Collagen-coated acrylic microspheres for embolotherapy: in vivo and in vitro characteristics. AJNR Am J Neuroradiol. 1997 Apr; 18(4) : 647-53．
58． Higo R, Asai M, Sugasawa M, Takeuchi N, Nemoto S. Preoperative embolization for paraganglioma. Auris Nasus Larynx. 1994; 21(2) : 122-5．
59． Shi HB, Suh DC, Lee HK, Lim SM, Kim DH, Choi CG, Lee CS, Rhim SC. Preoperative transarterial embolization of spinal tumor: embolization techniques and results. AJNR Am J Neuroradiol. 1999 Nov-Dec: 20(10) : 2009-15．
60． Nakabayashi K, Negoro M, Handa T, Keino H, Takahashi M, Sugita K. Evaluation of particulate embolic materials with MR imaging, scanning electron microscopy, and phase-contrast microscopy. AJNR Am J Neuroradiol. 1997 Mar; 18(3) : 485-91．
61． Aso N, Matsunaga N, Fukuda T, Sakamoto I, Ashizawa K, Aikawa H. Isomoto I, Hayashi K, Fukushima T, Morikawa M. Multiple intrahepatic aneurysms following transcatheter arterial embolization. Work in progress. Radiology. 1994 Dec; 193(3) : 743-6．
62． Ugwoke MI, Kinget R. Influence of processing variables on the properties of gelatin microspheres prepared by the Emulsification
solvent extraction technique. J Microencapsul 1998 May-Jun;15(3) :273-281
63． Chuang VP, et al. Ivalon embolizalion in abdominal neoplasms. A.IK 1981, 136:729．
64． 魏树礼,刘秀英,于海霞.聚乙烯醇微球的研究.北京医科大学学报 : 1990, 2 (22) : 133-135
65． Steinberg EP, Moore RD, Powe NR, Gopalan R, Davidoff AJ, Lilt M, Graziano S, Brinker JA. Safety and cost effectiveness of high-osmolality as compared with low-osmolality contrast material in patients undergoing cardiac angiography. N Engl J Med. 1992 Feb 13: 326(7) : 425-30．
66． Davis WL, Nelson JA, Barry WH. Effects of contrast media on cultured myocardial cells. Invest Radiol. 1986 Aug; 21(8) : 626-30．
67． Thanoo BC, Jayakrishnan A. Barium sulphate-loaded p(HEMA) microspheres as artificial emboli: preparation and properties. Biomaterials. 1990 Sep; 11(7) : 477-81．
68． Ikenberry S, Lappas JC, Hana MP, Rex DK. Defecography in healthy subjects: comparison of three contrast media. Radiology. 1996 Oct; 201(1) : 233-8．
69． Rauch D, Drescher P, Knes JM, Madsen PO. Variable effects of iodinated contrast media on different rabbit arteries in vitro. Urol Res. 1997:25 Suppl 1:S21-3．
70． Motoji N, Shigematsu A, Minegishi A. Comparison of the effects of ioversol and other contrast media on the blood-brain barrier. Biol Pharm Bull. 1994 Feb: 17(2) :257-61．
71． Thanoo BC, Jayakrishnan A. Barium sulphate-loaded p(HEMA) microspheres as artificial emboli: preparation and properties. Biomaterials. 1990 Sep: 11(7) :477-81．
72． Gunther R, Klose K, Thelen M, Jacobi G. Superselective embolisation in the urogenital tract with tissue adhesives . ROFO Fortschr Geb Rontgenstr Nuklearmed. 1981 May: 134(5) :536-9．
73． Komatsu T, Nishide H, Tsuchida E. Structure and solution properties of lipidheme-microsphere. Artif Cells Blood Substit Immobil Biotechnol. 1994: 22(3) :855-60．
74． Yi SW, Kim YH, Kwon IC, Chung JW, Park JH, Choi YW, Jeong SY. Stable lipiodolized emulsions for hepatoma targeting and treatment by transcatheter arterial chemoembolization. J Control Release. 1998 Jan 2: 50(l-3) :135-43．
75． Tranbahuy P, Borsik M, Herman P, Wassef M, Casasco A. Direct intratumoral embolization of juvenile angiofibroma. Am J Otolaryngol. 1994 Nov-Dec: 15(6) :429-35．
2．高国栋，易声禹．血管内栓塞剂的应用进展与评价．国外医学，神经外科分册．1992，19(5)：235-237
3. Bilateral traumatic carotid-cavernous fistulae. Surg Neurol. 1975 Feb; 3(2):105-7.
4. The role of transvenous embolization in the treatment of intracranial dural arteriovenous fistulas. Neurosurgery. 1997 Jun; 40(6): 1133-41
5. Cheng DX, Tang MZ. Preparation of magnetic albumin microspheres carrying adriamycin and its localization in rabbit lung [J]. Di-si Junyi Daxue Xuebao (J Fourth Mil Med Univ) 1996; 17(1): 39-41
6. Liang ZH, Wang ZM, Zhang HX, Qi LJ, Guo WP, Wang YQ, Ni DH, Guan Y, Li WX. Effect of interventional thermotherapy through hepatic artery on liver function in dog [J]. Di-si Junyi Daxue Xuebao (J Fourth Mil Med Univ) 2000; 21(4): 430-432
7. Zhang JL, Ning MF. Interventional separating operation to cure aneurysm of the main artery [J]. Di-si Junyi Daxue Xuebao (J Fourth Mil Med Univ) 1997:18 (supplement) : 108-110
8. Liu Yz, Ni FC, Zhu XL, Shao GL, Ding Y. The preoperative application of superselective external carotid artery branch embolization in craniofacial tumor [J]. Clinic radiology, 1999; 18(8): 491-493
9. Thornton J, Dovey Z, Alazzaz A, Misra M, Aletich VA, Debrun GM, Ausman JI, Charbel FT. Surgery following endovascular coiling of intracranial aneurysms. Surg Neurol. 2000 Nov; 54(5): 352-60.
10． Morris P. Detachable balloon embolization: safety balloon technique. AJNR Am J Neuroradiol. 2000 May; 21(5) : 984． No abstract available.
11． Rosso D, Hammond RR, Pelz DM. Cavernous aneurysm rupture with balloon occlusion of a direct carotid cavernous fistula: postmortem examination. AJNR Am J Neuroradiol. 1999 May; 20(5) : 771-3．
12． Mironov A. Selective transparenchymal venous embolisation for dural arteriovenous fistulae. Neuroradiology. 2000 May; 42(5) : 388．
13． Kaji T, Hama Y, Iwasaki Y, Kyoto Y, Kusano S. Preoperative embolization of meningiomas with pial supply: successful treatment of two cases. Surg Neurol. 1999 Sep; 52(3) :270-3．
14． Lylyk P, Vinuela F, Vinters HV, Dion J, Bentson J, Duckwiler G, Lin T. Use of a new mixture for embolization of intracranial vascular malformations. Preliminary experimental experience. Neuroradiology. 1990; 32(4) : 304-10．
15． Kinugasa K, Mandai S, Tsuchida S, Kamata I, Ohmoto T. Direct thrombosis of a pseudoaneurysm after obliteration of a carotid-cavernous fistula with cellulose acetate polymer: technical case report-Neurosurgery. 1994 Oct; 35(4) : 755-9: discussion 759-60．
16． Teng MM, Chen CC, Lirng JF, Chen SS, Lee LS, Chang T.N-butyl-2-cyanoacrylate for embolisation of carotid aneurysm. Neuroradiology. 1994: 36(2) : 144-7．
17． Kallmes DF, Evans AJ, Kaptain GJ, Mathis JM, Jensen ME, Jane JA, Dion JE. Hemorrhagic complications in embolization of a meningioma: case report and review of the literature. Neuroradiology. 1997 Dec: 39(12) : 877-80． Review.
18． Defraigne JO, Sakalihassan N, Antoine P, Thiry A, Limet R. Carotid chemodectomas. Experience with nine cases with reference to
preoperative embolization and malignancy. Acta Chir Belg. 1997 Oct: 97(5) : 220-8．
19． Higashida RT, Halbach VV, Barnwell SL, Dowd C, Dormandy B, Bell J, Hieshima GB. Treatment of intracranial aneurysms with preservation of the parent vessel: results of percutaneous balloon embolization in 84 patients. AJNR Am J Neuroradiol. 1990 Jul-Aug: 11(4) :633-40．
20． Raymond J, Venne D, Alias S, Roy D, Oliva VL, Denbow N, Salazkin I, Leclerc G. Healing mechanisms in experimental aneurysms. I. Vascular smooth muscle cells and neointima formation. J Neuroradiol. 1999 Mar: 26(1) :7-20．
21． Lanman TH, Martin NA, Vinters HV. The pathology of encephalic arteriovenous malformations treated by prior embolotherapy. Neuroradiology. 1988: 30(1) : 1-10．
22． Rao VR, Ravimandalam K, Jayakrishnan A, Thanoo BC, Radhakrishnan VV, Gupta AK, Kumar S, Joseph S, Unni M, Rao AS. Hydrolysed microspheres from cross-linked polymethyl methacrylate (Hydrogel). A new embolic material for interventional neuroradiology. J Neuroradiol. 1991: 18(1) : 61-9．
23． Flandroy P, Grandfils C, Collignon J, Thibaut A, Nihant N, Barbette S, Jerome R, Teyssie P. (D, L) polylactide microspheres as embolic agent. A preliminary study. Neuroradiology. 1990: 32(4) :311-5．
24． Bendszus M, Klein R, Burger R, Warmuth-Metz M, Hofmann E, Solymosi L. Efficacy of trisacryl gelatin microspheres versus polyvinyl alcohol particles in the preoperative embolization of meningiomas. AJNR Am J Neuroradiol. 2000 Feb: 21 (2) :255-61．
25. Spenlehauer G, et al. Formation and characterization of cisplatin loadcd poly(d, l-lactide) microspheres for chemoembolization, J pharm Sci 1986: 75:750.
26．吴功柱，魏如槐，熊国军．5-氟脲嘧啶明胶微球化学交联固化研究．J 中国药房：1998 9(4)：154-155．
27. Berenstein A. Flow-controlled silicone fluid embolization. AJR Am J Roentgenol. 1980 Jun: 134(6):1213-8.
28. Miyazawa T, Murayama C, Yamanaka T, Fritz-Zieroth B. Cerebral embolization in rats induced by red blood cells treated with hypertonic X-ray contrast medium. Invest Radiol. 1993 Sep: 28(9):831-7.
29. Trocherie S, Alaoui F, Idee JM, Santus R, Court L. Electrocorticographic evaluation of iobitridol, a nonionic contrast medium, during selective cerebral arteriography in rabbits. AJNR Am J Neuroradiol. 1995 Sep; 16(8): 1637-42.
30. Hekster RE, Morre HH, Cleyndert P, Zapletal J, Sinnige LF, Bolstad B. Keetlapper Y. Intra-arterial digital subtraction angiography with isotonic dimeric (iodixanol) and monomeric (iohexol) nonionic contrast media: radiographic, clinical and neurophysiological evaluation. Neuroradiology. 1995 Jan: 37(1):48-50.
31．王剑红，陆彬，胥佩菱．肺靶向米托葸醌明胶微球的研究．药学学报，1995，30：549
32．王鹏，王玉珠，沈建民．均匀设计及其在药学中的应用．沈阳药学学报，1989，6：297
34. Montgomery DC. Response surface methodology. In: Montgomery DC. ed. Design and Analysis of Experiments. 2nd edition. New York: John Wiley & Sons, 1984. 445-474
35． Abu-Izza KA, Garcia-Contreras L, Lu DR. Preparation and evaluation of sustained release ATZ-loaded microspheres: optimization of the release characteristics using response surface methodology. J Pharm Sci, 1996, 85: 144
36． Abu-Izza KA, Garcia-Contreras L, Lu DR. Preparation and evaluation of sustained release ATZ-loaded microspheres. 2． Optimization of multiple response variables. J Pharm Sci, 1996, 85: 572
37． Molpeceres J, Guzman M, Aberturas MR, et al. Application of central composite designs to the preparation of polycaprolactone nanoparticles by solvent displacement. J Pharm Sci. 1996, 85: 206
38． Lou Y, Groves MJ, Klegerman ME. In-vivo and in-vitro targeting of a murine sarcoma by gelatin microparticles loaded with a glycan (PS1) . J Pharm Pharmacol. 1994 Nov; 46(11) :863-6．
39． Ford CW, Hamel JC, Stapert D, Yancey RJ. Establishment of an experimental model of a Staphylococcus aureus abscess in mice by use of dextran and gelatin microcarriers. J Med Microbiol. 1989 Apr; 28(4) :259-66．
40． Leung TW, Lau WY, Ho SK, Ward SC, Chow JH, Chan MS, Metreweli C, Johnson PJ, Li AK. Radiation pneumonitis after selective internal radiation treatment with intraarterial 90yttrium-microspheres for inoperable hepatic tumors. Int J Radiat Oncol Biol Phys. 1995 Nov 1 : 33(4) :919-24．
41． Kallskog O, Lindbom LO, Ulfendahl HR, Wolgast M. Regional and single glomerular blood flow in the rat kidney prepared for micropuncture. A methodological study. Acta Physiol Scand. 1975 Jun: 94(2) : 145-53．
42. Li H, Wang C, Wen Y, Wu H. Treatment of squamous cell carcinoma of the tongue using arterial embolism with cisplatin-ioaded albumin microspheres: a microstructural and ultrastructural investigation. Chin J Dent Res. 1999 Feb: 2(1):61-6.
43. Ho S, Lau WY, Leung TW, Chan M, Johnson PJ, Li AK. Clinical evaluation of the partition model for estimating radiation doses from yttrium-90 microspheres in the treatment of hepatic cancer. Eur J Nucl Med. 1997 Mar: 24(3): 293-8.
44. Nishioka Y, Kyotani S, Okamura M, Ohnishi S, Yamamoto Y, Kawashima Y, Tanada S, Nakamura T. A study of embolizing materials for chemo-embolization therapy of hepatocellular carcinoma: effects of particle size and dose on chitin-containing cisdiamminedichloroplatinum(Ⅱ) albumin microsphere antitumor activity in VX2 hepatic tumor model rabbits. Biol Pharm Bull. 1994 Sep: 17(9): 1251-5.
45. Nishioka Y, Kyotani S, Okamura M, Ohnishi S, Yamamoto Y, Tanada S, Nakamura T. A study of embolizing materials for chemo-embolization therapy of hepatocellular carcinoma: effects of chitin concentration on cis-diamminedichloroplatinum(Ⅱ) albumin microsphere properties and antitumor effect in VX2 hepatocellular carcinoma model rabbits. Biol Pharm Bull. 1993 Nov; 16(11): 1136-9.
46．李艳利，史永旭，姜涌明，等．壳聚糖多孔珠的制备及其作为亲和吸附剂载体的研究．药物生物技术：1998，5(4)：241-244
47. Vorlop K D, Klein J. In: Mosbach K ed. Methods in Enzymology, Acacemic press, Orlando, 1987, 135:259
48. Zimmermann A, Schubiger PA, Mettler D, Geiger L, Triller J, Rosier H. Renal pathology after arterial yttrium-90 microsphere administration in
pigs. A model for superselective radioembolization therapy. Invest Radiol. 1995 Dec; 30(12) :716-23．
49． Wollner IS, Knutsen CA, Ullrich KA, Chrisp CE, Juni JE, Andrews JC, Tuscan MJ, Stetson PL, Ensminger WD. Effects of hepatic arterial yttrium-90 microsphere administration alone and combined with regional bromodeoxyuridine infusion in dogs. Cancer Res. 1987 Jun 15; 47(12) : 3285-90．
50． Kassab AC, Xu K, Denkbas EB, Dou Y, Zhao S, Piskin E. Rifampicin carrying polyhydroxybutyrate microspheres as a potential chemoembolization agent. J Biomater Sci Polym Ed. 1997; 8(12) : 947-61．
51． Stridbeck H, Lorelius LE, Reuter SR. Collateral circulation following repeated distal embolization of the hepatic artery in pigs. Invest Radiol. 1984 May-Jun; 19(3) : 179-83．
52． Wright KC, Anderson JH, Gianturco C, Wallace S, Chuang VP. Partial splenic embolization using polyvinyl alcohol foam, dextran, polystyrene, or silicone. An experimental study in dogs. Radiology. 1982 Feb; 142(2) : 351-4．
53． Berenstein A, Kricheff Ⅱ. Catheter and material selection for transarterial embolization: technical considerations. Ⅱ. Materials. Radiology. 1979 Sep; 132(3) : 631-9．
54． Savastano S, Miotto D, Casarrubea G, Teso S, Chiesura-Corona M, Feltrin GP. Transcatheter arterial chemoembolization for hepatocellular carcinoma in patients with Child's grade A or B cirrhosis: a multivariate analysis of prognostic factors. J Clin Gastroenterol. 1999 Jun; 28(4) : 334-40
55． Wright KC, Greff RJ, Price RE. Experimental evaluation of cellulose acetate NF and ethylene-vinyl alcohol copolymer for selective arterial embolization. J Vasc Interv Radiol. 1999 Oct: 10(9) : 1207-18．
56． Koda Y, Kan Z, Wallace S, Kaminou T, Nakamura K, Yamada R. Hepatic microcirculatory changes induced by hepatic artery embolization in rats: original investigation. Invest Radiol. 1999 Feb; 34(2) : 160-6．
57． Derdeyn CP, Graves VB, Salamat MS, Rappe A. Collagen-coated acrylic microspheres for embolotherapy: in vivo and in vitro characteristics. AJNR Am J Neuroradiol. 1997 Apr; 18(4) : 647-53．
58． Higo R, Asai M, Sugasawa M, Takeuchi N, Nemoto S. Preoperative embolization for paraganglioma. Auris Nasus Larynx. 1994; 21(2) : 122-5．
59． Shi HB, Suh DC, Lee HK, Lim SM, Kim DH, Choi CG, Lee CS, Rhim SC. Preoperative transarterial embolization of spinal tumor: embolization techniques and results. AJNR Am J Neuroradiol. 1999 Nov-Dec: 20(10) : 2009-15．
60． Nakabayashi K, Negoro M, Handa T, Keino H, Takahashi M, Sugita K. Evaluation of particulate embolic materials with MR imaging, scanning electron microscopy, and phase-contrast microscopy. AJNR Am J Neuroradiol. 1997 Mar; 18(3) : 485-91．
61． Aso N, Matsunaga N, Fukuda T, Sakamoto I, Ashizawa K, Aikawa H. Isomoto I, Hayashi K, Fukushima T, Morikawa M. Multiple intrahepatic aneurysms following transcatheter arterial embolization. Work in progress. Radiology. 1994 Dec; 193(3) : 743-6．
62． Ugwoke MI, Kinget R. Influence of processing variables on the properties of gelatin microspheres prepared by the Emulsification
solvent extraction technique. J Microencapsul 1998 May-Jun;15(3) :273-281
63． Chuang VP, et al. Ivalon embolizalion in abdominal neoplasms. A.IK 1981, 136:729．
64． 魏树礼,刘秀英,于海霞.聚乙烯醇微球的研究.北京医科大学学报 : 1990, 2 (22) : 133-135
65． Steinberg EP, Moore RD, Powe NR, Gopalan R, Davidoff AJ, Lilt M, Graziano S, Brinker JA. Safety and cost effectiveness of high-osmolality as compared with low-osmolality contrast material in patients undergoing cardiac angiography. N Engl J Med. 1992 Feb 13: 326(7) : 425-30．
66． Davis WL, Nelson JA, Barry WH. Effects of contrast media on cultured myocardial cells. Invest Radiol. 1986 Aug; 21(8) : 626-30．
67． Thanoo BC, Jayakrishnan A. Barium sulphate-loaded p(HEMA) microspheres as artificial emboli: preparation and properties. Biomaterials. 1990 Sep; 11(7) : 477-81．
68． Ikenberry S, Lappas JC, Hana MP, Rex DK. Defecography in healthy subjects: comparison of three contrast media. Radiology. 1996 Oct; 201(1) : 233-8．
69． Rauch D, Drescher P, Knes JM, Madsen PO. Variable effects of iodinated contrast media on different rabbit arteries in vitro. Urol Res. 1997:25 Suppl 1:S21-3．
70． Motoji N, Shigematsu A, Minegishi A. Comparison of the effects of ioversol and other contrast media on the blood-brain barrier. Biol Pharm Bull. 1994 Feb: 17(2) :257-61．
71． Thanoo BC, Jayakrishnan A. Barium sulphate-loaded p(HEMA) microspheres as artificial emboli: preparation and properties. Biomaterials. 1990 Sep: 11(7) :477-81．
72． Gunther R, Klose K, Thelen M, Jacobi G. Superselective embolisation in the urogenital tract with tissue adhesives . ROFO Fortschr Geb Rontgenstr Nuklearmed. 1981 May: 134(5) :536-9．
73． Komatsu T, Nishide H, Tsuchida E. Structure and solution properties of lipidheme-microsphere. Artif Cells Blood Substit Immobil Biotechnol. 1994: 22(3) :855-60．
74． Yi SW, Kim YH, Kwon IC, Chung JW, Park JH, Choi YW, Jeong SY. Stable lipiodolized emulsions for hepatoma targeting and treatment by transcatheter arterial chemoembolization. J Control Release. 1998 Jan 2: 50(l-3) :135-43．
75． Tranbahuy P, Borsik M, Herman P, Wassef M, Casasco A. Direct intratumoral embolization of juvenile angiofibroma. Am J Otolaryngol. 1994 Nov-Dec: 15(6) :429-35．