壳聚糖微球制备优化及其乙酰化微球作为潜在栓塞材料的研究
|
摘要
经导管血管栓塞术(Transcatheter arterial embolization, TAE)是在X射线透视下，经导管向靶血管内注入或送入栓塞物质，使血管闭塞从而达到预期治疗目的的技术。它通过阻塞血管血流，减少病灶或身体某个特定部位的血液供给达到治疗疾病目的。该技术具有微创性、全程影像引导和选择性靶血管插管技术，使得栓塞的准确性和可控性大大增强，成为革命性的临床治疗方法。微球因其栓塞效果好、对特定组织器官的靶向性高、可以与化疗药结合可缓释药物等优点，从而受到越来越多的关注，是目前常见的栓塞载体。
壳聚糖(Chitosan)是甲壳质脱乙酰基后得到的一种天然阳离子多糖，化学名称为β-(1,4)-2-氨基-2-脱氧-D-葡聚糖。具有良好的生物相容性、生物可降解性、天然无毒、抑菌性、抗肿瘤、增强免疫及抗氧化活性等，在医药、食品、农业、生化、化工、环保等诸多领域都有一定的应用价值。近年来以壳聚糖及其衍生物为原料的有关栓塞剂一直是研究的热点，其既具有自身优良的生物学活性，又可以包载多种药物，起到物理栓塞和化学治疗双重作用。本文以壳聚糖为原料，采用乳化-交联法制备壳聚糖微球(CMs)及乙酰化微球(ACMs)，检测其理化性质及生物相容性，利用乙酰化后的微球进行兔耳模拟栓塞实验检测栓塞效果，为临床应用奠定基础。
采用O/W乳化交联法对现有的壳聚糖制备微球，通过单因素分析法和响应面分析法综合考察了壳聚糖浓度、乙酸浓度、Span80量、甲苯量、乳化转速、乳化时间、甲醛量和交联时间对微球制备的影响，通过Plackett-Burman实验设计、最陡爬坡实验及Box-Behnken实验设计分析各因素的主次效应、优化各因素水平，多次实验后得出微球制备工艺为：2%(w/v)壳聚糖用1.7%(v/v)的醋酸溶解，取100ml加入含7ml Span80和2ml tween-60的488ml甲苯中，1100rpm搅拌60min充分乳化，然后加入10ml甲醛溶液再搅拌60min进行固定，最后完成微球的制备。经重复实验得到微球实验值(8.03g)和理论值(7.93g)相差不大，所得微球表面光滑、球形完整、形状规则。
经乙酰化CMs得到乙酰化壳聚糖微球(ACMs)，微球表面光滑、球形完整，分散良好。FT-IR显示ACMs在1595cm~(-1)处出现乙酰氨基特征吸收峰。壳聚糖、CMs、ACMs的脱乙酰度分别为90.57%、84.83%和20.92%，说明形成微球后有5.7%的氨基发生交联反应，之后又有63.9%的氨基被乙酰化。CMs溶胀率与pH值呈反比，ACMs溶胀率受pH值影响较小。同时，两种微球溶胀率受环境温度影响都很大，随着温度升高而增加。微球热稳定性良好，在121℃、150kPa加热1h无明显变化，室温静置3个月后，形态依然完整。ACMs在溶菌酶的作用下酶解速度大于CMs，8周后两者质量分别下降了58.1%和40.7%，降解后的微球表面凹凸不平、出现空腔。
两种微球均能吸附BSA，由于CMs上氨基更多，所以蛋白吸附量比ACMs的大，达到吸附平衡时间也长。ACMs在低浓度(10mg/ml)和高浓度(50mg/ml)时溶血率均小于5%，而CMs在高浓度时明显溶血；ACMs所诱导的血栓形成反应较小，血栓量明显少于CMs，结果说明ACMs具有良好的血液相容性。MTT法比较了两种微球对胎鼠成纤维细胞(MEFs)的毒性，MEFs细胞能在稍小粒径(132μm、260μm)的两种微球上生长良好，而在大粒径(429μm)上无法生长，MEFs在CMs上的增殖率随着孵育时间的延长而降低，但在ACMs上增殖率随着孵育时间的延长而上升。通过蛋白吸附、血液相容性、细胞毒性实验表明ACMs具更好的血液相容性和细胞相容性。
对两种微球进行体内生物安全性评价。材料浸提液无皮肤致敏性和刺激性，对兔眼角膜也无刺激性。以高剂量(0.5ml/10g)通过尾静脉注射比腹腔注射对动物的刺激略大，注射后24h时体重下降，但之后恢复正常，而腹腔注射对小鼠无影响，表明材料浸提液无潜在急毒性。将微球植入大鼠肌肉后，术后3d、7d、14d时对大鼠肝、肾功能无影响；但植入炎症反应导致WBC水平升高(P<0.05)，7d后之后恢复正常；微球在体内逐渐被降解，没有引起明显的组织排异反应，有良好的组织相容性。ACMs栓塞兔耳动脉3d后，兔耳发炎水肿，耳尖由于血管被堵出现发黑、结痂现象；栓塞后7d，兔耳消肿，耳尖明显发黑、结痂、缺血性坏死；栓塞15d，耳尖部位小动脉萎缩消失，周围组织干性坏死，部分发生脱落，与坏死组织交界的边缘表皮萎缩增厚；结果表明ACMs有明显栓塞效果。
检测了盐酸阿霉素(ADM HCl)载药微球的包封率、载药量及体外缓释行为。两种微球包封率和载药量分别为54.8±1.23%、11.1±0.61%，由于脱水作用，导致未干燥的CMs的药物包封率和载药量均高于干燥后的微球(分别为62.53%、13.67%)。载药微球体外释药研究表明，两种载药微球在pH4.0介质中缓释率要在比在pH7.2介质中大，且ACMs缓释效果优于CMs，存在明显缓释作用。
实验发现壳聚糖微球，尤其是乙酰化壳聚糖微球具有良好的血液相容性、细胞相容性、组织相容性，生物安全性高，栓塞效果明显，可以作为临床上潜在的血管栓塞材料。
Transcatheter arterial embolization (TAE) is a medical technology that embolismmaterial is injected or sent to vascular by catheter in the X-ray and blocked bloodvessel so as to achieve the purpose of expected treatment. It could treat diseasesthrough clogging blood flow; reduce the blood supply of nidus or body parts. Owingto minimally invasive, image guide and selective target blood vessels catheterization,this technology make the accuracy and controllable of embolism greatly enhanced andbecome a revolutionary clinical treatment. The microspheres have many advantageson good effect in embolism, target ability in particular tissue and control release fromdrug encapsulation. Microsphere is the most common embolism carrier appliedwidely and attracts more and more attention.
Chitosan, the N-deacetylated derivative of chitin, is a natural cationpolysaccharide. Chemical name is β-(1,4)-2-amino-2-deoxy-D-glucan. Chitosan isused in many field such as medicine, food, agriculture, biochemical, chemical,environmental protection and so on, due to its useful features such as biocompatibility,biodegradability, low toxicity, antibacterial activity, antitumor, enhance immunity andantioxidant activity, etc. In recent years, embolic agents are made from Chitosan andits derivatives have been focused by many researchers. It is not only an excellentbiological activity but also a drug carries, and have dual role in physical embolismand chemical treatment. The Chitosan microspheres (CMs) and acetylated Chitosanmicrospheres (ACMs) are prepared by emulsion cross-linking method. Thephysicochemical property and biocompatibility of microsphere are investigated by aseries experiment, and then ACMs are used for embolizing trial on animal, whichcould provide some useful references for further in vivo clinical applications.
CMs are prepared by W/O emulsion cross-linking method using single factor analysis and response surface methodology (RSM). Meanwhile, the factors effectingCMs preparation are comprehensive survey such as Chitosan concentration, aceticacid concentration, Span80volume, toluene volume, stirring speed, emulsified time,formaldehyde volume and cross-linking time. These factors levels are optimized byPlackett-Burman design, the steepest ascent experiment and Box-Behnken design.The best preparation conditions for CMs via many experiments are shown as follows:2%(w/v) Chitosan dissolved in1.7%(v/v) acetic acid, and then100ml Chitosansolution were added into488ml toluene with7ml Span80and2ml tween-60, themixture were stirred at1100rpm for60min,10ml formaldehyde solution was addedto the system with continuous stirring for60min. The microspheres with smoothsurface are prepared, thus, the maximum predicted value of CMs (120mesh-60mesh)(7.93g) and experimental value (8.03g) are not significant.
ACMs with smooth surface and good dispersion are made by acetylating CMs.The characteristic absorption peak of-NHCOCH3groups appear in1595cm-1asshown in FT-IR spectra. The degree of deacetylation (DD) of Chitosan, CMs, ACMsis90.57%,84.83%and20.92%, respectively. It is showed that5.7%of amino iscross-linked in CMs, and then63.9%is acetylated in ACMs. Swelling rate (SR) ofCMs varies inversely as the pH value but less influence for ACMs. While, SR of CMsand ACMs is more effected by environmental temperature, increasing with risingtemperature, otherwise decreasing. The structure of CMs/ACMs remain stable afterautoclaving at121℃,150kPa for1h, the morphology of microsphere is perfectafter3month under room temperature. The degradation rate of ACMs is faster thanCMs in lysozyme, the mass decreased by58.1%and40.7%, respectively. Some cavityand uneven surface appears on microsphere after degradation.
The amount of adsorbed protein on CMs is more than on ACMs and also longerin the time of adsorption equilibrium, due to more amino group in CMs. Hemolysisrate (HR) of ACMs in10mg/ml and50mg/ml all less than5%, but obvioushemolysis for CMs in50mg/ml (HR>5%). Blood clots formed reaction on ACMs islight, and the weight of blood clots on ACMs is less than on CMs, it is showed thatACMs has good blood compatibility avoid hemolysis than CMs. Cytotoxicity of CMs/ACMs to mouse embryo fibroblasts (MEFs) proliferation is investigated byMTT method, the results shows that MEFs successfully proliferate on microsphere(132μm and260μm) but not on microsphere (429μm). Apparently, relative growthrate (RGR) of MEFs for CMs is decrease with incubated time but increase with timefor ACMs. Therefore, it is showed that ACMs have better haemocompatibility and cells compatibility via protein adsorption, blood compatibility and cytotoxicityexperiments.
Biological safety in vivo of CMs/ACMs is evaluated. Extract of material have nohypersensitized and hormesis effect on skin and cornea of rabbit. Hormesis of tailintravenous injection (i.v) with high doses (0.5ml/10g) is slightly stronger thanintraperitoneal injection (i.p) to mice. The weight drops after24h after i.v and thenrecovers increase, and it is keeping increase after i.p, the results shows that extract ofmaterial have no potential toxicity. The liver and kidney function of rat is normal after3d,7d and14d as CMs/ACMs is implanted in muscle, but levels of white blood cell(WBC) rise after3d and7d (p<0.05) due to inflammatory response by implanting andthen return to normal. Microspheres (CMs/ACMs) are gradually degradated in vivo,and has good histocompatibility because of no causing significant tissue rejection.Rabbit ear artery is embolized with ACMs for3d, inflammation and edema in ear,scabby phenomenon in ear tip because of vascular barrier. After7d, inflammation andedema disappear in ear, there is obviously scabby, ischemic necrosis in ear tip. After15d, arteriole atrophy disappears in ear tip, surrounding tissues is coagulation necrosisand partly fall off, edge skin border with necrotic tissue become atrophy andthickening. The result shows that ACMs have an obvious effect on vesselembolization.
Loading efficiency (LE), loading content (LC) and control release behaviors invitro of doxorubicin hydrochloride (ADM HCl) loading microspheres(ADM HCl-CMs/ACMs) are evaluated in this study. The LE and LC of CMs/ACMsare also about54.8±1.23%,11.1±0.61%, moreover, the LE and LC of undried CMshigher than dried CMs (62.53%,13.67%, respectively) because of dehydration. Thedynamic dialysis method is employed to study in vitro control release behaviors of ADM HCl-CMs/ACMs. Release rate of ADM HCl in pH4.0medium is faster than inpH7.0medium. Comparing to CMs, ACMs shows an obviously controlled releasestate in the experiment and has some advantages in the drug releasing.
It is found that CMs, especially ACMs have advantages in haemocompatibility,cytocompatibility, histocompatibility, high biological safety, and effectiveembolization, could be used as a potential vascular embolic material for clinicalapplication.
壳聚糖(Chitosan)是甲壳质脱乙酰基后得到的一种天然阳离子多糖，化学名称为β-(1,4)-2-氨基-2-脱氧-D-葡聚糖。具有良好的生物相容性、生物可降解性、天然无毒、抑菌性、抗肿瘤、增强免疫及抗氧化活性等，在医药、食品、农业、生化、化工、环保等诸多领域都有一定的应用价值。近年来以壳聚糖及其衍生物为原料的有关栓塞剂一直是研究的热点，其既具有自身优良的生物学活性，又可以包载多种药物，起到物理栓塞和化学治疗双重作用。本文以壳聚糖为原料，采用乳化-交联法制备壳聚糖微球(CMs)及乙酰化微球(ACMs)，检测其理化性质及生物相容性，利用乙酰化后的微球进行兔耳模拟栓塞实验检测栓塞效果，为临床应用奠定基础。
采用O/W乳化交联法对现有的壳聚糖制备微球，通过单因素分析法和响应面分析法综合考察了壳聚糖浓度、乙酸浓度、Span80量、甲苯量、乳化转速、乳化时间、甲醛量和交联时间对微球制备的影响，通过Plackett-Burman实验设计、最陡爬坡实验及Box-Behnken实验设计分析各因素的主次效应、优化各因素水平，多次实验后得出微球制备工艺为：2%(w/v)壳聚糖用1.7%(v/v)的醋酸溶解，取100ml加入含7ml Span80和2ml tween-60的488ml甲苯中，1100rpm搅拌60min充分乳化，然后加入10ml甲醛溶液再搅拌60min进行固定，最后完成微球的制备。经重复实验得到微球实验值(8.03g)和理论值(7.93g)相差不大，所得微球表面光滑、球形完整、形状规则。
经乙酰化CMs得到乙酰化壳聚糖微球(ACMs)，微球表面光滑、球形完整，分散良好。FT-IR显示ACMs在1595cm~(-1)处出现乙酰氨基特征吸收峰。壳聚糖、CMs、ACMs的脱乙酰度分别为90.57%、84.83%和20.92%，说明形成微球后有5.7%的氨基发生交联反应，之后又有63.9%的氨基被乙酰化。CMs溶胀率与pH值呈反比，ACMs溶胀率受pH值影响较小。同时，两种微球溶胀率受环境温度影响都很大，随着温度升高而增加。微球热稳定性良好，在121℃、150kPa加热1h无明显变化，室温静置3个月后，形态依然完整。ACMs在溶菌酶的作用下酶解速度大于CMs，8周后两者质量分别下降了58.1%和40.7%，降解后的微球表面凹凸不平、出现空腔。
两种微球均能吸附BSA，由于CMs上氨基更多，所以蛋白吸附量比ACMs的大，达到吸附平衡时间也长。ACMs在低浓度(10mg/ml)和高浓度(50mg/ml)时溶血率均小于5%，而CMs在高浓度时明显溶血；ACMs所诱导的血栓形成反应较小，血栓量明显少于CMs，结果说明ACMs具有良好的血液相容性。MTT法比较了两种微球对胎鼠成纤维细胞(MEFs)的毒性，MEFs细胞能在稍小粒径(132μm、260μm)的两种微球上生长良好，而在大粒径(429μm)上无法生长，MEFs在CMs上的增殖率随着孵育时间的延长而降低，但在ACMs上增殖率随着孵育时间的延长而上升。通过蛋白吸附、血液相容性、细胞毒性实验表明ACMs具更好的血液相容性和细胞相容性。
对两种微球进行体内生物安全性评价。材料浸提液无皮肤致敏性和刺激性，对兔眼角膜也无刺激性。以高剂量(0.5ml/10g)通过尾静脉注射比腹腔注射对动物的刺激略大，注射后24h时体重下降，但之后恢复正常，而腹腔注射对小鼠无影响，表明材料浸提液无潜在急毒性。将微球植入大鼠肌肉后，术后3d、7d、14d时对大鼠肝、肾功能无影响；但植入炎症反应导致WBC水平升高(P<0.05)，7d后之后恢复正常；微球在体内逐渐被降解，没有引起明显的组织排异反应，有良好的组织相容性。ACMs栓塞兔耳动脉3d后，兔耳发炎水肿，耳尖由于血管被堵出现发黑、结痂现象；栓塞后7d，兔耳消肿，耳尖明显发黑、结痂、缺血性坏死；栓塞15d，耳尖部位小动脉萎缩消失，周围组织干性坏死，部分发生脱落，与坏死组织交界的边缘表皮萎缩增厚；结果表明ACMs有明显栓塞效果。
检测了盐酸阿霉素(ADM HCl)载药微球的包封率、载药量及体外缓释行为。两种微球包封率和载药量分别为54.8±1.23%、11.1±0.61%，由于脱水作用，导致未干燥的CMs的药物包封率和载药量均高于干燥后的微球(分别为62.53%、13.67%)。载药微球体外释药研究表明，两种载药微球在pH4.0介质中缓释率要在比在pH7.2介质中大，且ACMs缓释效果优于CMs，存在明显缓释作用。
实验发现壳聚糖微球，尤其是乙酰化壳聚糖微球具有良好的血液相容性、细胞相容性、组织相容性，生物安全性高，栓塞效果明显，可以作为临床上潜在的血管栓塞材料。
Transcatheter arterial embolization (TAE) is a medical technology that embolismmaterial is injected or sent to vascular by catheter in the X-ray and blocked bloodvessel so as to achieve the purpose of expected treatment. It could treat diseasesthrough clogging blood flow; reduce the blood supply of nidus or body parts. Owingto minimally invasive, image guide and selective target blood vessels catheterization,this technology make the accuracy and controllable of embolism greatly enhanced andbecome a revolutionary clinical treatment. The microspheres have many advantageson good effect in embolism, target ability in particular tissue and control release fromdrug encapsulation. Microsphere is the most common embolism carrier appliedwidely and attracts more and more attention.
Chitosan, the N-deacetylated derivative of chitin, is a natural cationpolysaccharide. Chemical name is β-(1,4)-2-amino-2-deoxy-D-glucan. Chitosan isused in many field such as medicine, food, agriculture, biochemical, chemical,environmental protection and so on, due to its useful features such as biocompatibility,biodegradability, low toxicity, antibacterial activity, antitumor, enhance immunity andantioxidant activity, etc. In recent years, embolic agents are made from Chitosan andits derivatives have been focused by many researchers. It is not only an excellentbiological activity but also a drug carries, and have dual role in physical embolismand chemical treatment. The Chitosan microspheres (CMs) and acetylated Chitosanmicrospheres (ACMs) are prepared by emulsion cross-linking method. Thephysicochemical property and biocompatibility of microsphere are investigated by aseries experiment, and then ACMs are used for embolizing trial on animal, whichcould provide some useful references for further in vivo clinical applications.
CMs are prepared by W/O emulsion cross-linking method using single factor analysis and response surface methodology (RSM). Meanwhile, the factors effectingCMs preparation are comprehensive survey such as Chitosan concentration, aceticacid concentration, Span80volume, toluene volume, stirring speed, emulsified time,formaldehyde volume and cross-linking time. These factors levels are optimized byPlackett-Burman design, the steepest ascent experiment and Box-Behnken design.The best preparation conditions for CMs via many experiments are shown as follows:2%(w/v) Chitosan dissolved in1.7%(v/v) acetic acid, and then100ml Chitosansolution were added into488ml toluene with7ml Span80and2ml tween-60, themixture were stirred at1100rpm for60min,10ml formaldehyde solution was addedto the system with continuous stirring for60min. The microspheres with smoothsurface are prepared, thus, the maximum predicted value of CMs (120mesh-60mesh)(7.93g) and experimental value (8.03g) are not significant.
ACMs with smooth surface and good dispersion are made by acetylating CMs.The characteristic absorption peak of-NHCOCH3groups appear in1595cm-1asshown in FT-IR spectra. The degree of deacetylation (DD) of Chitosan, CMs, ACMsis90.57%,84.83%and20.92%, respectively. It is showed that5.7%of amino iscross-linked in CMs, and then63.9%is acetylated in ACMs. Swelling rate (SR) ofCMs varies inversely as the pH value but less influence for ACMs. While, SR of CMsand ACMs is more effected by environmental temperature, increasing with risingtemperature, otherwise decreasing. The structure of CMs/ACMs remain stable afterautoclaving at121℃,150kPa for1h, the morphology of microsphere is perfectafter3month under room temperature. The degradation rate of ACMs is faster thanCMs in lysozyme, the mass decreased by58.1%and40.7%, respectively. Some cavityand uneven surface appears on microsphere after degradation.
The amount of adsorbed protein on CMs is more than on ACMs and also longerin the time of adsorption equilibrium, due to more amino group in CMs. Hemolysisrate (HR) of ACMs in10mg/ml and50mg/ml all less than5%, but obvioushemolysis for CMs in50mg/ml (HR>5%). Blood clots formed reaction on ACMs islight, and the weight of blood clots on ACMs is less than on CMs, it is showed thatACMs has good blood compatibility avoid hemolysis than CMs. Cytotoxicity of CMs/ACMs to mouse embryo fibroblasts (MEFs) proliferation is investigated byMTT method, the results shows that MEFs successfully proliferate on microsphere(132μm and260μm) but not on microsphere (429μm). Apparently, relative growthrate (RGR) of MEFs for CMs is decrease with incubated time but increase with timefor ACMs. Therefore, it is showed that ACMs have better haemocompatibility and cells compatibility via protein adsorption, blood compatibility and cytotoxicityexperiments.
Biological safety in vivo of CMs/ACMs is evaluated. Extract of material have nohypersensitized and hormesis effect on skin and cornea of rabbit. Hormesis of tailintravenous injection (i.v) with high doses (0.5ml/10g) is slightly stronger thanintraperitoneal injection (i.p) to mice. The weight drops after24h after i.v and thenrecovers increase, and it is keeping increase after i.p, the results shows that extract ofmaterial have no potential toxicity. The liver and kidney function of rat is normal after3d,7d and14d as CMs/ACMs is implanted in muscle, but levels of white blood cell(WBC) rise after3d and7d (p<0.05) due to inflammatory response by implanting andthen return to normal. Microspheres (CMs/ACMs) are gradually degradated in vivo,and has good histocompatibility because of no causing significant tissue rejection.Rabbit ear artery is embolized with ACMs for3d, inflammation and edema in ear,scabby phenomenon in ear tip because of vascular barrier. After7d, inflammation andedema disappear in ear, there is obviously scabby, ischemic necrosis in ear tip. After15d, arteriole atrophy disappears in ear tip, surrounding tissues is coagulation necrosisand partly fall off, edge skin border with necrotic tissue become atrophy andthickening. The result shows that ACMs have an obvious effect on vesselembolization.
Loading efficiency (LE), loading content (LC) and control release behaviors invitro of doxorubicin hydrochloride (ADM HCl) loading microspheres(ADM HCl-CMs/ACMs) are evaluated in this study. The LE and LC of CMs/ACMsare also about54.8±1.23%,11.1±0.61%, moreover, the LE and LC of undried CMshigher than dried CMs (62.53%,13.67%, respectively) because of dehydration. Thedynamic dialysis method is employed to study in vitro control release behaviors of ADM HCl-CMs/ACMs. Release rate of ADM HCl in pH4.0medium is faster than inpH7.0medium. Comparing to CMs, ACMs shows an obviously controlled releasestate in the experiment and has some advantages in the drug releasing.
It is found that CMs, especially ACMs have advantages in haemocompatibility,cytocompatibility, histocompatibility, high biological safety, and effectiveembolization, could be used as a potential vascular embolic material for clinicalapplication.
引文
Agnihotri S. A., Mallikarjuna N. N., Aminabhavi T. M., et al. Recent advances on chitosan-basedmicro-and nanoparticles in drug delivery. Journal of Controlled Release,2004,100(1):5-28.
Akbuga J., Bergisadi N. Effect of formulation variables on cis-platin loaded Chitosan microsphereproperties. Journal of Microencapsulation,1999,16(6):697-703.
Alpar H. O., Somavarapu S., Atuah K. N., et al. Biodegradable mucoadhesive particulates fornasal and pulmonary antigen and DNA delivery. Advanced Drug Delivery Reviews,2005,57(3):411-430.
Aranaz I., Mengíbar M., Harris R., et al. Functional characterization of chitin and Chitosan.Current Chemical Biology,2009,3(2),203-230.
Basketter D. A., Selbie E., Scholes E. W., et al. Results with OECD recommended positive controlsensitizers in the maximization, Buehler and local lymph node assays. Food and ChemicalToxicology,1993,31(1):63-67.
Bendszus M., Martin-Schrader I., Warmuth-Metz M., et al. MR imaging–and MRspectroscopy–revealed changes in meningiomas for which embolization was performedwithout subsequent surgery. American Journal of Neuroradiology,2000,21(4):666-669.
Bendszus M., Rao G., Burger R., et al. Is there benefit of preoperative meningioma embolization?Neurosurgery,2000,47(6):1306-1312.
Berger J., Reist M., Mayer J. M., et al. Structure and interactions in covalently and ionicallycrosslinked chitosan hydrogels for biomedical applications. European Journal ofPharmaceutics and Biopharmaceutics.2004,57(1):19-34.
Berthelsen B., Lofgren J., Svendsen P., et al. Embolization of cerebral arteriovenousmalformations with burcrylate experience in a first series of29patients. Acta Radiologica,1990,31(1):13-21.
Berthold A., Cremer K., Kreuter J. Preparation and characterization of Chitosan microspheres asdrug carrier for prednisolone sodium phosphate as model for anti-inflammatory drugs.Journal of Controlled Release,1996,39(1):17-25.
Bhattarai N., Ramay H. R., Gunn J., et al. PEG-grafted chitosan as an injectable thermosensitivehydrogel for sustained protein release. Journal of Controlled Release,2005,103(3):609-624.
Bodmeier R., Chen H. G., Paeratakul O. A novel approach to the oral delivery of micro-ornanoparticles. Pharmaceutical research.1989,6(5):413-117.
Boucard N., Viton C., Agay D., et al. The use of physical hydrogels of chitosan for skinregeneration following third-degree burns. Biomaterials,2007,28(24):3478-3488.
Box G. E. P., Behnken D. W. Some new three level designs for the study of quantitative variables.Technometrics,1960,2(4),455-475.
Box G. E. P., Hunter J. S., Hunter, W. G. Statistics for experimenters: an introduction to design,data analysis and model building. New York: John willey and Sons.1990.
Brooks S. H., Mickey M. R. Optimum estimation of gradient direction in steepest ascentexperiments. Biometrics,1961,17(1),48-56.
Buehler E. V. Delayed contact hypersensitivity in the Guinea pig. Arch Dermatol,1965,91(2):171-175.
Burns N. L., Holmberg K., Brink C. Influence of surface charge on protein adsorption at anamphoteric surface: effects of varying acid to base ratio. Journal of Colloid and InterfaceScience,1996,178(1):116-122.
Calvo P., Vila-Jato J. L., Alonso M. J. Evaluation of cationic polymer-coated nanocapsules asocular drug carriers. International Journal of Pharmaceutics,1997,153(1):41-50.
Carre o-Gómez B., Duncan R. Evaluation of the biological properties of soluble chitosan andchitosan microspheres. International Journal of Pharmaceutics,1997,148(2):231-240.
Charnsangavej C., Chuang V. P., Wallace S., et al. Angiographic classification of hepatic arterialcollaterals. Radiology,1982,144(3):485-494.
Chen X. G., Liu C. S., Liu C. G., et al. Preparation and biocompatibility of chitosan microcarriersas biomaterial. Biochemical Engineering Journal,2006,27(3):269-274.
Chen X. G., Liu W. S., Lang G. H., et al. Manufacture of chitin microshpheres. China, Vol.ZL96115714.3,2002.
Cho S. M., Choi H. K. Preparation of mucoadhesive chitosan-poly(acrylic acid) microspheres byinterpolymer complexation and solvent evaporation method II. Archives of PharmacalResearch,2005,28(5):612-618.
Choi C. Y., Kim S. B., Park P. K., et al. Effect of N-acylation on structure and properties ofchitosan fibers. Carbohydrate Polymers,2007,68(1):122-127.
Denis F. A., Hanarp P., Sutherland D. S., et al. Protein adsorption on model surfaces withcontrolled nanotopography and chemistry. Langmuir,2002,18(3):819-828.
Desai K. G. H., Park H. J. Preparation and characterization of drug-loadedchitosan–tripolyphosphate microspheres by spray drying. Drug Development Research,2005,64(2):114-128.
Dutta P. K., Dutta J., Tripathi V. S. Chitin and Chitosan: chemistry, properties and applications.Journal of Scientific and Industrial Research,2004,63(1):20-31.
Ei-Hameed M. D. A., Kellaway I. W. Preparation and in vitro characterization of mucoadhesivepolymeric microspheres as intra-nasal delivery system. European Journal of Pharmaceuticsand Biopharmaceutics,1997,44(1):53-60
El-Ghannam A., Ducheyne P., Shapiro I. M. Bioactive material template for in vitro, synthesis ofbone. Journal of Biomedical Materials Research,1995,29(3):359-370.
Filipovic-Grcic J., Perissutti B., Moneghini M., et al. Spray-dried carbamazepine-loaded Chitosanand HPMC microspheres: preparation and characterization. Journal of Pharmacy andPharmacology,2003,55(7):921-931.
Fischer D., Li Y. X., Ahlemeyer B., et al. In vitro cytotoxicity testing of polycations: influence ofpolymer structure on cell viability and hemolysis. Biomaterials,2003,24(7):1121-1131.
Frankild S., Vélund A., Wahlberg J. E., et al. Comparison of the sensitivities of the buehler testand the Guinea pig maximization test for predictive testing of contact allergy. ActaDermato-Venereologica,2000,80(4):256-262
Giunchedi P., Genta I., Conti B., et al. Preparation and characterization of ampicillin loadedmethylpyrrolidinone chitosan and chitosan microspheres. Biomaterials,1998,19(1-3):157-161.
Guan Y. L., Shao L., Kang J. L., et al. pH Effect on correlation between water state and swellingkinetics of the crosslinked chitosan/polyether semi-IPN hydrogel. Journal of AppliedPolymer Science,1996,62(8):1253-1258.
Gupta K. C., Jabrail F. H. Effects of degree of deacetylation and cross-linking on physicalcharacteristics, swelling and release behavior of Chitosan microspheres. CarbohydratePolymers,2006,66(1):43-54.
Hansen M. B., Nielsen S. E., Berg K. Re-examination and further development of a precise andrapid dye method for measuring cell growth/cell kill. Journal of Immunological Methods,1989,119(2):203-210.
Harris R., Lecumberri E., Mateos-Aparicio I., et al. Chitosan nanoparticles and microspheres forthe encapsulation of natural antioxidants extracted from Ilex paraguariensis. CarbohydratePolymers,2011,84(2):803-806.
Harris R., Pa os I., Acosta N., et al. Preparation and characterization of chitosan microspheres forcontrolled release of tramadol. Journal of Controlled Release,2008,132(3): e76-e77.
He P., Davis S. S., Illum L. Chitosan microspheres prepared by spry drying. International Journalof Pharmaceutics,1999,187(1):53-65.
He P., Davis S. S., Illum L. In vitro evaluation of the mucoadhesive properties of chitosanmicrospheres. International Journal of Pharmaceutics,1998,166(1):75-88.
Helander I. M., Nurmiaho-Lassila E. L., Ahvenainen R., et al. Chitosan disrupts the barrierproperties of the outer membrane of Gram-negative bacteria. International Journal of FoodMicrobiology,2001,71(2–3):235-244.
Hirano S. Chitin and chitosan as novel biotechnological materials. Polymer International,1999,48(8):732-734.
Huang R. H., DU Y. M., Yang J. H., et al. Influence of functional groups on the in vitroanticoagulant activity of chitosan sulfates. Carbohydrate Research,2003,338(6):483-489.
Huang Y. C., Yeh M. K., Chiang C. H. Formulation factors in preparing BTM-Chitosanmicrospheres by spray drying method. International Journal of Pharmaceutics,2002,242(1-2):239-242.
Ikarashi Y., Ohno K., Momma J., et al. Assessment of contact sensitivity of four thiourea rubberaccelerators: Comparison of two mouse lymph node assays with the guinea pig maximizationtest. Food and Chemical Toxicology,1994,32(11):1067-1072.
Ikeda I., Sugano M., Yashida K., et al. Dietary fibre and lipid absorption: interference of chitosanand its hydrolyzate with cholesterol and fatty acid absorption and metabolic consequences inrats. In: Kritchevsky D., Bonefield C., editors. Dietary Fibre in Health and Disease. St. Paul,MN: Eagan Press,1995. pp:95–106.
Imai Y., Nose Y. A new method for evalution of antithrombogenicity of materials. Journal ofBiomedical Materials Research,1972,6(3):165-172.
Inoyatov N., Cellebi. N., Acarturk F. Preparation and evaluation of a prolonged releasepentoxifylline tablet with chitosan. Pharmazeutische Industrie,1998,60(5):472-475.
Jahan R., Murayama Y., Gobin Y. P., et al. Embolization of arteriovenous malformations withOnyx: clinicopathological experience in23patients. Neurosurgery,2001,48(5):984-995.
Jameela S.R., Jayakrishnan A. Glutaraldehyde cross-linked Chitosan microspheres as a long actingbiodegradable drug delivery vehicle: studies on the in vitro releases of mitoxantrone and invivo degradation of microspheres in rat muscle. Biomaterials,1995,16(10):769-775.
Je J. Y., Kim S. K. Chitosan Derivatives Killed Bacteria by Disrupting the Outer and InnerMembrane. Journal of Agricultural and Food Chemistry,2006,54(18):6629-6633.
Jia Z. S., Li Q.B. Determination of the deacetylation degree of Chitosan by two abrupt changepotential titration method. Chemical World,2001,(5):240-241.
Jumaa M., Furkert F. H., Muller B. W. et al. A new lipid emulsion formulation with highantimicrobial efficacy using chitosan. European Journal of Pharmaceutics andBiopharmaceutics,2002,53(1):115-123.
Kaibara M., Kawamoto K., Yanagida S., et al. In vitro evaluation of antithrombogenicity ofhybrid-type vascular vessel models based on analysis of the mechanism of blood coagulation.Biomaterials,1995,16(16):1229-1234.
Kamiyama K., Onishi H., Machida Y., et al. Biodisposition characteristics of N-succinyl-chitosanand glycol-chitosan in normal and tumor-bearing mice. Biological and pharmaceuticalbulletin,1999,22(2):179-186.
Kanke M., Katayama H., Tsuzuki S., et al. Appilcation of chitin and chitosan to pharmaceuticalpreparations. I. Film prepatation and in vitro dissolution. Chemical and PharmaceuticalBulletin,1989,37(2):523-525.
Kawashima Y., Handa T., Kasai A., et al. Novel method for the preparation of controlled-releasetheophylline granules coated with a polyelectrolyte complex of sodiumpolyphosphate–Chitosan. Journal of Pharmaceutical Sciences,1985,74(3):264–268.
Kean T., Thanou M. Biodegradation, biodistribution and toxicity of Chitosan. Advanced DrugDelivery Reviews,2010,62(1):3-11.
Khalid M. N., Ho L., Agnely F., et al. Swelling properties and mechanical characterization of asemi-interpenetrating chitosan/polyethylene oxide network: Comparison with a chitosanreference gel. STP pharma sciences,1999,9(4):359-364.
Khor E., Lim L. Y. Implantable applications of chitin and chitosan. Biomaterials,2003,24(13):2339-2349.
Kimber I., Basketter D. A., Berthold K., et al. Skin sensitization testing in potency and riskassessment. Toxicological Sciences,2001,59(2):198-208.
Kinugasa K., Mandai S., Terai Y., et al. Direct thrombosis of aneurysms with cellulose acetatepolymer part2: Preliminary clinical experience. Journal of Neurosurgery,1992,77(4):501-507.
Kockisch S., Rees G. D., Young S. A., et al. In situ evaluation of drug-loaded microspheres on amucosal surface under dynamic test conditions. International Journal of Pharmaceutics,2004,276(1–2):51-58.
Kosaraju S. L., D’ath L., Lawrence A. Preparation and characterisation of chitosan microspheresfor antioxidant delivery. Carbohydrate Polymers,2006,64(2):163-167.
Kowalski S. M., Borror C. M., Montgomery D. C. A modified path of steepest ascent for split-plotexperiments. Journal of Quality Technology,2005,37(1):75-83.
Kratz G., Arnander C., Swedenborg J., et al. Heparin-Chitosan Complexes Stimulate WoundHealing in Human Skin. Scandinavian Journal of Plastic and Reconstructive Surgery andHand Surgery,1997,31(2):119-123.
Kristiansen A., V rum K. M., Hrasdalen H. Quantitative studies of the non-productive binding oflysozyme to partially N-acetylated chitosans: Binding of large ligands to a one-dimensionalbinary lattice studied by a modified McGhee and von Hippel model. Biochimica etBiophysica Acta,1998,1425(1):137-150.
Lamprecht A., Yamamoto H., Takeuchi H., et al. pH-sensitive microsphere delivery increases oralbioavailability of calcitonin. Journal of Controlled Release,2004,98(1):1-9
Lee K. Y., Ha W. S., Park W. H. Blood compatibility and biodegradability of partially N-acylatedchitosan derivatives. Biomaterials,1995,16(16):1211-1216.
Li S., Wang X. T., Zhang X. B., et al. Studies on alginate-chitosan microcapsules and renal arterialembolization in rabbits. Journal of Controlled Release,2002,84(3):87-98.
Liang T. W., Chen Y. J., Yen Y. H., et al. The antitumor activity of the hydrolysates of chitinousmaterials hydrolyzed by crude enzyme from Bacillus amyloliquefaciens V656. ProcessBiochemistry,2007,42(4):527-534.
Lim C. K., Yaacob N. S., Ismail Z., et al. In vitro biocompatibility of chitosan porous skinregenerating templates (PSRTs) using primary human skin keratinocytes. Toxicology in Vitro,2010,24(3):721-727.
Liu H., Du Y., Wang X. H., et al. Chitosan kills bacteria through cell membrane damage.International Journal of Food Microbiology,2004,95(2):147-155.
Liu X. F., Guan Y. L., Yang D. Z., et al. Antibacterial action of chitosan and carboxymethylatedchitosan. Journal of Applied Polymer Science,2001,79(7):1324-1335.
Lv Y., Chen X. G., Wang Q. Z., et al. Synthesis and characterization of chitosan-basedbiomaterials modified with different active groups and their relationship with cytotoxicity.Journal of Wuhan University of Technology--Materials Science Edition,2007,22(4):695-700.
Machida Y., Nagai T., Abe M, et al. Use of chitosan and hydroxypropylchitosan in drugformulations to effect sustained release. Drug Design Delivery.19861(2):119-30.
Macieira-Coelho A., Berumen L., Avrameas S. Properties of protein polymers as substratum forcell growth in vitro. Journal of Cellular Physiology,1974,83(3):379-388.
Macleod G. S., Collett J. H. Fell J. T. The potential use of mixed films of pectin, chitosan andHPMC for bimodal drug release. Journal of Controlled Release,1999,58(3):303-310.
Magnusson B, Kligman A. M. Allergic contact dermatitis in the guinea pig: Identification ofcontact allergens. Charles C Thomas, Springfield,1970:102-123.
Makarand V. R.isbuda, Anandwardhan A Hardikar, Sujata V Bhat, Ramesh R Bhonde.PH-sensitive freeze-dried Chitosan-polyvinyl pyrrolidone hydrogels as controlled releasesystem for antibiotic delivery. Journal of Controlled Release.2000,68(1):23-30
Mansoor M. A. Permeability and blood compatibility properties of chitosan-poly (ethylene oxide)blend membranes for haemodialysis. Biomaterials,1995,16(8):593-599.
Mao C., Zhao W. B., Zhu A. P., et al. A photochemical method for the surface modification of poly(vinyl-chloride) with O-butyrylchitosan to improve blood compatibility. ProcessBiochemistry,2004,39(9):1151-1157.
Mcclave S. A., Kaiser S. C., Wright R. A., et al. Prospective randomized comparison ofesophageal variceal sclerotherapy agents: sodium tetradecyl sulfate versus sodium morrhuate.Gastrointestianl Endosccopy,1990,36(6):567-571.
Mi F. l., Tan Y. C., Liang H. F., et al. In vivo biocompability and degradability a novelinjectable-chitosan-based implant. Biomaterials,2002,23(1):181-191
Miyazaki S., Yamaguchi H., Takada M., et al. Pharmaceutical application of biomedical polymers.XXIX. Preliminary study on film dosage form prepared from chitosan for oral drug delivery.Acta pharmaceutica Nordica,1990,2(6):401-406.
Myers R. H., Montgomery D. C. Christine M. Anderson-Cook.) Response surface methodology:process and product optimization using designed experiments (3rd). New York:John willeyand Sons,2009.
Na K., Bum L. T., Park K. H., et al. Self-assembled nanoparticles of hydrophobically-modifiedpolysaccharide bearing vitamin H as a targeted anti-cancer drug delivery system. EuropeanJournal of Pharmaceutical Sciences,2003, l8(2):165-173.
No H. K., Park N. Y., Lee S. H., et al. Antibacterial activity of chitosans and chitosan oligomerswith different molecular weights. International Journal of Food Microbiology,2002,74(1-2):65-72.
Nordtveit R. J., V rum K. M., Smidsrod O. Degradation of fully water-soluble, partiallyN-acetylated chitosans with lysozyme. Carbohydrate Polymers,1994,23(4):253-260.
Nordtveit R. J., V rum K. M., Smidsrod O. Degradation of partially N-acetylated chitosans withhen egg white and human lysozyme. Carbohydrate Polymers,1996,29(2):163-167.
Ofori-Kwakye K., Fell J. T., Sharma H. L., et al. Gamma scintigraphic evaluation of film-coatedtablets intended for colonic or biphasic release. International Journal of Pharmaceutics,2004,270(1–2):307-313.
Ohya Y., Shiratania M., Kobayashia H., et al. Release Behavior of5-Fluorouracil fromChitosan-Gel Nanospheres Immobilizing5-Fluorouracil Coated with Polysaccharides andTheir Cell Specific Cytotoxicity. Journal of Macromolecular Science, Part A: Pure andApplied Chemistry.1994,31(5):629～642.
Okamoto Y., Yano R., Miyatake K., et al. Effects of chitin and chitosan on blood coagulation.Carbohydrate Polymers,2003,53(3):337-342.
Oungbho K., Müller B. W. Chitosan sponges as sustained release drug carriers. InternationalJournal of Pharmaceutics,1997,156(2):229-237.
Outomuro D., Grana D. R., Azzato F., et al. Adriamycin-induced myocardial toxicity: Newsolutions for an old problem? International Journal of Cardiology,2007,117(1):6-15.
Pangburn S. H., Trescony P. V., Heller J. Lysozyme degradation of partially deacetylated chitin, itsfilms and hydrogels. Biomaterials,1982,3(2):105-108.
Pantaleone D., Yalpani M., Scollar M. Unusual susceptibility of chitosan to enzymic hydrolysis.Carbohydrate Research,1992,237(0):325-332.
Park J. S., Han T. H., Lee K. Y., et al. N-acetyl histidine-conjugated glycol chitosan self-assemblednanoparticles for intracytoplasmic delivery of drugs: endocytosis, exocytosis and drug release.Journal of Controlled Release,2006,115(1):37-45.
Peniche H., Osorio A., Acosta N., et al. Preparation and characterization of superparamagneticchitosan microspheres: Application as a support for the immobilization of tyrosinase. Journalof Applied Polymer Science,2005,98(2):651–657
Plackett R. L., Burman, J. P. The design of optimum multifctoria experiments. Biometrika,1946,33(4),305-325.
Quinton P. M., Philpott C. W. A role for anionic sites in epithelial architecture. Effects of cationicpolymers on cell membrane structure. The Journal of cell biology,1973,56(3):787-796.
Rabea E. I., Badawy M. E. T., Stevens C. V., et al. Chitosan as Antimicrobial Agent:Applications and Mode of Action. Biomacromolecules,2003,4(6):1457-1465.
Radi Hejazi, Mansoor Amiji. Stomach-specific anti-H. pylori therapy: Part III: Effect of chitosanmicrospheres crosslinking on the gastric residence and local tetracycline concentrations infasted gerbils. International Journal of Pharmaceutics,2004,272(1–2):99–108.
Rinaudo M. Chitin and chitosan: Properties and applications. Progress in Polymer Science,2006,31(7):603-632.
Risbud M. V., Hardikar A. A., Bhat S. V., et al. PH-sensitive freeze-dried Chitosan-polyvinylpyrrolidone hydrogels as controlled release system for antibiotic delivery. Journal ofControlled Release.2000,68(1):23-30
Ritz H. L., Buehler E.V. Procedure for conducting the guinea pig assay. Current Concepts inDermatology, Drill V.A. and Lazar P.(eds), New York: Academic Press,1980.25-40.
Roberts G. A. F. Chitin Chemistry. London: Macmillan Press,1992.100-150.
Sarah Nsereko, Mansoor Amiji. Localized delivery of paclitaxel in solid tumors frombiodegradable chitin microparticle formulations, Biomaterials,2002,23(13):2723-2731.
Satink R. G., Piest H., Helden G., et al. The infrared spectrum of the benzene--Ar cation. TheJournal of Chemical Physics,1999,111(24):10750-10753.
Scheinman M. M. Catheter Ablation. Present role and projected impact on health care for patientswith cardiac arrhythmias. Circulation,1991,83(5):1489-1498
Shelma R., Sharma C. P. Development of lauroyl sulfated chitosan for enhancinghemocompatibility of Chitosan. Colloids and Surfaces B: Biointerfaces,2011,84(2):561-570.
Shim D, Wechsler D. S., Lloyd T. R., et al. Haemolysis following coil embolization of a patentductusarteriosus. Catheterization Cardiovasc Diagn,1996,39:287-290.
Shu X. Z., Zhu K. J. Controlled drug release properties of ionically cross-linked chitosan beads:the influence of anion structure. International Journal of Pharmaceutics.2002,233(1-2):217-225
Singhal J. P., Ray A. R. Synthesis of blood compatible polyamide block copolymers. Biomaterials,2002,23(4):1139-1145.
Spies J. B., Allison S., Flick P., et al. Spherical polyvinyl alcohol versus Iris-acryl gelatinmicrospheres for uterine artery embolization for leiomyomas: results of a limited randomizedcomparative study. Journal of Vascular and Interventional Radiology,2005,16:1431-1437.
Stiidbeck H., Ekelunk L., Jonsson N. Segmental hepaticarterial occlusion with absolute ethanol indomestic swine. Acta Radiologica. Diagnosis (Stockholm),1984,25(4):331-335.
Sugiu K, Kinugasa K, Mandai S, et al. Direct thrombosis of experimental aneurysms withcellulose acetate polymer(CAP): technical, angiographic follow up, and histological study.Neurosugery,1995,83(3):531-538
Suzuki K., Mikami T., Okawa Y., et al. Antitumor effect of hexa-N-acetylchitohexaose andchitohexaose. Carbohydrate Research,1986,151:403-408.
Taguchi T. Liver tumor targeting of drugs: Spherex, a vascular occlusive agent. Gan to KagakuRyoho,1995,22(7):969-976.
Tokunaga K, Kinugasa K, Kawada S, et al. Embolization of cerebral arteriovenous malformationwith cellulose acetate polymer: a clinical, radiological, and histological study. Neurosurgery,1999,44(5):981-989
Van der Lubben I. M., Verhoef J. C., Borchard G., et al. Chitosan and its derivatives in mucosaldrug and vaccine delivery. European Journal of Pharmaceutical Sciences,2001,14(3):201-207.
V rum K. M., Myhr M. M., Hierde R. J., et al. In vitro degradation rates of partially N-acetylatedchitosans in human serum. Carbohydrate Research,1997,299(1–2):99-101.
Wang L. Y., Gu Y. H., Zhou Q. Z., et al. Preparation and characterization of uniform-sizedchitosan microspheres containing insulin by membrane emulsification and a two-stepsolidification process. Colloids and Surfaces B: Biointerfaces,2006,50(2):126-135.
Wang L. Y., Ma G. H., Su Z. G. Preparation of uniform sized chitosan microspheres by membraneemulsification technique and application as a carrier of protein drug. Journal of ControlledRelease,2005,106(1–2):62-75.
Yalpani M., Pantaleone D. An examination of the unusual susceptibilities of aminoglycans toenzymatic hydrolysis. Carbohydrate Research,1994,256(1):159-175.
Yamamoto H., Kuno Y., Sugimoto S., et al. Surface-modified PLGA nanosphere with chitosanimproved pulmonary delivery of calcitonin by mucoadhesion and opening of the intercellulartight junctions. Journal of Controlled Release.2005,102(2):373-381
Yamashita K., Taki W., Kikuchi H. et al. A cationic polymer, Eduragit-E, as a new liquid embolicmaterial for arteriovenous malformations. Neuroradialogy,1996,38(suppl1): S151-S156
Yang J., Tian F. Wang Z., et al. Effect of chitosan molecular weight and deacetylation degree onhemostasis. Journal of Biomedical Materials Research Part B: Applied Biomaterials,2008,84B (1):131-137.
Yoshikawa M, Sunaga M, Ebara M, et al. Hepatic arterial infusion of carboplatin mixed withdegradable starch microspheres by using implanted reservoir in patients with advancedhepatocellular carcinoma. European Cancer Organization,2005,3(2):212-213
Yoshino T., Machida Y., Onishi H., et al. Preparation and Characterization of ChitosanMicrospheres Containing Doxifluridine. Drug Development and Industrial Pharmacy,2003,29(4):417-427.
Zhang J., Chen X. G., Li Y. Y., et al. Self-assembled nanoparticles based on hydrophobicallymodified chitosan as carriers for doxorubicin. Nanomedicine: nanotechnology, biology, andmedicine,2007,3(4):258-265.
Zhao G. J, Jiang Y. M., Sun L. S., et al. Comparative Studies on the Properties and InfraredSpectra of Chitosans from Different Sources, Journal of Functional Polymers,1998,9:403-407.
陈庆华.肝动脉栓塞微球的动物体内行为和药效学研究.中国医药工业杂志，1990，21（10）：472-477.
陈新梅.壳聚糖微球研究进展.中国药师，2009，12（6）：734-737.
程光森，彭秀斌，陈加源，等.不同栓塞材料在急性内脏出血介入栓塞中的应用.介入放射学杂志，2008，17（3）：475-477.
程宇慧，廖工铁，侯世祥，等.颈外动脉栓塞化疗用氟尿嘧啶白蛋白微球的研制.中国药学杂志，1993，28（8）：479-481.
蒋挺大.壳聚糖.北京：化学工业出版社，2001，31-48.
孔晓龙.丝裂霉素肝动脉栓塞明胶微球的研究.广西医科大学学报，1997，14（3）：49-51.
李裕波，林进令，刘志明.白芨作为血管栓塞剂的应用.介入放射学杂志，2010，19（10）：835-838.
梁艳，卢文玉，闻建平. Minitab软件在多杀菌素发酵条件优化中的应用.中国抗生素杂志，2008，33（11）：659-688.
凌锋，李铁林，刘树山.介入神经放射学.北京：人民卫生出版社.1991：1-50.
刘超.酰化壳聚糖的合成及其自组装药用囊泡的研究：[硕士学位论文].福建：华侨大学，2004.
刘晨光，刘成圣，孟祥红，等.壳聚糖作为药物缓释材料的研究进展.高技术通讯，2003，（3）：98-102
刘正坤，魏树礼，兰传青.顺铂聚乳酸微球的药物释放特性及肝动脉栓塞研究.药学学报，1993，28（10）：792-797
罗华丽，鲁在君.壳聚糖作为药物缓释载体的研究进展.高分子通报，2006，（7）：25-30.
马廉亭，于译，秦尚振，等.经导管注入真丝微粒和线段治疗脑动静脉崎形.中华外科杂志.1991，29（8）：516-518.
孙萍，朱立华，杨桂文，等.水溶性壳聚糖的降血糖作用研究.山东医药，2007，47（10）：23-24
王爱红，壳聚糖及其乙酰化衍生物微球用于动脉栓塞材料的实验研究：[硕士学位论文].山东：中国海洋大学，2009
王大山，安利国，杨桂文.壳聚糖对巨噬细胞的双向免疫调节作用.生命的化学.2009，29（1）：60-63
王鸿，沈月新.不同脱乙酰度壳聚糖的抑菌性.上海水产大学学报，2001，10（4）：380-382
王怀玉，董利民，昝青峰，等.乳化交联法制备壳聚糖微球粘连原因分析.功能材料，2007，38（A05）：1923-1925
王启钊，壳聚糖及其衍生物微球的制备以及作为介入治疗材料的基础研究：[硕士学位论文].山东：中国海洋大学，2006
王晓玲.甲壳素和壳聚糖在食品工业中应用的新进展，食品研究与开发，2007，28（10）：163-166.
王亚敏，石庭森，蒲永林.顺铂壳聚糖微球肝动脉栓塞化疗的动物实验和治疗肝癌的临床研究.北京医科大学学报，1995，27（5）：381-384.
王增寿，胡伟，张华，等.多柔比星壳聚糖微球的制备及其特性研究.医药导报，2007，26（7）：720-723.
王增寿，张华，朱光辉，等.脑用表盐酸阿霉素壳聚糖微球的制备及其特性考察.中国医院药学杂志，2007，27（2）：148-152
魏涛，唐粉芳，高兆兰，等.壳聚糖降血脂、降血糖及增强免疫作用的研究.食品科学.2000，21（4）：48-52.
杨熙章，杨利，陈自谦，等.动脉栓塞术治疗失功能移植肾.介入放射学杂志，2008，17（7）：484-485.
杨于彬.生物医学工程与介入性诊疗技术.世界医疗器械，1997，39）：50-52.
易志远.壳聚糖载药微球的制备及其释药性能研究：：[硕士学位论文].南宁：广西大学，2010.
袁敏，川建明，苏国强，等.碘油/无水乙醇肝阶段性栓塞的犬实验研究.中国医学计算机成像杂志，2001，7（5）：342-349.
张和平，李天晓，韩新巍，等.超选择动脉栓塞术在头颈部疚病治疗中的应用研究.中国综合临床，2004，20（7）：594-595.
张慧珠.疏水改性多糖及其叶酸偶合体作为纳米药物载体的研究：[博士学位论文].北京：中国协和医科大学生物医学工程专业，2009.
赵成如，史文红，金刚.医用介入栓塞材料.中国医疗器械信息，2007，13（8）：1-10.
郑爱萍，郝睿，褚丽云，等.鼻用氟脲嘧啶壳聚糖微球的体外释放及溶胀影响因素.沈阳药科大学学报，2006，23（2）：74-79.
郑爱萍，于少云，赵莹，等.鼻用氟尿嘧啶壳聚糖微球的制备及其特性研究.北京大学学报（医学版），2004，36（3）：300-306.
邹巧根，韦萍卜，陈居芹，等.欧阳平凯.用于肿瘤栓塞术的药用材料研究进展.药物进展，2008，32（1）：28-32.
邹英华，蒋学祥，彭勃，等.国产PVA微球肝动脉栓塞的实验研究.中华放射学杂志，1989，23（6）：330-332.
Akbuga J., Bergisadi N. Effect of formulation variables on cis-platin loaded Chitosan microsphereproperties. Journal of Microencapsulation,1999,16(6):697-703.
Alpar H. O., Somavarapu S., Atuah K. N., et al. Biodegradable mucoadhesive particulates fornasal and pulmonary antigen and DNA delivery. Advanced Drug Delivery Reviews,2005,57(3):411-430.
Aranaz I., Mengíbar M., Harris R., et al. Functional characterization of chitin and Chitosan.Current Chemical Biology,2009,3(2),203-230.
Basketter D. A., Selbie E., Scholes E. W., et al. Results with OECD recommended positive controlsensitizers in the maximization, Buehler and local lymph node assays. Food and ChemicalToxicology,1993,31(1):63-67.
Bendszus M., Martin-Schrader I., Warmuth-Metz M., et al. MR imaging–and MRspectroscopy–revealed changes in meningiomas for which embolization was performedwithout subsequent surgery. American Journal of Neuroradiology,2000,21(4):666-669.
Bendszus M., Rao G., Burger R., et al. Is there benefit of preoperative meningioma embolization?Neurosurgery,2000,47(6):1306-1312.
Berger J., Reist M., Mayer J. M., et al. Structure and interactions in covalently and ionicallycrosslinked chitosan hydrogels for biomedical applications. European Journal ofPharmaceutics and Biopharmaceutics.2004,57(1):19-34.
Berthelsen B., Lofgren J., Svendsen P., et al. Embolization of cerebral arteriovenousmalformations with burcrylate experience in a first series of29patients. Acta Radiologica,1990,31(1):13-21.
Berthold A., Cremer K., Kreuter J. Preparation and characterization of Chitosan microspheres asdrug carrier for prednisolone sodium phosphate as model for anti-inflammatory drugs.Journal of Controlled Release,1996,39(1):17-25.
Bhattarai N., Ramay H. R., Gunn J., et al. PEG-grafted chitosan as an injectable thermosensitivehydrogel for sustained protein release. Journal of Controlled Release,2005,103(3):609-624.
Bodmeier R., Chen H. G., Paeratakul O. A novel approach to the oral delivery of micro-ornanoparticles. Pharmaceutical research.1989,6(5):413-117.
Boucard N., Viton C., Agay D., et al. The use of physical hydrogels of chitosan for skinregeneration following third-degree burns. Biomaterials,2007,28(24):3478-3488.
Box G. E. P., Behnken D. W. Some new three level designs for the study of quantitative variables.Technometrics,1960,2(4),455-475.
Box G. E. P., Hunter J. S., Hunter, W. G. Statistics for experimenters: an introduction to design,data analysis and model building. New York: John willey and Sons.1990.
Brooks S. H., Mickey M. R. Optimum estimation of gradient direction in steepest ascentexperiments. Biometrics,1961,17(1),48-56.
Buehler E. V. Delayed contact hypersensitivity in the Guinea pig. Arch Dermatol,1965,91(2):171-175.
Burns N. L., Holmberg K., Brink C. Influence of surface charge on protein adsorption at anamphoteric surface: effects of varying acid to base ratio. Journal of Colloid and InterfaceScience,1996,178(1):116-122.
Calvo P., Vila-Jato J. L., Alonso M. J. Evaluation of cationic polymer-coated nanocapsules asocular drug carriers. International Journal of Pharmaceutics,1997,153(1):41-50.
Carre o-Gómez B., Duncan R. Evaluation of the biological properties of soluble chitosan andchitosan microspheres. International Journal of Pharmaceutics,1997,148(2):231-240.
Charnsangavej C., Chuang V. P., Wallace S., et al. Angiographic classification of hepatic arterialcollaterals. Radiology,1982,144(3):485-494.
Chen X. G., Liu C. S., Liu C. G., et al. Preparation and biocompatibility of chitosan microcarriersas biomaterial. Biochemical Engineering Journal,2006,27(3):269-274.
Chen X. G., Liu W. S., Lang G. H., et al. Manufacture of chitin microshpheres. China, Vol.ZL96115714.3,2002.
Cho S. M., Choi H. K. Preparation of mucoadhesive chitosan-poly(acrylic acid) microspheres byinterpolymer complexation and solvent evaporation method II. Archives of PharmacalResearch,2005,28(5):612-618.
Choi C. Y., Kim S. B., Park P. K., et al. Effect of N-acylation on structure and properties ofchitosan fibers. Carbohydrate Polymers,2007,68(1):122-127.
Denis F. A., Hanarp P., Sutherland D. S., et al. Protein adsorption on model surfaces withcontrolled nanotopography and chemistry. Langmuir,2002,18(3):819-828.
Desai K. G. H., Park H. J. Preparation and characterization of drug-loadedchitosan–tripolyphosphate microspheres by spray drying. Drug Development Research,2005,64(2):114-128.
Dutta P. K., Dutta J., Tripathi V. S. Chitin and Chitosan: chemistry, properties and applications.Journal of Scientific and Industrial Research,2004,63(1):20-31.
Ei-Hameed M. D. A., Kellaway I. W. Preparation and in vitro characterization of mucoadhesivepolymeric microspheres as intra-nasal delivery system. European Journal of Pharmaceuticsand Biopharmaceutics,1997,44(1):53-60
El-Ghannam A., Ducheyne P., Shapiro I. M. Bioactive material template for in vitro, synthesis ofbone. Journal of Biomedical Materials Research,1995,29(3):359-370.
Filipovic-Grcic J., Perissutti B., Moneghini M., et al. Spray-dried carbamazepine-loaded Chitosanand HPMC microspheres: preparation and characterization. Journal of Pharmacy andPharmacology,2003,55(7):921-931.
Fischer D., Li Y. X., Ahlemeyer B., et al. In vitro cytotoxicity testing of polycations: influence ofpolymer structure on cell viability and hemolysis. Biomaterials,2003,24(7):1121-1131.
Frankild S., Vélund A., Wahlberg J. E., et al. Comparison of the sensitivities of the buehler testand the Guinea pig maximization test for predictive testing of contact allergy. ActaDermato-Venereologica,2000,80(4):256-262
Giunchedi P., Genta I., Conti B., et al. Preparation and characterization of ampicillin loadedmethylpyrrolidinone chitosan and chitosan microspheres. Biomaterials,1998,19(1-3):157-161.
Guan Y. L., Shao L., Kang J. L., et al. pH Effect on correlation between water state and swellingkinetics of the crosslinked chitosan/polyether semi-IPN hydrogel. Journal of AppliedPolymer Science,1996,62(8):1253-1258.
Gupta K. C., Jabrail F. H. Effects of degree of deacetylation and cross-linking on physicalcharacteristics, swelling and release behavior of Chitosan microspheres. CarbohydratePolymers,2006,66(1):43-54.
Hansen M. B., Nielsen S. E., Berg K. Re-examination and further development of a precise andrapid dye method for measuring cell growth/cell kill. Journal of Immunological Methods,1989,119(2):203-210.
Harris R., Lecumberri E., Mateos-Aparicio I., et al. Chitosan nanoparticles and microspheres forthe encapsulation of natural antioxidants extracted from Ilex paraguariensis. CarbohydratePolymers,2011,84(2):803-806.
Harris R., Pa os I., Acosta N., et al. Preparation and characterization of chitosan microspheres forcontrolled release of tramadol. Journal of Controlled Release,2008,132(3): e76-e77.
He P., Davis S. S., Illum L. Chitosan microspheres prepared by spry drying. International Journalof Pharmaceutics,1999,187(1):53-65.
He P., Davis S. S., Illum L. In vitro evaluation of the mucoadhesive properties of chitosanmicrospheres. International Journal of Pharmaceutics,1998,166(1):75-88.
Helander I. M., Nurmiaho-Lassila E. L., Ahvenainen R., et al. Chitosan disrupts the barrierproperties of the outer membrane of Gram-negative bacteria. International Journal of FoodMicrobiology,2001,71(2–3):235-244.
Hirano S. Chitin and chitosan as novel biotechnological materials. Polymer International,1999,48(8):732-734.
Huang R. H., DU Y. M., Yang J. H., et al. Influence of functional groups on the in vitroanticoagulant activity of chitosan sulfates. Carbohydrate Research,2003,338(6):483-489.
Huang Y. C., Yeh M. K., Chiang C. H. Formulation factors in preparing BTM-Chitosanmicrospheres by spray drying method. International Journal of Pharmaceutics,2002,242(1-2):239-242.
Ikarashi Y., Ohno K., Momma J., et al. Assessment of contact sensitivity of four thiourea rubberaccelerators: Comparison of two mouse lymph node assays with the guinea pig maximizationtest. Food and Chemical Toxicology,1994,32(11):1067-1072.
Ikeda I., Sugano M., Yashida K., et al. Dietary fibre and lipid absorption: interference of chitosanand its hydrolyzate with cholesterol and fatty acid absorption and metabolic consequences inrats. In: Kritchevsky D., Bonefield C., editors. Dietary Fibre in Health and Disease. St. Paul,MN: Eagan Press,1995. pp:95–106.
Imai Y., Nose Y. A new method for evalution of antithrombogenicity of materials. Journal ofBiomedical Materials Research,1972,6(3):165-172.
Inoyatov N., Cellebi. N., Acarturk F. Preparation and evaluation of a prolonged releasepentoxifylline tablet with chitosan. Pharmazeutische Industrie,1998,60(5):472-475.
Jahan R., Murayama Y., Gobin Y. P., et al. Embolization of arteriovenous malformations withOnyx: clinicopathological experience in23patients. Neurosurgery,2001,48(5):984-995.
Jameela S.R., Jayakrishnan A. Glutaraldehyde cross-linked Chitosan microspheres as a long actingbiodegradable drug delivery vehicle: studies on the in vitro releases of mitoxantrone and invivo degradation of microspheres in rat muscle. Biomaterials,1995,16(10):769-775.
Je J. Y., Kim S. K. Chitosan Derivatives Killed Bacteria by Disrupting the Outer and InnerMembrane. Journal of Agricultural and Food Chemistry,2006,54(18):6629-6633.
Jia Z. S., Li Q.B. Determination of the deacetylation degree of Chitosan by two abrupt changepotential titration method. Chemical World,2001,(5):240-241.
Jumaa M., Furkert F. H., Muller B. W. et al. A new lipid emulsion formulation with highantimicrobial efficacy using chitosan. European Journal of Pharmaceutics andBiopharmaceutics,2002,53(1):115-123.
Kaibara M., Kawamoto K., Yanagida S., et al. In vitro evaluation of antithrombogenicity ofhybrid-type vascular vessel models based on analysis of the mechanism of blood coagulation.Biomaterials,1995,16(16):1229-1234.
Kamiyama K., Onishi H., Machida Y., et al. Biodisposition characteristics of N-succinyl-chitosanand glycol-chitosan in normal and tumor-bearing mice. Biological and pharmaceuticalbulletin,1999,22(2):179-186.
Kanke M., Katayama H., Tsuzuki S., et al. Appilcation of chitin and chitosan to pharmaceuticalpreparations. I. Film prepatation and in vitro dissolution. Chemical and PharmaceuticalBulletin,1989,37(2):523-525.
Kawashima Y., Handa T., Kasai A., et al. Novel method for the preparation of controlled-releasetheophylline granules coated with a polyelectrolyte complex of sodiumpolyphosphate–Chitosan. Journal of Pharmaceutical Sciences,1985,74(3):264–268.
Kean T., Thanou M. Biodegradation, biodistribution and toxicity of Chitosan. Advanced DrugDelivery Reviews,2010,62(1):3-11.
Khalid M. N., Ho L., Agnely F., et al. Swelling properties and mechanical characterization of asemi-interpenetrating chitosan/polyethylene oxide network: Comparison with a chitosanreference gel. STP pharma sciences,1999,9(4):359-364.
Khor E., Lim L. Y. Implantable applications of chitin and chitosan. Biomaterials,2003,24(13):2339-2349.
Kimber I., Basketter D. A., Berthold K., et al. Skin sensitization testing in potency and riskassessment. Toxicological Sciences,2001,59(2):198-208.
Kinugasa K., Mandai S., Terai Y., et al. Direct thrombosis of aneurysms with cellulose acetatepolymer part2: Preliminary clinical experience. Journal of Neurosurgery,1992,77(4):501-507.
Kockisch S., Rees G. D., Young S. A., et al. In situ evaluation of drug-loaded microspheres on amucosal surface under dynamic test conditions. International Journal of Pharmaceutics,2004,276(1–2):51-58.
Kosaraju S. L., D’ath L., Lawrence A. Preparation and characterisation of chitosan microspheresfor antioxidant delivery. Carbohydrate Polymers,2006,64(2):163-167.
Kowalski S. M., Borror C. M., Montgomery D. C. A modified path of steepest ascent for split-plotexperiments. Journal of Quality Technology,2005,37(1):75-83.
Kratz G., Arnander C., Swedenborg J., et al. Heparin-Chitosan Complexes Stimulate WoundHealing in Human Skin. Scandinavian Journal of Plastic and Reconstructive Surgery andHand Surgery,1997,31(2):119-123.
Kristiansen A., V rum K. M., Hrasdalen H. Quantitative studies of the non-productive binding oflysozyme to partially N-acetylated chitosans: Binding of large ligands to a one-dimensionalbinary lattice studied by a modified McGhee and von Hippel model. Biochimica etBiophysica Acta,1998,1425(1):137-150.
Lamprecht A., Yamamoto H., Takeuchi H., et al. pH-sensitive microsphere delivery increases oralbioavailability of calcitonin. Journal of Controlled Release,2004,98(1):1-9
Lee K. Y., Ha W. S., Park W. H. Blood compatibility and biodegradability of partially N-acylatedchitosan derivatives. Biomaterials,1995,16(16):1211-1216.
Li S., Wang X. T., Zhang X. B., et al. Studies on alginate-chitosan microcapsules and renal arterialembolization in rabbits. Journal of Controlled Release,2002,84(3):87-98.
Liang T. W., Chen Y. J., Yen Y. H., et al. The antitumor activity of the hydrolysates of chitinousmaterials hydrolyzed by crude enzyme from Bacillus amyloliquefaciens V656. ProcessBiochemistry,2007,42(4):527-534.
Lim C. K., Yaacob N. S., Ismail Z., et al. In vitro biocompatibility of chitosan porous skinregenerating templates (PSRTs) using primary human skin keratinocytes. Toxicology in Vitro,2010,24(3):721-727.
Liu H., Du Y., Wang X. H., et al. Chitosan kills bacteria through cell membrane damage.International Journal of Food Microbiology,2004,95(2):147-155.
Liu X. F., Guan Y. L., Yang D. Z., et al. Antibacterial action of chitosan and carboxymethylatedchitosan. Journal of Applied Polymer Science,2001,79(7):1324-1335.
Lv Y., Chen X. G., Wang Q. Z., et al. Synthesis and characterization of chitosan-basedbiomaterials modified with different active groups and their relationship with cytotoxicity.Journal of Wuhan University of Technology--Materials Science Edition,2007,22(4):695-700.
Machida Y., Nagai T., Abe M, et al. Use of chitosan and hydroxypropylchitosan in drugformulations to effect sustained release. Drug Design Delivery.19861(2):119-30.
Macieira-Coelho A., Berumen L., Avrameas S. Properties of protein polymers as substratum forcell growth in vitro. Journal of Cellular Physiology,1974,83(3):379-388.
Macleod G. S., Collett J. H. Fell J. T. The potential use of mixed films of pectin, chitosan andHPMC for bimodal drug release. Journal of Controlled Release,1999,58(3):303-310.
Magnusson B, Kligman A. M. Allergic contact dermatitis in the guinea pig: Identification ofcontact allergens. Charles C Thomas, Springfield,1970:102-123.
Makarand V. R.isbuda, Anandwardhan A Hardikar, Sujata V Bhat, Ramesh R Bhonde.PH-sensitive freeze-dried Chitosan-polyvinyl pyrrolidone hydrogels as controlled releasesystem for antibiotic delivery. Journal of Controlled Release.2000,68(1):23-30
Mansoor M. A. Permeability and blood compatibility properties of chitosan-poly (ethylene oxide)blend membranes for haemodialysis. Biomaterials,1995,16(8):593-599.
Mao C., Zhao W. B., Zhu A. P., et al. A photochemical method for the surface modification of poly(vinyl-chloride) with O-butyrylchitosan to improve blood compatibility. ProcessBiochemistry,2004,39(9):1151-1157.
Mcclave S. A., Kaiser S. C., Wright R. A., et al. Prospective randomized comparison ofesophageal variceal sclerotherapy agents: sodium tetradecyl sulfate versus sodium morrhuate.Gastrointestianl Endosccopy,1990,36(6):567-571.
Mi F. l., Tan Y. C., Liang H. F., et al. In vivo biocompability and degradability a novelinjectable-chitosan-based implant. Biomaterials,2002,23(1):181-191
Miyazaki S., Yamaguchi H., Takada M., et al. Pharmaceutical application of biomedical polymers.XXIX. Preliminary study on film dosage form prepared from chitosan for oral drug delivery.Acta pharmaceutica Nordica,1990,2(6):401-406.
Myers R. H., Montgomery D. C. Christine M. Anderson-Cook.) Response surface methodology:process and product optimization using designed experiments (3rd). New York:John willeyand Sons,2009.
Na K., Bum L. T., Park K. H., et al. Self-assembled nanoparticles of hydrophobically-modifiedpolysaccharide bearing vitamin H as a targeted anti-cancer drug delivery system. EuropeanJournal of Pharmaceutical Sciences,2003, l8(2):165-173.
No H. K., Park N. Y., Lee S. H., et al. Antibacterial activity of chitosans and chitosan oligomerswith different molecular weights. International Journal of Food Microbiology,2002,74(1-2):65-72.
Nordtveit R. J., V rum K. M., Smidsrod O. Degradation of fully water-soluble, partiallyN-acetylated chitosans with lysozyme. Carbohydrate Polymers,1994,23(4):253-260.
Nordtveit R. J., V rum K. M., Smidsrod O. Degradation of partially N-acetylated chitosans withhen egg white and human lysozyme. Carbohydrate Polymers,1996,29(2):163-167.
Ofori-Kwakye K., Fell J. T., Sharma H. L., et al. Gamma scintigraphic evaluation of film-coatedtablets intended for colonic or biphasic release. International Journal of Pharmaceutics,2004,270(1–2):307-313.
Ohya Y., Shiratania M., Kobayashia H., et al. Release Behavior of5-Fluorouracil fromChitosan-Gel Nanospheres Immobilizing5-Fluorouracil Coated with Polysaccharides andTheir Cell Specific Cytotoxicity. Journal of Macromolecular Science, Part A: Pure andApplied Chemistry.1994,31(5):629～642.
Okamoto Y., Yano R., Miyatake K., et al. Effects of chitin and chitosan on blood coagulation.Carbohydrate Polymers,2003,53(3):337-342.
Oungbho K., Müller B. W. Chitosan sponges as sustained release drug carriers. InternationalJournal of Pharmaceutics,1997,156(2):229-237.
Outomuro D., Grana D. R., Azzato F., et al. Adriamycin-induced myocardial toxicity: Newsolutions for an old problem? International Journal of Cardiology,2007,117(1):6-15.
Pangburn S. H., Trescony P. V., Heller J. Lysozyme degradation of partially deacetylated chitin, itsfilms and hydrogels. Biomaterials,1982,3(2):105-108.
Pantaleone D., Yalpani M., Scollar M. Unusual susceptibility of chitosan to enzymic hydrolysis.Carbohydrate Research,1992,237(0):325-332.
Park J. S., Han T. H., Lee K. Y., et al. N-acetyl histidine-conjugated glycol chitosan self-assemblednanoparticles for intracytoplasmic delivery of drugs: endocytosis, exocytosis and drug release.Journal of Controlled Release,2006,115(1):37-45.
Peniche H., Osorio A., Acosta N., et al. Preparation and characterization of superparamagneticchitosan microspheres: Application as a support for the immobilization of tyrosinase. Journalof Applied Polymer Science,2005,98(2):651–657
Plackett R. L., Burman, J. P. The design of optimum multifctoria experiments. Biometrika,1946,33(4),305-325.
Quinton P. M., Philpott C. W. A role for anionic sites in epithelial architecture. Effects of cationicpolymers on cell membrane structure. The Journal of cell biology,1973,56(3):787-796.
Rabea E. I., Badawy M. E. T., Stevens C. V., et al. Chitosan as Antimicrobial Agent:Applications and Mode of Action. Biomacromolecules,2003,4(6):1457-1465.
Radi Hejazi, Mansoor Amiji. Stomach-specific anti-H. pylori therapy: Part III: Effect of chitosanmicrospheres crosslinking on the gastric residence and local tetracycline concentrations infasted gerbils. International Journal of Pharmaceutics,2004,272(1–2):99–108.
Rinaudo M. Chitin and chitosan: Properties and applications. Progress in Polymer Science,2006,31(7):603-632.
Risbud M. V., Hardikar A. A., Bhat S. V., et al. PH-sensitive freeze-dried Chitosan-polyvinylpyrrolidone hydrogels as controlled release system for antibiotic delivery. Journal ofControlled Release.2000,68(1):23-30
Ritz H. L., Buehler E.V. Procedure for conducting the guinea pig assay. Current Concepts inDermatology, Drill V.A. and Lazar P.(eds), New York: Academic Press,1980.25-40.
Roberts G. A. F. Chitin Chemistry. London: Macmillan Press,1992.100-150.
Sarah Nsereko, Mansoor Amiji. Localized delivery of paclitaxel in solid tumors frombiodegradable chitin microparticle formulations, Biomaterials,2002,23(13):2723-2731.
Satink R. G., Piest H., Helden G., et al. The infrared spectrum of the benzene--Ar cation. TheJournal of Chemical Physics,1999,111(24):10750-10753.
Scheinman M. M. Catheter Ablation. Present role and projected impact on health care for patientswith cardiac arrhythmias. Circulation,1991,83(5):1489-1498
Shelma R., Sharma C. P. Development of lauroyl sulfated chitosan for enhancinghemocompatibility of Chitosan. Colloids and Surfaces B: Biointerfaces,2011,84(2):561-570.
Shim D, Wechsler D. S., Lloyd T. R., et al. Haemolysis following coil embolization of a patentductusarteriosus. Catheterization Cardiovasc Diagn,1996,39:287-290.
Shu X. Z., Zhu K. J. Controlled drug release properties of ionically cross-linked chitosan beads:the influence of anion structure. International Journal of Pharmaceutics.2002,233(1-2):217-225
Singhal J. P., Ray A. R. Synthesis of blood compatible polyamide block copolymers. Biomaterials,2002,23(4):1139-1145.
Spies J. B., Allison S., Flick P., et al. Spherical polyvinyl alcohol versus Iris-acryl gelatinmicrospheres for uterine artery embolization for leiomyomas: results of a limited randomizedcomparative study. Journal of Vascular and Interventional Radiology,2005,16:1431-1437.
Stiidbeck H., Ekelunk L., Jonsson N. Segmental hepaticarterial occlusion with absolute ethanol indomestic swine. Acta Radiologica. Diagnosis (Stockholm),1984,25(4):331-335.
Sugiu K, Kinugasa K, Mandai S, et al. Direct thrombosis of experimental aneurysms withcellulose acetate polymer(CAP): technical, angiographic follow up, and histological study.Neurosugery,1995,83(3):531-538
Suzuki K., Mikami T., Okawa Y., et al. Antitumor effect of hexa-N-acetylchitohexaose andchitohexaose. Carbohydrate Research,1986,151:403-408.
Taguchi T. Liver tumor targeting of drugs: Spherex, a vascular occlusive agent. Gan to KagakuRyoho,1995,22(7):969-976.
Tokunaga K, Kinugasa K, Kawada S, et al. Embolization of cerebral arteriovenous malformationwith cellulose acetate polymer: a clinical, radiological, and histological study. Neurosurgery,1999,44(5):981-989
Van der Lubben I. M., Verhoef J. C., Borchard G., et al. Chitosan and its derivatives in mucosaldrug and vaccine delivery. European Journal of Pharmaceutical Sciences,2001,14(3):201-207.
V rum K. M., Myhr M. M., Hierde R. J., et al. In vitro degradation rates of partially N-acetylatedchitosans in human serum. Carbohydrate Research,1997,299(1–2):99-101.
Wang L. Y., Gu Y. H., Zhou Q. Z., et al. Preparation and characterization of uniform-sizedchitosan microspheres containing insulin by membrane emulsification and a two-stepsolidification process. Colloids and Surfaces B: Biointerfaces,2006,50(2):126-135.
Wang L. Y., Ma G. H., Su Z. G. Preparation of uniform sized chitosan microspheres by membraneemulsification technique and application as a carrier of protein drug. Journal of ControlledRelease,2005,106(1–2):62-75.
Yalpani M., Pantaleone D. An examination of the unusual susceptibilities of aminoglycans toenzymatic hydrolysis. Carbohydrate Research,1994,256(1):159-175.
Yamamoto H., Kuno Y., Sugimoto S., et al. Surface-modified PLGA nanosphere with chitosanimproved pulmonary delivery of calcitonin by mucoadhesion and opening of the intercellulartight junctions. Journal of Controlled Release.2005,102(2):373-381
Yamashita K., Taki W., Kikuchi H. et al. A cationic polymer, Eduragit-E, as a new liquid embolicmaterial for arteriovenous malformations. Neuroradialogy,1996,38(suppl1): S151-S156
Yang J., Tian F. Wang Z., et al. Effect of chitosan molecular weight and deacetylation degree onhemostasis. Journal of Biomedical Materials Research Part B: Applied Biomaterials,2008,84B (1):131-137.
Yoshikawa M, Sunaga M, Ebara M, et al. Hepatic arterial infusion of carboplatin mixed withdegradable starch microspheres by using implanted reservoir in patients with advancedhepatocellular carcinoma. European Cancer Organization,2005,3(2):212-213
Yoshino T., Machida Y., Onishi H., et al. Preparation and Characterization of ChitosanMicrospheres Containing Doxifluridine. Drug Development and Industrial Pharmacy,2003,29(4):417-427.
Zhang J., Chen X. G., Li Y. Y., et al. Self-assembled nanoparticles based on hydrophobicallymodified chitosan as carriers for doxorubicin. Nanomedicine: nanotechnology, biology, andmedicine,2007,3(4):258-265.
Zhao G. J, Jiang Y. M., Sun L. S., et al. Comparative Studies on the Properties and InfraredSpectra of Chitosans from Different Sources, Journal of Functional Polymers,1998,9:403-407.
陈庆华.肝动脉栓塞微球的动物体内行为和药效学研究.中国医药工业杂志，1990，21（10）：472-477.
陈新梅.壳聚糖微球研究进展.中国药师，2009，12（6）：734-737.
程光森，彭秀斌，陈加源，等.不同栓塞材料在急性内脏出血介入栓塞中的应用.介入放射学杂志，2008，17（3）：475-477.
程宇慧，廖工铁，侯世祥，等.颈外动脉栓塞化疗用氟尿嘧啶白蛋白微球的研制.中国药学杂志，1993，28（8）：479-481.
蒋挺大.壳聚糖.北京：化学工业出版社，2001，31-48.
孔晓龙.丝裂霉素肝动脉栓塞明胶微球的研究.广西医科大学学报，1997，14（3）：49-51.
李裕波，林进令，刘志明.白芨作为血管栓塞剂的应用.介入放射学杂志，2010，19（10）：835-838.
梁艳，卢文玉，闻建平. Minitab软件在多杀菌素发酵条件优化中的应用.中国抗生素杂志，2008，33（11）：659-688.
凌锋，李铁林，刘树山.介入神经放射学.北京：人民卫生出版社.1991：1-50.
刘超.酰化壳聚糖的合成及其自组装药用囊泡的研究：[硕士学位论文].福建：华侨大学，2004.
刘晨光，刘成圣，孟祥红，等.壳聚糖作为药物缓释材料的研究进展.高技术通讯，2003，（3）：98-102
刘正坤，魏树礼，兰传青.顺铂聚乳酸微球的药物释放特性及肝动脉栓塞研究.药学学报，1993，28（10）：792-797
罗华丽，鲁在君.壳聚糖作为药物缓释载体的研究进展.高分子通报，2006，（7）：25-30.
马廉亭，于译，秦尚振，等.经导管注入真丝微粒和线段治疗脑动静脉崎形.中华外科杂志.1991，29（8）：516-518.
孙萍，朱立华，杨桂文，等.水溶性壳聚糖的降血糖作用研究.山东医药，2007，47（10）：23-24
王爱红，壳聚糖及其乙酰化衍生物微球用于动脉栓塞材料的实验研究：[硕士学位论文].山东：中国海洋大学，2009
王大山，安利国，杨桂文.壳聚糖对巨噬细胞的双向免疫调节作用.生命的化学.2009，29（1）：60-63
王鸿，沈月新.不同脱乙酰度壳聚糖的抑菌性.上海水产大学学报，2001，10（4）：380-382
王怀玉，董利民，昝青峰，等.乳化交联法制备壳聚糖微球粘连原因分析.功能材料，2007，38（A05）：1923-1925
王启钊，壳聚糖及其衍生物微球的制备以及作为介入治疗材料的基础研究：[硕士学位论文].山东：中国海洋大学，2006
王晓玲.甲壳素和壳聚糖在食品工业中应用的新进展，食品研究与开发，2007，28（10）：163-166.
王亚敏，石庭森，蒲永林.顺铂壳聚糖微球肝动脉栓塞化疗的动物实验和治疗肝癌的临床研究.北京医科大学学报，1995，27（5）：381-384.
王增寿，胡伟，张华，等.多柔比星壳聚糖微球的制备及其特性研究.医药导报，2007，26（7）：720-723.
王增寿，张华，朱光辉，等.脑用表盐酸阿霉素壳聚糖微球的制备及其特性考察.中国医院药学杂志，2007，27（2）：148-152
魏涛，唐粉芳，高兆兰，等.壳聚糖降血脂、降血糖及增强免疫作用的研究.食品科学.2000，21（4）：48-52.
杨熙章，杨利，陈自谦，等.动脉栓塞术治疗失功能移植肾.介入放射学杂志，2008，17（7）：484-485.
杨于彬.生物医学工程与介入性诊疗技术.世界医疗器械，1997，39）：50-52.
易志远.壳聚糖载药微球的制备及其释药性能研究：：[硕士学位论文].南宁：广西大学，2010.
袁敏，川建明，苏国强，等.碘油/无水乙醇肝阶段性栓塞的犬实验研究.中国医学计算机成像杂志，2001，7（5）：342-349.
张和平，李天晓，韩新巍，等.超选择动脉栓塞术在头颈部疚病治疗中的应用研究.中国综合临床，2004，20（7）：594-595.
张慧珠.疏水改性多糖及其叶酸偶合体作为纳米药物载体的研究：[博士学位论文].北京：中国协和医科大学生物医学工程专业，2009.
赵成如，史文红，金刚.医用介入栓塞材料.中国医疗器械信息，2007，13（8）：1-10.
郑爱萍，郝睿，褚丽云，等.鼻用氟脲嘧啶壳聚糖微球的体外释放及溶胀影响因素.沈阳药科大学学报，2006，23（2）：74-79.
郑爱萍，于少云，赵莹，等.鼻用氟尿嘧啶壳聚糖微球的制备及其特性研究.北京大学学报（医学版），2004，36（3）：300-306.
邹巧根，韦萍卜，陈居芹，等.欧阳平凯.用于肿瘤栓塞术的药用材料研究进展.药物进展，2008，32（1）：28-32.
邹英华，蒋学祥，彭勃，等.国产PVA微球肝动脉栓塞的实验研究.中华放射学杂志，1989，23（6）：330-332.