CN113999406A - 一种多功能抗菌水凝胶敷料的制备方法及应用 - Google Patents
一种多功能抗菌水凝胶敷料的制备方法及应用 Download PDFInfo
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- CN113999406A CN113999406A CN202111312519.XA CN202111312519A CN113999406A CN 113999406 A CN113999406 A CN 113999406A CN 202111312519 A CN202111312519 A CN 202111312519A CN 113999406 A CN113999406 A CN 113999406A
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Abstract
本发明为一种多功能抗菌水凝胶敷料的制备方法及应用。该凝胶敷料由抗菌活性季铵盐功能化的刚性天然聚糖与柔性聚丙烯酰胺网络组成双网络、二维纳米材料苯硼酸功能化石墨烯作为纳米填料,在预聚合的多巴胺中聚合制备而成。本发明得到的抗菌敷料解决了目前伤口敷料力学性能差、黏附性能缺失、抗生素类药物滥用的问题,并且此发明不受加工条件精密程度的限制、制备方法简单、工艺条件温和、安全可靠、生物相容性和经济性更好。
Description
技术领域:
本发明属于生物材料制备技术领域,尤其是涉及一种可拉伸、可黏附、可促进耐药菌感染伤口愈合、生物相容性优异的多功能抗菌水凝胶敷料的制备方法。
背景技术:
皮肤作为人体的第一道屏障,在抵御外力、机体免疫、感受调节、物理或化学刺激缓冲、防止营养和电解质流失等方面起着不可或缺的作用。然而,皮肤是最容易受到伤害的,包括烧伤、擦伤、撕裂、挫伤、临床外科手术或其他表面损伤。此外,伤口处理不当引起的细菌感染也是人类健康的一大威胁。纱布,绑带等传统的临床伤口处理方式,不仅存在创面覆盖不全、组织粘合效果差、吸水和保水能力不足、易引起继发感染等问题,而且在频繁换药时容易造成不必要的出血,撕破新组织而延缓愈合过程。此外,上述敷料不具备与皮肤相匹配的力学性能导致正常的肢体活动受阻。因此,设计一种可伸缩、黏附、抗菌、生物相容性的伤口敷料具有重要的临床意义。
水凝胶已成为组织修复领域最有竞争力的候选者。3D结构和促进细胞水合作用可以促进气体和营养物质的交换,并为表皮细胞迁移提供一个潮湿的环境,以加速伤口愈合。近年来,水凝胶已成功应用于多个组织修复领域,但此类敷料设计往往倾向于通过药物或细胞因子传递来实现相应的功能。同时,应用受到复杂的制备方式、不可控的药物释放、较高的制造成本和药物相关副作用的限制,特别是抗生素的滥用导致耐药性的产生已经日益严重。此外,水凝胶的丰富的孔结构和良好的黏附性容易造成微生物粘附,引起炎症或免疫反应,可见水凝胶具有良好的抗菌性能,这对其临床应用至关重要。而对于水凝胶敷料的抗菌活性,现在应用较多的方式有以下几种:(1)无机金属纳米粒子。包括银(Ag)、金(Au)、锌(Zn)或其他含金属纳米粒子被用于构建纳米水凝胶复合体系。然而,这种策略由于不确定的细胞毒性、不可降解性和精密的制备过程导致应用受阻。(2)壳聚糖(CS)、部分季铵盐壳聚糖(QAS-CS)和多肽等抗菌活性材料被开发为长效抗菌水凝胶是一种可行且有效的方法。但这些方法同样存在一定的障碍,如生理条件下的不溶性限制了CS的应用,多肽水凝胶容易快速降解,部分QAS-CS需要反复治疗或额外使用过量的抗生素,较低的负载量以及细胞毒性同样也是较大的挑战。(3)近红外(NIR)光热疗法由于靶向选择性、远程可控性、抗菌广谱性等优点,近年来在感染创面治疗方面得到了进一步的研究。稳定高效的光热材料的选择以及光热材料如何构建水凝胶体系也是亟待解决的问题。
发明内容:
本发明的目的是在于克服上述现有技术的不足之处,提供一种多功能抗菌水凝胶敷料的制备方法及应用,此多功能抗菌水凝胶是由抗菌活性季铵盐功能化的刚性天然聚糖与柔性聚丙烯酰胺网络组成双网络、二维纳米材料苯硼酸功能化石墨烯作为纳米填料,在预聚合的多巴胺中聚合制备而成;该抗菌敷料解决了目前伤口敷料力学性能差、黏附性能缺失、抗生素类药物滥用的问题,并且此发明不受加工条件精密程度的限制、制备方法简单、工艺条件温和、安全可靠、生物相容性和经济性更好。
为了实现上述目的,本发明提供的技术方案为:
一种多功能抗菌水凝胶敷料的制备方法,该方法包括如下步骤:
A将抗菌性极佳的二羟基和恶二唑基修饰的季铵盐(QAS),通过异佛尔酮二异氰酸酯(IPDI)偶联水溶性较好的天然抗菌活性聚糖羧甲基壳聚糖(CMCS),构建新型的季铵化羧甲基壳聚糖(QCS)。
B将二维光热材料(GO)进行3-氨基苯硼酸(PBA)功能化并进行还原反应制备功能化还原氧化石墨烯(rGB),以增加细胞亲和性,防止GO在水凝胶中发生团聚现象。此外,苯硼酸可与细菌表面的聚糖形成硼酸酯键进行细菌固定。rGB可通过PBA上的二醇键通过后续化学反应负载到水凝胶上,解决石墨烯应用过程中被细胞摄取而产生细胞毒性难题。
C在原位聚合形成凝胶的过程中,先对多巴胺(DA)进行预聚合,后在引发剂过硫酸铵(APS)中进行二次聚合,赋予体系优异的黏附性能。
D将一定比例季铵盐抗菌活性聚糖(QCS)、丙烯酰胺(AM)溶解到预聚合的多巴胺(DA)溶剂中并按一定比例加入3-氨基苯硼酸功能化的还原氧化石墨烯(rGB),混合均匀后通过原位引发聚合制备水凝胶。
具体包括如下步骤:
步骤A
A1将IPDI、QAS加入到DMF中,氮气气氛、20~40℃、搅拌下反应1~5h,反应完毕,加入无水乙醚产生沉淀,将沉淀真空干燥,得固体物质A1产物;
其中,IPDI:QAS的摩尔比为1:1,每10mL DMF加入1~2mmol的IPDI;
A2将A1产物与CMCS加入到DMF中,氮气气氛保护下20~40℃连续搅拌12~24h;
其中,A1产物与CMCS的摩尔比为0.1~0.8;每20mL DMF加0.3~0.9g CMCS;
A3反应完毕,将A2所得混合溶液置于截留分子量为4000~8000Da的透析袋中用去离子水透析3~7天,后进行冷冻干燥,得到物质A;
步骤B
B1向氧化石墨烯(GO)溶液中加入3-氨基苯基硼酸(PBA),在50~70℃下剧烈搅拌反应2~3h,制备得3-氨基苯硼酸功能化的氧化石墨烯(GB);
其中,溶液中,氧化石墨烯的浓度为0.5~1.5mg/mL;氧化石墨烯与3-氨基苯基硼酸(PBA)的质量比为1:1~1:3;
所述的剧烈搅拌的转数为1000~1300rpm/min;
B2在B1得到的混合物中加入抗坏血酸钠,将温度提高到80~90℃并不断搅拌,持续1~2h;
其中,溶液中,氧化石墨烯与抗坏血酸钠的质量比为1:1.5~1:2;
B3反应后B2溶液转移到离心管中,在10000~12000rpm/min转速下离心15~30min,水洗后进行冻干处理,得到B;
步骤C
C1将多巴胺盐酸盐溶解于三羟甲基氨基甲烷盐酸盐缓冲溶液(pH=8.5)中配制成溶液;
其中,溶液中,多巴胺的浓度为20~50mg/mL;
C2将C1所得溶液在空气气氛中剧烈搅拌15~20min,使DA进行初步的预聚合,得到物质C;所述的剧烈搅拌为800~1000rpm/min;
步骤D
D1将物质C加入到去离子水中,得到敷料溶剂;每2.5~4mL去离子水加入100~400μL物质C;
D2将物质A、物质B和丙烯酰胺(AM)加入到敷料溶剂中搅拌,得到混合液;
其中,每2.5~4mL敷料溶剂加入200~800mg物质A、2~10mg的物质B、1~1.5g丙烯酰胺(AM);
D3将N,N-亚甲基双丙烯酰胺(MBA)、过硫酸铵(APS)、N,N,N,N-四甲基二胺(TMEDA)加入到混合液中,搅拌后倒入聚四氟乙烯模具中,20~30℃下反应100~400s,得到多功能抗菌水凝胶敷料;
每2.5~4mL混合液中加入0.6~1.2mg N,N’-亚甲基双丙烯酰胺,100~150mg过硫酸铵,2~3μL N,N,N,N-四甲基二胺;
所述的方法制备的多功能抗菌水凝胶敷料,用于医疗抗菌敷料。
具体用于伤口愈合过程创伤愈合敷料、抗菌敷料、医用胶黏剂、医用手术缝合线和人工组织皮肤。
本发明的实质性特点为:
当前技术中,小分子季铵盐抗菌剂在应用过程中具有局部浓度过高易产生机体毒性和机体清除速率快而导致治疗时间短暂的缺点。本发明中选用抗菌性能好的QAS季铵盐(2-羟基-N-(2-羟乙基)-N-甲基-N-(2-((5-苯基-1,3,4-恶二唑-2-基)硫)乙基)乙烷-1-胺)作为抗菌剂,其化学结构中使用羟基恶二唑代替传统季铵盐中的长链烷基或苄基而避免了季铵盐生物相容性差的难题。之后,我们将QAS通过化学键修饰到天然聚糖羧甲基壳聚糖(CMCS)上,制备具有良好生物相容性的高分子抗菌剂QCS。QCS解决了目前季铵盐突释的问题并获得长期抗菌活性。当QAS与CMCS的投料摩尔比为0.8:1时,接枝率为9.1%,此接枝率的QCS兼具QAS负载量高和水溶性好的优点。
还原氧化石墨烯(rGO)相对于氧化石墨烯(GO)具有近红外光热效率高、分散性能好、生物相容性好等优点,可应用于光热抗菌,但石墨烯较高具有的细胞毒性而使其应用受到了限制。本发明中采用苯硼酸(PBA)对GO表面功能化修饰,并进一步采用温和的抗坏血酸钠还原GO为rGO,制备表面含有苯硼酸的还原氧化石墨烯(rGB)。rGB可通过PBA上的二醇键通过后续化学反应负载到水凝胶上,解决石墨烯应用过程中被细胞摄取而产生细胞毒性难题。
此外,目前抗菌水凝敷料面临着与皮肤力学性能不匹配和对皮肤黏附性低等缺点。本发明采用聚丙烯酰胺(PAM)为基本水凝胶网络,以QCS和rGB分别作为有机和无机抗菌剂,与具有组织粘附性的聚多巴胺进行复合制备具有皮肤粘附性的柔性抗菌水凝胶。当QCS:PAM的质量比为4%、rGB:PAM的质量比为0.05%时,DA:PAM的质量比为0.3%时,得到力学强度为58.6kPa、断裂伸长率为1544%、黏附强度达为16.33kPa,与皮肤力学性能相匹配的可粘附抗菌水凝胶。
本发明的有益效果为:
1此发明制备的多功能水凝胶具有与皮肤相匹配的力学性能,可以作为伤口敷料便于固定与更换,特别是适用于特殊区域的创面损伤,如关节处,腋窝,肌肉处等。
2此发明制备的多功能水凝胶具有优良的黏附性能,可以紧密的黏附在组织表面,解决与组织处固定困难、覆盖不完全等问题。同时替代绷带或医用胶带,解决部分病人对医用材料存在过敏现象的问题。
3此发明制备的多功能水凝胶具有极佳的抗菌性能。季铵盐抗菌策略与光热抗菌策略协同展现出持久的抗菌能力和最小化的机体损伤。经体外抗菌实验验证对MRSA和E.coli均有显著的抗菌效果(>99%)。
4此发明制备的多功能水凝胶具有丰富的孔结构和优异的吸水和保水能力。一方面为各种细胞的浸润、增殖和分化,以及创面血管的萌发提供物理支撑;另一方面多孔结构和QCS中的正电荷同时起到促进细胞迁移和止血的功能。
5本发明制备的多功能水凝胶具有良好的生物相容性。经过体外细胞毒性实验和荧光染色证实此水凝胶细胞相容性好,对人体皮肤组织无刺激性,符合机体运用条件。
6本发明制备的多功能水凝胶制备方法简单,不易受到精细操作的制约。
7本发明制备的多功能水凝胶适用细菌感染创面的敷料以及组织再生辅助材料等。动物实验证实在无药物或细胞因子传递的情况下能明显加速细菌感染伤口愈合。
附图说明
图1为本发明实施例1的结构示意图;
图2为本发明实施例4的溶液-凝胶相转变示意图;
图3是本发明效果实施例中CMCS、QAS、QAS-IPDI、QCS的紫外光谱图;
图4是本发明效果实施例中CMCS以及不用接枝率QAS的1H NMR谱图;
图5是本发明效果实施例中CMCS、rGB、PDA、PAM以及QCS/rGB/PDA-PAM水凝胶的FT-IR谱图;
图6是本发明效果实施例中rGB、GO以及GB拉曼光谱图;
图7是本发明效果实施例中QCS/rGB/PDA-PAM水凝胶敷料冻干后的扫描电镜图;
图8是本发明效果实施例中QCS/rGB/PDA-PAM水凝胶敷料力学性能表征图;其中,图8(a)为DA/AM为0.3wt%定值的情况下,不同rGB/AM,QAS/AM组成的水凝胶单轴拉伸测试应变柱状图,图8(b)为当rGB/AM=0.05wt%,QAS/AM=4wt%,DA/AM=0.3wt%时,固定应变为80%时单轴循环压缩应力应变图;
图9是本发明效果实施例中QCS/rGB/PDA-PAM水凝胶敷料黏附性能表征图;
图10是本发明效果实施例中QCS/rGB/PDA-PAM水凝胶敷料抗菌性能表征图,其中,图10(a)为QCS/rGB/PDA-PAM水凝胶抗菌性能典型照片,图10(b)为MRSA细菌死亡率;图10(c)为E.coli细菌死亡率;
图11是本发明效果实施例中QCS/rGB/PDA-PAM水凝胶敷料修复小鼠细菌感染伤口图;其中,图11(a)第0、5、10、15天创面愈合的典型照片。图11(b)各组统计伤口收缩面积图。
具体实施方式
本发明的多功能抗菌水凝胶敷料的制备方法,该方法包括如下步骤:
A将抗菌性极佳的二羟基和恶二唑基修饰的季铵盐(QAS),通过异佛尔酮二异氰酸酯(IPDI)偶联水溶性较好的天然抗菌活性聚糖羧甲基壳聚糖,构建新型的季铵化羧甲基壳聚糖(QCS)。
B将二维光热材料(GO)进行3-氨基苯硼酸(PBA)功能化并进行还原反应制备功能化还原氧化石墨烯(rGB)以增加细胞亲和性,防止GO在水凝胶中发生团聚现象。此外,苯硼酸可与细菌表面的聚糖形成硼酸酯键进行细菌固定。rGB可通过PBA上的二醇键通过后续化学反应负载到水凝胶上,解决石墨烯应用过程中被细胞摄取而产生细胞毒性难题。
C在原位聚合形成凝胶的过程中,先对多巴胺(DA)进行预聚合,后在引发剂过硫酸铵(APS)中进行二次聚合,赋予体系优异的黏附性能。
D将一定比例季铵盐抗菌活性聚糖(QCS)、丙烯酰胺(AM)溶解到预聚合的多巴胺(DA)溶剂中并按一定比例加入3-氨基苯硼酸功能化的还原氧化石墨烯(rGB),混合均匀后通过原位引发聚合制备水凝胶。
水凝胶多孔的结构赋予了其良好的吸水和保水特性以及愈合过程中生长因子的物理支撑;抗菌活性聚糖的加入,不仅因自身的抗菌活性和接枝季铵盐使水凝胶拥有持久的抗菌活性,而且其与聚丙烯酰胺(PAM)通过物理/化学交联形成超分子弱相互作用构筑双网络结构。此外,由于抗菌活性聚糖链中携带正电荷,对止血、细胞的迁移和增殖有着显著促进作用。纳米材料rGB的引入不仅作为光热材料实现稳定的光热转化效率,而且作为无机填料通过能量的转移机制使体系力学性能得到进一步的提高。同时,本发明在抗菌性能上体现出季铵盐抗菌与光热抗菌协同的作用,体外抗菌实验证实了协同策略对革兰氏阳性(MRSA)和阴性(E.coli)细菌均有显著的抗菌效果(>99%);PDA中游离的儿茶酚基团的存在使得此多功能水凝胶展现出自黏附和共黏附特性,更加贴合创面组织。典型的单轴拉伸/压缩实验验证了此发明具有优异的机械性能和应变恢复性能。通过体外细胞毒性试验、动物试验等进一步证明了该水凝胶不仅生物相容性优异,而且在无药物或细胞因子的情况下可以促进耐甲氧西林金黄色葡萄球菌(MRSA)感染的伤口修复。结合以上特点,这种可拉伸、可黏附、可光热转化、可促进MRSA感染伤口愈合的新型抗菌水凝胶敷料,在组织工程等生物医学领域有很大的应用潜力。
为更好的说明本发明的目的、技术方案和优点,下面将结合具体实施例对本发明作进一步说明。
实施例1季铵化羧甲基壳聚糖(QCS)的制备
取IPDI 0.275g(1.24mmol),QAS 0.5g(1.24mmol)置于25mL圆底烧瓶中,加入10mLDMF溶液,将混合液在25℃下以800~1000rpm/min的转速磁力搅拌反应3h,同时进行干燥氮气气氛保护,并用TLC法检测反应进度。反应完毕,使用-4℃无水乙醚沉淀并重复操作三次。沉淀真空干燥,得固体产物QAS-IPDI 0.54g(1.18mmol)。
将上述产物与CMCS(0.839g,CMCM与QAS-IPDI摩尔比为1:0.3)在20mL去DMF中25℃连续搅拌反应24h,磁力搅拌转速控制在800~1000rpm/min,同时进行干燥氮气气氛保护。反应完毕,将所得混合溶液置于截留分子量为8000Da的透析袋中,去离子水透析5天,-80℃冷冻后置于冷冻干燥机中,-50℃冻干,所得到的白色絮状物即为目标产物季铵化羧甲基壳聚糖(QCS)。
实施例2-3其他步骤同实施例1,不同之处为CMCS的质量由0.839g调整为0.503g、0.311g(即CMCS与QAS-IPDI的摩尔比调整为1:0.5和1:0.8)。
实施例1-3中,通过核磁共振氢谱计算所得QCS的取代度分别为2.6%、4.9%和9.1%。制备过程如图1所示。
在本实施例中,所述CMCS的分子量为20KDa,羧甲基化度80%;所述QAS的用量优选为0.5g;所述IPDI的用量优选为0.208g;CMCS与QAS-IPDI的摩尔比优选为1:0.8。
实施例4苯硼酸功能化还原氧化石墨烯(rGB)的制备
取2mL氧化石墨烯(GO)(5mg/mL)水溶液置于50mL玻璃烧瓶中,加入18mL去离子水后超声分散处理30min。后在上述溶液中加入30mg 3-氨基苯基硼酸(PBA),在水浴中70℃以1200rpm/min下剧烈磁力搅拌反应3h。在此条件下,制备得3-氨基苯硼酸功能化的氧化石墨烯(GB)。反应结束后,上述得到的混合物中加入20mg抗坏血酸钠,将水浴温度提高到80℃并维持原有搅拌速度不断搅拌,继续反应1h。反应完成后,自然冷却至室温,将所得混合溶液在转移至离心管中,在11000rpm/min的转速下离心30min,取底部沉淀,重复水洗三次。后进行冻干处理,得到苯硼酸功能化还原氧化石墨烯(rGB);后期使用时超声分散在水中即可。
实施例5预聚合多巴胺的制备
取20mg多巴胺盐酸盐溶解于1mL三羟甲基氨基甲烷盐酸盐缓冲溶液(盐酸调配pH=8.5)中配制成溶液。所得溶液在25℃以800rpm/min下磁力搅拌反应20min,使DA进行初步的预聚合,得到预聚合的多巴胺溶液(20mg/mL);
实施例6QCS/rGB/PDA-PAM(QGD-PAM)多功能水凝胶的制备
将实施例5所得产物取200μL均匀分散到2.5mL去离子水中,制备凝胶体系的溶剂。取400mg实施例3所得的取代度为9.1%的QCS产物,取5mg实施例4所得的rGB,1.0g丙烯酰胺(AM)均匀混合在得到的凝胶体系的溶剂中,并进行超声处理1min。在上述混合液中依次加入1.2mg N,N’-亚甲基双丙烯酰胺(MBA),100mg过硫酸铵(APS),2μL N,N,N’,N’-四甲基二胺(TMEDA),混合液在200rpm/min下磁力搅拌30s。后将得到的混合溶液倒入聚四氟乙烯模具中,25℃下反应400s,通过自由基原位聚合制备多功能水凝胶。如图2所示,通过倒瓶实验直观展示溶液-凝胶相转变。
效果实施例
1 UV-vis表征
取实施例1中的CMCS、QAS、QAS-IPDI、QCS配制0.1mmol/mL的测试液通过紫外光谱分析仪进行光谱扫描。扫描结果如图3所示,UV-vis光谱显示CMCS在扫描范围200-400nm内未见明显的吸收峰,QCS逐步聚合过程中在280nm处可以看到明显的苯环的特殊峰,证明QCS被成功制备。
2 1H NMR表征
精确称量实施例1-3中得到的不同接枝率的QCS、CMCS各5mg分别溶解在0.6mL氘代重水中,采用1H NMR精确地测定化学结构并通过峰面积积分法计算不同投料比的接枝率。QCS的1H NMR(图4)清楚地显示出8.0-7.5、3.8-4.2和2.82ppm的主要信号峰。在8.0-7.5ppm的峰值是由于芳香族基团的质子,在3.8-4.2ppm是CMCS本身特征质子,以及2.82处的特征峰为IPDI作为偶联剂时-NH-CH2-时的特征质子峰。通过1H NMR分析可知,QCS被成功制备。
3 FT-IR表征
取实施例1所得的QCS、实施例4所得的rGB、实施例5所得的冻干后的PDA以及实施例6所得的QCS/rGB/PDA-PAM水凝胶测定红外光谱。如图5所示,在1402cm-1处的C-N拉伸峰来自于PDA和PAM的伯酰胺;1620cm-l处的峰为PDA衍生的伯胺的N-H震动伸缩峰,表明多巴胺在体系中成功聚合;QCS/rGB/PDA-PAM水凝胶中在1252cm-1处出现一个新峰,与苯基胺中的C-N伸缩有关,表明PDA的儿茶酚基团与PAM的氨基相互作用。此外,在1500-1000cm-1指纹由于PDA与PDA之间、QCS与PDA之间的π-π共轭堆积效应变得相对平滑。620cm-1处的GO特征峰证实了其在QCS/rGB/PDA-PAM水凝胶中的存在。此外,PDA、QCS和PAM之间形成了氢键,导致-OH的吸收峰从3410cm-1向大波长偏移到3430cm-1。
4苯硼酸功能化的还原氧化石墨烯(rGB)的拉曼光谱表征
取实施例4中的rGB、GO和GB使用拉曼光谱仪测定拉曼光谱。拉曼光谱如图6所示,可以观察到还原前后的D特征峰位置保持不变,G特征峰从1582cm-1偏移到1576cm-1,并且经过还原后D特征峰半峰宽减小,说明成功还原为rGB。通过计算ID/IG可以清楚的发现功能化前后从0.904上升到1.032,这说明PBA功能化GO时消耗了GO表面的含氧官能团(环氧基团、-COOH)。还原后上升到1.081,证明加入抗坏血酸钠后GB被还原为rGB。5QCS/rGB/PDA-PAM水凝胶的TEM表征
使用透射电子显微镜观察实施例6制备的QCS/rGB/PDA-PAM水凝胶微观形貌确定多孔结构。如图7所示,TEM结果表明,此凝胶具有丰富的微孔结构(孔径大小为36.4±5.8μm),且孔结构均匀致密,可供在伤口愈合过程中生长因子或营养的输送。
6 QCS/rGB/PDA-PAM水凝胶的力学性能表征
使用微机控制电子万能试验机,通过单轴拉伸、压缩实验证明实施例6制备的水凝胶具有较好的拉伸性能和应力恢复性能。如图8(a)、8(b)可以观察到,这些水凝胶具有良好的延展性(481%-1544%),优于人类皮肤的延展性(60-75%),其中力学强度为58.6kPa。图8(b)显示,当应变为80%时,凝胶没有明显的损伤,这表明这些水凝胶可以承受高应变的压缩并能恢复到原有状态。
7 QCS/rGB/PDA-PAM水凝胶的黏附性能表征
使用微机控制电子万能试验机,通过搭接拉伸实验证明实施例6制备的水凝胶具有可调节的黏附性能。图9显示,黏附强度可达到16.6kPa,高于商业化的纤维蛋白胶(3kPa)。此黏附性能保证此水凝胶敷料在应用的过程中与组织的紧密贴合并达到完全覆盖伤口的目的。
8 QCS/rGB/PDA-PAM水凝胶的抗菌性能表征
将MRSA(~106CFU/mL)和E.coli(~106CFU/mL)与实施例6制备的水凝胶在37℃共培养6h,然后将处理过的细菌培养液铺于琼脂平板上,孵育12h。在培养皿上拍摄相应的菌落形成单位(CFU),以评价实施例4制备的水凝胶的抗菌活性。同时,采用近红外激光辐照和非近红外激光辐照对制备的水凝胶的抗菌性能进行评价。图10(a)中各组代表性图片显示出季铵盐抗菌和近红外光热抗菌存在协同作用。定量统计后(图10(b)),灭菌效果明显优于其他组别(P*<0.05)。
9 QCS/rGB/PDA-PAM水凝胶感染创面修复性能表征
在小鼠背部建立全皮损伤MRSA细菌感染模型,实施例6制备的水凝胶敷贴于创口处。与未经任何处理的小鼠进行创伤对比,拍照记录愈合过程并计算伤口收缩率。如图11(a),11(b)所示,可见水凝胶敷料可以将伤口愈合周期从21天缩短到15天并在此过程中未见明显的感染现象。经计算得第12天愈合面积达到90%以上且与对照组之间存在较大得差异(P*<0.05)。
通过以上实施例和表征分析我们可以看出,本发明中抗菌活性材料由天然抗菌活性聚糖通过IPDI偶联带有正电荷的QAS。不仅具有刚性CMCS以增强水凝胶的力学性能,而且具有抗菌广谱性和低毒性的正电荷季铵盐基团,以提供高效和持久的抗菌性能。此外,带正电的QAS有助于吸引带负电的表皮纤维细胞,从而促进细胞爬行和增殖,促进皮肤的愈合。
本发明中的光热材料rGB由GO表面功能化PBA以达到其在水凝胶中有良好的分散效果并降低GB的细胞毒性,保证生物相容性。此外,本发明避开传统的恶劣还原条件(较高或低pH溶液、高温和毒性还原剂),采用细胞相容性优良的生物有机化合物抗坏血酸钠进行替代,还原后可提高rGB与哺乳动物细胞之间的细胞亲和力。同时,rGB一方面作为稳定的光热材料提供高效率的光热转化;另一方面作为纳米无机填料通过能量转移耗散策略赋予体系可调的弹性模量。rGB中的PBA与细菌表面的糖蛋白生成硼酸酯键,起到了固定和捕获细菌的作用。
本发明借鉴贻贝材料的粘附性,在多巴胺的预聚合溶液中进行原位自由基聚合反应制备水凝胶。多巴胺具有极好的生物相容性,进一步提高材料的亲水性。此外,引入具有粘附性的儿茶酚、氨基基团,可以在材料表面形成水化层,与组织处的多肽和蛋白质中的氨基、硫醇和咪唑有很高的潜在亲和力(非共价/氢键等),使材料具有良好的组织黏附性。同时,通过改变多巴胺的占比实现水凝胶自粘附和共黏附性能的调控。
本发明中的3D凝胶网络是由非共价键(如氢键、范德华力和静电相互作用)和交联聚合物的共价键维持。刚性的QCS和柔性的PAM网络通过PDA的非共价键交联缠绕组成双网络结构,以及体系中存在的物理交联和化学交联相结合的交联方式使得此水凝胶显示出具有与皮肤相匹配的力学性能。值得注意的是rGB作为纳米填料加入到体系中,提供更多的交联位点,使体系的各向韧性性能在宏观上得到了进一步的提高。
本发明未尽事宜为公知技术。
Claims (5)
1.一种多功能抗菌水凝胶敷料的制备方法,其特征为该方法包括如下步骤:
A将抗菌性极佳的二羟基和恶二唑基修饰的季铵盐(QAS),通过异佛尔酮二异氰酸酯(IPDI)偶联水溶性较好的天然抗菌活性聚糖羧甲基壳聚糖(CMCS),构建新型的季铵化羧甲基壳聚糖(QCS);
B将二维光热材料(GO)进行3-氨基苯硼酸(PBA)功能化,并进行还原反应制备功能化还原氧化石墨烯(rGB);
C先对多巴胺(DA)进行预聚合,后在引发剂过硫酸铵(APS)中进行二次聚合;
D将一定比例季铵盐抗菌活性聚糖(QCS)、丙烯酰胺(AM)溶解到预聚合的多巴胺(DA)溶剂中并按一定比例加入3-氨基苯硼酸功能化的还原氧化石墨烯(rGB),混合均匀后通过原位引发聚合制备水凝胶。
2.如权利要求1所述的多功能抗菌水凝胶敷料的制备方法,其特征为该方法具体包括如下步骤:
步骤A
A1将IPDI、QAS加入到DMF中,氮气气氛、20~40℃、搅拌下反应1~5h,反应完毕,加入无水乙醚产生沉淀,将沉淀真空干燥,得固体物质A1产物;
其中,IPDI:QAS的摩尔比为1:1,每10mL DMF加入1~2mmol的IPDI;
所述的溶剂为DMF;
A2将A1产物与CMCS加入到DMF中,氮气气氛保护下20~40℃连续搅拌12~24h;
其中,A1产物与CMCS的摩尔比为0.1~0.8;每20mL DMF中加0.3~0.9g CMCS;
A3反应完毕,将A2所得混合溶液置于截留分子量为4000~8000Da的透析袋中用去离子水透析3~7天,后进行冷冻干燥,得到物质A;
步骤B
B1向氧化石墨烯(GO)溶液中加入3-氨基苯基硼酸(PBA),在50~70℃下剧烈搅拌反应2~3h,制备得3-氨基苯硼酸功能化的氧化石墨烯(GB);
其中,氧化石墨烯的浓度为0.5~1.5mg/mL;氧化石墨烯与3-氨基苯基硼酸(PBA)的质量比为1:1~1:3;
B2在B1得到的混合物中加入抗坏血酸钠,将温度提高到80~90℃并不断搅拌,持续1~2h;
其中,氧化石墨烯与抗坏血酸钠的质量比为1:1.5~1:2;
B3反应后B2溶液转移到离心管中,在10000~12000rpm/min转速下离心15~30min,水洗后进行冻干处理,得到B;
步骤C
C1将多巴胺盐酸盐溶解于三羟甲基氨基甲烷盐酸盐缓冲溶液(pH=8.5)中配制成溶液;
其中,多巴胺的浓度为20~50mg/mL;
C2将C1所得溶液剧烈搅拌15~20min,使DA进行初步的预聚合,得到物质C;
步骤D
D1将物质C加入到去离子水中,得到敷料溶剂;每2.5~4mL去离子水加入100~400μL物质C;
D2将物质A、物质B和丙烯酰胺(AM)加入到敷料溶剂中搅拌,得到混合液;
其中,每2.5~4mL敷料溶剂加入200~800mg物质A、2~10mg的物质B、1~1.5g丙烯酰胺(AM);
D3将N,N-亚甲基双丙烯酰胺(MBA)、过硫酸铵(APS)、N,N,N,N-四甲基二胺(TMEDA)加入到混合液中,搅拌后倒入聚四氟乙烯模具中,20~30℃下反应100~400s,得到多功能抗菌水凝胶敷料;
每2.5~4mL混合液中加入0.6~1.2mg N,N-亚甲基双丙烯酰胺,100~150mg过硫酸铵,2~3μL N,N,N,N-四甲基二胺。
3.如权利要求2所述的多功能抗菌水凝胶敷料的制备方法,其特征为步骤B中所述的剧烈搅拌的转数为1000~1300rpm/min;步骤c中所述的剧烈搅拌为800~1000rpm/min。
4.如权利要求1所述的方法制备的多功能抗菌水凝胶敷料的应用,其特征为用于医疗抗菌敷料。
5.如权利要求1所述的方法制备的多功能抗菌水凝胶敷料的应用,其特征为具体用于伤口愈合过程创伤愈合敷料、抗菌敷料、医用胶黏剂、医用手术缝合线和人工组织皮肤。
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