CN115124738B - 一种双层仿生载药水凝胶及其制备与应用 - Google Patents
一种双层仿生载药水凝胶及其制备与应用 Download PDFInfo
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Abstract
本发明公开了一种双层仿生载药水凝胶及其制备与应用，该水凝胶包含：外层水凝胶与内层水凝胶；所述的外层水凝胶为，聚乙烯醇水溶液经定向冷冻形成聚乙烯醇水凝胶，并在0.5～1.5mol/L硫酸钠溶液浸泡，在浸泡结束后去除盐离子而获得的；所述的内层水凝胶由以下组分制得：负载药物、聚乙烯醇、壳聚糖、京尼平、水和pH调节剂；所述的外层水凝胶与内层水凝胶分别具有强韧性和柔软粘弹性这两种截然不同的力学性能。本发明解决了现有水凝胶伤口敷料的拉伸强度和韧性普遍较弱，在应用于伤口修复时不耐摩擦、拉伸、挤压等力学损伤的问题。本发明的水凝胶可用于开放性战创伤深度感染创面，具有保护、抗炎、止血、修复和抗耐药菌等功效。
Description
技术领域
本发明属于医用材料领域，具体涉及一种双层仿生载药水凝胶及其制备与应用。
背景技术
目前应用于伤口护理的伤口敷料主要包括传统伤口敷料和现代伤口敷料，其中传统伤口敷料通常用于干燥、干净的伤口，例如纱布、绷带等，但传统伤口敷料无法将致病菌阻隔在伤口外面从而导致伤口感染，同时在用传统伤口敷料护理伤口时纱布或绷带等会与伤口粘连，在换药时给病人带来痛苦和二次损伤。与传统伤口敷料相比，现代伤口敷料具有创面润湿性、气体交换、渗出物吸收、不粘连创面、促进自溶创面清创等优点。其中，水凝胶伤口敷料由于具有良好的生物相容性、较好的吸水性和保湿性以及良好的透气性等优点，成为了现代伤口敷料的研究重点。
水凝胶伤口敷料经过多年的研究发展，各研究人员根据不同的伤口类型研发了不同种类的水凝胶伤口敷料，这些伤口敷料具有创面润湿性、气体交换、渗出物吸收、不粘连创面、抗菌性等优点，但这些水凝胶伤口敷料的拉伸强度和韧性普遍较弱，在应用于伤口修复时不耐摩擦、拉伸、挤压等力学损伤，容易被破坏，失去保护和修复创伤部位的效果。抗菌性作为伤口敷料的一个重要性能指标，其抗菌效果的好坏对于伤口敷料极为重要，目前水凝胶伤口敷料的抗菌性主要是通过材料本身具有抗菌性或负载具有抗菌性药物来实现的，而材料本身的抗菌性较弱对于强感染性耐药的致病菌杀灭能力较弱，不能起到理想的抗感染作用。
聚乙烯醇(PVA)是通过醋酸乙烯水解得到的高分子聚合物，它具有良好的水溶性、无毒、无刺激、生物相容性好等优点，同时还可以通过反复冻融、辐射、化学交联方式进行交联，因此被广泛应用于生物医学领域。目前，利用定向冷冻和Hofmeister效应的协同作用可以制备具有超高力学强度且力学强度可在较大范围内调控的聚乙烯醇(PVA)水凝胶。但目前还尚未出现用于皮肤伤口敷料的此类水凝胶，这是因为通过这种方式制备的水凝胶结构致密均匀，如果在制备的同时加入其他成分或是负载药物或活性因子，则其力学性能会受到严重影响，而PVA本身也不具备抗菌抗炎能力。
壳聚糖是通过甲壳素脱乙酰基后的一种碱性氨基多糖，它具有杀菌、止血、促进细胞增殖以及生物相容性高等优点，因此被广泛应用于伤口敷料领域。京尼平是由杜仲或栀子中的栀子苷经β-葡萄糖苷酶水解后的产物，其分子中含有大量的羟基、羧基等活性基团，极易与含自由氨基的化合物(如壳聚糖、明胶等)反应，因此常被用作交联剂，作为天然的交联剂其毒性比常用的化学交联剂戊二醛低10000倍，同时京尼平还具有抗炎、抗氧化的作用。然而作为水凝胶其力学性能较低，难以抵抗较大外力的冲击或摩擦，作为敷料使用时易破损而失去作用。此外，壳聚糖水凝胶成胶后很难再与其他水凝胶或材料牢固结合在一起，粘附能力很低。
发明内容
本发明的目的是提供一种双层仿生载药水凝胶及其制备与应用，解决了现有水凝胶伤口敷料的拉伸强度和韧性普遍较弱，在应用于伤口修复时不耐摩擦、拉伸、挤压等力学损伤的问题。本发明的水凝胶可用于开放性战创伤深度感染创面，具有保护、抗炎、止血、修复和抗耐药菌等功效。
为了达到上述目的，本发明提供了一种双层仿生载药水凝胶，该水凝胶包含：外层水凝胶与内层水凝胶；
所述的外层水凝胶为，聚乙烯醇水溶液经定向冷冻形成聚乙烯醇水凝胶，并在0.5～1.5mol/L硫酸钠溶液浸泡(1.5mol/L硫酸钠是饱和浓度)，在浸泡结束后去除盐离子而获得的；
所述的内层水凝胶由以下组分制得：负载药物、聚乙烯醇、壳聚糖、京尼平、水和pH调节剂；
所述的外层水凝胶与内层水凝胶通过物理交联形成分子间的氢键及微晶从而无缝结合；内层与外层的结构及力学性能的迥异(外层强韧而内层软弹)。
所述的负载药物为抗菌药物；
所述的内层水凝胶为双网络结构，该双网络结构包括第一网络和第二网络；所述第一网络为聚乙烯醇通过反复冻融的方式形成的三维网络结构，该网络结构是由PVA分子链间的氢键、微晶和不同结合态的水在不同尺度上组合而成；
所述第二网络为京尼平与壳聚糖经分子化学交联作用形成。
优选地，所述的外层水凝胶中聚乙烯醇水溶液的质量分数为5％～10％。
更优选地，所述的外层水凝胶中聚乙烯醇水溶液的质量分数为5％。外层水凝胶中的PVA的浓度越高其力学性能越强，但要控制其力学性能在皮肤-肌腱的仿生力学区间。从仿生角度考虑，浓度越低，含水量越高越近似生理组织，因此浓度为5％的是最佳的选择。
优选地，所述的内层水凝胶中聚乙烯醇、壳聚糖和京尼平的质量分数分别为5％～10％、2～4％、0.01％～0.05％。内层水凝胶中聚乙烯醇、壳聚糖和京尼平的质量分数分别为5％～10％、2～4％、0.01％～0.05％制备的水凝胶具有很好的生物相容性。
优选地，所述的pH调节剂为弱酸，壳聚糖只有在弱酸环境下才溶解，冰醋酸的作用是溶解壳聚糖，冰醋酸的浓度为1％，且冰醋酸对其生物相容性无影响。
优选地，所述的抗菌药物为万古霉素。负载药物并不改性交联以及不发生特性变化处理，故抗菌药物体现的是自身的抗菌性能。
本发明提供了一种所述的双层仿生载药水凝胶的制备方法，该方法包含：
外层水凝胶的制备方法：聚乙烯醇水溶液经定向冷冻形成聚乙烯醇水凝胶，并在硫酸钠溶液浸泡，在浸泡结束后去除盐离子得到外层聚乙烯醇水凝胶；
内层水凝胶前驱液的制备方法：取壳聚糖，加入水搅拌均匀，加入冰乙酸并搅拌至壳聚糖溶解，加入聚乙烯醇加热搅拌溶解，得到聚乙烯醇/壳聚糖混合溶液；
向制得的聚乙烯醇/壳聚糖混合溶液中加入万古霉素水溶液搅拌，再加入京尼平水溶液并避光搅拌，得到内层溶液；
然后将制备的外层水凝胶置于模具中，再向模具中加入内层溶液，在无菌且避光下冻融若干次，得到双层仿生载药水凝胶。
优选地，所述的壳聚糖、聚乙烯醇均通过紫外照射灭菌，水通过高温高压灭菌锅进行灭菌。
优选地，所述内层水凝胶前驱液的制备，加入聚乙烯醇加热至90℃搅拌溶解。
本发明提供了一种所述的双层仿生载药水凝胶在医用材料中的应用。
本发明的一种双层仿生载药水凝胶及其制备与应用，解决了现有水凝胶伤口敷料的拉伸强度和韧性普遍较弱，在应用于伤口修复时不耐摩擦、拉伸、挤压等力学损伤的问题，具有以下优点：
1、本发明通过一段时间的反复冻融(物理交联)使外层PVA与内层溶液内的PVA形成牢固的分子链接，内层的PVA通过反复冻融的方式形成的第一网络(三维)结构，同时伴随的京尼平化学交联作用使壳聚糖分子形成第二网络，从而获得了与外层水凝胶牢固结合且力学性能类似皮下组织、具有较好粘附性的内层双网络水凝胶。
2、本发明采用定向冷冻+盐析技术制备外层水凝胶，并通过对盐离子种类和浓度的控制调控外层水凝胶的力学性能，使其与皮肤的力学性能相类似。
3、本发明由于外层水凝胶具有和皮肤相似的力学性能，可以耐受高强度的挤压、拉扯、摩擦，因此可以在保持创面部位干燥、清洁的同时保护皮肤创伤部位免受外部不良刺激。
4、本发明内层水凝胶由于万古霉素等强力抗菌试剂的载入极大的提高了敷料的抗菌性，使其对金黄色葡萄球菌等强致病菌有着强杀灭作用。
5、本发明京尼平在作为交联剂的同时还起到了抗炎、抗氧化的作用，同时壳聚糖水凝胶类似皮下组织的柔软湿润和粘附力使其对创面形成了密闭式的填充，与创面界面紧密结合，从而有效防止再次感染，有利于促进伤口的修复。而内外层之间的紧密结合使得内层不易发生内外层剥离移位，有效的起到了创面保护与再生修复同步进行的作用。
附图说明
图1为本发明双层载药水凝胶的结构示意图。
图2为本发明外层水凝胶的扫描电镜图。其中a为外层水凝凝胶横截面图；b为外层水凝胶纵截面图。
图3为本发明内层水凝胶的扫描电镜图。
图4为本发明双层水凝胶的扫描电镜图。
图5为本发明双层仿生载药水凝胶力学性能图。其中a为外层水凝胶拉伸过程应力-应变曲线图；b为水凝胶杨氏模量与皮肤杨氏模量关系图(大圈区域表示水凝胶的杨氏模量范围)。
图6所示为本发明水凝胶内、外层力学性能图。
图7为本发明内层水凝胶的红外光谱(FTIR)图。
图8为本发明双层水凝胶的细胞毒性评价图。
图9为内层水凝胶抗氧化性能(DPPH)图。
图10为本发明双层水凝胶的抑菌对比图，其中a为大肠杆菌，b为表皮葡萄球菌，c为金黄色葡萄球菌。
图11为本发明双层水凝胶黏附性能图，其中a为手，b为肘关节，c为玻璃，d为塑料。
具体实施方式
下面将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做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
外层聚乙烯醇(PVA)水凝胶的制备方法，该方法包含：
(1)称取5g PVA倒入烧杯中，并向烧杯中加入95mL的UP水，在90℃水浴加热搅拌下充分溶解，冷却并超声消泡，制得质量分数为5％的PVA溶液。
(2)向定向冷冻装置加入液氮，待定向冷冻装置温度恒定时，将装有步骤(1)制得的PVA溶液的模具置于定向冷冻装置上，待PVA溶液完全冻结后从定向冷冻装置上移去模具并进行脱模，将脱模后的PVA水凝胶放入硫酸钠溶液中浸泡72h，随后将PVA水凝胶在UP水中浸泡48h并每4小时更换一次UP水以去除PVA水凝胶中的盐离子，得到外层PVA水凝胶。通过调节PVA浓度和盐析液浓度来调节外层PVA水凝胶的力学性能。
内层水凝胶前驱液的制备方法，该方法包含：
(1)称取2g的壳聚糖倒入烧杯中并向烧杯中加入100mL的UP水，在磁力搅拌器上搅拌均匀后，向烧杯中加入1mL的冰乙酸并继续搅拌至壳聚糖完全溶解，制得壳聚糖溶液。
(2)向步骤(1)制得的壳聚糖溶液加入5g的PVA，并在90℃水浴加热搅拌下至PVA完全溶解，冷却并超声消泡，得到PVA与壳聚糖的质量比为5:2的PVA/壳聚糖混合溶液。
(3)将京尼平溶解在UP水中配制成质量分数为1％的京尼平溶液；将万古霉素溶解在UP水中配制成质量分数为8％的万古霉素溶液。
其中，上述壳聚糖、PVA、烧杯、搅拌子均通过紫外照射灭菌，UP水则通过高温高压灭菌。京尼平浓度超过交联所需浓度，以增强其抗炎作用。
双层仿生载药水凝胶的制备方法，该方法包含：
(1)取内层水凝胶前驱液的步骤(2)中制得的PVA/壳聚糖(聚乙烯醇与壳聚糖的质量比为5:2)溶液加入到灭菌的烧杯中，并加入内层水凝胶前驱液的步骤(3)中制得的万古霉素溶液(每毫升水凝胶中含有8mg万古霉素)，置于磁力搅拌器上搅拌均匀，随后加入内层水凝胶前驱液的步骤(3)中制得的京尼平溶液(每毫升水凝胶中含有0.1mg京尼平)并避光搅拌均匀，得到内层溶液。
(3)将外层聚乙烯醇(PVA)水凝胶的步骤(2)中制备的4ml外层PVA水凝胶去除多余的UP水后置于模具中，并向模具中加入4ml步骤(1)得到内层溶液，将其放置无菌且避光的容器中并反复冻融三次，随后在室温下静置3天，得到双层仿生载药水凝胶。
内层前驱液中的PVA与外层水凝胶中的PVA通过反复冻融形成分子链接，并在内层交联形成第一网络。于此同时，京尼平通过化学交联方式使壳聚糖形成第二网络。通过调节双网络系统交联参数，可以获得柔软湿润、粘附性好、抗炎止血促修复的类似皮下组织的内层水凝胶。而万古霉素的载入极大的提升了水凝胶的抗革兰氏阳性耐药菌感染的能力，适用于战创伤等严重感染创口的护理。
如图1所示，为本发明双层水凝胶的结构示意图。其中A图为双层水凝胶的结构示意图，表明了内外两层具有不同的微孔结构。B图为双层水凝胶的光学照片，表明内外两层水凝胶紧密的结合在一起。
实验例1微观形貌
如图2所示，为本发明外层水凝胶的横截面a和纵剖面b的微观形貌，证明了所制备的外层水凝胶具有定向微孔结构。
如图3所示，内层水凝胶的横截面的扫描电镜图，表明了内层水凝胶具有不规则的多孔结构使其具有较强的吸水性能。
如图4所示，双层水凝胶的横截面和纵截面的扫描电镜图，证实了该双层水凝胶的内外两层紧密的结合在一起，同时也证明了双层水凝胶外层具有定向微孔结构，内层具有不规则的多孔结构，因此双层水凝胶的外层和内层结构上的显著性差异。
实验例2力学性能
用万能力学机测量材料的拉伸性能。
如图5所示，为本发明水凝胶力学性能图。其中图5a为在不同浓度的硫酸钠溶液中盐析4天后去除盐离子的外层水凝胶拉伸过程应力-应变曲线图；图5b为外层水凝胶杨氏模量与皮肤杨氏模量关系图(大圈区域表示水凝胶的杨氏模量范围)。图5a中外层PVA水凝胶的最大拉伸强度为1.544±0.273MPa，最大伸长率为906.3441±53.9486％，并且可以通过调节盐析时盐离子的浓度制备出不同力学性能的水凝胶，因此本发明采用定向冷冻和盐析具有协同作用；图5b中最大杨氏模量为170.3547KPa，可调节范围涵盖了皮肤的杨氏模量，并且含水量在75％左右，与皮肤含水量(71.77％)相当。因此本发明的双层仿生载药水凝胶的外层水凝胶具有和皮肤相似的力学性能，可以耐受高强度的挤压、拉扯、摩擦，因此可以在保持创面部位干燥、清洁的同时保护皮肤创伤部位免受外部不良刺激。
如图6所示，为本发明水凝胶内外层力学性能图。由6可以看出外层水凝胶与内层水凝胶的力学性能区别，结构决定性能，性能反映结构，再次验证了外层和内层结构上的显著性差异，与图4的结果一致。因此由6可以得出外层的定向微孔结构可以显著提高材料的力学性能。
实验例3红外光谱
用红外光谱仪对材料进行全反射扫描。如图7所示，为本发明内层水凝胶的红外光谱。纯PVA水凝胶的红外光谱在3200-3600cm-1处为羟基(-OH)的伸缩振动引起的吸收峰，2937和2917cm-1处分别为烷基(C-H)的不对称和对称伸缩振动引起的吸收峰，1425cm-1处为烷基(C-H)的面内弯曲振动引起的吸收峰，1329cm-1处为羟基(-OH)的面内弯曲振动引起的吸收峰，1092cm-1处为C-O-C伸缩振动引起的吸收峰，848cm-1处为C-C伸缩振动引起的吸收峰。壳聚糖的红外光谱在1634cm-1处为酰胺键的-C＝O的伸展引起的吸收峰，1554cm-1处为酰胺键的-NH的弯曲引起的吸收峰，1408cm-1处为酰胺键的C-N伸展引起的吸收峰，1073cm-1处为壳聚糖的糖基结构，890cm-1处为壳聚糖的吡喃糖环。CS/PVA复合水凝胶的红外光谱表明壳聚糖和聚乙烯醇的特征峰均出现在CS/PVA的复合水凝胶中。京尼平交联后的CS/PVA复合水凝胶的红外光谱与CS/PVA复合水凝胶的红外光谱相比在1634cm-1处为的吸收峰相对变强，这可能是壳聚糖与京尼平发生交联反应后形成了大量的酰胺基，这表明了壳聚糖与京尼平发生了交联反应，同时添加京尼平后的复合水凝胶变成蓝色也证明了京尼平与壳聚糖发生了反应。
实验例4细胞毒性
根据依照ISO 10993-5:1999和GB/T 16886.5-2003标准对不同载药量的水凝胶进行生物相容性评价，其中VCM＝x mg/mL表示每毫升水凝胶中含有多少毫克万古霉素。第一天：VCM＝0mg/mL，VCM＝2mg/mL，VCM＝5mg/mL和VCM＝8mg/mL组的细胞相对增殖率(RGR)分别为90.69％，108.89％，109.31％和107.94％。第三天：VCM＝0mg/mL，VCM＝2mg/mL，VCM＝5mg/mL和VCM＝8mg/mL组的细胞相对增殖率(RGR)分别为74.23％，83.13％，99.27％和95.68％。
如图8所示，为本发明双层仿生载药水凝胶细胞相容性评价图。结合图8结果，根据表1所列评分标准对样品细胞毒性程度进行评价可知：本发明双层仿生载药水凝胶试样评分为1级，无细胞毒性，能作为医用材料。
表1细胞相对增殖度(RGR)评价
其中：
实验例5抗氧化性
如图9所示，采用了DPPH自由基的清除法对水凝胶的抗氧化性能进行评价。由图9结果可见，随着水凝胶的含量增加，其在517nm处的吸收峰也随之减弱，表明对DPPH自由基具有较强的清除效果。
实验例6抑菌性能
如图10所示，采用了抑菌圈法对载万古霉素5mg/ml的水凝胶的抑菌性能进行评价，其中A为大肠杆菌，B为表皮葡萄球菌，C为金黄色葡萄球菌。根据图10结果所示载药水凝胶组对大肠杆菌、表皮葡萄球菌、金黄色葡萄球菌具有较强的抑制效果，而未载药的水凝胶并没有明显的抑制效果。未载药的水凝胶为表现出抑制效果不佳是因为壳聚糖的抗菌效果较弱，因此对较高浓度的细菌并没有明显抑制效果。
实验例7粘附性能
如图11所示，为本发明水凝胶在不同材质物品上黏附效果图，其中A为手，B为肘关节，C为玻璃，D为塑料。由图11可见，水凝胶黏贴在竖直放置的手背、肘关节、塑料以及玻璃上，均不会脱落，粘附性均很好。
尽管本发明的内容已经通过上述优选实施例作了详细介绍，但应当认识到上述的描述不应被认为是对本发明的限制。在本领域技术人员阅读了上述内容后，对于本发明的多种修改和替代都将是显而易见的。因此，本发明的保护范围应由所附的权利要求来限定。
Claims (8)
1.一种双层仿生载药水凝胶，其特征在于，该水凝胶包含：
外层水凝胶与内层水凝胶；
所述的外层水凝胶为，聚乙烯醇水溶液经定向冷冻形成聚乙烯醇水凝胶，并在0.5～1.5mol/L硫酸钠溶液浸泡，在浸泡结束后去除盐离子而获得的；
所述的外层水凝胶中聚乙烯醇水溶液的质量分数为5％～10％；
所述的内层水凝胶由以下组分制得：负载药物、聚乙烯醇、壳聚糖、京尼平、水和pH调节剂；
所述的内层水凝胶中聚乙烯醇、壳聚糖和京尼平的质量分数分别为5％～10％、2～4％、0.01％～0.05％；
所述的外层水凝胶与内层水凝胶通过物理交联形成分子间的氢键及微晶从而无缝结合；
所述的负载药物为抗菌药物；
所述的内层水凝胶为双网络结构，该双网络结构包括第一网络和第二网络；
其中，所述第一网络为聚乙烯醇通过反复冻融的方式形成的三维网络结构，该网络结构是由PVA分子链间的氢键、微晶和不同结合态的水在不同尺度上组合而成；
所述第二网络为京尼平与壳聚糖经分子化学交联作用形成；
所述的双层仿生载药水凝胶由外层水凝胶置于模具中，再向模具中加入内层溶液，在无菌且避光下冻融若干次得到。
2.根据权利要求1所述的双层仿生载药水凝胶，其特征在于，所述的外层水凝胶中聚乙烯醇水溶液的质量分数为5％。
3.根据权利要求1所述的双层仿生载药水凝胶，其特征在于，所述的pH调节剂为弱酸。
4.根据权利要求1所述的双层仿生载药水凝胶，其特征在于，所述的抗菌药物为万古霉素。
5.一种如权利要求1-4中任意一项所述的双层仿生载药水凝胶的制备方法，其特征在于，该方法包含：
外层水凝胶的制备方法：聚乙烯醇水溶液经定向冷冻形成聚乙烯醇水凝胶，并在硫酸钠溶液浸泡，在浸泡结束后去除盐离子得到外层聚乙烯醇水凝胶；
内层水凝胶前驱液的制备方法：取壳聚糖，加入水搅拌均匀，加入冰乙酸并搅拌至壳聚糖溶解，加入聚乙烯醇加热搅拌溶解，得到聚乙烯醇/壳聚糖混合溶液；
向制得的聚乙烯醇/壳聚糖混合溶液中加入万古霉素水溶液搅拌，再加入京尼平水溶液并避光搅拌，得到内层溶液；
然后将制备的外层水凝胶置于模具中，再向模具中加入内层溶液，在无菌且避光下冻融若干次，得到双层仿生载药水凝胶。
6.根据权利要求5所述的双层仿生载药水凝胶的制备方法，其特征在于，所述的壳聚糖、聚乙烯醇均通过紫外照射灭菌，水通过高温高压灭菌锅进行灭菌。
7.根据权利要求5所述的双层仿生载药水凝胶的制备方法，其特征在于，所述内层水凝胶前驱液的制备，加入聚乙烯醇加热至90℃搅拌溶解。
8.一种如权利要求1-4中任意一项所述的双层仿生载药水凝胶在医用材料中的应用。
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