摘要
壳聚糖/β-甘油磷酸钠是一种温度敏感性材料，在低温或者室温的环境下，呈液态，当温度升高到37℃时，逐渐呈现凝胶样的固态，利用这种温度敏感导致物理性质改变的特性，作为实验的依据，探讨其是否具有栓塞动静脉畸形的潜力，此项实验研究首先对壳聚糖/β-甘油磷酸钠，按照7:1的比例配制成溶液，在体外温度处于37℃时，测定其发生凝胶化过程中粘度值发生的变化，总共检测5个样本，结果显示，当时间平均超过130秒时，材料的粘度达到了一定程度，以后增加不明显，可以得出，在温度为37℃时，7：1壳聚糖/β-甘油磷酸钠溶液发生凝胶化的时间至少需要130s。
我们利用一种比较简易的体外AVM模型进行栓塞实验，将重约12g，直径约为2mm的数枚玻璃珠装入一个体积为10ml的注射器中，作为“畸形血管团”，玻璃珠与玻璃珠的间隙相当于畸形血管的血管腔，玻璃珠容器的一端通过输液器与生理盐水瓶与相连，作为“供血动脉”，另一端与直径约为2mm的输液器管相连，作为“引流静脉”，为了模拟颅内动脉压，将生理盐水瓶放置在玻璃珠容器上150cm高处，使通过畸形血管团的流速为0.3ml/s，将容纳有玻璃珠的“血管畸形团”浸在恒温水浴锅里，将温度调至37℃，循环用的生理盐水也是加热至37℃，不断循环使用的，按相同比例配置的壳聚糖/β-甘油磷酸钠溶液，栓塞了5个模型，其中4个模型栓塞成功，检查注射用的1ml注射器内壁，没有发现材料粘管。在栓塞完毕后，将成功栓塞的注射器两端封好，放入37℃恒温箱中，6个月后取出，观察未见降解、碎裂等现象，并将容器打开，发现材料与玻璃珠粘连紧密，材料在玻璃珠之间弥散良好，并没有发生降解。体外模拟栓塞实验的结果表明，壳聚糖/β-甘油磷酸钠溶液作为一种温度敏感性栓塞材料，可以有效栓塞体外AVM模型，弥散效果好，时间上可控，可以进一步进行动物实验研究。
最后将此材料应用于生物体内的栓塞研究，选用兔的肾动脉以及颈总动脉作为体内栓塞对象，首先选取9只兔子，三只一组，两组进行肾动脉栓塞实验，一组进行颈总动脉栓塞实验。对于肾动脉栓塞，采用导管介入的方法来完成，通过股动脉插管，置入4F造影导管，用2毫升造影剂行腹主动脉造影，清晰显示双侧肾动脉及其分支。然后将造影导管撤出，用微导管置入一侧肾动脉，造影充分显示该侧肾动脉及其分支。利用1.5-2毫升壳聚糖/β-甘油磷酸钠溶液顺利栓塞一侧肾动脉。栓塞过程可见材料能够达到肾动脉二级分支，术后立即造影显示肾动脉及其分支完全被栓塞材料封堵。材料推注时间控制在2分钟左右。术中无异位栓塞、粘管、导管堵塞等并发症。整个栓塞过程以及术后冲洗导管都顺利进行，没有发现材料导致导管的堵塞现象。在3个月的观察期中通过造影复查没有发现肾动脉再通。病理检查显示，术后2周可以看到栓塞侧肾脏较对侧明显苍白，肿大，而未栓塞的肾脏则大小正常，未发生肿胀。肾组织HE染色，可见肾小动脉被栓塞材料完全栓塞，管腔内可见机化的血栓、金属颗粒。但是有部分切片染色后，出现有栓塞材料从切片上脱落现象。术后3个月栓塞侧肾脏较对侧明显变小，且苍白；肾皮质变薄，肾髓质发生严重的液化性坏死。组织学显示，正常肾小球结构完全消失，被纤维组织所代替，近肾门处的动脉管腔内，可见材料以及金属颗粒，未见血栓。
对于颈总动脉的栓塞，采用手术直接注入材料的方法，即采用颈前正中切口，分离暴露好一侧颈总动脉，先用准备好的一根缝线在远端结扎颈总动脉，然后用血管夹在近端临时夹闭颈总动脉，用1毫升注射器抽取适量加入钽粉的材料，从颈总动脉远端、结扎处近端侧穿刺进去血管腔，然后注入约0.2ml左右的材料，并在穿刺点处用准备好的缝线结扎颈总动脉，抽出注射器，并将注入材料的颈总动脉还纳入组织深部，皮肤对合，保温。5分钟后，将颈总动脉重新暴露，将血管夹取下，逐层缝合筋膜以及皮肤。3个月后，病理检查显示，血管与周围组织粘连紧密，不易分离。病理学检查显示，血管腔内被机化的血栓以及材料充盈。体内栓塞实验证明壳聚糖/β-甘油磷酸钠，具备较好的弥散能力以及抗高压力血流冲击的能力。通过对此材料体外温度敏感特性的测定，栓塞体外AVM模型的尝试，以及对动物肾动脉与颈总动脉的栓塞效果的观察，综合评判，可以得出，壳聚糖/β-甘油磷酸钠具有作为一种可以栓塞AVM的潜力。
Chitosan/β-glycerophosphate sodium is a thermosensitive material,and it isliquid at low or normal tempreture.when tempreture increases to37℃,the materialbecomes solidity like gels gradually,We use its thermosensitive property asexperiment basis,and probe whether the material is fit for embolism of arteriovenousmalformation.Firstly,Chitosan and β-glycerophosphate sodium are mixed to solutionby the scale of7:1,And we measure5spesmens，change of viscosity in their gelling at37℃,The result is that the viscosity reach a peak when time passes130s,We canconclude that time which Chitosan/β-glycerophosphate sodium solution of a scale of7:1become gel needs at least130s at37℃.
We used an simple AVM model in vitro to do the embolic experiment,Twelvegrams of glass beads with a diameter of2mm were packed into a10ml disposableplastic syringe as an kind of deformed arteriolar,and the gap among glass beadsresemble lumina of defoemed vessels,One side of glass bead containers linked withthe physiological salt water bottles by infusion set as a supplied artery,and the otherside of the containers linked by infusion set with a diameter of2mm as drainingvenules,For imitating the intracranial pressure,The height of the saline bottle wasadjusted to150cm to maintain the saline flow rate through the column at0.3ml/s. Weput the containers soak in the thermostatic water bath at37℃,and the saline cycledwere heated up to37℃for cycle use,We embolized5models by Chitosan/β-glycerophosphate sodium solution with the same scale,Four models were allembolized successfully.There were no materials in the syringe set used inembolism,After embolism,we sealed the good embolitic containers and put in theconstant temperature box at37℃,The materials were not degradable and broken after6months,we opened these containers and observed that materials and beads wereadhesive closely,not degradable,and materials dispersed among beads very well.In vitro,the embolism experiment indicates that Chitosan/β-glycerophosphate sodiumcan effectively embolize AVM model as a thermosensative embolitic material，Itsdispersion effect is good,and embolitic time is controlled well,it needs further researchin vivo.
Finally the material used as the embolism research in vivo,We choose renalartery and common carotid artery of rabbit as embolism object, Firstly,we selectednine rabbits,three one each group,the two groups used renal artery embolizationexperiment,and one group used to carotid artery embolization experiment. For renalartery embolization,we used the method of catheter intervention to do the abdominalaorta radiography with2ml contrast agents through femoral artery intubation and4Fradiography catheter, and clearly showed bilateral renal artery and its branches. Thenwe withdrawed radiography catheter, and changed microcatheter to put in the renalartery and fully showed the renal artery and its branches by radiography again. Weused1.5-2ml chitosan/β-glycerophosphate sodium solution to embolize renal arterysuccessfully.Embolitic materials can achieve renal artery secondary branches,immediately radiography after the embolism show that renal artery and its branches iscompletely blocked embolism by materials.The inject time of material was2minutesapproximately.There were no ectopic embolization， sticky pipe,and tube jamcomplications. The whole process and rinse catheter after embolization were carriedout smoothly，and we did not find tube jam phenomenon in catheter. In the threemonths observation period,we did not find renal artery recanalisation by radiography.Histopathological examination showed,after two weeks embolized kidney wasobviously pale,swelling,but another side kidney was normal, did not happenswelling.Kidney tissues HE dyeing,we could find the renal artery was embolized bymaterials completely,and there were organizing thrombus,metal particles in the lumenof vessels, But embolism materials falled off from some slices after dyeing,3monthsafter embolization,the embolized kidney decreased significantly,and becomedpale;Renal cortical becomed thin, and medullary happened serious liquefactionnecrosis.Histology showed that normal glomerulus structure completelydisappeared,replaced by fibrous tissue,and there was materials and metal particles inrenal artery lumen near the renal door,we did not find thumbus.
For common carotid artery embolism,we injected directly into the material withsurgical operation method,It adopted the midline incision of neck,separated andexposed well common carotid artery, we used suture to ligate common carotid arteryat distal side,then clipped temporarily it in the proximal side by artery clamp,using1ml syringe extracted material with tantalum powder,the materials of0.2ml wereinjected to the common carotid artery from the ligation place proximal side,andcommon carotid artery was ligated at the place of puncture and syringe waswithdrawed at the same time,we put the embolized artery into tissue to keep warm.Five minutes later, we withdrawed vascular clip, and sutured fascia and skin step bystep. After3months, pathology examination showed, vessel and the surroundingtissue were adhesive closely, and it was not easy to separate. Pathology examinationshows that, there are organizing thrombus and materials in the lumen of vessels, Theexperiment in vivo proved Chitosan/β-glycerophosphate sodium has the gooddispersion ability and good resistance to high pressure blood blow.Throughtemperature sensitive characteristics measuring in vitro, and model AVM embolismtrail in vitro, and observation of the animal renal artery and common carotid arteryembolization effect, We can get a comprehensive evaluation thatChitosan/β-glycerophosphate sodium has a kind of potential as AVM embolizationmaterial.
引文
[1]赵继宗,王硕,隋大立,等.2086例脑动静脉畸形临床特征和手术治疗结果分析[J].中华神经外科杂志,2004,20(2):113-117.
[2] CASTEL JP,KANTOR G.Postoperative morbidity and mortality aftermicrosurgical exclusion of cerebral arteriovenous malformations.Current data andanalysis of recent literature[J].Neurochirurgie,2001,47:369-383.
[3] MORGAN MK,ROCHFORD AM,TSAHTSARLIS A,et al.Surgical risksassociated with the management of Grade I and II brain arteriovenousmalformations[J].Neurosurgery,2004,54(4):832-837.
[4] MORGAN MK,DRUMMOND KJ,GRINNELL V,et al.Surgery for cerebralarteriovenous malformation:risks related to lenticuostriate arterial supply [J].Neurosurgery,1997,86(5):801-805.
[5]王东,刘宁,陈海峰,等.脑干占位病变15例显微手术[J].南京医科大学学报,2003,23(4):359-361.
[6] DAVIDSON AS,MORGAN MK.How safe is arteriovenous malformationsurgery?A prospective,observational study of surgery as first-line treatment forbrain arteriovenous malformations[J].Neurosurgery,2010,66(3):498-504.
[7] LUNSFORD LD,KONDZIOLKA D,FLICKINGER J,et al. Stereotacticradiosurgery for arteriovenous malformations of the brain. J Neurosurg,1991,75:512-24.
[8] STEINER L,LEKSELL L,GREITZ T,et al.Stereotaxic radiosurgery for cerebra1arteriovenous ma1formations.Report of a case[J].Aeta Chir (Seand),1972,138(5):459-464.
[9] MARUYAMA K,SHIN M,TAGO M,et al.Gamma Knife surgery forarteriovenous malformations involving the corpurs callosum [J].Neurosurg,2005,102(Suppl):49-52.
[10]LUNSFORD LD,KONDZIOLKA D,FLIEKINGERL C,et al.stereotaxic radiosurgery for cerebral arteriovenous malformations of the brain [J].Neurosurg,1991,759(4):512-524.
[11]IZAWA M,HAYASHI M,CHERNOV M,et al.Long-term complications aftergamma knife surgery for arteriovenous malformations [J].Neurosurg,2005,102(Suppl):34-37.
[12]SZEIFERT GT,KEMENY AA,TIMPERLEY WR,et al.The potentia lrole ofMyofibroblasts in the obliteration of arteriovenous malformations after radiosurgery[J].Neuorosurgery,1997,40(1):61-66.
[13]梁军潮，王伟民，吴洪勋，等；脑AVM的伽玛刀立体定向放射手术研究[J].中国微侵袭神经外科杂志，2004，9(2):65-68.
[14]柏秀松，封亚平，封雨，等.X-刀放射治疗脑动静脉畸形合并胶质瘤1例[J].中华神经外科疾病研究杂志，2004，3(4):372-373.
[15]SHINY M,KAWAMOTO S,KURITAL H,et al.Retrospeetive analysis of a10-yearexperience of stereotactic radio surgery for arteriovenous malformation inchildren and adoleseents[J].Neuorosurg,2002,97(4):753-758.
[16]BERTHELSEN B,LOFGREN J,SVENDSEN P.Embolization of cerebralarteriovenous malformations with bucrylate: Experiences in a first series of29patients. Acta Radiol1990,31:13-21.
[17]FOURNIER D,TERBRUGGE KG,WILLINSKY R,et al.Endovascular treatmentof intracerebral arteriovenous malformations. J Neurosurg1991,75:228-33.
[18]HURST RW,BERENSTEIN A,KUPERSMITH MJ,et al.Deep centralarteriovenous malformations of the brain: The role of endovascular treatment. JNeurosurg,1995,82:190-195.
[19]WIKHOLM G..Occlusion of cerebral arteriovenous malformations with N-butylcyanoacrylate is permanent. AJNR Am J Neuroradiol,1995,16:479-482.
[20]WILMS G,GOFFIN J,PLETS C,et al.Embolization of arteriovenousmalformations of the brain: preliminary experience. J Belge Radiol,1993,76:299-303.
[21]HEILMAN CB,KWAN ES,KLUCZNIK RP,et al;Elimination of a cirsoidaneurysm of the scalp by direct percutaneous embolization with thrombogeniccoils. Case report. Journal of neurosurgery,1990-Aug,73（2）,296-300.
[22]HENDRIX LE,MEYER GA,ERICKSON SJ,Cirsoid aneurysm treatment bypercutaneous injection of sodium tetradecyl sulfate. Surgical neurology,1996Dec,46(6):557-560.
[23]KASDON DL,ALTEMUS LR,STEIN BM,Embolization of a traumaticarteriovenous fistula of the scalp with radiopaque Gelfoam pledgets. Case reportand technical note. Journal of neurosurgery,1976-Jun,44(6),753-756.
[24]KHODADAD G.Arteriovenous malformations of the scalp. Annals of surgery1973-Jan,177(1):79-85.
[25]MAROTTA TR,BERENSTEIN A,ZIDE B.The combined role of embolizationand tissue expanders in the management of arteriovenous malformations of thescalp.AJNR. American journal of neuroradiology,1994-Aug15(7),1240-1246.
[26]MATHIS J M,DENARDO A J,JENSEN M E,et al.Arteriovenous fistula of thescalp after hair transplantation treated by endovascular embolization.Annals ofplastic surgery,1994-Dec,33(6)633-637.
[27]杜浩，马廉亭，吴佐泉.血管内颗粒栓塞材料的研究进展[J].中国临床神经外科杂志，2007，12(6):375-378.
[28]姜除寒，吴中学，脑动静脉畸形的非粘附性液体栓塞材料，国外医学脑血管疾病分册，2000,10.8（5）255-258.
[29]HOWINGTON JU,KERBER CW,HOPKINS N,et al.Liquid embolic agents in thetreatment of intracranial arteriovenous malformations[J].Neurosurg Clin NAm,2005,16:355-363.
[30]DEBRUN GM, ALETICH V, AUSMAN JI, et al. Embolization of the nidus ofbrain arteriovenous malformations with N-butyl cyanoacrylate.Neurosurgery1997,40:112-120.
[31]DEMERITT JS,PILE-SPELLMAN J,MAST H,et al. Outcome analysis ofpreoperative embolization with N-butyl cyanoacrylate in cerebral arteriovenousmalformations. AJNR Am J Neuroradiol,1995,16:1801-1807.
[32]FOURNIER D,TERBRUGGE KG,WILLINSKY R, et al. Endovascular treatmentof intracerebral arteriovenous malformations: experience in49cases. J Neurosurg1991,75:228-233.
[33]WIKHOLM G,LUNDQVIST C,SVENDSEN P.Embolization of cerebralarteriovenous malformations.Part I.Technique,morphology,and complications.Neurosurgery,1996,39:448-457.
[34]MOON HEE HAN, SU OK SEONG, HONG DAE KIM, CraniofacialArteriovenous Malformation: Preoperative Embolization with Direct Punctureand Injection of n-Butyl Cyanoacrylate Radiology,June1999,211:3661-666.
[35]OOWAKI H,MATSUDA S,SAKAI N,et al.Non-adhesive eyanoaerylate as anembolic material for endovaseular neurosurgery.[J].Biomaterials,2000,21:1039-1046.
[36]CHALOUPKA JC,VI UELA F,VINTERS HV,et al.Technical feasibility andhistopathologic studies of ethylene vinyl copolymer (EVAL) using a swineendovascular embolization model. AJNR Am J Neuroradiol,1994.15:1107-1115.
[37]SAMPEI K,HASHIMOTO N,KAZEKAWA K,et al.Histological changes in braintissue and vasculature after intracarotid infusion of organic solvents in rats.Neuroradiology,1994,38:291-294.
[38]MURAYAMAY,VINUELA F,ULHOA A,et al.Nonadhesive liquid embolic agentfor cerebral arteriovenous malformations:Preliminary histoPathological studies inswine rete mirabile[J].Neurosurgery,1998,43(5):1164-175.
[39]JOHN C.CHALOUPKA,DANIEL C.HUDDLE,JONATHAN ALDERMAN,etal.A reexamination of the Angiotoxicity of Superselective Injection of DMSO inthe Swine Rete Embolization Model.AJNR Am J Neuroradiol,1999.March.20:401-410.
[40]AKIN ED,PERKINS E,ROSS IB.Surgical handling characteristics of an ethylenevinyl alcohol copolymer compared with N-butyl cyanoaerylate used forembolization of vessels in an arteriovenous malforrnation resection model inswine[J]. J Neurosurg,2003,98(2):366-370.
[41]TAKI W,YONEKAWA Y,IWATA H,et al.A new liquid material for embolizationof arteriovenous malformations[J].AJNR Am J Neuroradiol,1990,11(l):163-168.
[42]HOWINGTON JU,KERBER CW,HOPKINS N,et al.Liquid embolic agents in thetreatment of intracranial arteriovenous malformations.[J].Neurosurg ClinNAm,2005,16:355-363.
[43]DUFFNER F,RITZ R,BORNEMANN A,et al: Combined therapy of cerebralarteriovenous malformations:histological differences between a nonadhesiveliquid embolic agent and n-butyl-2-cyanoacrylate (NBCA).Clin Neuropathol2002,21:13-17.
[44]VINTERS HV,DEBRUN G,KAUFMANN JC,et al:Pathology of arteriovenousmalformations embolized with isobutyl-2-cyanoacrylate (bucrylate).Report oftwo cases.[J]Neurosurg,1981,55:819-825.
[45]VINTERS HV,GALIL KA,LUNDIE MJ,et al: The histotoxicity of cyanoacrylates.A selective review.Neuroradiology1985,27:279-291.
[46]NBCA TRIAL INVESTIGATORS: N-butyl cyanoacrylate embolization ofcerebral arteriovenous malformations: results of a prospective, randomized,multi-center trial. AJNR Am J Neuroradiol,2002,23:748-755.
[47]JAHAN R,MURAYAMA Y,GOBIN YP,et al;Embolization of arteriovenousmalformations with Onyx:clinicopathological experience in23patients.Neurosurgery,2001,48:984-987.
[48]PIEROT L,JANUEL AC,HERBRETEAU D,et al.Endovascular treatment of brainarteriovenous malformations using Onyx: preliminary results of a prospectivemulticenter study. Interv Neuroradiol,2005,11:159-164.
[49]PéREZ-HIGUERAS A,ROSSI LOPEZ R,Quinones Taria D.Endovasculartreatment of cerebral AVM: our experience with Onyx. Interv Neuroradiol,2005,11:141-157.
[50]MANDAI S,KINUGASA K,OHMOTO T.Direct thrombosis of aneurysms withcellulose acetate Polymer.Part Ⅱ:results of thrombosis in experimentalaneurysms[J].J Neurosurg,1992,77:497-500.
[51]KINUGASA K,MANDAIS,TERAI Y.Direct thrombosis of aneurysms withcellulose acetate Polymer.Part11;Preliminary clinical experience.[J].J Neurosurg,1992,77:501-507.
[52]TOKUNAGA K,KINUGASA K,MEGURO T,et al.Embolization of cerebralarteriovenous malformations with cellulose acetate polymer. Histological study ofthe resected specimens.interv Neuroradiol.1998Nov30;4Suppl1:117-20.
[53]姜除寒，吴中学，王忠诚，等.聚氨酯栓塞脑动静脉畸形的动物实验研究[J].中国神经精神疾病杂志,2002,28(4):276-279.
[54]DUDEEK O,JORDANO,HOFLHLANN KT,et al.Intrinsically radiopaqueiodine-containing polyvinyl alcohol as a liquid embolic agent:evaluation inexperimental Wide-necked aneurysms.[J].J Neurosurg,2006,104(2):290-297.
[55]HAMADA JL,KAI Y,MORIOKA M,et al.A nonadhesive liquid embolic agenteomposed of ethylenevinyl alcohol copolymer and ethanol mixture for thetreatment of cerebral arteriovenous malformations:experimental study.[J].JNeurosurg,2002,97(4):889-895.
[56]HAMDAJL,KAIY,MORIOKA M,et al.A mixture of ethylene vinyl alcoholcopolymer and ethanol yielding a nonadhesive liquid embolic agent to treatcerebral arteriovenous malformations:initial clinical experience[J].J Neurosurg,2002,97(4):881-888.
[57]KAZEKAWA K,IWATA H,SHIMOZURU T,et al.Nontoxic embolic liquids fortreatment of arteriovenous malformations[J].J Biomed MaterRes,1997,38(2):79-86.
[58]KLISEH J,YIN L,REQUEJO F,et al.Liquid2-Poly-hydroxyethyl-methaerylateembolization of experimental artefiovenous malformations:feasibility study [J].Am J Neuroradiol,2002,23(3):422-429.
[59] KLISEH J,SEHELLHAMMER F,ZITT J,et al.Combined stent implantation andembolization with liquid2-polyhydroxyethyl methacrylate for treatment ofexperimental canine wide-necked aneurysms[J].Neuroradiology,2002,44(4)503-512.
[60]MASSOUD TF,JI C,VINUELA F,et al.An experimental arteriovenousmalformation model in swine: anatomic basis and construction technique. AJNRAm J Neuroradiol1994,15:1537-1545
[61]POTHMANN D,ULUSANS S,PROLS F,et al. Liquid2-P-HEMA forendovaseular tumor therapy in vivo feasibility study.[J].Med Sci Monit,2004march,10(8):BR.286-293.
[62]YAMASHITA K,TAKI W,IWATA H,et al.A cationic polymer.Eudragit Earteriovenous malformations[J].Neuroradiology,1996,38(SuPPl1):151-156.
[63]SADATO A,NUMAGUEHI Y,TAKI W,et al.Non-adhensive liquid embolic agent:role of its components in histologic changes in embolized arteries [J]AeadRadiol,1998,5(3):198-206.
[64]SADATO A,TAKI W,IKADA Y,et al.Experimental study and clinical use ofpoly(vinyl acetate)emulsion as liquid embolization material [J]. Neuroradiology,1994,36(8):634-641.
[65]PARK S1,LEE DY,WON JY,et al.Renal artery embolization using a new liquidembolic material obtained by partial hydrolysis of polyvinyl acetate(Embol):initial experience in six patients[J].Koroan J Radiol,2000,l(3):121-126.
[66]SUNG KB,PARK SS,YOON HK.et al. Study on effectiveness and safety of portalvein embolization using a new liquid embolic material (Embol-78-12) in pigs. JKorean Radiol Soc,1999,40:237-246.
[67]PARK SS,YOON HK,LEE NS.et al. Portal vein embolization with use of a newliquid embolic material: An experimental study. J Vasc Interv Radiol1999,10:339-345.
[68]MATSUMARU Y,HYODO A,NOSE T,et al.Application of thermosensitivepolymers as a new embolic material for intravascular neurosurgeryI [J].JBiomater Sci Polym Edn,1996,7(9):795-804.
[69]SHENG XZ,LIU ZQ,WU LB,et al.Technical feasibility and histopathologicstudies of poly(N-isopropylaerylamide)as a non-adhesive embolic agent in swinerete mirabile[J].Chin Med J(Eng),2006,119(5):391-396.
[70]HIRANO S,NOISHIKI Y. J Biomed Mater Res1985,19:413-417.
[71]LEE KY,HA WS,PARK WH. Biomaterials1995,16:1211-1216.
[72]SAKAI K,KATSUMI R,ISOBE A,Nanjo F.Biochem Biophys Acta1991,1079:65-72.
[73]HIRANO S,TSUCHIDA H,NAGANO N.Biomaterials1989,10:574-576.
[74] CELIK O,AKBUGA J.Preparation of superoxide dismutase loaded chitosanmicrospheres: charaeterization and release studies[J].Eur J Pharm Biopharm,2007,66(1):42-47.
[75]AGNIHOTRI SA,ALNINABHAVI TM.Novel interpenetrating networkchitosan-poly (ethylene oxide-g-acrylamide)hydrogel microspheres for theeontrolled release of capecitabine[J].Int J Pharm,2006,324(2):103-115.
[76]徐静，陈红，曾宪仕，等.壳聚糖及其衍生物在生物医药中的研究进[J].化学研究与应用，2010(9):1097-1101.
[77]聂宏光，陈磊，王岩，等.羧甲基壳聚糖对大鼠单一心室肌细胞ATP钾电流的作用[J].中国海洋药物，2008(1):25-27.
[78]袁菊萍，黄金华，陆媛.壳聚糖抗动脉粥样硬化的实验研究[J].医药导报，2009(6).698-699.
[79]杨军坷，吴宗贵，郭延松，等.壳聚糖对大鼠动脉粥样硬化的影响及机制探讨[J].心血管康复医学杂志，2007(5).488-492.
[80]SONG L,ZHU D,LIU L,et al.Evaluation of the coagulation properties ofarginine-chitosan/DNA nanopartieles[J]. J Biomed Mater Res B Appl Biomater2010,95(2):374-379.
[81]ROUSSY J,VAN VOOREN M,DEMPSEY BA,et al.Influence of chitosancharacteristics on the coagulation and the flocculation of bentonite suspensions[J].Water Res,2005,39(14):3247-3258.
[82]TANG H,ZHANG P,KIEFT TL,et al.Antibacterial action of a novelfunctionalized chitosan-arginine against Gram-negative bacteria [J].ActaBiomater,2010,6(7):2562-2571.
[83]BROWN C A,WANG B,OH J H.Antimicrobial activity of lactoferrin againstfoodborne pathogenic baeteria ineorporated into edible chitosan film [J].J FoodProt,2008,71(2):319-324.
[84]CHENITE A,CHAPUT C,WANG D,et al.Novel injectable neutral solutions ofchitosan form biodegradable gels in situ [J].Biomaterials,2000,21(21):2155-2161.
[85]RUEL-GARIEPY E,CHENITE A,CHAPUT C,et al.Charaeterization ofthermosensitive chitosan gels for the sustained delivery of drugs [J].Int JPharm,2000,203(1-2):89-98.
[86]甄勇，许侃，陈学思，等.应用组织工程材料栓塞动脉瘤的初步研究[J].中华医学杂志，2009,89(11):5.727-731.
[87] YUBO WANG,QI LUO,NING XU,et.al.In Vivo Assessment of Chitosan/β-Glyceroph-osphate as a New Liquid Embolic Agent [J].Interventional Neuroradiolog.2011Mar,17(1):87-92.
[88]陈益清,孙多先,刘静怡等.微囊化海藻酸离子移变凝胶的制备、结构与性能[J].高等学校化学学报,2003,24(1):117-120.
[89]刘群,薛伟明,于炜婷等.海藻酸钠-壳聚糖微胶囊膜强度的研究[J].高等学校化学学报,2002,23(7):1417-1420.
[90]郑洪河,王利亚,张虎成等.海藻酸钠溶液溶胶-凝胶相转变过程的光谱学研究[J].光谱学与光谱分析,1998,18(5):547-550
[91]VIEGAS TX,REEVE LE,Henry RL.Medical uses of in-situ formed gels [P].USPat.5318780,7June l994.
[92]MURATA Y,TONIWA S,MIYAMOTO E,et al.Preparation of alginate gel beadscontaining chitosan salt and their function,[J].International Journal ofPharmaceutics,1999,176:265-268
[93]MURATA Y,KONTANI Y,OHMAE H,et al.Behavior of alginate gel beadscontaining chitosan salt prepared with water-soluble vitamins [J].EruopeanJounra1of Pharmacetuics and Biopharmacetuics,2002,53:249-251.
[94]MURATA Y,SASAKI N,MIYAMOTO E,et al.Use of floating alginate gel beadsfor stomach-specific drug delivery [J].European Journal of Pharmaceutics andBiopharmaceutics,2000,50:221-226.
[95]马建标,王红军,何炳林.壳聚糖与胶原或海藻酸复合物海绵的制备以及人胎儿皮肤成纤维细胞在其中的生长.自然科学进展,2002,10(10):896-903.
[96]ALEXANDER D.AUGST, HYUN JOON KONG, David J. Mooney. AlginateHydrogels as Biomaterials.[J]. Macromol. Biosci,2006,6,623-633.
[97]RACHEL GLICKLIS,LILIA SHAPIRO,RIAD AGBARIA,et al： HepatocyteBehavior Within Three-Dimensional Porous Alginate Scaffolds[J]. BiotechnologyAnd Bioengineering,2000Feb67,（3）.344-353.
[98]KIM SH,JANG JW,JUNG SH,et al：Chondrogenesis of Rat Bone MarrowStromal Cells in Transforming Growth Factor-beta1Loaded Alginate Bead in InVivo.[J].Tissue Engineering And Regenerative Medicine,2008Dec5.4（6）.650-659..
[99] BECKER TA,PREUL MC,BICHARD WD,et al：Preliminary investigation ofcalcium alginate gel as a biocompatible material for endovascular aneurysmembolization in vivo.[J].Neurosurgery.2007Jun,60(6):1119-1127.
[100] MARUYAMA K,KAWAHARA N,SHIN M,et al.The risk of hemorrhage afterradiosurgery for cerebral arteriovenous malformations.N Engl J Med2005,352:146-53.
[101] HOEY MF,COURAGE GR,NEWTON TH.et al.Management of vascularmalformations of the mandible and maxilla: Review and report of two casestreated by embolization and surgical obliteration.[J].Oral Surg.197028:696.
[102] TAYLOR BG,ETHEREDGE SN,Hemangiomas of the mandible and maxillapresenting as surgical emergencies. Am J Surg.1964.108:574.
[103] AZZOLINI A,BERTANI A,RIBERTI C.Superselective embolization andimmediate surgical treatment: Our present approach to treatment of largevascular hemangiomas of the face. Ann Plast Surg,19829:42.
[104] DJINDJIAN R,COPHIGNON J,THéRON J,et al.Embolization bysuperselective arteriography from the femoral route in neuroradiology.Reviewof60cases:I. Technique,indications,complications.Neuroradiology,19736:20.
[105] LEIKENSOHN J R,EPSTEIN L I,VASCONEZ LO. Superselectiveembolization and surgery of noninvoluting hemangiomas and AVmalformations,Plast.Reconstr.Surg,1981,68:143.
[106] MERLAND JJ,RICHé MC,HADJEAN E.The Use of SuperselectiveArteriography, Embolization and Surgery in the Current Management ofCervicocephalic Vascular Malformations (350cases).In H.B. Williams(Ed.),Symposium on Vascular Malformations and Melanotic Lesions. St Louis:Mosby,1983,135-143.
[107] MARUYAMA K,KAWAHARA N,SHIN M,et al.The risk of hemorrhage afterradiosurgery for cerebral arteriovenous malformations.N Engl J Med2005,352:146-53.
[108] CHALOUPKA JC,VINUELA F,ROBERT J,et al.An in vivo arteriovenousmalformation model in swine:preliminary feasibility and natural historystudy.AJNR Am J Neuroradiol.1994May,15(5):945-50.
[109] MASSOUD TF, JI C,VINUELA F.et al.Labortory simulations and training inendovascular embolotherapy with a swine arteriovenous malformation model[J]. AJNR Am J Neuroradiol,1996,17(2):271-219.
[110] MURAYAMA Y,MASSOUD TF,VI NUELA F.Hemodynamic changes inarterial feeders and draining veins during embolotherapy of arteriovenousmalformations: an experimental study in a swine model [J].Neurosurgery,1998,43(1):96-104.
[111] MASSOUD TF, VINTERS AV, CHAO RH.et al.Histopathologic characteristicsof a chronic arteriovenous malformation in a swine model: preliminary study[J].AJNR Am J Neuroradiol,2000,21(7):1268-1276.
[112]李健于耀宇赵振伟，脑动静脉畸形动物模型的初步建立，中国临床神经外科杂志.2010.11.15,(11),668-671.
[113] SIEKMANN R,WAKHLOO AK,LIEBER BB,et al.Modification of apreviously described arteriovenous malformation model in theswine:endovascular and combined surgical endovascular construction andhemodynamics [J].AJNR,2000,21:1722-1725.
[114] KLISCH J,REQUEJO F,YIN L,et al.The two-in-one model:a new variation ofthe arteriovenous malformation model in swine [J].Neuroradiology,2001,43:393-397.
[115] WAKHLOO AK,LIEBER BB,SIEKMANN R,et al.Acute and chronic swinerete arteriovenous malformation models:hemodynamics and vascularremodeling, AJNR Am J Neuroradiol,200526:1702-1706.
[116] BECKER TA,KIPKE DR,PREUL MC,et al.In vivo assessment of calciumalginate gel for endovascular embolization of a cerebral arteriovenousmalfmation model using the swine rete mirabile [J].Neurosurgery,2002,51:453-458.
[117] QIAN Z,CLIMENT S,MAYNAR M,et al.A simplified arteriovenousmalformation model in sheep:feasibility study.AJNR,1999,20(5):765-770.
[118] ATHULA KARUNANYAKA,JIAN TU,AMY WATLING.et al.Endothelialmolecular changes in a rodent model of arteriovenous malformation.[J] JNeurosurg,2008Dec,109(6):1165-72.
[119] PIETILA TA,ZABRAMSKI JM,THELLIER JA,et al.Animal model for cerebralarteriovenous malformation [J].Acta Neruochir(Wien),2000,142:1231-1240.
[120] BATES MC,DORROS G,PARODI J,et al.Reversal of the directionof internalcarotid artery blood flow by occlusion of the common and external Carotidarteries in a swine model [J].Catheter Cardiovasc Interv,2003,60(2):270-275.
[121] JARRY C,CHAPUT C,CHENITE A,et al.Effeets of steam sterilization onthermogelling ehitosan-based gels[J].J Biomed Mater Res,2001,58(1):127-135.
[122] JARRY C,LEROUX J C,HAECK J,et al.Irradiating or autoclaving chitosan/polyolsolutions:Effect on thermogelling chitosan-beta-glycerophosPhatesystems [J]. Chem Pharm Bull(Tokyo),2002,50(10):1335-1340.
[123] PARK S,YOON H,SUH DC,et al.An arteriovenous malformation model fortesting liquid embolic materials.AJNR Am J Neuroradiol,1997,18(10):1892-1896.
[124] KEHTER CW,HEEHT ST,KNOX K.Arteriovenous malformation model fortraining and research.AJNR Am J neuroradiol,1997,18(8):1229-1232.
[125] HEEHT ST,HORTON JA,KERBER CW.Hemodynamics of the central nervoussystem arteriovenous malformation nidus during particular embolization：acomputer model.Neuroradiology,1991,33（1）:62-64.
[126] YAMASHITA K,TAKI W,LWATA H.A cationic polymer,Eudragit-E,as a newliquid embolic material for arteriovenous malformations.Neuroradiology.1996May,38Suppl1:S151-156.
[127] HISAYUKI OOWAKI,SHOJIRO MATSUDA,NOBUYUKI SAKAI.etal.Non-adhesive cyanoacrylate as an embolic material for endovascularneurosurgery.Biomaterials,200021.1039-1046.
[128] HIROYUKI TAKAO,YUICHI MURAYAMA,MASAKI EBARA.et al.Newthermoreversible liquid embolic agent for embolotherapy:technical report.Neuroradiology,2009,51:95-98.
