CN106397674A - 一种温敏性防术后粘连纤维素改性材料及其制备方法与应用 - Google Patents
一种温敏性防术后粘连纤维素改性材料及其制备方法与应用 Download PDFInfo
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Abstract
本发明公开了一种温敏性防术后粘连纤维素改性材料及其制备方法与应用。本发明首先将具有抗细胞粘附或蛋白质非特异性吸附性质的磺酸甜菜碱型两性离子单体接枝共聚到温敏的甲基纤维素主链上,再通过低温溶解法配制该接枝共聚物水溶液。室温下该接枝共聚物水溶液为易于注射或涂覆的粘性液体,在人体温度下可自发快速形成水凝胶,具有可逆的溶胶‑凝胶相转变特性。基于本发明制备的温敏性防术后粘连纤维素改性材料,生物相容性好、抗细胞粘附和组织粘连能力强,能适用于复杂手术创面或伤口部位的防粘连处理,具有较高的手术操作便利性和防术后粘连有效性。
Description
技术领域
本发明属于生物医用水凝胶材料制备技术领域,具体涉及一种温敏性防术后粘连纤维素改性材料及其制备方法与应用。
背景技术
随着各项外科手术的大量开展,术后生物组织粘连问题日益突出。粘连一般是手术后的创伤、感染或其他因素所导致的伤口部位与周围组织或器官之间发生了非正常联结而形成的异常结构。术后粘连不仅影响手术效果,还可导致严重的术后并发症,如小肠梗阻、妇女盆腔粘连等,使手术失败。因此,寻找有效的方法预防术后粘连一直生物医学工程领域的重要课题。
至今应用最广泛的防粘连手段是植入物理阻隔材料,通过隔开受伤组织与周围的器官从而防止发生粘连。常用的防粘连阻隔材料主要有以下三类:一是固态膜材料,如专利CN103044700A公开的一种术后防粘连膜材料、专利CN104436317A公开的一种术后防粘连高分子薄膜等,此类材料因已预先成型,手术过程中不易操作且难以适用于某些复杂的伤口部位,其应用受到限制;二类是水液体类物质,如专利CN103271939A公开的一种手术用防粘连冲洗液,这类材料具有很好的流动性,可注射或涂覆于复杂的伤口部位,但容易流失,阻隔时间不够长、效果有限;三是水凝胶类物质,在一定条件下具有流动性,亦可注射或涂覆在复杂的手术创面或伤口部位,且阻隔时间相对较长,如Yeo等学者报道的可原位交联双组份水凝胶(Biomaterials,2006,27:4698-4705;Biomaterials,2007,28:3418-3426),但其制备时使用了一定毒性的化学交联剂。从防术后组织粘连的作用机制考虑,要将有关物理阻隔手段成功应用于防术后 粘连,防粘连阻隔材料应具有良好的抗蛋白质非特异性吸附或细胞粘附性能,但上述物理阻隔材料普遍不具有这方面性能,致使其应用效果不够理想。
发明内容
为了克服现有技术的缺点与不足,本发明的首要目的在于提供一种温敏性防术后粘连纤维素改性材料的制备方法,即以具有温敏和优良生物相容性的甲基纤维素为主链、以具有抗细胞粘附或蛋白质非特异性吸附性质的磺酸甜菜碱型两性离子聚合物为侧链构建防术后粘连纤维素改性材料。
本发明的另一目的在于提供基于上述制备方法得到的温敏性防术后粘连纤维素改性材料。该纤维素改性材料不使用有潜在毒性的化学交联剂,在室温下其水溶液为易于注射或涂覆的粘性液体,在人体温度下则可自发快速形成水凝胶,具有可逆的溶胶-凝胶相转变特性。
本发明的再一目的在于提供上述温敏性防术后粘连纤维素改性材料作为防盲肠术后粘连材料的用途。
本发明的目的通过下述技术方案实现:
一种温敏性防术后粘连纤维素改性材料的制备方法,具体包括如下步骤:
(1)在甲基纤维素水溶液中,加入两性离子单体甲基丙烯酰乙基磺基甜菜碱、引发剂和N,N,N',N'-四甲基乙二胺,在氮气或氩气保护下进行自由基接枝聚合反应,反应完成后透析并冷冻干燥,得到甲基纤维素接枝甲基丙烯酰乙基磺基甜菜碱两性离子单体共聚物;
(2)将步骤(1)制得的甲基纤维素接枝甲基丙烯酰乙基磺基甜菜碱两性离子单体共聚物溶于缓冲液,配制成共聚物水溶液,即为所述温敏性防术后粘连纤维素改性材料。
步骤(1)中所述的甲基纤维素水溶液,是将甲基纤维素加入到70~80℃热蒸馏水中,再置于冰水浴中继续搅拌至完全透明而制得。所述甲基纤维素水溶液质量分数优选为1.0%~4.0%。
步骤(1)中所述的甲基丙烯酰乙基磺基甜菜碱与甲基纤维素水溶液中的甲基纤维素的质量比为(1:2)~(1:8)。
步骤(1)中所述的引发剂、N,N,N',N'-四甲基乙二胺与甲基丙烯酰乙基磺基甜菜碱的质量比为(1:1:20)~(1:1:10),更优选为1:1:10。
步骤(1)中所述的自由基接枝聚合反应的条件优选为25~45℃,时间12~24h。
步骤(1)中所述的引发剂为过硫酸铵、硫酸钾和过硫酸钠中的至少一种,优选为过硫酸铵。
步骤(2)中所述的缓冲液为磷酸氢二钠-磷酸二氢钠缓冲液(pH=7.4)、乙酸-乙酸钠缓冲液(pH=6.8)、柠檬酸-柠檬酸钠缓冲液(pH=7.2)或柠檬酸-氢氧化钠-盐酸缓冲液(pH=7.0)。
步骤(2)中所述的共聚物水溶液,是将甲基纤维素接枝甲基丙烯酰乙基磺基甜菜碱两性离子单体共聚物加入缓冲液中,再置于冰水浴中搅拌至完全溶解,并在4℃冰箱内放置过夜而制得。所述共聚物水溶液的质量分数优选为10%~20%。
本发明还提供了一种通过上述制备方法制备得到的温敏性防术后粘连纤维素改性材料。
本发明还提供了上述温敏性防术后粘连纤维素改性材料作为体内伤口防粘连敷料的应用方法,例如可作为防盲肠术后粘连材料。所述的温敏性防术后粘连纤维素改性材料可单独使用,也可添加其他外用药物后使用。
所述的温敏性防术后粘连纤维素改性材料单独使用,是指直接将甲基纤维素接枝甲基丙烯酰乙基磺基甜菜碱两性离子单体共聚物水溶液注射于体内伤口处,在体温下即可形成水凝胶。
所述的温敏性防术后粘连纤维素改性材料添加其他外用药物后使用,其步骤如下:
(A)称取1-100毫克药物(如氨芐青霉素),加入甲基纤维素接枝甲基丙 烯酰乙基磺基甜菜碱两性离子单体共聚物水溶液中,低温搅拌溶解后置于4℃冰箱内放置过夜,制得包埋药物的共聚物水溶液,室温下为易于注射的粘性液体;
(B)将步骤(A)所得包埋药物的共聚物水溶液注射于体内伤口处,在体温下即可形成负载药物的水凝胶。
与现有技术相比,本发明具有以下优点及有益效果:
(1)本发明采用的主要原料为来源丰富且具有生物安全性和生物降解性的甲基纤维素,价格便宜。
(2)本发明不使用化学交联剂,仅靠甲基纤维素链段的温敏独特性质在水溶液中进行物理交联,安全无毒。
(3)本发明所得的温敏性防术后粘连纤维素改性材料的凝胶化温度为30~35℃,室温下为易于注射或涂覆的粘性液体,在人体温度下则可自发快速形成水凝胶,具有可逆的溶胶-凝胶相转变特性。
(4)本发明所得的温敏性防术后粘连纤维素改性材料可用作体内伤口防粘连敷料,在生物医用材料领域具有一定的应用前景。
(5)本发明操作简易,对设备要求低,适用性广。
附图说明
图1为制备温敏性防术后粘连纤维素改性材料的工艺流程图。
图2为实施例2制得的温敏性防术后粘连纤维素改性材料水凝胶样品的动态温度扫描曲线(G':储能模量,G”:损耗模量):△代表甲基纤维素接枝甲基丙烯酰乙基磺基甜菜碱两性离子单体共聚物水凝胶的G'—温度曲线;□代表甲基纤维素接枝甲基丙烯酰乙基磺基甜菜碱两性离子单体共聚物水凝胶的G”—温度曲线。
图3为温敏性防术后粘连纤维素改性材料的细胞粘附生长情况显微镜照片。
图4为温敏性防术后粘连纤维素改性材料应用于大鼠盲肠伤口模型的照片。
具体实施方式
下面结合实施例和附图对本发明作进一步详细的描述,但本发明的实施方式不限于此。除非特别说明,实施例中所涉及的试剂、方法均为本领域常用的试剂和方法。
实施例1
(1)称取1.0克粘度为15cP的甲基纤维素(MC)加入到50mL 80℃的蒸馏水,然后将烧瓶置于冰水浴中继续搅拌使其完全溶解,呈透明液体状。再称取0.5克甲基丙烯酰乙基磺基甜菜碱(DMAPS)加入到烧瓶并继续搅拌,并通入氮气保护。然后加入50毫克过硫酸铵(APS)作引发剂和65微升N,N,N',N'-四甲基乙二胺(TEMED,密度0.775g/mL,下同)作促进剂,在氮气气氛下25℃条件下反应24小时。反应完后,将反应液全部转移到截留分子量为8000的透析袋中,用去离子水透析3天,冻干后得到甲基纤维素接枝甲基丙烯酰乙基磺基甜菜碱两性离子单体共聚物。
(2)称量1克步骤(1)制得的甲基纤维素接枝甲基丙烯酰乙基磺基甜菜碱两性离子单体共聚物,并加入5毫升pH=7.4的磷酸氢二钠-磷酸二氢钠缓冲液,置于冰水浴中不断搅拌使其溶解。在4℃冰箱中放置过夜使气泡逸出后,得到质量分数为20%的共聚物水溶液,并置于4℃下保存。
(3)将共聚物水溶液加热至37℃,即转变为不流动的凝胶状,得到甲基纤维素接枝甲基丙烯酰乙基磺基甜菜碱两性离子单体共聚物水凝胶样品。
实施例2
(1)称取1.2克粘度为15cP的甲基纤维素(MC)加入到50mL 80℃的蒸馏水,然后将烧瓶置于冰水浴中继续搅拌使其完全溶解,呈透明液体状。再称取0.3克甲基丙烯酰乙基磺基甜菜碱(DMAPS)加入到烧瓶并继续搅拌,并通入氮气保护。然后加入30毫克过硫酸铵(APS)作引发剂和40微升N,N,N', N'-四甲基乙二胺(TEMED)作促进剂,在氮气气氛下45℃条件下反应12小时。反应完后,将反应液全部转移到截留分子量为8000的透析袋中,用去离子水透析3天,冻干后得到甲基纤维素接枝甲基丙烯酰乙基磺基甜菜碱两性离子单体共聚物。
(2)称量1克步骤(1)制得的甲基纤维素接枝甲基丙烯酰乙基磺基甜菜碱两性离子单体共聚物,并加入10毫升pH=7.4的磷酸氢二钠-磷酸二氢钠缓冲液,置于冰水浴中不断搅拌使其溶解。在4℃冰箱中放置过夜使气泡逸出后,得到质量分数为10%的共聚物水溶液,并置于4℃下保存。
(3)将共聚物水溶液加热至37℃,即转变为不流动的凝胶状,得到甲基纤维素接枝甲基丙烯酰乙基磺基甜菜碱两性离子单体共聚物水凝胶样品。
(4)共聚物水凝胶的凝胶化温度利用ARES/RFS型高级旋转流变仪(TA,USA)进行测定,夹具为25毫米的平板夹具,在20℃下将1mL 10%的共聚物水溶液均匀涂抹到平板上,立刻在动态温度扫描模式下进行测量。测量条件:频率(Frequency)为1rad/s,形变(Strain)为1%,扫描温度范围为25~40℃,升温速率为1℃/分钟,平板夹具的间距(Gap)由实验实际调整为准,该实验一般取0.8毫米。
结果如图2所示,当储能模量G'大于损耗模量G”时,样品已形成凝胶状态,此时的温度则是样品的凝胶化温度,其值为33℃。
实施例3
(1)参考实施例2配制出质量分数为10%的甲基纤维素接枝甲基丙烯酰乙基磺基甜菜碱两性离子单体共聚物水溶液,并置于4℃下保存。
(2)称量1克粘度为15cP的甲基纤维素并加入10毫升pH=7.4的磷酸氢二钠-磷酸二氢钠缓冲液,置于冰水浴中不断搅拌使其溶解。在4℃冰箱中放置过夜使气泡逸出后,得到质量分数为10%的甲基纤维素水溶液,并置于4℃下保存。
(3)分别用甲基纤维素水溶液和甲基纤维素接枝甲基丙烯酰乙基磺基甜菜碱两性离子单体共聚物水溶液均匀覆盖细胞培养板的一半面积,培养板的另外一半面积用作空白对照。将培养板置于37℃的细胞培养箱中,使凝胶样品充分形成。将人鼻咽上皮细胞NP69均匀种在培养板上,并置于含5%CO2的37℃细胞培养箱中培养过夜,然后用噻唑蓝(MTT)对细胞进行染色,并用显微镜观察细胞的粘附生长情况。
(4)结果如图3所示,可见甲基纤维素水凝胶样品表面上有较多的细胞粘附生长,而甲基纤维素接枝甲基丙烯酰乙基磺基甜菜碱两性离子单体共聚物水凝胶样品表面上的细胞数目较少,说明共聚物水凝胶具有抗细胞粘附生长的性质。
实施例4
(1)参考实施例2配制出质量分数为10%的甲基纤维素接枝甲基丙烯酰乙基磺基甜菜碱两性离子单体共聚物水溶液,并置于4℃下保存。
(2)称量1克粘度为15cP的甲基纤维素并加入10毫升pH=7.4的磷酸氢二钠-磷酸二氢钠缓冲液,置于冰水浴中不断搅拌使其溶解。在4℃冰箱中放置过夜使气泡逸出后,得到质量分数为10%的甲基纤维素水溶液,并置于4℃下保存。
(3)称量100毫克氨芐青霉素,加入到步骤(1)制得的共聚物水溶液,低温搅拌至完全溶解,制得包埋氨芐青霉素的共聚物水溶液,并置于4℃下保存。
(4)称量100毫克氨芐青霉素,加入到步骤(2)制得的甲基纤维素水溶液,低温搅拌至完全溶解,制得包埋氨芐青霉素的甲基纤维素水溶液,并置于4℃下保存。
(5)用3%戊巴比妥(30毫克/千克)对200~250克清洁级SD大鼠进行腹腔注射麻醉后,剪去腹部的毛并用75%酒精消毒。在超净台上,对SD大鼠开腹后,在盲肠上划开一道约0.5厘米的伤口,然后分别注射负载氨芐青霉素的甲 基纤维素水溶液和负载氨芐青霉素的甲基纤维素接枝甲基丙烯酰乙基磺基甜菜碱两性离子单体共聚物水溶液覆盖伤口。静置5分钟待其形成凝胶后,将盲肠复位,将腹部切口用手术缝合线缝上,继续喂养。
(6)手术一周后,将SD大鼠处死,重新剖开腹部切口,观察原盲肠伤口处的粘连情况。结果如图4所示,可见使用甲基纤维素水凝胶的大鼠出现盲肠与盲肠间的粘连,而使用甲基纤维素接枝甲基丙烯酰乙基磺基甜菜碱两性离子单体共聚物水凝胶的大鼠的原盲肠伤口处愈合正常。
上述实施例为本发明较佳的实施方式,但本发明的实施方式并不受上述实施例的限制,其他的任何未背离本发明的精神实质与原理下所作的改变、修饰、替代、组合、简化,均应为等效的置换方式,都包含在本发明的保护范围之内。
Claims (10)
1.一种温敏性防术后粘连纤维素改性材料的制备方法,其特征在于,包括如下步骤:
(1)在甲基纤维素水溶液中,加入两性离子单体甲基丙烯酰乙基磺基甜菜碱、引发剂和N,N,N',N'-四甲基乙二胺,在氮气或氩气保护下进行自由基接枝聚合反应,反应完成后透析并冷冻干燥,得到甲基纤维素接枝甲基丙烯酰乙基磺基甜菜碱两性离子单体共聚物;
(2)将步骤(1)制得的甲基纤维素接枝甲基丙烯酰乙基磺基甜菜碱两性离子单体共聚物溶于缓冲液,配制成共聚物水溶液。
2.根据权利要求1所述的一种温敏性防术后粘连纤维素改性材料的制备方法,其特征在于,步骤(1)中所述的甲基丙烯酰乙基磺基甜菜碱与甲基纤维素水溶液中的甲基纤维素的质量比为(1:2)~(1:8)。
3.根据权利要求1所述的一种温敏性防术后粘连纤维素改性材料的制备方法,其特征在于,步骤(1)中所述的引发剂、N,N,N',N'-四甲基乙二胺与甲基丙烯酰乙基磺基甜菜碱的质量比为(1:1:20)~(1:1:10)。
4.根据权利要求1所述的一种温敏性防术后粘连纤维素改性材料的制备方法,其特征在于,步骤(1)中所述的自由基接枝聚合反应的条件为25~45℃,时间12~24h。
5.根据权利要求1所述的一种温敏性防术后粘连纤维素改性材料的制备方法,其特征在于,步骤(1)中所述的甲基纤维素水溶液,是将甲基纤维素加入到70~80℃热蒸馏水中,再置于冰水浴中继续搅拌至完全透明而制得。
6.根据权利要求1所述的一种温敏性防术后粘连纤维素改性材料的制备方法,其特征在于,步骤(1)中所述的引发剂为过硫酸铵、硫酸钾和过硫酸钠中的至少一种。
7.根据权利要求1所述的一种温敏性防术后粘连纤维素改性材料的制备方法,其特征在于,步骤(2)中所述的缓冲液为磷酸氢二钠-磷酸二氢钠缓冲液、乙酸-乙酸钠缓冲液、柠檬酸-柠檬酸钠缓冲液或柠檬酸-氢氧化钠-盐酸缓冲液。
8.根据权利要求1所述的一种温敏性防术后粘连纤维素改性材料的制备方法,其特征在于,步骤(2)中所述的共聚物水溶液,是将甲基纤维素接枝甲基丙烯酰乙基磺基甜菜碱两性离子单体共聚物加入缓冲液中,再置于冰水浴中搅拌至完全溶解,并在4℃冰箱内放置过夜而制得。
9.一种温敏性防术后粘连纤维素改性材料,其特征在于,其由权利要求1至8任一项所述的一种温敏性防术后粘连纤维素改性材料的制备方法制备得到。
10.权利要求9所述的温敏性防术后粘连纤维素改性材料作为体内伤口防粘连敷料的应用。
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CN107537059B (zh) * | 2017-10-01 | 2020-06-05 | 山东煜和堂药业有限公司 | 一种双组份可溶性两性离子水凝胶敷料及其制备方法 |
CN108752530A (zh) * | 2018-05-09 | 2018-11-06 | 同济大学 | 可负载细胞的温敏性水凝胶材料、温敏性水凝胶及其制备方法与应用 |
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CN110384831B (zh) * | 2019-06-30 | 2021-10-08 | 天津大学 | 用于术后防粘连的两性离子水凝胶及交联剂、聚合物的制备方法 |
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CN114835826B (zh) * | 2022-04-22 | 2023-08-22 | 深圳华源再生医学有限公司 | 一种两性离子纤维素及其制备方法与应用 |
CN115322397A (zh) * | 2022-09-23 | 2022-11-11 | 福州大学 | 一种预防术后腹腔粘连的两性离子水凝胶及其制备方法 |
CN115322397B (zh) * | 2022-09-23 | 2024-04-30 | 福州大学 | 一种预防术后腹腔粘连的两性离子水凝胶及其制备方法 |
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