CN113893386A - 一种喷涂干粉凝胶敷料及其制备方法 - Google Patents
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Abstract
本发明公开了一种喷涂干粉制备的凝胶敷料,由亲水聚合物制备成凝胶经过冷冻粉碎干燥成粉末,以喷涂的方式到达组织表面,吸水后通过离子络合、氢键或静电力原位实现粉间交联以及组织粘合。本发明敷料应用前为干燥的粉末,易于储存,不含引发剂、单体,生物相容性高,干粉可以吸收湿组织表面的水分,消除粘附屏障,实现快速的湿组织粘附,对组织的粘附强度高,可以达到10‑50kpa;干粉的本质是模块化,可根据需要添加功能材料,可利用喷涂装置将干粉施加到伤口表面;水凝胶敷料借助于水引发成致密的水凝胶层并实现组织强粘附,在水的引发下,溶胀的颗粒在伤口表面原位自组装成凝胶块体,并实现对大面积,不规整伤口生物组织的紧密粘合。
Description
技术领域
本发明涉及水凝胶粘合剂领域,具体来说是一种喷涂干粉的凝胶敷料制备方法。
背景技术
在过去的几十年里,组织粘合剂作为一种可替代传统外科手术缝合的方法发展十分迅速。1-5相比于传统的手术线缝合的操作费时,有些位置不便操作,对组织有损伤以及会引起组织的异物炎症反应,组织粘合剂具有使用方便、操作时间短、组织损伤小等优点,是解决这些问题的有效方法之一,适用于微创手术。6目前,较于组织粘合剂的广泛研究及开发,用于临床的产品却寥寥无几且其应用场景受限,不能充分满足临床需求。其原因主要包括:凝胶材料输送能力差(不能到达狭窄区域);生物安全性低;对组织的粘附力弱。理想的水凝胶敷料应该便于输送以到达狭窄的损伤空间,生物安全性高以免损害周围组织,强组织粘附以避免作用中途脱落,此外还必须考虑实施方案的便捷性以降低对临床操作人员的要求。就单纯的粘附受损组织,其通常是有液体覆盖以及形状不规则的,就极具挑战性。7-8例如,组织表面的水和层作为粘附屏障阻碍了粘合材料与组织间构建分子键合,无法达成及时粘附;受损组织的不规则创口对粘附材料与组织间实现亲密贴合提出了更高的要求。再考虑到所用材料自身及实施方案的安全性及简易化,开发能契合临床使用的组织粘合剂变的更加困难。现有的组织粘合剂大致可分为生物材料类9,氰基丙烯酸酯类10以及水凝胶类3,5,11-13。生物材料类,比如纤维蛋白,可生物降解,通常不会导致炎症反应,但是提供粘附力弱,不适用与对机械性能要求高的组织修复。氰基丙烯酸酯类可与组织形成强粘附力,但是它的水引发聚合策略限制了其对湿伤口的粘附(过多血液会妨碍粘附)。水凝胶类组织粘合剂因其有高含水量,促愈合等优势,发展前景广阔,主要包括水凝胶块体和可注射水凝胶粘合剂,但是仍然面临上述开发困境。比如块状水凝胶不便运输,难以用于狭窄组织的微创修复;可注射水凝胶(溶胶-凝胶转换通常由化学交联前驱体实现)因其潜在的生物毒性及难把控的凝胶时间极大地拖延了临床应用的步伐。
发明内容
本申请提供一种喷涂干粉的凝胶敷料制备方法,针对现有的水凝胶敷料可运输能力差,生物安全性低等应用困难问题。
为实现上述目的,本发明采用的技术方案是:一种喷涂干粉制备的凝胶敷料,由亲水聚合物制备成水凝胶经过冷冻干燥粉碎成粉末,通过喷涂在组织表面吸水后通过作用力原位实现粉间交联以及组织粘合,作用力包含离子络合、氢键或/和静电力(设计机理如图1所示)。
作为本发明一种实施方法,凝胶敷料基于离子络合制备,亲水聚合物为聚丙烯酸(PAA),具体步骤包括:
1)制备PAA水凝胶:将丙烯酸、络合剂、APS溶于去离子水中,其中络合剂为丙烯酸的0.1-1.0mol%,APS为丙烯酸1/1000-1/100wt%,水含量为丙烯酸1-20倍,搅拌均匀,溶液除气,转移到密封的玻璃瓶中,放置于20℃以上的烘箱中,获得PAA水凝胶;
2)制备PAA干粉:PAA水凝胶通过透析除去单体以及平衡pH到4-7pH,将处理过的水凝胶块体打碎成凝胶粉末,转移到冷冻干燥机中,通过冻干的方式获得凝胶干粉。
进一步的,络合剂包括Fe3+、Ag+、Ca2+、Ba2+或Zn2+金属盐。
进一步的,所述络合剂为FeCl3。
作为本发明第二种实施方法,凝胶敷料基于氢键制备,亲水聚合物包括聚丙烯酸聚乙烯醇(PAA),具体步骤包括:
1)PVA-TA水凝胶的制备:将20g的PVA加入80g去离子水中,90℃加热搅拌4h,制备20wt%PVA水溶液;将20g的单宁酸(TA)加入80g去离子水,并充分溶解,制得20wt%TA水溶液;将PVA溶液与TA溶液按照0.25-4混合,手动搅拌3-5min;将混合溶液以3000r/min离子30min,收集沉淀物为PVA-TA水凝胶;
2)制备PVA-TA干粉:将步骤1)获得的PVA-TA水凝胶冷冻研磨成水凝胶粉末,经冷冻粉碎干燥获得PVA-TA干粉。
进一步的,所述PVA溶液与TA溶液体积比1:1,标记为PVA10-TA10。
作为本发明第三种实施方法,凝胶敷料基于静电相互作用制备,亲水聚合物包括聚电解质,具体步骤包括:
1)制备聚电解质双网络水凝胶:称取N,N,N-三甲基-3-(2-甲基烯丙酰氨基)-1-氯化丙铵(MPTC)50w%单体水溶液、对苯乙烯磺酸钠(NaSS)溶于去离子水中,制备10-40wt%单体水溶液,引入0.1-1mol%APS,待其充分溶解后,除气,置于烘箱,获得的PMPTC(PNaSS)溶液干燥,制粉,获得PMPTC粉末;称取MPTC 50w%单体水溶液、NaSS溶于去离子水中,制备10-40wt%单体水溶液,加入0.5-2mol%MBAA,优选1mol%,以及5-15wt%PMPTC(PNaSS)粉末,充分溶解后,引入0.1-1mol%APS,除气,置于烘箱,制得PMPTC、NaSS双网络凝胶;
2)制备PMPTC、PNaSS混合干粉:将步骤1)获得的PMPTC、PNaSS双网络水凝胶冷冻研磨成水凝胶粉末,经冷冻干燥获得PMPTC、PNaSS干粉。
进一步的,步骤(1)中,所述单体水溶液浓度为20wt%。
进一步的,步骤(1)中,所述APS浓度为0.5mol%。
本发明干粉的使用方法为:粉末装载在粉瓶内,通过载气将粉末带出,经由细管输送到指定位置,其中喷枪主体为三通装置,一端连接有粉瓶,一端接有进气通道,一端接有细导管(出粉口),导管的直径1-4mm。
本发明的有益技术效果是:本发明敷料应用前为干燥的粉末,易于储存,不含引发剂、单体,生物相容性高,干粉可以吸收湿组织表面的水分,消除粘附屏障,实现快速的组织粘附,对组织的粘附强度高,可以达到10-50kpa;干粉本质是模块化的,可根据需要添加功能材料,可利用喷涂装置将干粉施加到伤口表面;水凝胶敷料借助于水引发成致密的水凝胶层并实现组织强粘附,即在水的引发下,溶胀的颗粒在伤口表面原位自组装成凝胶块体,并实现对大面积,不规整伤口生物组织的紧密粘合。
附图说明
为了更清楚地说明本发明实施例或现有技术中的技术方案,下面将对实施例或现有技术描述中所需要使用的附图作简单地介绍,显而易见地,下面描述中的附图仅仅是本发明的一些实施例,对于本领域普通技术人员来讲,在不付出创造性劳动性的前提下,还可以根据这些附图获得其他的附图。
图1本发明的设计机理示意图及应用展示;
图2是实施例1基于离子络合的制备PAA干粉宏观及微观形貌;
图3是应用实施例4喷涂本发明PAA干粉喷粉装置图;
图4是应用实施例4伤口闭合测试法对PAA0.5粉末策略原位制备的水凝胶力学性能测试;
图5是应用实施例4干粉制备PAA凝胶对多种组织的粘附力;
图6是应用实施例4多种样品对猪皮的粘附强度图;
图7是应用实施例4植入PAA,PVA-TA和PMPTC/PNaSS水凝胶14天后,小鼠背部组织切片图;
具体实施方式
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作出创造性劳动前提下所获得的所有其他实施例,都属于本发明保护的范围。
实施例1
一种基于离子络合喷涂干粉凝胶敷料的制备方法,所用的制备原料为聚丙烯酸(PAA),具体步骤包括:
1)制备PAA水凝胶:将2g丙烯酸,0.5mol%FeCl3,2mg APS溶于8g去离子水中,搅拌均匀,溶液除气,转移到密封的玻璃瓶中,放置于20-40℃的烘箱中,24小时后,获得PAA水凝胶;
按照上述步骤,调节FeCl3的含量,多种PAA水凝胶被制备:PAA0.1,PAA0.25,PAA0.75以及PAA1。
2)制备PAA干粉:PAA水凝胶通过透析除去单体以及平衡pH到5,具体将凝胶置于3500的透析袋中,然后将其先后置于大量的去离子水和PBS缓冲液中透析,直到pH为5,将处理过的水凝胶块体打碎成凝胶粉末,转移到冷冻干燥机中,通过冻干的方式获得凝胶干粉,制备干粉的宏观及微观形貌如图2所示。
实施例2
一种基于氢键的喷涂干粉凝胶敷料基于氢键制备方法,制备原料为聚乙烯醇(PVA)和单宁酸(TA),具体步骤包括:
1)PVA-TA水凝胶的制备:将20g的PVA加入80g去离子水中,90℃加热搅拌4h,制备20wt%PVA水溶液,将20g的TA加入80g去离子水,并充分溶解,制得20wt%TA水溶液,将PVA溶液与TA溶液1:1混合,手动搅拌3-5min,将混合溶液以3000r/min离子30min,收集沉淀物为PVA10-TA10水凝胶;
根据以上步骤,改变配比,另外三种PVA20-TA20,PVA20-TA10,PVA10-TA5水凝胶可获得;
2)制备PVA-TA干粉:将步骤1)获得的PVA-TA水凝胶冷冻研磨成水凝胶粉末,经冷冻干燥获得PVA-TA干粉。
实施例3
一种基于静电相互作用喷涂干粉凝胶敷料的制备方法,制备原料为聚N,N,N-三甲基-3-(2-甲基烯丙酰氨基)-1-氯化丙铵(PMPTC)、聚对苯乙烯磺酸钠(PNaSS),具体步骤包括:
1)制备聚电解质双网络水凝胶:称取4g聚N,N,N-三甲基-3-(2-甲基烯丙酰氨基)-1-氯化丙铵(MPTC)50w%单体水溶液、2g对苯乙烯磺酸钠(NaSS)溶于6g去离子水中,引入0.5mol%APS,待其充分溶解后,除气,置于60℃烘箱8h,获得的PMPTC溶液干燥,制粉,获得PMPTC粉末;称取4gMPTC 50w%单体水溶液、2g NaSS溶于6g去离子水中,加入1mol%MBAA以及1gPMPTC、NaSS粉末,充分溶解后,引入0.5mol%APS,除气,置于60℃烘箱8h,制得PMPTC、NaSS双网络凝胶;
2)制备PMPTC、PNaSS混合干粉:将步骤1)获得的PMPTC、PNaSS双网络水凝胶冷冻研磨成水凝胶粉末,经冷冻干燥获得PMPTC、PNaSS干粉。
应用实施例1
以基于离子络合的制备的PAA干粉为例。
将制备的PAA干粉装填到电动喷粉器的载粉盒内,直接喷涂在湿的猪皮上(体外)或小鼠背部创面(体内)。分别通过体外伤口闭合测试以及小鼠背部组织切片探究探究凝胶的黏附性能以及生物相容性。
1、粉末喷涂
如图3所示,粉末装载在粉瓶内,通过载气将粉末带出,经由细管输送到指定位置。其中喷枪主体为三通装置,一端连接有粉瓶,一端接有进气通道,一端接有细导管(出粉口),导管的直径(1mm-4mm)。
2、粉末组装水凝胶对组织的粘附性能
如图4所示,水凝胶对组织的粘附强度通过伤口闭合测试法(wound closuretest)测得。图5展示了PAA粉末组装的凝胶其对不同组织的粘附强度。此外,不同粉末对猪皮的粘附强度也被测试展示在图6。
3、体内的生物相容性
体外生物相容性通过小鼠皮下植入凝胶测试。不同凝胶材料的皮下植入组织切片展示在图7。结果表明此方案制备的水凝胶敷料均展示出较高的生物安全性。
最后所应说明的是:以上实施例仅用以说明而非限制本发明的技术方案,尽管参照上述实施例对本发明进行了详细说明,本领域的普通技术人员应该理解:依然可以对本发明进行修改或者等同替换,而不脱离本发明的精神和范围的任何修改或局部替换,其均应涵盖在本发明的权利要求范围当中。
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Claims (10)
1.一种喷涂干粉制备的凝胶敷料,其特征是,由亲水聚合物制备成的水凝胶经过冷冻干燥粉碎成粉末,通过喷涂在组织表面吸水后通过作用力原位实现粉间交联以及组织粘合。
2.根据权利要求1所述凝胶敷料,其特征是,所述作用力包括离子络合、氢键或/和静电力。
3.根据权利要求1-2任一项所述凝胶敷料的制备方法,其特征是,所述凝胶敷料基于离子络合制备,亲水聚合物为聚丙烯酸(PAA),具体步骤包括:
1)制备PAA水凝胶:将丙烯酸、络合剂、APS溶于去离子水中,其中络合剂为丙烯酸的0.1-1.0mol%,APS为丙烯酸1/1000-1/100wt%,水含量为丙烯酸1-20倍,搅拌均匀,溶液除气,转移到密封的玻璃瓶中,放置于20℃以上的烘箱中,获得PAA水凝胶;
2)制备PAA干粉:PAA水凝胶通过透析除去单体以及平衡pH到4-7pH,将处理过的水凝胶块体打碎成凝胶粉末,转移到冷冻干燥机中,通过冻干的方式获得凝胶干粉。
4.根据权利要求3所述凝胶敷料的制备方法,其特征是,所述络合剂为离子络合剂,包括Fe3+、Ag+、Ca2+、Ba2+或Zn2+金属盐。
5.根据权利要求3或4所述凝胶敷料的制备方法,其特征是,所述络合剂为FeCl3。
6.根据权利要求1-2任一项所述凝胶敷料的制备方法,其特征是,所述凝胶敷料基于氢键制备,亲水聚合物为聚乙烯醇(PVA),具体步骤包括:
1)PVA-TA水凝胶的制备:将20g的PVA加入80g去离子水中,90℃加热搅拌4h,制备20wt%PVA水溶液;将20g的单宁酸(TA)加入80g去离子水,并充分溶解,制得20wt%TA水溶液;将PVA溶液与TA溶液按照0.25-4混合,手动搅拌3-5min;将混合溶液以3000r/min离子30min,收集沉淀物为PVA-TA水凝胶;
2)制备PVA-TA干粉:将步骤1)获得的PVA-TA水凝胶冷冻研磨成水凝胶粉末,经冷冻粉碎干燥获得PVA-TA干粉。
7.根据权利要求6所述制备方法,其特征在于,步骤(1)中,所述PVA溶液与TA溶液体积比1:1,标记为PVA10-TA10。
8.根据权利要求1-2任一项所述凝胶敷料的制备方法,其特征是,所述凝胶敷料基于静电相互作用制备,亲水聚合物为聚电解质,具体步骤包括:
1)制备聚电解质双网络水凝胶:称取N,N,N-三甲基-3-(2-甲基烯丙酰氨基)-1-氯化丙铵(MPTC)50w%单体水溶液、对苯乙烯磺酸钠(NaSS)溶于去离子水中,制备10-40wt%单体水溶液,引入0.1-1mol%APS,待其充分溶解后,除气,置于烘箱,获得的PMPTC(PNaSS)溶液干燥,制粉,获得PMPTC粉末;称取MPTC 50w%单体水溶液、NaSS溶于去离子水中,制备10-40wt%单体水溶液,加入0.5-2mol%MBAA,以及5-15wt%PMPTC(PNaSS)粉末,充分溶解后,引入0.1-1mol%APS,除气,置于烘箱,制得PMPTC、NaSS双网络凝胶;
2)制备PMPTC、PNaSS混合干粉:将步骤1)获得的PMPTC、PNaSS双网络水凝胶冷冻研磨成水凝胶粉末,经冷冻干燥获得PMPTC、PNaSS干粉。
9.根据权利要求8所述制备方法,其特征在于,步骤(1)中,所述单体水溶液浓度为20wt%。
10.根据权利要求8所述制备方法,其特征在于,步骤(1)中,所述APS浓度为0.5mol%。
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CN115025279A (zh) * | 2022-06-30 | 2022-09-09 | 西安交通大学 | 预防术后粘连的可喷涂天然水凝胶体系及其制备和应用 |
CN115025279B (zh) * | 2022-06-30 | 2023-03-28 | 西安交通大学 | 预防术后粘连的可喷涂天然水凝胶体系及其制备和应用 |
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