CN117298331A - 一种用于创面修复的改性海藻糖基水凝胶 - Google Patents
一种用于创面修复的改性海藻糖基水凝胶 Download PDFInfo
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- CN117298331A CN117298331A CN202311257094.6A CN202311257094A CN117298331A CN 117298331 A CN117298331 A CN 117298331A CN 202311257094 A CN202311257094 A CN 202311257094A CN 117298331 A CN117298331 A CN 117298331A
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- Prior art keywords
- trehalose
- based hydrogel
- modified
- triazin
- reaction
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Classifications
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- A—HUMAN NECESSITIES
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Abstract
本发明提供了一种用于创面修复的改性海藻糖基水凝胶,该改性海藻糖基水凝胶采用海藻糖与多羧酸化合物经过酯化缩聚、卤素取代后,与三嗪胺类化合物进行反应,获得一种氢键增强、具有形状记忆性的抗菌水凝胶。将该改性海藻糖基水凝胶用于创面敷料中,能够有效提高创面敷料的力学性能;所述改性海藻糖基水凝胶具有响应温度的形变功能,可抑制创面的组织增生,完善创面敷料在一些特殊场景中的应用。
Description
技术领域
本发明涉及高分子材料领域,尤其涉及一种用于创面修复的改性海藻糖基水凝胶。
背景技术
水凝胶是一种具有三维网络结构的新型功能高分子材料,它在水中能够吸收大量的水分溶胀,并在溶胀后继续保持其原有结构而不被溶解。水凝胶独特优异的性能使其受到生物医学领域的广泛关注,首先,水凝胶拥有很高的含水量,且结构类似于人体细胞外基质,比其他任何合成生物材料都结晶活体组织,表面粘附蛋白质及细胞的能力很弱,故其具有很好的生物相容性;其次,水凝胶软而柔韧的特性可以使其对周围组织的机械刺激及损伤最小化;再次,水凝胶具有优异的渗透性,便于营养物质及代谢物质的运输,可维持凝胶内细胞的生存及繁殖。因为自身的优异性能,水凝胶可用作药物/蛋白质传递载体、组织再生载体、生物传感器以及术后防粘连的抗菌敷料。
市面上所存在的抗菌水凝胶主要有银系抗菌水凝胶、季铵盐类抗菌水凝胶、多肽类抗菌水凝胶及天然大分子抗菌水凝胶,其中,银系抗菌水凝胶一般是将银纳米颗粒分散或物理包埋在水凝胶材料中,容易导致银粒子流失,而凝胶的抗菌性依赖于银活性物质的释放,故抗菌时效一般较短;同时,不可避免地村子啊易变色、成本较高、易对环境产生污染等问题。季铵盐类抗菌水凝胶的制备涉及时间较长的季铵化反应及条件苛刻的开环聚合,且不具备良好的降解性能,其抗菌性仅限于12h内。多肽类抗菌水凝胶是将抗菌多肽物理包埋入常用的水凝胶中,其抗菌性依赖于抗菌肽的释放,实际应用具有一定的局限性;另外,抗菌肽的制备成本也高。天然大分子抗菌水凝胶普遍存在的问题就是力学性能较差,储能模量不足以支撑应用。
理想的抗菌水凝胶材料应具有高效的抗菌活性、好的生物相容性、良好的生物可降解性、简易温和的制备方法及廉价的成本,目前报道的抗菌水凝胶很少能兼顾这些性能,因此开发新型的满足全面要求的抗菌水凝胶仍然是一种挑战。
发明内容
为了现有技术中存在的一些问题,本发明提供一种具有持久性抗菌效果、力学性能优良及对创面保护性较好的改性海藻糖基水凝胶,具体技术方案如下:
一种用于创面修复的改性海藻糖基水凝胶,包含如下原料:海藻糖,多元羧酸和三嗪胺类化合物。
在本发明的一些实施方式中,所述多元羧酸为二元脂肪酸。
为了不破坏分子链内部及分子链间的氢键,在本发明的一些实施方式中,所述二元脂肪羧酸中,羧酸基团之间的亚烃基碳原子数为1-6,具体地,可以是丙二酸、甲基丙二酸、丁二酸、甲基丁二酸、戊二酸、1,2-环丙烷二羧酸、2,2-二甲基琥珀酸、己二酸、庚二酸、4-甲基庚二酸、1,3-环己二甲酸、1,4-环己二甲酸等。
在本发明的一些实施方式中,所述三嗪胺类化合物为N-甲基-1,3,5-三嗪-2-胺(CAS:4039-99-0)、2-氨基-4-(甲基氨基)-1,3,5-三嗪(CAS:58228-69-6)、(4-氨基-S-三嗪-2-基)-二甲基-胺(CAS:4039-98-9)、N2,N4-二甲基-1,3,5-三嗪-2,4-二胺(CAS:30368-50-4)、三聚氰胺(CAS:108-78-1)、N-四甲基三聚氰胺(CAS:16268-54-5)、N-甲基-1,3,5-三嗪-2,4,6-三胺(CAS:13452-77-2)、N,N-二甲基-1,3,5-三嗪-2,4,6-氰胺(CAS:1985-46-2)、N,N',N''-三甲基-1,3,5-三嗪-2,4,6-三胺(CAS:2827-46-5)、N-(甲氧基甲基)-1,3,5-三嗪-2,4,6-三胺(CAS:194032-41-2)、N2,N4,N6-三(甲氧基甲基)-1,3,5-三嗪-2,4,6-三胺(CAS:2420-27-1)、2-N-(4-甲氧基苯基)-1,3,5-三嗪-2,4-二胺(CAS:4460-15-5)、2-甲基-4-甲胺基-6-甲氧基均三嗪(CAS:5248-39-5)中的至少一种。
在本发明中,所用三嗪胺类化合物中至少含有一个伯胺或仲胺,在制备所述改性海藻糖基水凝胶时,利用中间产物卤代聚酯与三嗪胺类化合物中的伯胺或仲胺发生取代反应,制得具有烷基胍结构的改性海藻糖基水凝胶。发明人通过实验发现,三嗪胺类化合物引入的嗪环,能够有效地增强所述改性海藻糖基水凝胶的力学性能:一方面,嗪环上的氨基与分子主链上海藻糖结构中的羟基之间形成氢键“软”区域,另一方面,分子链之间,嗪环与嗪环之间形成氢键“硬”区域,“软硬”区域氢键交联网络的协同作用方式,显著增强了水凝胶的力学性能。
一种所述用于创面修复的改性海藻糖基水凝胶的制备方法,包含如下步骤:
S1:将海藻糖与多元羧酸置于充满惰性气体的反应器中,并向其中加入路易斯酸催化剂和不与水混溶的有机溶剂,将体系温度升高,在55-75℃的条件下进行酯化反应,并进行冷凝回流除去水份,待不再有水份产生即可停止酯化反应;待体系冷却至室温后,抽真空并升温进行缩聚反应,获得以海藻糖和羧酸化合物为反应单体的聚酯;
S2:将S1所得聚酯与卤氢酸混合均匀后,在加热的条件下进行取代反应,并进行冷凝回流除去水份,反应结束后加入无水乙醇进行洗涤干燥,得到卤代聚酯;
S3:将三嗪胺类化合物与腈类溶剂混合,在冰水浴和惰性气氛的保护下,滴加S2中所得卤代聚酯的腈类混合溶液,于室温下搅拌反应20-24h,减压去除溶剂,并用酯类溶剂洗涤,之后真空抽滤去除酯类溶剂,即得所述改性海藻糖基水凝胶。
在本发明的一些实施方式中,所述S1中,海藻糖与多元羧酸的摩尔比为1:1-1.5。
在本发明的一些实施方式中,所述S1中,有机溶剂为苯、甲苯、氯仿、四氯化碳、甲醚、乙醚、环己烷中的至少一种;缩聚反应的条件为150-200℃、110-130Pa。
在本发明的一些实施方式中,所述S2中,所加卤氢酸的摩尔质量为海藻酸摩尔质量的1.5-1.8倍;聚酯与卤氢酸的反应条件为80-110℃,4-6h。
在本发明的一些实施方式中,所述S3中,三嗪胺类化合物的摩尔量为所用卤氢酸摩尔量的1-1.2倍;腈类溶剂为乙腈、丙腈、丙烯腈中的至少一种;酯类溶剂为乙酸乙酯、乙酸丁酯、碳酸二甲酯中的至少一种。
在本发明中,所述改性海藻糖基水凝胶的制备原理在于:海藻糖分子中的部分羟基与二元脂肪羧酸的羧基发生酯化缩聚反应后,所得聚酯化合物中含氧六元环上剩下的羟基与卤氢酸发生取代反应,形成的卤代聚酯再与三嗪胺类化合物中的伯胺或仲胺上的氢原子发生取代反应。由于所述改性海藻糖分子中起到增强力学性能的“软”氢键区域涉及到胺基与含氧六元环上羟基之间的氢键,那么海藻糖的含氧六元环结构上所连羟基不可全部与羧基及胺基结合。因此,在制备过程中,所用海藻糖与所用多元羧酸的摩尔量之比适宜在1:1-1.5范围内,所用卤氢酸的摩尔量不宜超过海藻糖摩尔量的1.5-1.8倍,所用三嗪胺类化合物的摩尔量不宜超过所用卤氢酸摩尔量的1-1.2倍,否则,所得水凝胶的力学性能将有所损失。若用量过度,“硬”氢键区域逐渐增大,所得水凝胶刚性增强,不易形变,由此会影响到实际应用所需的柔韧性。
在本发明的一些实施方式中,所述改性海藻糖基水凝胶与卡波姆、羟苯甲酯、甘油混合制备创面敷料,应用于创面修复领域。
有益效果:与现有技术相比,本发明提供的改性海藻糖基水凝胶具有以下优点:
1,所述改性海藻糖基水凝胶以聚酯为分子主链,具有良好的生物相容性及可生物降解性;生物降解后,残留的三嗪环可回收用于除草剂的生产,实现资源循环利用;
2,内部形成的“软”“硬”氢键区域以协同作用实现对所述改性海藻糖基水凝胶力学性能的显著增强;因为“软”“硬”区域的氢键在环境温度变化时,各自的解离、恢复速度不同,使得所述改性海藻糖基水凝胶的柔韧性及形状可根据环境温度(创面局部温度较高)而变化,结合海藻糖的热稳定性,能够抑制创面的组织增生,实现无疤痕修复;
3,通过较简单、成本较低的方法制备所得,因为烷基胍结构的形成,所述改性海藻糖基水凝胶具有优异的抗菌性能。
具体实施方式
下面结合实例对本发明作进一步详细描述。需要说明的是,下面的实施例及对比例为本发明的示例,仅用来说明本发明,而不用来限制本发明。在不偏离本发明主旨或范围的情况下,可进行本发明构思内的其他组合和各种改良。
实施例1
S1:将0.2mol(68.4g)海藻糖与0.2mol(20.8g)丙二酸置于充满氮气的反应器中,并向其中加入0.89g路易斯酸催化剂氯化铝和200ml苯,将体系温度升高,55℃的条件下进行酯化反应,并进行冷凝回流除去水份,待不再有水份产生即可停止酯化反应;待体系冷却至室温后,抽真空并升温至150℃、110Pa条件下进行缩聚反应,获得以海藻糖和羧酸化合物为反应单体的聚酯;
S2:将S1所得聚酯与0.3mol(24.3g)溴化氢混合均匀后,在80℃下进行取代反应,并进行冷凝回流除去水份,反应4h,结束后加入无水乙醇进行洗涤干燥,得到溴代聚酯;
S3:将0.3mol(33g)N-甲基-1,3,5-三嗪-2-胺(CAS:4039-99-0)与100ml乙腈混合,在冰水浴和氮气的保护下,滴加100mlS2中所得卤代聚酯的乙腈溶液,于室温下搅拌反应24h,减压去除乙腈,并用乙酸乙酯洗涤,之后真空抽滤去除乙酸乙酯,即得所述改性海藻糖基水凝胶#1。
实施例2
S1:将0.2mol(68.4g)海藻糖与0.24mol(35.0g)2,2-二甲基琥珀酸置于充满氮气的反应器中,并向其中加入1.03g路易斯酸催化剂氯化铝和200ml苯,将体系温度升高,65℃的条件下进行酯化反应,并进行冷凝回流除去水份,待不再有水份产生即可停止酯化反应;待体系冷却至室温后,抽真空并升温至180℃、120Pa条件下进行缩聚反应,获得以海藻糖和2,2-二甲基琥珀酸为反应单体的聚酯;
S2:将S1所得聚酯与0.35mol(28.35g)溴化氢混合均匀后,在100℃下进行取代反应,并进行冷凝回流除去水份,反应5h,结束后加入无水乙醇进行洗涤干燥,得到溴代聚酯;
S3:将0.42mol(58.5g)N-甲基-1,3,5-三嗪-2,4,6-三胺(CAS:13452-77-2)与100ml乙腈混合,在冰水浴和氮气的保护下,滴加100mlS2中所得卤代聚酯的乙腈溶液,于室温下搅拌反应24h,减压去除乙腈,并用乙酸乙酯洗涤,之后真空抽滤去除乙酸乙酯,即得所述改性海藻糖基水凝胶#2。
实施例3
S1:将0.2mol(68.4g)海藻糖与0.3mol(51.6g)1,4-环己二甲酸置于充满氮气的反应器中,并向其中加入1.2g路易斯酸催化剂氯化铝和200ml苯,将体系温度升高,75℃的条件下进行酯化反应,并进行冷凝回流除去水份,待不再有水份产生即可停止酯化反应;待体系冷却至室温后,抽真空并升温至200℃、130Pa条件下进行缩聚反应,获得以海藻糖和1,4-环己二甲酸为反应单体的聚酯;
S2:将S1所得聚酯与0.36mol(29.16g)溴化氢混合均匀后,在110℃下进行取代反应,并进行冷凝回流除去水份,反应6h,结束后加入无水乙醇进行洗涤干燥,得到溴代聚酯;
S3:将0.432mol(111.46g)N2,N4,N6-三(甲氧基甲基)-1,3,5-三嗪-2,4,6-三胺(CAS:2420-27-1)与100ml乙腈混合,在冰水浴和氮气的保护下,滴加100mlS2中所得卤代聚酯的乙腈溶液,于室温下搅拌反应24h,减压去除乙腈,并用乙酸乙酯洗涤,之后真空抽滤去除乙酸乙酯,即得所述改性海藻糖基水凝胶#3。
实施例4
制作过程同实施例3,不同之处在于,所用1,4-环己二甲酸的摩尔量为0.4mol(68.8g),所用溴氢酸摩尔量为0.4mol(36.4g),得所述改性海藻糖基水凝胶#4。
对比例1
制作过程同实施例3,不同之处在于,不进行S3。
对比例2
制作过程同实施例3,不同之处在于,在S1中不添加1,4-环己二甲酸进行酯化缩聚反应。
对实施例1-4及对比例1-2所得改性海藻糖基水凝胶进行如下性能测试:
力学性能测试:利用万能实验机(CMT6103,深圳新三思公司)对水凝胶试样进行拉伸强度测试,试样规格为30×6×1.2mm,测试标距为15mm,室温条件下,拉伸速率为100mm/min;
降解性:将一系列固含量为20%的水凝胶(1ml)放入含20mlPBS(0.02mol/L,pH=7.4)的离心管中,置于37℃水浴中,并每天更换新鲜PBS溶液。间隔30天的时间,取出水凝胶样品,用去离子水冲洗多次,然后冷冻干燥称重,通过质量损失进行评价,按照以下公式计算质量损失:
式中,Wi为初始干胶质量,Wt为降解t天后干胶质量。
按照重量份数计,分别将0.03份上述实施例1-4及对比例1-2所得改性海藻糖基水凝胶与0.075份卡波姆、0.02份羟苯甲酯、2份甘油混合,使用三乙醇胺将体系pH调至中性(若无需调整则不加),然后补充纯化水至100份的体系总重量,即得含有改性海藻糖基水凝胶的创面敷料。对敷料进行如下性能测试:
抗菌性:将创面敷料剪切成直径为10mm,厚度为2mm的圆形凝胶试样,将0.1ml金黄色葡萄球菌置于牛肉汤中,37℃下恒温培养24h,稀释10-6倍,制成待测菌悬液,移取0.1ml菌悬液至凝胶试样表面,培养12h,使用灭菌水洗涤敷料样品,吸取0.1ml洗涤液,在培养皿上继续培养24h,记录培养皿上的菌落数,并做空白对照试验,使用公式
计算试样的抗菌率,式中S0为空白对照实验组的菌落数,S1为各试样的菌落数,P为抗菌率;
创面愈合性:采用本发明制备的抗菌创面敷料对27例小鼠创面进行临床观察治疗,试验小鼠平均年龄24个月,人为创伤面积为20mm×20mm,创伤部分为小鼠背部,且均经过麻醉和消毒处理。27例小鼠分为9组,每组分别对应实施例1-7及对比例1所得抗菌创面敷料覆盖创面和不使用敷料处理的空白组。伤后3天内,每天于09:00时更换创面敷料,创伤3天后,每2天于09:00时更换创面敷料,直至创面愈合,在整个换药期间进行创面观察;
实施例1-4及对比例1-2所得水凝胶的性能测试结果详见表1、表2。
由表1的结果可知,本发明所提供的改性海藻糖基水凝胶具有优异的拉伸强度及断裂伸长率,在柔韧性方面有较好的表面,且其经过30天PBS的处理,内部的聚酯主链能够基本降解,说明该水凝胶在降解方面无需额外的能量输入,残留的三嗪环可回收并利用在除草剂的生产,实现资源循环利用。由实施例4及对比例1-2的数据可知,所述改性海藻糖基水凝胶的力学性能主要是由于聚酯链与三嗪环之间的相互作用,若原料配比不合适,将会导致所得水凝胶的柔韧性收到影响,虽然拉伸强度增加,但断裂伸长率有降低;若不添加三嗪胺类化合物引入三嗪环支链或不添加羧酸类化合物制取聚酯主链,则所得水凝胶的力学性能大大降低,生物降解性也随之降低。
由表2的结果可知,本发明所提供的含有改性海藻糖基水凝胶的创面敷料具有良好的抗菌性以及对创面的修复度:在15天内,伤口愈合,且无明显疤痕。但若是所用改性海藻糖基水凝胶的制备过程中未引入三嗪胺类化合物(对比例1),所得创面敷料的抗菌性则大大降低;伤口的愈合速度也放缓;若所用改性海藻糖基水凝胶的制备过程中不添加羧酸类化合物(对比例2),所得创面敷料的抗菌性不及实施例所提供的创面敷料产品,对伤口的保护及促愈合性均有减弱。
综上可知,本发明提供的所述改性海藻糖基水凝胶具有优秀的力学性能、良好的可生物降解性,与卡波姆、羟苯甲酯、甘油混合制备所得创面敷料的抗菌性及对创口的保护性均表现优异,在创面修复领域具有可观的应用前景。
Claims (10)
1.一种用于创面修复的改性海藻糖基水凝胶,其特征在于,包含如下原料:海藻糖,多元羧酸和三嗪胺类化合物。
2.根据权利要求1所述用于创面修复的改性海藻糖基水凝胶,其特征在于,所述多元羧酸为二元脂肪酸。
3.根据权利要求2所述用于创面修复的改性海藻糖基水凝胶,其特征在于,所述二元脂肪酸中,羧酸基团之间的亚烃基碳原子数为1-6。
4.根据权利要求1所述用于创面修复的改性海藻糖基水凝胶,其特征在于,所述三嗪胺类化合物为N-甲基-1,3,5-三嗪-2-胺、2-氨基-4-(甲基氨基)-1,3,5-三嗪、(4-氨基-S-三嗪-2-基)-二甲基-胺、N2,N4-二甲基-1,3,5-三嗪-2,4-二胺、三聚氰胺、N-四甲基三聚氰胺、N-甲基-1,3,5-三嗪-2,4,6-三胺、N,N-二甲基-1,3,5-三嗪-2,4,6-氰胺、N,N',N''-三甲基-1,3,5-三嗪-2,4,6-三胺、N-(甲氧基甲基)-1,3,5-三嗪-2,4,6-三胺、N2,N4,N6-三(甲氧基甲基)-1,3,5-三嗪-2,4,6-三胺、2-N-(4-甲氧基苯基)-1,3,5-三嗪-2,4-二胺、2-甲基-4-甲胺基-6-甲氧基均三嗪中的至少一种。
5.权利要求1-4任意一种所述用于创面修复的改性海藻糖基水凝胶的制备方法,其特征在于,包含如下步骤:
S1:将海藻糖与多元羧酸置于充满惰性气体的反应器中,并向其中加入路易斯酸催化剂和不与水混溶的有机溶剂,将体系温度升高,在55-75℃的条件下进行酯化反应,并进行冷凝回流除去水份,待不再有水份产生即可停止酯化反应;待体系冷却至室温后,抽真空并升温进行缩聚反应,获得以海藻糖和羧酸化合物为反应单体的聚酯;
S2:将S1所得聚酯与卤氢酸混合均匀后,在加热的条件下进行取代反应,并进行冷凝回流除去水份,反应结束后加入无水乙醇进行洗涤干燥,得到卤代聚酯;
S3:将三嗪胺类化合物与腈类溶剂混合,在冰水浴和惰性气氛的保护下,滴加S2中所得卤代聚酯的腈类混合溶液,于室温下搅拌反应20-24h,减压去除溶剂,并用酯类溶剂洗涤,之后真空抽滤去除酯类溶剂,即得所述改性海藻糖基水凝胶。
6.根据权利要求5所述改性海藻糖基水凝胶的制备方法,其特征在于,所述S1中,海藻糖与多元羧酸的摩尔比为1:1-1.5。
7.根据权利要求5所述改性海藻糖基水凝胶的制备方法,其特征在于,所述S1中,有机溶剂为苯、甲苯、氯仿、四氯化碳、甲醚、乙醚、环己烷中的至少一种;缩聚反应的条件为150-200℃、110-130Pa。
8.根据权利要求5所述改性海藻糖基水凝胶的制备方法,其特征在于,所述S2中,所加卤氢酸的摩尔质量为海藻酸摩尔质量的1.5-1.8倍;聚酯与卤氢酸的反应条件为80-110℃,4-6h。
9.根据权利要求5所述改性海藻糖基水凝胶的制备方法,其特征在于,所述S3中,三嗪胺类化合物的摩尔量为所用卤氢酸摩尔量的1-1.2倍;腈类溶剂为乙腈、丙腈、丙烯腈中的至少一种;酯类溶剂为乙酸乙酯、乙酸丁酯、碳酸二甲酯中的至少一种。
10.权利要求1-4任意一项所述改性海藻糖基水凝胶,其特征在于,与卡波姆、羟苯甲酯、甘油混合制成创面敷料,应用在创面修复领域。
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