CN117883629A - 一种复合水凝胶及其制备方法和应用 - Google Patents
一种复合水凝胶及其制备方法和应用 Download PDFInfo
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Abstract
本发明涉及水凝胶敷料技术领域,尤其是涉及一种用于促进创面愈合的复合水凝胶及其制备方法。本发明中,PG10@PDA复合水凝胶、LIN@PG10@PDA载药水凝胶以及LIN@PG10@PDA‑NIR水凝胶均能够提高糖尿病伤口的修复效果,LIN@PG10@PDA‑NIR水凝胶的效果尤其显著,本发明的LIN@PG10@PDA‑NIR水凝胶为通过近红外光热诱导的负载利格列汀药物的智能响应型水凝胶,通过材料学表征表明该水凝胶是具有良好多孔结构和溶胀性能的弹性体,NIR光照有助于水凝胶中药物的阶梯释放;通过细胞及动物实验进一步验证了复合水凝胶材料良好的生物相容性、促进细胞迁移和通过促进VEGF等促血管生成因子表达而促进血管新生和成熟的作用,从而实现促进创面愈合的作用。
Description
技术领域
本发明涉及水凝胶敷料技术领域,尤其是涉及一种复合水凝胶及其制备方法和应用。
背景技术
糖尿病足是指糖尿病患者与下肢远端神经异常和不同程度的周围血管病变相关的足部(踝关节或踝关节以下的部分)感染、溃疡和(或)深层组织破坏,糖尿病足溃疡的发病机制有下肢血管病变、周围神经病变和感染等。糖尿病慢性创面不仅增加公共医疗消耗和患者负担,而且严重影响患者的生活质量和身心健康,有效治疗糖尿病慢性伤口、恢复皮肤组织功能是临床亟待解决的重点和难点。
目前,常见用于伤口治疗的材料包括医用纱布以及由壳聚糖、海藻酸钠、明胶、聚乙二醇等为基质的敷料。其中医用纱布在更换时易损伤肉芽组织,壳聚糖、海藻酸钠、明胶、聚乙二醇等不具备慢性伤口微环境的响应性,因此,开发具有慢性伤口微环境响应性药物释放的新型医用敷料在临床上具有迫切需求。相较于传统敷料,在新型的伤口修复材料中,水凝胶与细胞外基质相似,是一种常用的药物释放载体,能够负载药物、细胞、因子等,与其他敷料相比,水凝胶敷料具有高亲水性和良好的生物相容性,使其可以吸收大量的水分或生物液体,利于药物的载入,为伤口提供理想的潮湿环境,减少组织坏死,加速上皮组织再生,并且使药物可以在黏膜或者体液中保持较为持续的释放,可缩短伤口愈合时间、降低综合治疗成本,已广泛应用于组织愈合相关研究。
智能水凝胶,也称为环境响应型水凝胶,除了具备水凝胶的基本特征之外,其还具有感知外界环境信号和刺激包括温度、pH值、生物分子、电场、光、磁场和压力等变化的能力,这一类材料特殊的理化性能使其在生物体内药物控释的应用上具有很大的潜力。目前,各种不同类型的智能水凝胶已经广泛应用于生物传感器、组织修复和再生医学等多个领域,其“响应特性”在药物控释研究领域也成为现阶段研究热点。
因此,提供一种能够用于促进创面愈合的复合水凝胶是至关重要的。
发明内容
本发明的目的是针对现有技术中的不足,提供一种复合水凝胶及其制备方法和应用。
聚N-异丙基丙烯酰胺(poly N-isopropylacrylamide,PNIPAM)为温敏高分子,在32℃的水中完成体积转变,该温度被称为较低临界溶解温度(lower critical solutiontemperature,LCST),当环境温度高于此温度时,疏水作用增强,凝胶收缩,反之,亲水作用增强,水凝胶膨胀。近红外响应型水凝胶能够通过精确控制光源的辐照强度、辐照时间以及照射位点实现多方面的响应目的,但是传统近红外响应材料如氧化石墨烯、聚吡咯等因为潜在生物毒性等问题限制了其在生物医学领域的应用。仿贻贝材料聚多巴胺(polydopamine,PDA)纳米颗粒及PNIPAM可制备近红外响应型水凝胶,其不但具有良好的近红外光效转化效应,而且还有良好生物相容性、组织亲和性和黏附性。二肽基肽酶(dipeptidyl peptidase 4inhibitors,DPP-4)抑制剂,是目前使用广泛的口服降糖药,郑宏庭教授的团队通过基础及临床试验发现,此经典降糖药还可以加速糖尿病患者的溃疡创面愈合,减少疤痕形成,治疗糖尿病。水凝胶具有类细胞外基质特性,作为支架材料负载药物应用于皮肤创面,可促进创面愈合,口服DPP-4抑制剂类药物可促进创面愈合,目前尚无水凝胶负载DPP-4抑制剂用于创面愈合的研究。负载药物并且具有智能响应性的复合水凝胶有助于多方面对愈合进行调控,进一步促进创面愈合。
本发明的目的可以通过以下技术方案来实现:
本发明的第一个目的是提供一种PG10@PDA复合水凝胶的制备方法,包括以下步骤:
S1、将氨水与乙醇水溶液混匀,得到混合溶液;然后将混合溶液与盐酸多巴胺溶液混匀,氧化自聚合反应后后处理,得到PDANPs;
S2、将步骤S1制备得到的PDANPs与水混匀,得到PDANPs水溶液,然后将其加入GelMA水溶液与NIPAM水溶液的混合溶液中,然后加入引发剂引发原位自由基聚合,得到PG10@PDA复合水凝胶。
进一步地,步骤S1中,氧化自聚合反应过程中,温度为室温,时间为24-48h;步骤S2中,原位自由基聚合过程中,温度为室温,时间为24-48h。
本发明的第二个目的是提供一种通过上述制备方法制备得到的PG10@PDA复合水凝胶。
本发明的第三个目的是提供一种PG10@PDA复合水凝胶在制备促进创面愈合药物中的应用。
本发明的第四个目的是提供一种LIN@PG10@PDA载药水凝胶的制备方法,包括以下步骤:
将含LIN的储备液加入PG10@PDA复合水凝胶中,混匀后,蓝光下交联得到LIN@PG10@PDA载药水凝胶。
进一步地,交联过程处于400-410nm蓝光下,交联时间为1-5min;
更进一步地,交联过程处于405nm蓝光下,交联时间为1min。
本发明的第五个目的是提供一种通过上述方法制备得到的LIN@PG10@PDA载药水凝胶。
本发明的第六个目的是提供一种LIN@PG10@PDA载药水凝胶在制备促进创面愈合药物中的应用。
进一步地,所述LIN@PG10@PDA载药水凝胶无处理或进行近红外光诱导处理。
更进一步地,距离LIN@PG10@PDA载药水凝胶2cm处进行近红外光诱导处理,
其中,近红外光诱导过程中,波长为805-810nm,功率为0.8-1.2W/cm2,时间为1-5min;
优选地,波长为808nm,功率为1W/cm2,时间为2min。
与现有技术相比,本发明具有以下有益效果:
本发明中PG10@PDA复合水凝胶、LIN@PG10@PDA载药水凝胶以及LIN@PG10@PDA-NIR水凝胶均能够提高糖尿病伤口的修复效果,其中LIN@PG10@PDA-NIR水凝胶的效果尤其显著。
本发明通过近红外光照射实现智能响应,促进药物释放,促进血管新生和成熟,可显著提高骨糖尿病伤口的修复效果,具有重大临床意义和社会经济效益。
附图说明
图1为本发明的PG10@PDA、LIN@PG10@PDA、LIN@PG10@PDA-NIR、LIN@PG10@PDA-NIR置于PBS中2h,各水凝胶冻干后的SEM图像(2000×:scale bars=10μm;5000×:scale bars=5μm);
图2为实施例2制备得到的LIN@PG10@PDA水凝胶近红外照射2min的温度变化情况;
图3为GelMA、PG10、PG10@PDA水凝胶和LIN@PG10@PDA水凝胶的红外光谱分析;
图4为实施例1中PG10@PDA水凝胶应变1%时的流变性能;
图5为实施例2中LIN@PG10@PDA水凝胶在有无NIR照射情况下的药物释放情况;
图6为PG10@PDA、LIN@PG10@PDA、LIN@PG10@PDA-NIR水凝胶对HUVEC细胞的毒性实验;
图7为PG10@PDA、LIN@PG10@PDA、LIN@PG10@PDA-NIR水凝胶促进HUVEC细胞的成管和迁移;
图8为RT-PCR检测不同水凝胶组的VEGF基因表达。
具体实施方式
本发明提供一种PG10@PDA复合水凝胶的制备方法,包括以下步骤:
S1、将氨水与乙醇水溶液混匀,得到混合溶液;然后将混合溶液与盐酸多巴胺溶液混匀,氧化自聚合反应后后处理,得到PDANPs;
S2、将步骤S1制备得到的PDANPs与水混匀,得到PDANPs水溶液,然后将其加入GelMA水溶液与NIPAM水溶液的混合溶液中,然后加入引发剂引发原位自由基聚合,得到PG10@PDA复合水凝胶。
在本发明的一个实施方式中,步骤S1中,氧化自聚合反应过程中,温度为室温,时间为24-48h;步骤S2中,原位自由基聚合过程中,温度为室温,时间为24-48h。
本发明提供一种通过上述制备方法制备得到的PG10@PDA复合水凝胶。
本发明提供一种PG10@PDA复合水凝胶在制备促进创面愈合药物中的应用。
本发明提供一种LIN@PG10@PDA载药水凝胶的制备方法,包括以下步骤:
将含LIN的储备液加入PG10@PDA复合水凝胶中,混匀后,蓝光下交联得到LIN@PG10@PDA载药水凝胶。
在本发明的一个实施方式中,交联过程处于400-410nm蓝光下,交联时间为1-5min;
优选地,交联过程处于405nm蓝光下,交联时间为1min。
本发明提供一种通过上述方法制备得到的LIN@PG10@PDA载药水凝胶。
本发明提供一种LIN@PG10@PDA载药水凝胶在制备促进创面愈合药物中的应用。
在本发明的一个实施方式中,所述LIN@PG10@PDA载药水凝胶无处理或进行近红外光诱导处理。
在本发明的一个实施方式中,距离LIN@PG10@PDA载药水凝胶2cm处进行近红外光诱导处理,
其中,近红外光诱导过程中,波长为805-810nm,功率为0.8-1.2W/cm2,时间为1-5min;
优选地,波长为808nm,功率为1W/cm2,时间为2min。
下面结合附图和具体实施例对本发明进行详细说明。
下述实施例中,若无特殊说明,所用试剂均为市售试剂,所用监测手段及方法均为本领域常规检测手段及方法。
下述实施例中,盐酸多巴胺、氨水(NH3·H2O)、乙醇均为分析纯。
实施例1
本实施例提供一种用于促进创面愈合的复合水凝胶(PG10@PDA复合水凝胶)及其制备方法。
(S1)PDANPs的制备
(S101)取500ml烧杯,将80ml无水乙醇缓缓加入180ml超纯水中,形成乙醇水溶液;
(S102)在室温25℃磁力搅拌下,将2ml氨水加入乙醇水溶液,形成混合溶液;
(S103)1g盐酸多巴胺充分溶解于20ml超纯水中,形成盐酸多巴胺溶液;
(S104)盐酸多巴胺溶液与混合溶液缓慢混合(溶液颜色逐渐由黄棕色变为棕褐色);
(S105)室温25℃和避光(用锡纸将烧杯整体密封)的环境中,持续磁力搅拌反应36h(转速3000r/min),经氧化自聚合反应得到PDANPs粗产物;
(S106)分离纯化:为了得到均匀的PDANPs,将上述反应后的溶液产物离心纯化,使PDANPs均匀:10000rpm转速下离心15min,弃去上层清液,加入与先前溶液等量的乙醇分散下层沉淀,再次10000rpm转速下离心15min。该分离纯化步骤重复四次;
(S107)最后,置于80℃干燥箱中干燥48h至恒重,得到PDANPs(约0.25g)。
(S2)PG10@PDA复合水凝胶的制备
(S201)取15ml离心管,称取1g GelMA,加入10mL超纯水,40℃水浴,形成10%w/v的GelMA溶液;
(S202)取15ml离心管,称取NIPAM 0.8g,加入10mL超纯水,震荡溶解,形成8%w/v的NIPAM溶液;
(S203)称取10mg PDANPs(1mg/ml),加入10mL超纯水,超声震荡20min使纳米颗粒在溶液中均匀分散,得到PDANPs溶液;然后用移液枪将PDANPs溶液滴入GelMA溶液和GelMA溶液的混合溶液中;
(S204)加入30mg引发剂LAP,继续搅拌混匀,引发原位自由基聚合,得到PG10@PDA复合水凝胶(其SEM图如图1所示)。
实施例2
本实施例提供一种用于促进创面愈合的复合水凝胶(LIN@PG10@PDA载药水凝胶)及其制备方法。
(S3)将17mg利格列汀药物(LIN)溶解于1mL二甲基亚砜(DMSO)溶解中,制备得到17mg/mL LIN贮存液;
(S4)将0.1mL LIN贮存液加入17mL上述制备得到的PG10@PDA复合水凝胶溶液中,震荡混匀,采用405nm蓝光交联1min,制备得到用于促进创面愈合的复合水凝胶:LIN@PG10@PDA载药水凝胶(其SEM图如图1所示)。
进一步应用时,本实施例制备得到的LIN@PG10@PDA载药水凝胶可以直接使用;也可以经近红外光诱导后使用(标记为“LIN@PG10@PDA-NIR水凝胶”,其SEM图如图1所示);
其中,近红外光诱导过程具体如下:
NIR(808nm,1W/cm2)距离LIN@PG10@PDA载药水凝胶2cm处照射2min。
通过图2可以发现,经近红外光诱导处理后,LIN@PG10@PDA载药水凝胶的温度逐渐升高(温度由25℃左右升至41℃左右),平均升高15.97℃。
性能分析:
LIN@PG10@PDA-NIR置于PBS中2h后,冻干后的SEM图像如图1所示。图1的结果表明:负载利格列汀药物后,复合水凝胶孔径大小没有明显变化,近红外光照后,孔径明显缩小,PBS进行溶胀2h后孔径再次明显变大。近红外光照射收缩后的水凝胶在PBS中浸泡后体积可再次变大,这是由于水凝胶在室温PBS环境下可重新溶胀,说明其近红外刺激的形变具有可重复性。复合水凝胶对于近红外的刺激有体积收缩孔径变小的相应变化,并且此变化具有可回复和重复性,有利于载药和创面愈合的临床应用。
从GelMA的FTIR图谱上可以看到,在3060、1630、1535和1234cm-1出现了特征峰,对应于C-H键的振动峰、酰胺I的C=O伸缩振动峰、酰胺II的N-H弯曲振动峰、酰胺III的C-N伸缩振动峰以及N-H弯曲振动峰。相比GelMA的图谱,PG10样品在2970cm-1出现了新的吸收峰,该特征峰为NIPAM上的-CH3伸缩振动峰,表明PG10样品中含有NIPAM组分。当PDA加入后,得到PG10@PDA样品,而PDA上存在苯环和NH2,但在该样品中并未发现明显的苯环伸缩振动峰和N-H伸缩振动峰,可能是PG10@PDA样品中PDA的含量较少的原因。同样,相比PG10@PDA样品,LIN@PG10@PDA样品的FTIR图谱也没有明显的差异,说明加入较少含量的利格列汀药物(LIN)对样品的FTIR图谱不会引起明显的变化(图3)。
进一步检测水凝胶的流体力学行为,PG10@PDA复合水凝胶的储能模量(G')和损耗模量(G”)随频率变化如图4所示。利用动态模拟表征出的水凝胶的粘弹性能显示,随着频率增加,储能模量和损耗模量都有轻微的增加且无突变。PG10@PDA水凝胶的储能模量为损耗模量10倍左右,表明本研究水凝胶为较好的黏弹性体。
通过定量分析LIN@PG10@PDA和LIN@PG10@PDA-NIR组水凝胶药物随时间的释放情况,如图5的释放曲线所示,前3天累积释放量逐渐增加,之后释放量趋于平缓,第14天近红外光照组的药物释放量百分比高于未光照组(85.63±4.26%vs.55.19±6.65%,P<0.05)。结合电镜结果(图1),表明水凝胶受到近红外光照射后收缩、孔径变小,利于将药物释出(被挤出,从而释出),此后随着近红外激光的开关循环,从而表现出水凝胶中药物刺激响应性的阶梯释放。
如图6所示,运用CKK8法测得的吸光值表示对照组、PG10@PDA、LIN@PG10@PDA和LIN@PG10@PDA-NIR四组水凝胶的细胞增殖情况,浸提液培养HUVEC细胞1~3天,具体为:培养HUVEC细胞使用的内皮细胞培养基(endothelial cell medium,ECM)含5%胎牛血清(fetalbovine serum,FBS)和1%青霉素-链霉素;水凝胶浸提液提取:交联前水凝胶液体用0.22μmMillex GP膜过滤消毒,取500μl置于6孔板中,405nm蓝光交联,NIR(808nm,1W/cm2)照射组在水凝胶交联后距离水凝胶2cm照射2min,加入2ml ECM培养基,置于含5%CO2的37℃培养箱中培养24h或72h,提取复合水凝胶培养基浸提液待用。水凝胶浸提液组培养细胞每天的生长情况均优于对照组,说明这三组水凝胶的细胞毒性均较低,有利于细胞增殖及生长,且LIN@PG10@PDA-NIR组存活率最高,表明负载利格列汀药物的复合水凝胶及近红外光照射均有助于细胞增殖。
细胞成血管和迁移实验结果如图7所示。PG10@PDA、LIN@PG10@PDA和LIN@PG10@PDA-NIR三组较对照组均可显著促进管状结构的形成,其中LIN@PG10@PDA-NIR组促进新生血管形成的能力最强。
通过对RT-PCR结果分析表明,与对照组相比,PG10@PDA、LIN@PG10@PDA和LIN@PG10@PDA-NIR三组水凝胶浸提液培养72h的HUVEC细胞均能促进VEGF(图8)、成血管基因的表达,其中LIN@PG10@PDA-NIR组表达量最高。
本实施例通过建立糖尿病大鼠(本实验使用体重200~300g之间的8周龄雄性SD(Sprague-Dawley)大鼠来评估复合水凝胶在糖尿病创面愈合中的作用。SD大鼠术前称重,腹腔注射链脲佐菌素(streptozotocin,STZ,65mg/kg),制备糖尿病模型。一周后,随机血糖水平>11.1mmol/l者被视为糖尿病大鼠,并随机分为3天、7天和14天组,每组平行样本6~10只。用3%戊巴比妥钠溶液以45mg/kg腹腔注射实施麻醉,刮除背毛后,在每只大鼠背侧剪4个直径10mm的全层环形伤口。每只大鼠背部的四个皮肤创面分为4组:①对照组(空白,用医用无菌纱布覆盖);②PG10@PDA水凝胶组;③LIN@PG10@PDA水凝胶组;④LIN@PG10@PDA-NIR水凝胶组)背部全层皮肤缺损模型,以无菌纱布为对照组,对PG10@PDA组、LIN@PG10@PDA组和LIN@PG10@PDA-NIR组水凝胶在伤口愈合中的效果进行评估。在整个14天的实验过程中,各组均表现为伤口面积逐渐缩小,愈合率逐步提升,水凝胶组伤口面积均小于对照组,负载药物加近红外照射组伤口面积最小,愈合率最高。随着治疗时间增加,各组愈合率均明显升高,其中LIN@PG10@PDA-NIR组愈合率最高,高于对照组约50%。结果表明LIN@PG10@PDA-NIR水凝胶具有有效促进伤口愈合的性能。
为进一步观察创面愈合过程中组织再生情况,治疗过程中对皮肤组织进行组织形态学分析。对治疗后3天、7天和14天各组不同处理的皮肤组织进行HE染色,观察炎症反应与胶原填充情况。在3天时均可观察到明显表皮及真皮结构的缺损,与对照组相比,水凝胶处理组的创面炎症细胞浸润较少,对照组无胶原填充,水凝胶组仅有少量胶原填充;治疗7天后,水凝胶处理组皮肤组织增厚,胶原开始填充入缺损创面,其中LIN@PG10@PDA-NIR组胶原填充现象最为明显,毛囊及新生血管数量最多;治疗14天后,各组均已基本修复出完整表皮和真皮结构,并可见较多新生血管和毛囊,其中LIN@PG10@PDA-NIR组最为明显,且形态更接近正常皮肤组织。
综上述所,本发明提供一种通过近红外光热诱导的负载利格列汀药物的智能响应型水凝胶,通过材料学表征表明该水凝胶是具有良好多孔结构和溶胀性能的弹性体,NIR光照有助于水凝胶中药物的阶梯释放;通过细胞及动物实验进一步验证了复合水凝胶材料良好的生物相容性、促进细胞迁移和通过促进VEGF等促血管生成因子表达而促进血管新生和成熟的作用,从而实现促进创面愈合的作用。
上述的对实施例的描述是为便于该技术领域的普通技术人员能理解和使用发明。熟悉本领域技术的人员显然可以容易地对这些实施例做出各种修改,并把在此说明的一般原理应用到其他实施例中而不必经过创造性的劳动。因此,本发明不限于上述实施例,本领域技术人员根据本发明的解释,不脱离本发明范畴所做出的改进和修改都应该在本发明的保护范围之内。
Claims (10)
1.一种PG10@PDA复合水凝胶的制备方法,其特征在于,包括以下步骤:
S1、将氨水与乙醇水溶液混匀,得到混合溶液;然后将混合溶液与盐酸多巴胺溶液混匀,氧化自聚合反应后后处理,得到PDANPs;
S2、将步骤S1制备得到的PDANPs与水混匀,得到PDANPs水溶液,然后将其加入GelMA水溶液与NIPAM水溶液的混合溶液中,然后加入引发剂引发原位自由基聚合,得到PG10@PDA复合水凝胶。
2.根据权利要求1所述的一种PG10@PDA复合水凝胶的制备方法,其特征在于,
步骤S1中,氧化自聚合反应过程中,温度为室温,时间为24-48h;
步骤S2中,原位自由基聚合过程中,温度为室温,时间为24-48h。
3.一种通过权利要求1-2任一所述的制备方法制备得到的PG10@PDA复合水凝胶。
4.一种如权利要求3所述的PG10@PDA复合水凝胶在制备促进创面愈合药物中的应用。
5.一种LIN@PG10@PDA载药水凝胶的制备方法,其特征在于,包括以下步骤:
将含LIN的储备液加入权利要求3所述的PG10@PDA复合水凝胶中,混匀后,蓝光下交联得到LIN@PG10@PDA载药水凝胶。
6.根据权利要求5所述的一种LIN@PG10@PDA载药水凝胶的制备方法,其特征在于,交联过程处于400-410nm蓝光下,交联时间为1-5min。
7.一种通过权利要求5-6任一所述的制备方法制备得到的LIN@PG10@PDA载药水凝胶。
8.一种如权利要求7所述的LIN@PG10@PDA载药水凝胶在制备促进创面愈合药物中的应用。
9.根据权利要求8所述的一种LIN@PG10@PDA载药水凝胶在制备促进创面愈合药物中的应用,其特征在于,所述LIN@PG10@PDA载药水凝胶无处理或进行近红外光诱导处理。
10.根据权利要求9所述的一种LIN@PG10@PDA载药水凝胶在制备促进创面愈合药物中的应用,其特征在于,距离所述LIN@PG10@PDA载药水凝胶2cm处进行近红外光诱导处理;
其中,近红外光诱导过程中,波长为805-810nm,功率为0.8-1.2W/cm2,时间为1-5min。
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