CN113476645A - 一种用于糖尿病创面修复的抗菌水凝胶敷料及其制备方法 - Google Patents

一种用于糖尿病创面修复的抗菌水凝胶敷料及其制备方法 Download PDF

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CN113476645A
CN113476645A CN202110811536.1A CN202110811536A CN113476645A CN 113476645 A CN113476645 A CN 113476645A CN 202110811536 A CN202110811536 A CN 202110811536A CN 113476645 A CN113476645 A CN 113476645A
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calcium chloride
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汤钧
黄婷婷
袁博磊
金冠甬
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Abstract

一种用于糖尿病创面修复的抗菌水凝胶敷料及其制备方法，属于糖尿病创面愈合技术领域。其首先是配置TiO2/Ag3PO4磷酸盐悬浮液，再配置聚丙烯酸(PAA)水溶液、氯化钙水溶液和葡萄糖氧化酶(GOx)水溶液；然后将聚丙烯酸水溶液、氯化钙水溶液、葡萄糖氧化酶水溶液混合，剧烈搅拌下加入TiO2/Ag3PO4磷酸盐悬浮液，得到抗菌水凝胶敷料PAA@TiO2/Ag3PO4@GOx。本发明敷料在生理环境中能响应磷酸根，使Ca2+的逃逸，诱导凝胶降解，释放TiO2/Ag3PO4和GOx，GOx分解创面中的葡萄糖，降低局部血糖浓度。TiO2光照下催化H2O2生成活性氧，协同Ag+杀菌，进而降低创面血糖浓度，维持长效、高抗菌活性、低细胞毒性，促进糖尿病创口愈合。

Description

一种用于糖尿病创面修复的抗菌水凝胶敷料及其制备方法
技术领域
本发明属于糖尿病创面愈合技术领域，具体涉及一种用于糖尿病创面修复的抗菌水凝胶敷料及其制备方法，特别是涉及一种通过库伦相互作用制备的用于糖尿病创面修复且具有磷酸根浓度响应的抗菌水凝胶敷料及其制备方法。
背景技术
伤口愈合受损造成的糖尿病足是糖尿病患者常见的并发症，全球每年都有大量的人因为不愈合的糖尿病创口而截肢甚至死亡，给个人和国家带来了巨大的负担。近年来，伤口感染、高血糖的环境已被证明是影响慢性糖尿病伤口愈合的重要潜在因素。在过去的几十年中，由于无机抗菌系统成本低、广谱、高效抗菌，在后抗生素时代产生了特别重大的影响，已广泛应用于生物学和生物医学中。葡萄糖氧化酶(GOx)可以氧化分解葡萄糖，起到降低创面血糖的作用。然而，纳米粒子的高细胞毒性，短抗菌活性和葡萄糖氧化酶的不稳定性和不可控性限制了它们在的糖尿病创面的应用。因此，急需一种有效且安全的药物传递系统，来保持材料长效抗菌活性和稳定性，调节抗菌药物的毒性。
与传统的扩散控制药物递送系统相比，刺激响应智能水凝胶能够响应各种外源和/或内源性刺激(如pH、热、光、磁等)爆发性释放药物而受到广泛关注。然而一般的刺激响应药物释放体系又存在工艺复杂，原料高毒性和生物相容性差等不足。
综上所述，一种合成方法简单，具有生物相容性和生物可降解性的刺激响应药物释放体系的开发具有十分重大的意义。
发明内容
本发明的目的是提供一种用于糖尿病创面修复的抗菌水凝胶敷料及其制备方法。
本发明通过简单的一锅法，利用聚丙烯酸中羧酸根和钙离子的库仑相互作用形成预交联点，然后钙离子与扩散的磷酸根相互作用生成磷酸钙并诱导聚丙烯酸交联，同时将体系中的二氧化钛/磷酸银纳米粒子(TiO2/Ag3PO4 Nps)和葡萄糖氧化酶物理嵌入磷酸钙交联的聚丙烯酸凝胶网络进行原位装载以形成抗菌水凝胶PAA@TiO2/Ag3PO4@GOx(Gel)。通过该方法制备的水凝胶表现出磷酸盐敏感的刺激响应释放行为，通过凝胶网络交联点处的磷酸钙在不同浓度的磷酸盐缓冲溶液(PBS)中沉淀或溶解，使水凝胶可以根据磷酸盐的浓度改变状态。在常规环境下保持稳定，在生理环境(0.01M PBS)中能够响应磷酸根，促进钙离子的逃逸，提供足够的驱动力诱导水凝胶的逐渐降解，引起TiO2/Ag3PO4(Nps)和葡萄糖氧化酶的缓慢释放，葡萄糖氧化酶可以分解创面中的葡萄糖，降低局部血糖浓度，并产生副产物过氧化氢。二氧化钛组分在光照下催化过氧化氢生成活性氧(ROS)，和磷酸银组分中的银离子协同杀菌。在这种情况下，所获得的抗菌PAA@TiO2/Ag3PO4@GOx水凝胶(Gel)的长效抗菌活性可以显着增加，而细胞毒性略微降低，具有良好的生物相容性和生物降解性。这种独特的设计可降低创面血糖浓度，维持长效，高抗菌活性，低细胞毒性，促进糖尿病创口愈合。
为实现上述目的，本发明所述的一种用于糖尿病创面修复的抗菌水凝胶敷料的制备方法，其步骤如下：
(1)TiO2/Ag3PO4磷酸盐悬浮液的配置
称取TiO2/Ag3PO4纳米粒子(根据文献：J.W.Xu,Z.D.Gao,K.Han,Y.Liu andY.Y.Song,ACS Appl.Mater.Interfaces,2014,6,15122-15131合成)加入到pH＝7.0～7.5、0.1M的磷酸盐缓冲溶液(PBS)中，超声分散l0～20min得到均匀的TiO2/Ag3PO4磷酸盐悬浮液；
(2)聚丙烯酸水溶液的配置
称取聚丙烯酸加入到去离子水中，室温磁力搅拌10～15h，得到均匀的聚丙烯酸水溶液；
(3)氯化钙水溶液的配置
称取氯化钙加入到去离子水中，室温磁力搅拌10～15h，得到均匀的氯化钙水溶液；
(4)葡萄糖氧化酶水溶液的配置
称取葡萄糖氧化酶加入到去离子水中，4℃磁力搅拌1.5～3.0h，得到均匀的葡萄糖氧化酶水溶液；
(5)抗菌水凝胶敷料的制备
将步骤(2)得到的聚丙烯酸水溶液与步骤(3)得到的氯化钙水溶液按体积比1～5：1的比例混合，然后加入步骤(4)得到的葡萄糖氧化酶水溶液(葡萄糖氧化酶水溶液与氯化钙水溶液的体积用量比为0.1～1：1)，再在剧烈搅拌(500～1500rmp)下、在1～20秒内加入步骤(1)得到的TiO2/Ag3PO4磷酸盐悬浮液(TiO2/Ag3PO4磷酸盐悬浮液与氯化钙水溶液的体积用量比为0.1～10：1)，从而得到本发明所述的用于糖尿病创面修复的抗菌水凝胶敷料。
进一步的，聚丙烯酸的分子量为5千～45万。
进一步的，TiO2/Ag3PO4磷酸盐悬浮液的浓度为0.1～10mg/mL，葡萄糖氧化酶水溶液的浓度为0.1～5mg/mL，聚丙烯酸水溶液的浓度为1～50mg/mL，氯化钙水溶液的浓度为1.1～55.5mg/mL。
本发明所述的一种用于糖尿病创面修复的抗菌水凝胶敷料，其是由上述方法制备得到。
附图说明
图1为本发明实施例1制备的抗菌水凝胶敷料的照片；表明该抗菌水凝胶敷料是一种柔软的灰褐色凝胶。
图2为本发明实施例1中无机纳米粒子TiO2/Ag3PO4(Nps)和抗菌水凝胶敷料PAA@TiO2/Ag3PO4@GOx(Gel)对大肠杆菌(E.coli)的抑制效果对比图。
图3为本发明实施例1中无机纳米粒TiO2/Ag3PO4(Nps)和抗菌水凝胶敷料PAA@TiO2/Ag3PO4@GOx(Gel)对金黄色葡萄球菌(S.aureus)的抑制效果对比图。
图4为本发明实施例1中无机纳米粒子TiO2/Ag3PO4(Nps)和抗菌水凝胶敷料PAA@TiO2/Ag3PO4@GOx(Gel)在不同浓度的PBS中的ROS释放曲线。
图5为本发明实施例1中抗菌水凝胶敷料PAA@TiO2/Ag3PO4@GOx(Gel)糖尿病创口愈合率随时间变化曲线。
图6为本发明实施例2制备的抗菌水凝胶敷料的的照片；表明该抗菌水凝胶敷料是一种柔软的灰褐色凝胶。
图7为本发明实施例2中抗菌水凝胶敷料PAA@TiO2/Ag3PO4@GOx(Gel)对大肠杆菌(E.coli)的抑制效果图。
图8为本发明实施例2中抗菌水凝胶敷料PAA@TiO2/Ag3PO4@GOx(Gel)对金黄色葡萄球菌(S.aureus)的抑制效果图。
具体实施方式
以下实施例是对本发明的进一步说明，但本发明并不局限于此。
除有特殊说明外，以下实施例中所用的方法均为常规方法。以下实施例中所用的试剂材料等，均为常规生化试剂。
实施例1.磷酸根浓度响应的抗菌水凝胶敷料的制备
(1)利用分析天平称取0.772g分子量为45万的聚丙烯酸于250mL烧杯中，向烧杯中加100mL去离子水，放入搅拌子，置于磁力搅拌器上室温搅拌12h，得到均匀的聚丙烯酸水溶液。
(2)称取1.1098g氯化钙于250mL烧杯中，向烧杯中加100mL去离子水，放入搅拌子，置于磁力搅拌器上室温搅拌12h，得到均匀的氯化钙水溶液。
(3)称取10mg葡萄糖氧化酶于20mL烧杯中，向烧杯中加10mL去离子水，放入搅拌子，置于磁力搅拌器上4℃搅拌2h，得到均匀的葡萄糖氧化酶水溶液。
(4)称取80mg TiO2/Ag3PO4纳米粒子加入40mL、pH＝7.2、0.1M磷酸盐缓冲溶液中，通过超声细胞破碎仪超声分散10min，获得均匀悬浮液。
(5)先取聚丙烯酸水溶液10mL于100mL烧杯中，再加入10mL氯化钙水溶液和1mL葡萄糖氧化酶水溶液，在剧烈搅拌下(1000rmp)、5秒内注入4mL、TiO2/Ag3PO4磷酸盐悬浮液，得到抗菌水凝胶敷料，如图1。
图2、图3为制备的无机纳米粒子和抗菌水凝胶敷料对大肠杆菌、金色葡萄球菌的抑制效果对比实验。如图所示，在制备的抗菌水凝胶敷料周围出现了明显的抑菌圈，且均抑菌圈直径均大于单独TiO2/Ag3PO4纳米粒子的抑菌圈直径。
图4为制备的无机纳米粒子在0.01M PBS中和抗菌水凝胶敷料在0-0.1M PBS中缓释活性氧的趋势图，利用活性氧的释放评估材料的抗菌活性。如图所示，0.01M PBS中的TiO2/Ag3PO4(Nps，对照组)，在开始光照后一小时内释放出大量ROS，然后逐渐降低，在24小时达到相对低的水平。相反，制备的抗菌水凝胶PAA@TiO2/Ag3PO4@GOx(Gel)中ROS的释放可以通过一系列浓度的PBS触发(0-0.1M)，当PBS浓度为0-0.05M时，ROS的产量可控生长，并在7小时左右达到最大值。然而，当PBS浓度增加至0.1M时，前12小时内几乎没有ROS释放，表明制备的水凝胶的崩解被高磷酸盐浓度抑制，纳米粒子的逸出受到限制，从而达到了持久抑菌的目的。
图5为制备的抗菌水凝胶敷料在促进糖尿病创口愈合的伤口愈合率随时间变化图。由图可知，制备的水凝胶敷料第8天的伤口愈合率可以达到80％以上，可以明显促进糖尿病创口愈合。
实施例2.磷酸根浓度响应的抗菌水凝胶敷料的制备
(1)利用分析天平称取2.166g分子量为25万的聚丙烯酸于250mL烧杯中，向烧杯中加100mL去离子水，放入搅拌子，置于磁力搅拌器上搅拌10h，得到均匀的聚丙烯酸水溶液。
(2)称取1.6647g氯化钙于250mL烧杯中，向烧杯中加100mL去离子水，放入搅拌子，置于磁力搅拌器上搅拌13h，得到均匀的氯化钙水溶液。
(3)称取5mg葡萄糖氧化酶于20mL烧杯中，向烧杯中加10mL去离子水，放入搅拌子，置于磁力搅拌器上4℃搅拌2h，得到均匀的葡萄糖氧化酶水溶液。
(4)称取100mg TiO2/Ag3PO4纳米粒子加入40mL、pH＝7.2、0.1M磷酸盐缓冲溶液中，通过超声细胞破碎仪超声分散10min，获得均匀悬浮液.
(5)先取聚丙烯酸水溶液15mL于100mL烧杯中，再加入10mL氯化钙水溶液和2mL葡萄糖氧化酶水溶液，在剧烈搅拌下(1500rmp)、5秒内注入4mL、TiO2/Ag3PO4磷酸盐悬浮液，得到抗菌水凝胶敷料，如图6。
(6)图7、图8为制备的抗菌水凝胶敷料对大肠杆菌、金色葡萄球菌的抑制效果实验。如图所示，在制备的抗菌水凝胶敷料周围出现了明显的抑菌圈，表明抗菌水凝胶敷料具有较好的抗菌效果。

Claims (5)

1.一种用于糖尿病创面修复的抗菌水凝胶敷料的制备方法，其步骤如下：
(1)TiO2/Ag3PO4磷酸盐悬浮液的配置
称取TiO2/Ag3PO4纳米粒子加入到pH＝7.0～7.5、0.1M的磷酸盐缓冲溶液中，超声分散l0～20min得到均匀的TiO2/Ag3PO4磷酸盐悬浮液；
(2)聚丙烯酸水溶液的配置
称取聚丙烯酸加入到去离子水中，室温磁力搅拌10～15h，得到均匀的聚丙烯酸水溶液；
(3)氯化钙水溶液的配置
称取氯化钙加入到去离子水中，室温磁力搅拌10～15h，得到均匀的氯化钙水溶液；
(4)葡萄糖氧化酶水溶液的配置
称取葡萄糖氧化酶加入到去离子水中，4℃磁力搅拌1.5～3.0h，得到均匀的葡萄糖氧化酶水溶液；
(5)抗菌水凝胶敷料的制备
将步骤(2)得到的聚丙烯酸水溶液与步骤(3)得到的氯化钙水溶液混合，然后加入步骤(4)得到的葡萄糖氧化酶水溶液，再在剧烈搅拌下、在1～20秒内加入步骤(1)得到的TiO2/Ag3PO4磷酸盐悬浮液，得到用于糖尿病创面修复的抗菌水凝胶敷料。
2.如权利要求1所述的一种用于糖尿病创面修复的抗菌水凝胶敷料的制备方法，其特征在于：聚丙烯酸的分子量为5千～45万。
3.如权利要求1所述的一种用于糖尿病创面修复的抗菌水凝胶敷料的制备方法，其特征在于：TiO2/Ag3PO4磷酸盐悬浮液的浓度为0.1～10mg/mL，葡萄糖氧化酶水溶液的浓度为0.1～5mg/mL，聚丙烯酸水溶液的浓度为1～50mg/mL，氯化钙水溶液的浓度为1.1～55.5mg/mL。
4.如权利要求1所述的一种用于糖尿病创面修复的抗菌水凝胶敷料的制备方法，其特征在于：聚丙烯酸水溶液与氯化钙水溶液的用量体积比1～5：1，葡萄糖氧化酶水溶液与氯化钙水溶液的体积用量比为0.1～1：1，TiO2/Ag3PO4磷酸盐悬浮液与氯化钙水溶液的体积用量比为0.1～10：1。
5.一种用于糖尿病创面修复的抗菌水凝胶敷料，其特征在于：是由权利要求1～4任何一项所述的方法制备得到。
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