温敏性壳聚糖/甘油磷酸钠栓塞猪脑动静脉畸形模型的实验研究
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摘要
脑动静脉畸形（cerebral arteriovenous malformation，cAVM）是一种较常见的脑血管发育异常所致的先天性脑血管病。多在40岁以下的中青年发病，临床表现为颅内出血、癫痫、脑缺血、局部神经功能障碍及头痛。在形态学上，cAVM为一条或数条供血动脉与一条或数条引流静脉间有一异常的畸形血管团，在供血动脉及引流静脉之间有一个或多个瘘口，其间多缺乏毛细血管床，畸形血管团无正常的弹力层和内膜。在血液动力学上，畸形血管团内多处于高血流量，高灌注状态，具有通过低阻力病灶的动静脉分流。长期的高灌注状态使得静脉弹力层异常增厚、缺乏弹性，局部可形成静脉瘤，多发生破裂出血，严重危害患者的健康。因此，对于这些病人通常要进行积极的治疗。
cAVM治疗方法分为传统手术切除治疗、血管内介入栓塞治疗及放射治疗。其中介入栓塞治疗对患者创伤最小，为患者所青睐。近年来，随着介入材料的更新、栓塞材料的改进以及神经介入医生通过大量的临床实践提高了介入技巧和临床经验。血管内栓塞cAVM已经发展成为切除手术之外最有效的治疗手段之一。但是目前临床应用的栓塞材料均存在局限性，成为制约其疗效的主要因素。
理想的栓塞材料应具备：1）材料为液体，弥散性良好，能保证足够长的注射时间；2）栓塞效果持久；3）无毒性，无致畸、致癌、致突变；4）有良好的组织相容性；5）易于控制，不黏管；6）在栓塞过程中可见到栓塞剂显影；7）复查时栓塞剂不显影。
壳聚糖（Chitosan CS）与甘油磷酸钠（Glycerophosphate Salt GP）以一定的比例混合后，在室温23℃下为液态，在生理体温37℃下转变为水凝胶。本研究应用温度敏感性CS/GP水凝胶栓塞猪的脑动静脉畸形模型。
首先经过显微血管吻合技术建立猪的脑动静脉畸形模型，经过血管造影证实模型是否成功。通过调整壳聚糖的脱乙酰度（Deacetylation Degree DD）、分子量（Mw）及与甘油磷酸钠的体积比，探索二者混合后适合介入栓塞的成胶时间。加入不同浓度及不同产品液态显影剂（ContrastAgent CA）。应用成胶时间适合作为栓塞材料的CS/GP/CA混合液，栓塞猪的脑动静脉畸形模型。栓塞后3天，2周，8周复查血管造影，检查是否存在血管再通现象。行组织学检查，观察栓塞剂是否对血管壁有损害。通过此实验研究，旨在探索一种新型不黏管、能够栓塞脑动静脉畸形的液体栓塞材料。
Objectives
The goal of this study was to analyze the feasibility of embolization of cerebralarteriovenous malformation by thermosensitive chitosan(CH)/β-glycerophosphate disodiumsalt (β-GP) hydrogels through in vivo/in vitro experiments.
Methods
1. To study the effects that thermosensitive chitosan(CH)/β-glycero-phosphate disodiumsalt(β-GP) solution-sol/gel system has on the gelation time and mechanical properties afterdifferent contrast agents (CA) were added at37℃in order to determine contrast agent releasefrom hydrogel.
2. Nine swines were selected as experimental animals. Cerebral arterio-venous malformationmodel of swines was built with Rete Mirabile（REM）of swines used as nidus, one commoncarotid artery and internal jugular vein anastomosed using microsurgical technique, andexternal carotid artery ligated. The swines were put into three groups with three in one group,and arteriography was operated to common carotid arteries of swines in acute phase(1-3daysafter operation),subacute phase(1-3weeks after operation) and chronic phase(over3weeksafter operation). This is to evaluate whether the model has been successfully built througharteriography.
3. Chitosan(CH)/β-glycerophosphate disodium salt (β-GP) with addition of the appropriatecontrast agent(CA) was used to conduct embolization experiment of cerebral arteriovenousmalformation model of swines.
3.1To prepare2%w/v chitosan and12%w/v β-glycerophosphate disodium salt solution, andto mix it with contrast agent20%v/v Visipaque with their volume ratio of1:1:1at23℃. Toprepare fresh when it will be used.To determine gelation time with inverted tube test.
3.2To embolize bilateral rete mirabile of swines with chitosan/β-glycerophosphatedisodium salt/Visipaque solution and sol/gel tran-sition system.
3.2.1Eighteen swines were divided into two groups: Low flow experimental group：One group was nine swines directly embolism on one side of the REM; High flow experimentalgroup: The other group was nine swines embolism on two sides of the REM aftersuccessfully-built cerebral arteriovenous malformation models with common carotid arteryand internal jugular vein anastomosis. To conduct femoral artery puncture with Seldingertechnique, put6F catheter sheath inside femoral artery, insert5F angiography catheterselectively into the other common carotid artery of the anastomosis of blood vessel, injectVisipaque contrast agent using high pressure injector to perform angiography (injection rate4ml/s, dosage6ml) to understand the basics of AP, REM and connected arteries. Change6Fguiding catheter with the head end close to AP, conduct digital subtraction angiography(dosage6ml, rate4ml/min, pressure300mmHg). And then place a Tracker18microcatheter/Seeker14microguidewire combina-tion through guiding catheter superselectively into thestart area of REM via AP. Next, after angiography, conduct superselective angiograms usingnonionic isotonic Visipaque (dosage2ml, rate1ml/min, pressure180mmHg). Injectchitosan/β-glycerophosphate disodium salt/Visipaque solution and sol/gel transition systemthrough a microcatheter (injection rate0.2ml-0.5ml/min, dosage0.3-0.5ml, injection time1.5-3min). In order to observe the degree of embolization, conduct DSA with the injection ofcontrast agent after fluoroscopic observation of the embolization of embolic agent and theflow direction with hand push contrast agent “smoking”during the injection of embolic agent.Continue to inject embolic agent if REM fails to be occluded completely until REM does notdevelop through microcatheter angiography. Use Tracker10microcatheter to enter RA andAA superselectively to conduct superselective angiograms. Inject chitosan/β-glycero-phosphate disodium salt/Visipaque solution and sol/gel transition system(injection rate0.2ml-0.3ml/min, dosage0.1-0.2ml, injection time1.5-3min) until REM does not developthrough guiding catheter angiography. After embolotherapy, slowly withdraw themicrocatheter., press the puncture site for15minutes, and apply sterile pressure dressing.
3.2.2Low flow experimental animals and high flow experimental group were separately putinto3groups, with3swines in each group. They were re-examined with angiography1week,2weeks and8weeks after embolization respectively to evaluate the existence ofrevascularization.
3.2.3After re-examinations with angiography1week,2weeks and8weeks afterembolization, the swines in each group were executed with over-dose narcotic amobarbital（100mg/kg), and then were subsequently conducted REM histological examination.
4. Statistical analysis
Experimental data are reported as means±SD. Data were analyzed using one wayanalysis of chi square tests with a minimum confidence level (p <0.05) for statisticalsignificance.
Results
1. chitosan (CH)/β--glycerophosphate disodium salt (β-GP) hydrogels have goodbiocompatibility, thermosensitivity and high viscosity. The addition of contrast agent ofcertain concentration did not impede the formation of thermosensitive chitosan hydrogels.
2. The chitosan (CH)/β--glycerophosphate disodium salt (β-GP) solution has high viscosityat23℃, while it is good for the control of injection rate when it forms hydrogels at37℃.
3. Same volume mixed solution of94%degree of deacetylation (DD) and2%w/v chitosan,12%w/v β--glycerophosphate disodium salt and20%v/v nonionic isotonic Visipaque hasmoderate gelation time at37℃(120.00±1.82s), which is good for embolism injection.
4. The cerebral arteriovenous malformation model was successfully built throughmicrosurgical formation end-to-end anastomosis arteriovenous fistula between the rightcommon carotid artery and the internal jugular vein. With angiography, it could be seen thatblood flew through three feeding arteries, i.e, ascending pharyngeal artery AP, ramusanastomoticus RA and arteria anastomotica AA. Nidus (bilateral retia mirabilia), throughdraining vein, i.e., right ascending pharyngeal artery and right common carotid artery, goesinto the right internal jugular vein via the anastomotic stoma. It proved that this model wasacute and subacute phase animal model, which can be experimented for new embolismmaterials.
5. The chitosan (CH)/β--glycerophosphate disodium salt (β-GP) hydrogel embolized thecerebral arteriovenous malformation model of swines, and REM was completely embolized.Eighteen swines of embolism was successful except one swine cause convulsions, stoppage of breathing and death in interventional procedure. Due to the embolization of REM and externalcarotid artery at the same time, one swine was found to develop ipsilateral facial paralysis,masticatory muscle weakness, little intake of food and emaciation.
6. Angiography was conducted again after1week,2weeks and8weeks of embolization, andrevascularization was not seen.
7. Histological examination. REM sample was generally found to be gray, tough and easy tobe peeled. Light microscopic examination (HE staining):3days after embolization bloodvessel lumens were filled with hydrogels, the vascular intima remain intact and the necrosis ofit was not seen. No neutrophils in blood vessel lumens or obvious inflammatory reactionswere found.2weeks after embolization scattered macrophages were found through REMlight microscopic exam, blood vessel lumens were still filled with hydrogels, thrombusformed, vascular intima did not drop, slight inflammatory change was found within bloodvessel lumens, scattered lymph cells were discovered in adventitia of blood vessel, thenecrosis of vascular walls was not seen.8weeks after embolization arterioles were still filledwith hydrogels through REM light microscopic exam, slight inflammatory reactions werefound, no necrosis or dropping of vascular intima was found, that is to say inflammatorymacrophages swallowed hydrogels, the vascular intima remain intact, and medial membranestructure remain normal.
Conclusion
Thermosensitive chitosan(CH)/β--glycerophosphate disodium salt (β-GP) hydrogels canembolize cerebral arteriovenous malformation model of swines, and have the potential ofbecoming new embolic materials.
cAVM治疗方法分为传统手术切除治疗、血管内介入栓塞治疗及放射治疗。其中介入栓塞治疗对患者创伤最小，为患者所青睐。近年来，随着介入材料的更新、栓塞材料的改进以及神经介入医生通过大量的临床实践提高了介入技巧和临床经验。血管内栓塞cAVM已经发展成为切除手术之外最有效的治疗手段之一。但是目前临床应用的栓塞材料均存在局限性，成为制约其疗效的主要因素。
理想的栓塞材料应具备：1）材料为液体，弥散性良好，能保证足够长的注射时间；2）栓塞效果持久；3）无毒性，无致畸、致癌、致突变；4）有良好的组织相容性；5）易于控制，不黏管；6）在栓塞过程中可见到栓塞剂显影；7）复查时栓塞剂不显影。
壳聚糖（Chitosan CS）与甘油磷酸钠（Glycerophosphate Salt GP）以一定的比例混合后，在室温23℃下为液态，在生理体温37℃下转变为水凝胶。本研究应用温度敏感性CS/GP水凝胶栓塞猪的脑动静脉畸形模型。
首先经过显微血管吻合技术建立猪的脑动静脉畸形模型，经过血管造影证实模型是否成功。通过调整壳聚糖的脱乙酰度（Deacetylation Degree DD）、分子量（Mw）及与甘油磷酸钠的体积比，探索二者混合后适合介入栓塞的成胶时间。加入不同浓度及不同产品液态显影剂（ContrastAgent CA）。应用成胶时间适合作为栓塞材料的CS/GP/CA混合液，栓塞猪的脑动静脉畸形模型。栓塞后3天，2周，8周复查血管造影，检查是否存在血管再通现象。行组织学检查，观察栓塞剂是否对血管壁有损害。通过此实验研究，旨在探索一种新型不黏管、能够栓塞脑动静脉畸形的液体栓塞材料。
Objectives
The goal of this study was to analyze the feasibility of embolization of cerebralarteriovenous malformation by thermosensitive chitosan(CH)/β-glycerophosphate disodiumsalt (β-GP) hydrogels through in vivo/in vitro experiments.
Methods
1. To study the effects that thermosensitive chitosan(CH)/β-glycero-phosphate disodiumsalt(β-GP) solution-sol/gel system has on the gelation time and mechanical properties afterdifferent contrast agents (CA) were added at37℃in order to determine contrast agent releasefrom hydrogel.
2. Nine swines were selected as experimental animals. Cerebral arterio-venous malformationmodel of swines was built with Rete Mirabile（REM）of swines used as nidus, one commoncarotid artery and internal jugular vein anastomosed using microsurgical technique, andexternal carotid artery ligated. The swines were put into three groups with three in one group,and arteriography was operated to common carotid arteries of swines in acute phase(1-3daysafter operation),subacute phase(1-3weeks after operation) and chronic phase(over3weeksafter operation). This is to evaluate whether the model has been successfully built througharteriography.
3. Chitosan(CH)/β-glycerophosphate disodium salt (β-GP) with addition of the appropriatecontrast agent(CA) was used to conduct embolization experiment of cerebral arteriovenousmalformation model of swines.
3.1To prepare2%w/v chitosan and12%w/v β-glycerophosphate disodium salt solution, andto mix it with contrast agent20%v/v Visipaque with their volume ratio of1:1:1at23℃. Toprepare fresh when it will be used.To determine gelation time with inverted tube test.
3.2To embolize bilateral rete mirabile of swines with chitosan/β-glycerophosphatedisodium salt/Visipaque solution and sol/gel tran-sition system.
3.2.1Eighteen swines were divided into two groups: Low flow experimental group：One group was nine swines directly embolism on one side of the REM; High flow experimentalgroup: The other group was nine swines embolism on two sides of the REM aftersuccessfully-built cerebral arteriovenous malformation models with common carotid arteryand internal jugular vein anastomosis. To conduct femoral artery puncture with Seldingertechnique, put6F catheter sheath inside femoral artery, insert5F angiography catheterselectively into the other common carotid artery of the anastomosis of blood vessel, injectVisipaque contrast agent using high pressure injector to perform angiography (injection rate4ml/s, dosage6ml) to understand the basics of AP, REM and connected arteries. Change6Fguiding catheter with the head end close to AP, conduct digital subtraction angiography(dosage6ml, rate4ml/min, pressure300mmHg). And then place a Tracker18microcatheter/Seeker14microguidewire combina-tion through guiding catheter superselectively into thestart area of REM via AP. Next, after angiography, conduct superselective angiograms usingnonionic isotonic Visipaque (dosage2ml, rate1ml/min, pressure180mmHg). Injectchitosan/β-glycerophosphate disodium salt/Visipaque solution and sol/gel transition systemthrough a microcatheter (injection rate0.2ml-0.5ml/min, dosage0.3-0.5ml, injection time1.5-3min). In order to observe the degree of embolization, conduct DSA with the injection ofcontrast agent after fluoroscopic observation of the embolization of embolic agent and theflow direction with hand push contrast agent “smoking”during the injection of embolic agent.Continue to inject embolic agent if REM fails to be occluded completely until REM does notdevelop through microcatheter angiography. Use Tracker10microcatheter to enter RA andAA superselectively to conduct superselective angiograms. Inject chitosan/β-glycero-phosphate disodium salt/Visipaque solution and sol/gel transition system(injection rate0.2ml-0.3ml/min, dosage0.1-0.2ml, injection time1.5-3min) until REM does not developthrough guiding catheter angiography. After embolotherapy, slowly withdraw themicrocatheter., press the puncture site for15minutes, and apply sterile pressure dressing.
3.2.2Low flow experimental animals and high flow experimental group were separately putinto3groups, with3swines in each group. They were re-examined with angiography1week,2weeks and8weeks after embolization respectively to evaluate the existence ofrevascularization.
3.2.3After re-examinations with angiography1week,2weeks and8weeks afterembolization, the swines in each group were executed with over-dose narcotic amobarbital（100mg/kg), and then were subsequently conducted REM histological examination.
4. Statistical analysis
Experimental data are reported as means±SD. Data were analyzed using one wayanalysis of chi square tests with a minimum confidence level (p <0.05) for statisticalsignificance.
Results
1. chitosan (CH)/β--glycerophosphate disodium salt (β-GP) hydrogels have goodbiocompatibility, thermosensitivity and high viscosity. The addition of contrast agent ofcertain concentration did not impede the formation of thermosensitive chitosan hydrogels.
2. The chitosan (CH)/β--glycerophosphate disodium salt (β-GP) solution has high viscosityat23℃, while it is good for the control of injection rate when it forms hydrogels at37℃.
3. Same volume mixed solution of94%degree of deacetylation (DD) and2%w/v chitosan,12%w/v β--glycerophosphate disodium salt and20%v/v nonionic isotonic Visipaque hasmoderate gelation time at37℃(120.00±1.82s), which is good for embolism injection.
4. The cerebral arteriovenous malformation model was successfully built throughmicrosurgical formation end-to-end anastomosis arteriovenous fistula between the rightcommon carotid artery and the internal jugular vein. With angiography, it could be seen thatblood flew through three feeding arteries, i.e, ascending pharyngeal artery AP, ramusanastomoticus RA and arteria anastomotica AA. Nidus (bilateral retia mirabilia), throughdraining vein, i.e., right ascending pharyngeal artery and right common carotid artery, goesinto the right internal jugular vein via the anastomotic stoma. It proved that this model wasacute and subacute phase animal model, which can be experimented for new embolismmaterials.
5. The chitosan (CH)/β--glycerophosphate disodium salt (β-GP) hydrogel embolized thecerebral arteriovenous malformation model of swines, and REM was completely embolized.Eighteen swines of embolism was successful except one swine cause convulsions, stoppage of breathing and death in interventional procedure. Due to the embolization of REM and externalcarotid artery at the same time, one swine was found to develop ipsilateral facial paralysis,masticatory muscle weakness, little intake of food and emaciation.
6. Angiography was conducted again after1week,2weeks and8weeks of embolization, andrevascularization was not seen.
7. Histological examination. REM sample was generally found to be gray, tough and easy tobe peeled. Light microscopic examination (HE staining):3days after embolization bloodvessel lumens were filled with hydrogels, the vascular intima remain intact and the necrosis ofit was not seen. No neutrophils in blood vessel lumens or obvious inflammatory reactionswere found.2weeks after embolization scattered macrophages were found through REMlight microscopic exam, blood vessel lumens were still filled with hydrogels, thrombusformed, vascular intima did not drop, slight inflammatory change was found within bloodvessel lumens, scattered lymph cells were discovered in adventitia of blood vessel, thenecrosis of vascular walls was not seen.8weeks after embolization arterioles were still filledwith hydrogels through REM light microscopic exam, slight inflammatory reactions werefound, no necrosis or dropping of vascular intima was found, that is to say inflammatorymacrophages swallowed hydrogels, the vascular intima remain intact, and medial membranestructure remain normal.
Conclusion
Thermosensitive chitosan(CH)/β--glycerophosphate disodium salt (β-GP) hydrogels canembolize cerebral arteriovenous malformation model of swines, and have the potential ofbecoming new embolic materials.
引文
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