CN115501382A - 一种缓释型水凝胶创伤敷料及其制备方法 - Google Patents
一种缓释型水凝胶创伤敷料及其制备方法 Download PDFInfo
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- CN115501382A CN115501382A CN202110695838.7A CN202110695838A CN115501382A CN 115501382 A CN115501382 A CN 115501382A CN 202110695838 A CN202110695838 A CN 202110695838A CN 115501382 A CN115501382 A CN 115501382A
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Abstract
本发明涉及一种缓释型水凝胶创伤敷料及其制备方法,所述缓释型水凝胶创伤敷料包括水凝胶、埃洛石纳米管、相变材料、药物和光热转化材料,其中,所述光热转化材料为有机光敏剂或者二维光热转化材料。缓释型水凝胶具有优良生物相容性,为伤口的愈合提供了湿润的环境,水凝胶中的药物从水凝胶中释放出来,减缓伤口愈合时期的炎症反应,避免伤口愈合时期的细菌感染,从而加速伤口愈合。
Description
技术领域
本发明属于生物材料领域,具体涉及一种缓释型水凝胶创伤敷料及其制备方法。
背景技术
皮肤是人体最大的器官,是人体的第一道防线。正常情况下,病原菌无法入侵皮肤引起疾病,也不会刺激机体的免疫系统。然而在外界作用下皮肤很容易受伤或由于疾病等造成皮肤缺损。其中伤口感染和皮肤创伤表明组织有一种或多种微生物感染能触发机体的免疫系统,引起炎症反应、组织损伤,从而减缓机体的修复过程。
为了促进伤口愈合和提高其伤口的抗感染能力,目前一般采用敷料覆盖伤口,来提供有利于伤口愈合的环境。在较长时间内,最普遍的外科创伤敷料是医用脱脂棉和纱布,但是其缺点十分显著。例如在使用过程中,无法保持创面的湿润,从而使得创伤愈合延迟。其次辅料纤维易脱落,容易造成异物反应,影响愈合。虽然当前不少研究者开发了新的创伤敷料,比如静电纺丝纤维膜用于创伤修复。同样,静电纺丝纤维也可以负载促进伤口愈合的药物,进行按需释放药物,但是其和医用脱脂棉一样,无法为伤口提供一个湿润的微环境。因此继续研究开发一种新型缓释型水凝胶能够按需控制释放,促进伤口愈合。
水凝胶体创伤敷料可以负载促进伤口愈合和抗感染的药物,并且提供水化环境,保持伤口湿润,促进坏死组织的溶解,提供有效的伤口清创。并且它无黏附易清除,可根据伤口大小来指定适应性的创伤敷料。
相变材料(PCMs)是一种新的热敏材料,其可以根据不同温度实现可逆的固液相转变。
埃洛石纳米管是一种一维天然的铝硅酸盐类粘土矿物,它的外径大约为50-60nm,内径为12-25nm,长度为600-700nm。它的产量可达上千吨,通过细胞培养和动物实验证明具有良好的生物相容性。
现有技术中,大多数水凝胶敷料无法进行可控的药物释放。通常是在水凝胶中简单的混合一些药物或者通过埃洛石纳米管进行简单载药,然后贴敷在伤口处,使药物扩散到伤口处。这些方法无法十分精确的控制药物释放的时间。因此为了加速伤口的愈合,新型水凝胶创伤敷料还待开发,可控持续释放药物的能力还需提高。
发明内容
本发明的目的之一是为解决现有大多数水凝胶敷料无法进行可控的药物释放的问题,通过提供一种缓释型水凝胶创伤敷料,实现在近红外光控制下的药物持续可控释放。
为了实现上述目的,本发明是通过以下技术方案实现的:
一种缓释型水凝胶创伤敷料,包括水凝胶、埃洛石纳米管、相变材料、药物和光热转化材料,其中,所述光热转化材料为有机光敏剂或者二维光热转化材料。所述水凝胶为生物相容性好的水凝胶。
上述技术方案中,以所述水凝胶的重量为100份计,包括埃洛石纳米管15~35份,优选为20~30份;包括相变材料150~800份的,优选为156~625份;药物包括100~800份,优选为40~600份;包括光热转化材料0.5~3.5份的,优选为0.75~1份。
上述技术方案中,所述埃洛石纳米管为3-氨丙基三乙氧基硅烷改性的埃洛石纳米管;所述相变材料和光热转化材料的质量和与所述埃洛石纳米管的比例为(4~8):1,优选为201:32。所述比例可以更好的实现近红外光照射下药物的释放。
上述技术方案中,所述相变材料和光热转化材料的质量之比为(180~220):1;优选为200:1。此比例在近红外光照射下,光热转化材料吸收的光能转化成的热能完全可以实现相变材料的固液转变。
上述技术方案中,所述相变材料包括月桂酸和硬脂酸,优选为月桂酸和硬脂酸的混合,混合比例为(3~5)∶1,进一步优选为4:1。上述优选比例的相变材料可实现在39℃下的固液转变,此温度和人体温度相似,不会对人体产生其它副作用。
上述技术方案中,所述有机光敏剂为吲哚菁绿、普鲁士蓝中的至少一种,优选为吲哚菁绿。吲哚菁绿是美国食品药物管理局(FDA)批准应用于临床的一种有机光敏试剂,并且其是一种性能优良的组织穿透剂,可以有效的将光能转化为热能,从而实现光热转化的功能。
上述技术方案中,所述二维光热转化材料为黑磷、石墨烯、氧化石墨烯和MXene材料中的至少一种,优选为黑磷。黑磷具有良好的光吸收和光热转化效率,生物相容性好,且其降解产物是对人体有益的磷酸根,无长期生物毒性。
上述技术方案中,所述药物为抗菌药物、消炎药或者止疼药。优选地,所述药物包括但不限于青霉素类药物、头孢类药物、四环素类药物、氯霉素类药物、大环酯类药物、林可霉素类、硝基咪唑类、抗菌多肽类药物、阿司匹林、对乙酰氨基苯、吲哚美锌、萘普生、双氯芬酸、布洛芬等消炎止痛类药物。
上述技术方案中,所述缓释型水凝胶创伤敷料在近红外光热条件下,实现药物的释放。
本发明的目的之二是为解决缓释型水凝胶创伤敷料释放过快且无法控制释放时间的问题,提供一种缓释型水凝胶创伤敷料的制备方法。
为了实现上述目的,本发明是通过以下技术方案实现的:
一种缓释型水凝胶创伤敷料的制备方法:先分散埃洛石纳米管,后加入药物,再加入溶解好的光热转化材料,清洗、重悬、离心得到负载药物的埃洛石纳米管,最后将负载药物的埃洛石纳米管与水凝胶前驱液进行混合
优选地,上述制备方法包括如下步骤:
(1)埃洛石纳米管的改性:将3-氨丙基三乙氧基硅烷(APTES)溶解于甲苯中,加入埃洛石粉末,超声分散20~30min。将上述悬浮液在110~130℃恒定搅拌下回流20~22h。将生成的混合物用甲苯洗涤5~8次以除去多余的有机硅烷,然后在110~130℃下烘干一夜以进一步固化。然后用去离子水洗涤混合物5~6次,然后将样品冷冻干燥一夜(这些步骤如有不同请直接修改)。
(2)将月桂酸(LA)和硬脂酸(SA)按照一定比例共同升温融化后混合,或者在溶剂中进行溶解后混合制得相变材料(PCM),其中,所述溶剂优选为二氯甲烷和甲醇的混合溶剂,混合比例进一步优选为4:1。
(3)取上述经过改性的埃洛石纳米管与PCM溶解到二甲基亚砜(DMSO)溶液中,将装有上述溶液的烧瓶进行超声15~25min。
(4)进一步,往上述超声完成后的烧杯内,再加入药物,进行超声25~35min,且在超声过程中,维持温度在25℃~30℃。
(5)进一步,将光敏剂或者光热转化材料加入到二甲基亚砜(DMSO)溶液中溶解。然后将溶解好的ICG溶液加入到上述超声好的烧瓶中,继续进行超声5~8min,温度控制在25~30℃。
(6)将上述溶解好的溶液,使用抽真空机进行抽真空10~20min,然后打开烧杯上方的活塞,进行放气5~10min,上述操作重复进行3~8次。
(7)将水凝胶前驱液水溶液和负载包覆药物的埃洛石纳米管搅拌,使其混合均匀。进而在添加离子交联剂或在紫外光照射下,发生交联反应,形成水凝胶创伤敷料。对于海藻酸盐类的水凝胶交联剂主要是离子交联剂,比如氯化钙等,甲基丙烯酰胺改性的水凝胶主要采用紫外可见光进行光照射下的交联,紫外光采用405nm下的光源进行照射。
与现有技术相比,本发明具有如下有益效果:
通过光热触发,实现负载药物的埃洛石纳米管负载药物的能力。埃洛石纳米管内部加载了相变材料(PCM)、药物和有机光敏剂或者二维光热转化材料,并且PCM同时包裹了药物和有机光敏剂或者二维光热转化材料。在近红外光照射下,有机光敏剂或者二维光热转化材料进行把光能转化为热能,使得埃洛石纳米管内部温度升高。PCM发生固-液转变,因此药物可以扩散出来,从而实现在近红外下,埃洛石纳米管对药物的可控释放。缓释型水凝胶具有优良生物相容性,为伤口的愈合提供了湿润的环境,水凝胶中的药物从水凝胶中释放出来,减缓伤口愈合时期的炎症反应,避免伤口愈合时期的细菌感染,从而加速伤口愈合。
附图说明
图1为实施例1不同含量埃洛石纳米管-PCM/吲哚菁绿-利福平的海藻酸钠水凝胶的温升曲线。
图2为实施例1不同含量埃洛石纳米管-PCM/吲哚菁绿-利福平的水凝胶在NIR光照下温度的变化(0,2,4min)统计图。
图3为负载埃洛石纳米管-PCM/吲哚菁绿-利福平的水凝胶与L929细胞共培养1,3,5,7天,对比不照射NIR和照射NIR的细胞增殖O.D.值统计图。
图4为实施案例1利福平药物在近红外光照射(+)下和不进行近红外光照射(-)下,药物释放曲线图。
图5为对比例1药物释放曲线图。
图6为实施例1埃洛石纳米管-PCM/吲哚菁绿-利福平的水凝胶制备示意图。
具体实施方式
下面结合具体实施例对本发明进行具体的描述,有必要在此指出的是以下实施例只用于对本发明的进一步说明,不能理解为对本发明保护范围的限制,本领域技术人员根据本发明内容对本发明做出的一些非本质的改进和调整仍属本发明的保护范围。
所用原料来源:
埃洛石纳米管(广州润沃材料科技有限公司),吲哚菁绿(安耐吉化学技有限公司),硬脂酸(Sigma),月桂酸(Sigma),硅烷偶联剂KH-550(Alfa Aesar),其他常规试剂均为市售。
以下实施例中所用的均为质量份。
实施例1
将质量比为4:1的月桂酸(LA)和硬脂酸(SA)简单物理混合制得相变材料(PCM)。
取240mg经过改性的埃洛石纳米管与1500mg的PCM溶解到5mL的二甲基亚砜(DMSO)溶液中,将装有上述溶液的烧瓶进行超声20min。
进一步,往上述超声完成后的烧杯内,再加入600mg的利福平(RFP),进行超声30min,且在超声过程中,维持温度在25℃~30℃。
进一步,将7.5mg的吲哚菁绿(ICG)加入到1mL的二甲基亚砜(DMSO)溶液中溶解,此过程中注意使用锡箔纸将装有ICG溶液的小烧杯包覆,避免ICG见光。然后将溶解好的ICG溶液加入到上述超声好的烧瓶中,加入后再次用锡箔纸进行包覆,继续进行超声5min,温度控制在25~30℃。
将上述溶解好的溶液,使用抽真空机进行抽真空15min,然后打开烧杯上方的活塞,进行放气5min,上述操作重复进行3次。
进一步,将抽放气之后的溶液导入离心管中,进行均分后每个离心管中的溶液为1mL/管,然后往离心管中加入6mL的DMSO溶剂。用1000μL移液枪反复进行吹打清洗,将吹打后的溶液用离心机进行离心,离心后将上层溶液去除,此过程离心操作重复两次,离心机的温度设置在25℃,转速4000rpm,离心5min。
最后在使用去离子水进行清洗,使用1000μL移液枪将上述溶液反复进行吹打,然后用离心机进行离心,去除上层液体,离心机的温度设置在10℃,转速4000rpm,离心3分钟。将上述操作反复重复多次,直到上层液体清澈,无污浊现象。
配置20mg/mL海藻酸盐水溶液,搅拌3h,使其溶液呈现透明均匀的形式;同时配置5mg/mL的氯化钙溶液。
取200mg的负载相变材料包覆吲哚菁绿和利福平的埃洛石纳米管加入到40mL上述配置好的20mg/mL的海藻酸盐水溶液,使用磁力搅拌器讲上述溶液搅拌10~15min。
往上述搅拌均匀的溶液中迅速加入40mL的5mg/mL的氯化钙溶液,放入摇床上进行摇匀,使其交联1h。
进一步,将交联好的水凝胶创伤敷料用清水清洗3次,清洗的总时长不超过10min。
实施例2
将质量比为4:1的月桂酸(LA)和硬脂酸(SA)简单物理混合制得相变材料(PCM)。
取240mg经过改性的埃洛石纳米管与1500mg的PCM溶解到5mL的二甲基亚砜(DMSO)溶液中,将装有上述溶液的烧瓶进行超声20min。
进一步,往上述超声完成后的烧杯内,再加入600mg的抗生素甲硝唑(MAN),进行超声30min,且在超声过程中,维持温度在25℃~30℃。
进一步,将7.5mg的吲哚菁绿(ICG)加入到1mL的二甲基亚砜(DMSO)溶液中溶解,此过程中注意使用锡箔纸将装有ICG溶液的小烧杯包覆,避免ICG见光。然后将溶解好的ICG溶液加入到上述超声好的烧瓶中,加入后再次用锡箔纸进行包覆,继续进行超声5min,温度控制在25~30℃。
将上述溶解好的溶液,使用抽真空机进行抽真空15min,然后打开烧杯上方的活塞,进行放气5min,上述操作重复进行3次。
进一步,将抽放气之后的溶液导入离心管中,进行均分后每个离心管中的溶液为1mL/管,然后往离心管中加入6mL的DMSO溶剂。用1000μL移液枪反复进行吹打清洗,将吹打后的溶液用离心机进行离心,离心后将上层溶液去除,此过程离心操作重复两次,离心机的温度设置在25℃,转速4000rpm,离心5min。
最后在使用去离子水进行清洗,使用1000μL移液枪将上述溶液反复进行吹打,然后用离心机进行离心,去除上层液体,离心机的温度设置在10℃,转速4000rpm,离心3分钟。将上述操作反复重复多次,直到上层液体清澈,无污浊现象。
配置20mg/mL海藻酸盐水溶液,搅拌3h,使其溶液呈现透明均匀的形式;同时配置5mg/mL的氯化钙溶液。
取200mg的负载相变材料包覆吲哚菁绿和抗生素甲硝唑的埃洛石纳米管加入到40mL上述配置好的20mg/mL的海藻酸盐水溶液,使用磁力搅拌器讲上述溶液搅拌10~15min。
往上述搅拌均匀的溶液中迅速加入40mL的5mg/mL的氯化钙溶液,放入摇床上进行摇匀,使其交联1h。
进一步,将交联好的水凝胶创伤敷料用清水清洗3次,清洗的总时长不超过10min。
实施例3
将质量比为4:1的月桂酸(LA)和硬脂酸(SA)简单物理混合制得相变材料(PCM)。
取240mg经过改性的埃洛石纳米管与1500mg的PCM溶解到5mL的二甲基亚砜(DMSO)溶液中,将装有上述溶液的烧瓶进行超声20min。
进一步,往上述超声完成后的烧杯内,再加入600mg的利福平(RFP),进行超声30min,且在超声过程中,维持温度在25℃~30℃。
进一步,将7.5mg的吲哚菁绿(ICG)加入到1mL的二甲基亚砜(DMSO)溶液中溶解,此过程中注意使用锡箔纸将装有ICG溶液的小烧杯包覆,避免ICG见光。然后将溶解好的ICG溶液加入到上述超声好的烧瓶中,加入后再次用锡箔纸进行包覆,继续进行超声5min,温度控制在25~30℃。
将上述溶解好的溶液,使用抽真空机进行抽真空15min,然后打开烧杯上方的活塞,进行放气5min,上述操作重复进行3次。
进一步,将抽放气之后的溶液导入离心管中,进行均分后每个离心管中的溶液为1mL/管,然后往离心管中加入6mL的DMSO溶剂。用1000μL移液枪反复进行吹打清洗,将吹打后的溶液用离心机进行离心,离心后将上层溶液去除,此过程离心操作重复两次,离心机的温度设置在25℃,转速4000rpm,离心5min。
最后在使用去离子水进行清洗,使用1000μL移液枪将上述溶液反复进行吹打,然后用离心机进行离心,去除上层液体,离心机的温度设置在10℃,转速4000rpm,离心3分钟。将上述操作反复重复多次,直到上层液体清澈,无污浊现象。
取200mg的负载相变材料包覆吲哚菁绿和利福平的埃洛石纳米管加入到40mL配置好的20mg/mL的甲基丙烯酰胺化明胶前驱体溶液中,使用磁力搅拌器讲上述溶液搅拌10~15min。
用紫外可见光照射10s左右将上述甲基丙烯酰胺化明胶交联固化。
进一步,将交联好的水凝胶创伤敷料用清水清洗3次,清洗的总时长不超过10min。
本发明实施例1的缓释型水凝胶创伤敷料与L929细胞共培养1,3,5,7天,对比不照射NIR和照射NIR的细胞增殖O.D.值统计图(附图3)在进行(+)和不进行(-)近红外光照射,对细胞的活性影响不大,也就是说进行近红外光照射,不会对组织周围细胞造成损害。
图4为实施案例1利福平药物在近红外光照射(+)下和不进行近红外光照射(-)下,药物释放曲线图。图4可以看出在不进行近红外照射下,在埃洛石纳米管中PCM包裹的药物基本上不释放,然而进行近红外光照射,PCM发生固液转变,使得药物很快释放出来。图中是进行了3次近红外光照射,可以看出进行了3次照射,药物释放了7.36μg/mL,而未进行照射的药物仅仅释放了1.5μg/mL左右。最终得出,在未进行近红外光照射下,药物缓慢释放,在进行近红外光照射期间,药物要比未进行近红外光照射下释放的快。在近红外光关闭下,药物释放速度迅速下降。
图6为实施例1埃洛石纳米管-PCM/吲哚菁绿-利福平的水凝胶制备示意图。其中,海藻酸钠水凝胶通过钙离子进行交联,形成水凝胶。水凝胶里面分散了负载PCM和利福平药物的埃洛石纳米管。
对比例1
一种可注射的原位形成水凝胶,将醛基改性的透明质酸和羧甲基改性的壳聚糖通过席夫碱基反应迅速形成水凝胶,在预凝胶中加入阿霉素(DOX)和吉他西滨(GEM)。用于局部控制GEM和DOX,用来防止局部癌症的复发。醛基透明质酸和羧甲基壳聚糖混合后,可迅速形成水凝胶,其中阿霉素和水凝凝胶材料发生偶联,而吉西他滨简单物理混合在水凝胶中。通过图4可以看出,GEM在三天内完全从凝胶中释放出来。在此过程中,负载吉他西滨和阿霉素的水凝胶形状没有改变,表明药物释放的扩散机制。相比之下,DOX在14天内缓慢释放,仅释放3.8%。与加载的GEM不同,DOX的释放必须通过水凝胶中化学键的断裂来触发。可以看出此方法得到的载药水凝胶,药物释放速度快,且释放机理是通过简单的扩散来实现的,无法实现可控释放。
此方法和本发明实施例相比,是基于单纯的扩散机制和化学键的断裂来触发药物释放的,而本发明是通过在近红外光照射下,使得PCM由固态转变成液态,使得负载的药物可以迅速释放,从而达到药物可控的快速释放。药物释放的快慢可以通过外部的近红外光来调控。
以上所述的实施例只是本发明的一种较佳方案,并非对本发明作任何形式上的限制,在不超出权利要求所记载的技术方案的前提下还有其它的变体及改型。
Claims (10)
1.一种缓释型水凝胶创伤敷料,包括水凝胶、埃洛石纳米管、相变材料、药物和光热转化材料,其中,所述光热转化材料为有机光敏剂或者二维光热转化材料。
2.根据权利要求1所述的创伤敷料,其特征在于:以所述水凝胶的重量为100份计,包括埃洛石纳米管15~35份,优选为20~30份;包括相变材料150~800份的,优选为156~625份;药物包括100~800份,优选为40~600份;包括光热转化材料0.5~3.5份的,优选为0.75~1份。
3.根据权利要求1或2所述的创伤敷料,其特征在于:所述埃洛石纳米管为3-氨丙基三乙氧基硅烷改性的埃洛石纳米管;所述相变材料和光热转化材料的质量和与所述埃洛石纳米管的比例为(4~8):1,优选为201:32;和/或,
所述相变材料和光热转化材料的质量之比为(180~220):1;优选为200:1。
4.根据权利要求1或2所述的创伤敷料,其特征在于:所述相变材料包括月桂酸和硬脂酸,优选为月桂酸和硬脂酸的混合,混合比例为(3~5):1,优选为4:1。
5.根据权利要求1或2所述的创伤敷料,其特征在于:所述有机光敏剂为吲哚菁绿、普鲁士蓝中的至少一种,优选为吲哚菁绿;和/或,
所述二维光热转化材料为黑磷、石墨烯、氧化石墨烯和MXene材料中的至少一种,优选为黑磷。
6.根据权利要求1或2所述的创伤敷料,其特征在于:所述水凝胶为海藻酸钠水凝胶及其衍生物的均聚物和共聚物水凝胶、明胶及衍生物的均聚物和共聚物水凝胶、透明质酸水凝胶及其衍生物的均聚物和共聚物水凝胶、壳聚糖水凝胶及其衍生物的均聚物和共聚物水凝胶、聚丙烯酰胺水凝胶及其衍生物的均聚物和共聚物水凝胶、聚乙烯醇水凝胶及其衍生物的均聚物和共聚物水凝胶,葡聚糖水凝胶、丝素蛋白水凝胶、聚乙二醇水凝胶、多肽水凝胶以及目前其它常见的生物相容性好的水凝胶中的至少一种。
7.根据权利要求1或2所述的创伤敷料,其特征在于:所述药物为抗菌药物、消炎药或者止疼药。
8.根据权利要求1或2所述的创伤敷料,其特征在于:所述缓释型水凝胶创伤敷料在近红外光热条件下,实现药物的释放。
9.一种根据权利要求1~8之任一项所述的缓释型水凝胶创伤敷料的制备方法:先分散埃洛石纳米管和相变材料(PCM),后加入药物,再加入分散好的光热转化材料,利用真空泵的负压将相变材料,药物和光热转化材料负载到埃洛石纳米管中,最后进行清洗、重悬、离心得到负载药物的埃洛石纳米管,最后将负载药物的埃洛石纳米管与水凝胶前驱液进行混合;其中,所述光热转化材料为二维光热转化材料时,将其按上述方式加入或者直接将其加入到水凝胶前驱液中。
10.根据权利要求9所述的方法,其特征在于:所述反应在超声中进行,反应温度为25℃~30℃;所述混合在添加离子交联剂或在紫外光照射下,发生交联;所述负载药物的埃洛石纳米管与水凝胶前驱液的混合比例为(3~6):1,优选为4:1。
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