CN113150323A - N-(2-羟丙基)甲基丙烯酰胺透明质酸水凝胶、制备方法及应用 - Google Patents
N-(2-羟丙基)甲基丙烯酰胺透明质酸水凝胶、制备方法及应用 Download PDFInfo
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Abstract
本发明公开了N‑(2‑羟丙基)甲基丙烯酰胺透明质酸水凝胶、制备方法及应用,属于医用生物材料领域。本发明的N‑(2‑羟丙基)甲基丙烯酰胺透明质酸水凝胶的制备方法,以N‑(2‑羟丙基)甲基丙烯酰胺和甲基丙烯酸缩水甘油酯接枝的透明质酸为原料,采用自由基聚合法,在紫外光照射和光引发剂的作用下,引发自由基聚合形成水凝胶,本发明的制备方法操作简便,反应条件温和,成本低廉,有效避免了交联剂及其他溶剂引入所造成的的细胞毒性等问题。本发明的N‑(2‑羟丙基)甲基丙烯酰胺透明质酸水凝胶,具有良好的力学性能,防止预防伤口粘连。
Description
技术领域
本发明属于医用生物材料领域,尤其是N-(2-羟丙基)甲基丙烯酰胺透明质酸水凝胶、制备方法及应用。
背景技术
腹腔粘连是普通腹盆腔手术的常见并发症,发生率日益升高,在盆腔手术中高达97%。腹腔粘连不仅会发生在相邻的手术创伤组织间,也可能发生在远离手术区域的组织中。尽管发生粘连后当时没什么明显症状,但后期的并发症诸多,更有甚者会造成肠梗阻,不孕等,严重影响患者的生活质量。术后粘连的形成会增加再次手术的难度,而且外科手术中的腹腔粘连松解术效果不加,容易造成二次粘连并增加了病人医疗费用。
目前在临床外科手术中应用的抗粘连药物种类繁多,大部分药物仅可以在一定程度上减轻粘连的严重程度,无法做到根本性地防止粘连的发生,应用效果较为有限。因此,术后抗粘连药物的优化和创新是改变腹腔粘连现状的必要途径。防治术后腹腔粘连的方法主要分为药物防治和屏障防治两大类,二者各具有优缺点。药物防治主要是从提高腹腔纤溶活性、降低组织炎症反应、加速细胞外基质及胶原蛋白纤维的降解角度出发发挥预防腹腔粘连的作用。其缺点是大部分抗粘连药物均为液体材料,成膜性较差,导致其在创面受损部位滞留时间短,并且单组份药物的使用只能从单一方面发挥作用,无法做到多效保护。而屏障防治的优点在于可以阻隔受损部位与腹腔其他器官直接接触,为受损腹膜提供良好的修复环境,延长间皮细胞自我修复时间;缺点是固体屏障类材料在手术过程中使用不便,机体会发生异物反应,导致术后腹腔感染。由于腹腔粘连的发生机制较为复杂涉及多种因素,仅使用药物治疗或屏障治疗都很难达到预期效果,将药物联合使用将会在很大程度上改变腹腔粘连的发生程度。
防粘连阻隔剂分为聚合物粘稠溶液和固体膜两大类。这些阻隔剂被设计用来覆盖在受损组织表面,尽量避免受损组织的接触。对于聚合物溶液,如以透明质酸钠为原料的“医用透明质酸钠水凝胶”的聚合物(其商品名为施沛克、施沛特、哈艾路、欣可聆等),由于其在体内降解吸收太快,在体内的滞留时间较短,导致效果不佳。对于固体膜,它不可能完全覆盖创面,更无法随着伤口的形状变化而随之调整,而且对于出血的创面膜的粘附性大打折扣,并且由于肠蠕动膜可能会从创面脱落,所以有时需要将膜缝合于创面上,增加了操作难度。而且在腹腔镜手术中,膜的应用极不方便。另外,固体膜的残留可能被生物膜包被起来而对创口愈合和人体有潜在危险。所以至今仍未找到一种理想的防粘连阻隔剂。
发明内容
本发明的目的在于聚合物粘稠溶液类的防粘连阻隔剂在体内降解吸收太快,在体内的滞留时间较短,导致防粘连效果不佳的缺点,提供N-(2-羟丙基)甲基丙烯酰胺透明质酸水凝胶、制备方法及应用。
为达到上述目的,本发明采用以下技术方案予以实现:
N-(2-羟丙基)甲基丙烯酰胺透明质酸水凝胶的制备方法,包括以下步骤:
1)将N-(2-羟丙基)甲基丙烯酰胺和甲基丙烯酸缩水甘油酯接枝的透明质酸溶于水中,得到混合水溶液;
所述混合水溶液中N-(2-羟丙基)甲基丙烯酰胺的浓度为4wt%-10wt%,甲基丙烯酸缩水甘油酯接枝的透明质酸的浓度为0.5wt%-5wt%;
2)将光引发剂加入到所述混合水溶液中,在波长320-400nm紫外光下照射1-3h,得到水凝胶。
进一步的,步骤2)中光引发剂为IRGACURE 2959。
进一步的,每100g混合水溶液中加入0.2-0.4gIRGACURE 2959。
进一步的,步骤1)的甲基丙烯酸缩水甘油酯接枝的透明质酸中的透明质酸的分子量为50000。
进一步的,还包括以下后处理:
将所述水凝胶利用盐水洗涤,之后依次经18G、20G、22G无菌针头之的挤压。
一种N-(2-羟丙基)甲基丙烯酰胺透明质酸水凝胶,根据本发明的制备方法制备得到。
进一步的,当水凝胶受到应变500%时,G’和G”迅速下降,而当应力恢复到0.1%时,G’值和G”值迅速恢复到初始水平。
进一步的,具有良好的生物相容性。
本发明的N-(2-羟丙基)甲基丙烯酰胺透明质酸水凝胶的应用,其特征在于,作为防粘连阻隔剂用于防止盲肠部位粘连。
与现有技术相比,本发明具有以下有益效果:
本发明的N-(2-羟丙基)甲基丙烯酰胺透明质酸水凝胶的制备方法,以N-(2-羟丙基)甲基丙烯酰胺和甲基丙烯酸缩水甘油酯接枝的透明质酸为原料,采用自由基聚合法,在紫外光照射和光引发剂的作用下,引发自由基聚合形成水凝胶,本发明的制备方法操作简便,反应条件温和,成本低廉,有效避免了交联剂及其他溶剂引入所造成的的细胞毒性等问题。
进一步的,通过在盐水中的溶胀过程除去未发应的过量单体和引发剂,避免引起细胞毒性;水凝胶依次挤压过18G、20G、22G无菌针头,以提高凝胶的可注射性,再凭借优异的自愈合性能融合在一起,得到最终的可注射水凝胶。
本发明的N-(2-羟丙基)甲基丙烯酰胺透明质酸水凝胶,具有良好的力学性能,防止预防伤口粘连;具有良好的自愈功能,在凝胶敷料因外力导致断裂时可以自行愈合;有可注射性,方便治疗过程中的应用;无细胞毒性,表现出良好的细胞相容性。
本发明的水凝胶作为防粘连阻隔剂用于防止盲肠部位粘连,能够预防腹腔术后粘连及粘连松绑术造成的二次粘连,通过注射器注射到伤口部位可以有效的隔离预防腹腔伤口之间的粘连,水凝胶的超亲水性可以避免细胞黏附,从而达到防止腹腔粘连的目的。
附图说明
图1为实施例1水凝胶胶化前后形态图,其中,图1(a)为N-(2-羟丙基)甲基丙烯酰与甲基丙烯酸缩水甘油酯接枝的透明质酸混合水溶液;图1(b)为加入光引发剂IRGACURE2959后的混合溶液;图1(c)紫外光引发后的水凝胶形态;
图2为实施例1的水凝胶生理盐水中完全溶胀后挤压后的形态图;
图3为实施例1的水凝胶的SEM图;
图4为实施例1的水凝胶剪切稀化测试图;
图5为实施例1的水凝胶频率扫描测试图;
图6为实施例1的水凝胶自愈合测试图,其中,图6(a)水凝胶自愈合图,图6(b)水凝胶自愈合流变测试;
图7为实施例1的水凝胶细胞相容性测试;
图8为实施例1的水凝胶防粘连效果图,其中,图8(a)为一次粘连实验中造模组图,图8(b)为一次粘连实验中商用凝胶欣可聆组图,图8(c)为一次粘连实验中N-(2-羟丙基)甲基丙烯酰胺透明质酸水凝胶图,图8(d)为二次粘连实验中造模组图,图8(e)为二次粘连实验中商用凝胶欣可聆组图,图8(f)为二次粘连实验中N-(2-羟丙基)甲基丙烯酰胺透明质酸水凝胶图;
图9为实施例1的水凝胶粘连手术后盲肠及腹壁的HE染色图,其中,图9(a)为正常组,图9(b)为造模组,图9(c)为欣可聆组,图9(d)为水凝胶组。
图10为实施例1的水凝胶粘连手术后盲肠及腹壁的Masson染色图,其中,图10(a)为正常组,图10(b)为造模组,图10(c)为欣可聆组,图10(d)为水凝胶组。
具体实施方式
为了使本技术领域的人员更好地理解本发明方案,下面将结合本发明实施例中的附图,对本发明实施例中的技术方案进行清楚、完整地描述,显然,所描述的实施例仅仅是本发明一部分的实施例,而不是全部的实施例。基于本发明中的实施例,本领域普通技术人员在没有做出创造性劳动前提下所获得的所有其他实施例,都应当属于本发明保护的范围。
需要说明的是,本发明的说明书和权利要求书及上述附图中的术语“第一”、“第二”等是用于区别类似的对象,而不必用于描述特定的顺序或先后次序。应该理解这样使用的数据在适当情况下可以互换,以便这里描述的本发明的实施例能够以除了在这里图示或描述的那些以外的顺序实施。此外,术语“包括”和“具有”以及他们的任何变形,意图在于覆盖不排他的包含,例如,包含了一系列步骤或单元的过程、方法、系统、产品或设备不必限于清楚地列出的那些步骤或单元,而是可包括没有清楚地列出的或对于这些过程、方法、产品或设备固有的其它步骤或单元。
下面结合附图对本发明做进一步详细描述:
实施例1
配制N-(2-羟丙基)甲基丙烯酰胺和甲基丙烯酸缩水甘油酯接枝的透明质酸的混合水溶液,所述混合水溶液中N-(2-羟丙基)甲基丙烯酰胺的浓度为4wt%甲基丙烯酸缩水甘油酯接枝的透明质酸的浓度为0.5wt%;
取100g混合水溶液,加入0.2gIRGACURE 2959,超声完全溶解后,在365nm紫外光下照射1h,得到水凝胶;
参见图1,图1(a)为N-(2-羟丙基)甲基丙烯酰与甲基丙烯酸缩水甘油酯接枝的透明质酸混合水溶液,图1(b)为加入光引发剂IRGACURE 2959后的混合溶液,图1(c)为紫外光引发后的水凝胶形态,由以上图可知,经过紫外光引发,由液态变成凝胶态,N-(2-羟丙基)甲基丙烯酰与甲基丙烯酸缩水甘油酯接枝的透明质酸在紫外光和光引发剂的作用下发生了聚合。
将实施例1得到的水凝胶进行以下后处理,置于生理盐水中浸泡三天,每天换水一次,除去未发应的过量单体和引发剂,随后水凝胶依次挤压过18G、20G、22G无菌针头,削弱凝胶内在的氢键作用力,再凭借优异的自愈合性能融合在一起,得到最终的可注射水凝胶,整个操作在无菌条件下进行,其形态图如图2所示,经后处理的还是呈凝胶态。
一、实施例1的水凝胶的形貌表征
将实施例1制得的可注射水凝胶样品置于真空冷冻干燥机中进行冷冻干燥,取出干燥后的水凝胶样品,在液氮中将样品切开。将水凝胶断面用导电胶固定,进行喷金,之后通过扫描电子显微镜来观察样品截面的微观形貌。如图3所示,从图3中可以观察到该水凝胶具有密集的三维网状孔隙结构,外观呈蜂窝状,该结构有利于氧分子、水分子、代谢产物和营养物质的传输和扩散,形成该水凝胶结构的机制可能是透明质酸分子结构中含有大量羧基和羟基,N-(2-羟丙基)甲基丙烯酰胺分子结构中羟基含量较多,亲水性基团与亲水性基团或者水分子形成氢键,从而形成了水凝胶的致密三维孔穴结构。
二、实施例1的水凝胶力学性能测试
采用安东帕流变仪(MCR302)对样品进行剪切黏度测试,剪切速率为0.1~1000S-1,温度37℃。如图4所示,在剪切速率为0.1-1000S-1时,水凝胶表现出稳定的剪切变稀行为,且粘度大约降低了两个数量级,表现出更优异的剪切变稀行为,说明其具有更良好的可注射性。对水凝胶进行频率扫描测试,频率范围为0.1-100HZ,应变为1%,温度37℃。如图5所示,在频率为0.1-100HZ时,可注射水凝胶的G’和G”一直保持稳定,表明水凝胶有很好的稳定性。
三、实施例1的水凝胶的自愈合实验
将水凝胶从注射器中推出,可以看到水凝胶快速自融合在一起,形成透明均一的水凝胶,如图6(a)所示。然后采用流变学的方法对N-(2-羟丙基)甲基丙烯酰胺透明质酸可注射水凝胶进行破裂-恢复行为的测试,如图6(b)所示,当凝聚物受到大应力时(500%),G’和G”迅速下降,表示凝聚物网络结构崩溃,但是当应力恢复到0.1%时,G’值和G”值迅速恢复到初始水平,显示出N-(2-羟丙基)甲基丙烯酰胺透明质酸可注射水凝胶高效快速的自愈合功能。
四、实施例1的水凝胶细胞相容性评价
采用噻唑蓝比色法(MTT法)来评价实施例1的水凝胶的冻干粉末的细胞相容性。选用的细胞株为L929细胞株。L929细胞用DMEM培养基(含有10%FBS及双抗),置于37℃,含5%CO2的培养箱中培养。将细胞以细胞密度1×104个/孔种植在96孔板中,培养24h。随后吸取并弃去培养基,加入含有不同浓度(0、50、100、200、400、800、1600μg/mL)的水凝胶的DMEM培养基。培养48h后,每个孔中加入200μL的噻唑蓝溶液(5mg/mL),37℃共培养4h,移除培养基并每孔中加入150μL的二甲亚砜溶液,结晶溶解后用酶标仪(Bio-Rad,Berkeley,CA)在波长490nm处测定其吸光值,计算细胞的存活率,细胞的存活率如图7所示。
图7显示在水凝胶浓度为0、50、100、200、400、800、1600μg/mL的范围内,与细胞共培养24h后,L929的活性均达到95%以上,证明水凝胶有良好的生物相容性,无明显的细胞毒性。
五、实施例1的水凝胶对腹腔粘连治疗效果评价
选用雄性SD大鼠(重量为200-230g)建立大鼠盲肠-腹壁粘连模型,并评价其治疗效果。采用异氟烷全程手术麻醉,消毒术区并铺洞布。寻找盲肠并用无菌干纱布摩擦其浆膜面直至损伤并伴有点状渗血,创面大小约2cm2,在大鼠腹壁用手术刀割除一个面积为2×2cm2的正方形创伤面。随后将摩擦后的盲肠置于腹膜创面位置,使两者对和以模拟在腹腔手术之后无法避免的腹膜损伤。术中未采取任何止血或者腹腔灌洗措施。在创面上分别应用0.5mL以下溶液后,双层缝合关腹,皮下注射青霉素。
30只SD大鼠随机分成三组,每组10只大鼠:
第一组为生理盐水对照组,在创伤面上滴加1mL生理盐水处理。
第二组为透明质酸钠水凝胶组,在创伤面上滴加1mL透明质酸钠水凝胶处理。
第三组为实施例1制备的N-(2-羟丙基)甲基丙烯酰胺透明质酸可注射水凝胶组,在创伤面上放置实施例1制备的1mL可注射水凝胶处理。
二次粘连类似上述操作建立腹腔-粘连模型,模型建立成功于7天后开腹,用手术镊子小心撕开粘连部位后,双层缝合关腹,皮下注射青霉素,构建成二次粘连模型;于7天后开腹,考察各组实验大鼠腹腔粘连情况。
30只SD大鼠随机分成三组,每组10只大鼠:
第一组为生理盐水对照组,在创伤面上滴加1mL生理盐水处理。
第二组为透明质酸钠凝胶组,在创伤面上滴加1mL透明质酸钠凝胶处理。
第三组为实施例1制备的N-(2-羟丙基)甲基丙烯酰胺透明质酸可注射水凝胶组,在创伤面上涂抹实施例1制备的1mL可注射水凝胶处理。
7天后,采用异氟烷麻醉动物,观察腹腔粘连情况并采用国际标准粘连评分方法进行粘连评分。0分:无粘连;1分:薄膜状粘附;2分:单根条索状粘连;3分:多根条索状粘连;4分:同时累及腹壁及内脏的致密粘连。每只大鼠的粘连程度以最高等级为准。
参见图8,图8(a)为一次粘连实验中造模组图,图8(b)为一次粘连实验中商用凝胶欣可聆组图,图8(c)为一次粘连实验中N-(2-羟丙基)甲基丙烯酰胺透明质酸水凝胶图,图8(d)为二次粘连实验中造模组图,图8(e)为二次粘连实验中商用凝胶欣可聆组图,图8(f)为二次粘连实验中N-(2-羟丙基)甲基丙烯酰胺透明质酸水凝胶图,7天之后使用生理盐水做阳性对照组的大鼠,腹壁和盲肠粘连非常严重,粘连面积都为4分。对于单纯的透明质酸钠水凝胶而言,7天之后打开腹腔观察发现3只大鼠没有发生粘连,其余的7只实验小鼠均有不同程度的粘连。而对于N-(2-羟丙基)甲基丙烯酰胺透明质酸水凝胶组而言,7天之后打开腹腔观察发现有9只大鼠(90%)没有发生粘连,仅仅有一只大鼠出现轻度的粘连。结果显示本发明所制备的N-(2-羟丙基)甲基丙烯酰胺透明质酸水凝胶具有良好的术后防粘连效果。
六、组织H&E染色和Masson染色
取出第五项测试的中在第7天处死大鼠的第三组和第一组的粘连的盲肠和腹壁,进行H&E染色和Masson染色,显微镜观察组织恢复或组织粘连情况。从图9和图10中可以看出,图9为H&E染色图,图9(a)为正常组,图9(b)为造模组,图9(c)为欣可聆组,图9(d)为水凝胶组;图10为Masson染色图,图10(a)为正常组,图10(b)为造模组,图10(c)为欣可聆组,图10(d)为水凝胶组,N-(2-羟丙基)甲基丙烯酰胺透明质酸的腹壁已经完全恢复,表面覆盖一层新生的间皮细胞,不会在发生粘连现象,而生理盐水对照组的腹壁和盲肠已经形成了致密的粘连组织。
本发明的实验数据均用SPSS15.0统计软件包处理,试验结果以均数加减标准差表示。计量数据采用Student’s T检测;各组之间的均数比较采用方差分析(ANOVA)。生存数据用Kaplan-Meier法计算,并采用Log-rank test进行统计学分析。粘连评分并不总是符合正态分布,因此中位粘连评分采用Mann-Whitney U-检验,粘连率的比较采用Fisher确切概率法。以P<0.05为统计学显著性界限。
上述实验结果综合表明,本发明所制备的溶菌酶/透明质酸水凝胶具有良好的防粘连效果,无任何毒副作用,同时在腹腔肿瘤术后的治疗有一定的应用前景。
实施例2
将1g分子量为50000透明质酸溶于99g去离子水配制成透明质酸水溶液,边搅拌边加入0.3g三乙胺和0.64g四丁基溴化铵催化反应;
搅拌20min后,加入6.8g甲基丙烯酸缩水甘油酯,室温下反应过夜后,在去离子水中透析4天后冷冻干燥(透析袋截留分子量为3500-7000),得到甲基丙烯酸缩水甘油酯接枝的透明质酸(HA-GMA);
配制N-(2-羟丙基)甲基丙烯酰胺和甲基丙烯酸缩水甘油酯接枝的透明质酸的混合水溶液,所述混合水溶液中N-(2-羟丙基)甲基丙烯酰胺的浓度为6wt%甲基丙烯酸缩水甘油酯接枝的透明质酸的浓度为2wt%;
取100g混合水溶液,加入0.3gIRGACURE 2959,超声完全溶解后,置于5mlEP管中,在320nm紫外光下照射3h,得到水凝胶。
实施例2的水凝胶经各项测试,性能与实施例1的水凝胶相当。
实施例3
配制N-(2-羟丙基)甲基丙烯酰胺和甲基丙烯酸缩水甘油酯接枝的透明质酸的混合水溶液,所述混合水溶液中N-(2-羟丙基)甲基丙烯酰胺的浓度为10wt%甲基丙烯酸缩水甘油酯接枝的透明质酸的浓度为5wt%;
取100g混合水溶液,加入0.4gIRGACURE 2959,超声完全溶解后,置于5mlEP管中,在400nm紫外光下照射2h,得到水凝胶。
实施例3的水凝胶经各项测试,性能与实施例1的水凝胶相当。
以上内容仅为说明本发明的技术思想,不能以此限定本发明的保护范围,凡是按照本发明提出的技术思想,在技术方案基础上所做的任何改动,均落入本发明权利要求书的保护范围之内。
Claims (9)
1.N-(2-羟丙基)甲基丙烯酰胺透明质酸水凝胶的制备方法,其特征在于,包括以下步骤:
1)将N-(2-羟丙基)甲基丙烯酰胺和甲基丙烯酸缩水甘油酯接枝的透明质酸溶于水中,得到混合水溶液;
所述混合水溶液中N-(2-羟丙基)甲基丙烯酰胺的浓度为4wt%-10wt%,甲基丙烯酸缩水甘油酯接枝的透明质酸的浓度为0.5wt%-5wt%;
2)将光引发剂加入到所述混合水溶液中,在波长320-400nm紫外光下照射1-3h,得到水凝胶。
2.根据权利要求1所述的N-(2-羟丙基)甲基丙烯酰胺透明质酸水凝胶的制备方法,其特征在于,步骤2)中光引发剂为IRGACURE 2959。
3.根据权利要求2所述的N-(2-羟丙基)甲基丙烯酰胺透明质酸水凝胶的制备方法,其特征在于,每100g混合水溶液中加入0.2-0.4gIRGACURE 2959。
4.根据权利要求1所述的N-(2-羟丙基)甲基丙烯酰胺透明质酸水凝胶的制备方法,其特征在于,步骤1)的甲基丙烯酸缩水甘油酯接枝的透明质酸中的透明质酸的分子量为50000。
5.根据权利要求1所述的N-(2-羟丙基)甲基丙烯酰胺透明质酸水凝胶的制备方法,其特征在于,还包括以下后处理:
将所述水凝胶利用盐水洗涤,之后依次经18G、20G、22G无菌针头之的挤压。
6.一种N-(2-羟丙基)甲基丙烯酰胺透明质酸水凝胶,其特征在于,根据权利要求1-5所述的制备方法制备得到。
7.根据权利要求6所述的N-(2-羟丙基)甲基丙烯酰胺透明质酸水凝胶,其特征在于,当水凝胶受到应变500%时,G’和G”迅速下降,而当应力恢复到0.1%时,G’值和G”值迅速恢复到初始水平。
8.根据权利要求6所述的N-(2-羟丙基)甲基丙烯酰胺透明质酸水凝胶,其特征在于,具有良好的生物相容性。
9.一种权利要求5所述的N-(2-羟丙基)甲基丙烯酰胺透明质酸水凝胶的应用,其特征在于,作为防粘连阻隔剂用于防止盲肠部位粘连。
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