CN111686092A - 一种多孔硅石墨烯量子点复合载药颗粒的制备方法及伤口敷料及伤口敷料的制备方法及用途 - Google Patents
一种多孔硅石墨烯量子点复合载药颗粒的制备方法及伤口敷料及伤口敷料的制备方法及用途 Download PDFInfo
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Abstract
本发明公开了一种多孔硅石墨烯量子点复合载药颗粒的制备方法及伤口敷料及伤口敷料的制备方法及用途,本发明利用生物无毒性的多孔硅/石墨烯量子点复合载药颗粒的特性实现高效药物递送,增加药效和有效期,同时实现了氧化刺激响应性的药物释放,和对糖尿病伤口活性氧的可视化监控;再将多孔硅/石墨烯量子点复合载药颗粒包覆在生物无毒性的柔性天然高分子凝胶上,制作成兼具诊疗效果的高分子伤口敷料,通过多孔硅/石墨烯量子点复合载药颗粒与高分子凝胶的协同作用,实现加快伤口愈合的作用;本发明有望突破糖尿病伤口难治愈的临床难题,便于糖尿病伤口患者及其他疾病伤口患者的自我健康管理和个性化诊疗敷料。
Description
技术领域
本发明涉及医药新材料领域,特别是一种多孔硅石墨烯量子点复合载药颗粒的制备方法及伤口敷料及伤口敷料的制备方法及用途。
背景技术
糖尿病是由于胰岛素分泌缺陷或其生物作用受损导致的代谢性疾病,慢性皮肤创伤或溃疡是由糖尿病引发的常见并发症之一,症状为持续疼痛的溃疡、并伴有真皮组织的解体,伤口长时间难愈合,并且面临着长期感染甚至截肢的风险。正常的伤口愈合过程涉及多种信号因子的协同作用及动态平衡,共同调控蛋白的表达,细胞的迁移、增殖及分化等过程。而糖尿病伤口部位存在免疫反应延迟,多种生长因子表达受损,新生血管形成异常,氧化应激增强,基质金属蛋白酶的高表达等异常,阻碍了伤口的正常愈合。慢性糖尿病伤口的难愈合性和高感染风险严重危及患者的生命健康,因此对糖尿病伤口病变和愈合过程的实时监控,并加以及时的干预和处理,对糖尿病导致的慢性皮肤创伤具有重要的临床意义。
对于糖尿病伤口的治疗,除伤口部位发生的多种病变导致的愈合困难之外,另一大难点在于高表达的基质金属蛋白酶会使临床最常用的多肽类药物的半衰期缩短和生物活性的丧失。这种情况下为了实现多肽类药物的高效利用,需要将多肽类药物负载在具备生物相容性和药物缓释功能的伤口敷料中。药物递送材料需具备生物相容性、生物体内的靶向性、药物负载和缓释能力、水溶性等条件。市场需要一种能够解决多肽类药物在生物体系内的不稳定、半衰期短的问题,市场需要一种可实现药物高效负载和缓释的纳米载药材料。
此外,由于糖尿病患者的慢性皮肤创伤的潜在感染风险较大,治疗过程中对病变的及时处理至关重要,因此,通过对伤口病变或愈合情况的实时跟踪与监控,根据监控结果对伤口实现反馈治疗的诊疗一体化技术可以发挥重要的临床价值。研究表明,糖尿病伤口发展情况的一种重要的生物标志物是伤口部位的活性氧水平,高血糖导致的缺氧环境引起伤口氧化应激加剧,伤口部位的活性氧水平会随着伤口的病变而升高,因此,市场也需要一种可监控糖尿病伤口活性氧水平,并提供氧化刺激响应性药物释放的诊疗一体化方法。本发明根据市场的需求给出一种能够实现多肽高效负载与缓释,同时实现可视化监控糖尿病伤口活性氧水平的新材料敷料的制备方法。
发明内容
为解决现有技术的不足,本发明的目的在于提供一种多孔硅石墨烯量子点复合载药颗粒的制备方法及伤口敷料及伤口敷料的制备方法及用途,本发明的敷料具有高效负载药物与缓释药物的作用,增加了药效和有效期;同时实现可视化的监控糖尿病伤口活性氧水平,实现了伤口的反馈性治疗;能够促进伤口部位表皮细胞增殖和伤口部位表皮细胞迁移,加快伤口愈合。
为了实现上述目标,本发明采用如下的技术方案:
一种多孔硅石墨烯量子点复合载药颗粒的制备方法,包括:
步骤一,制备多孔硅/石墨烯量子点复合颗粒:
1)将单晶硅片经表面洗涤预处理后经过电化学刻蚀、电化学剥离、弱氧化活化后得到具有荧光特性的多孔硅颗粒;
2)将含羧基的碳材料在高温下加热,加入去离子水稀释,获得具有荧光特性的石墨烯量子点溶液;
3)将多孔硅颗粒分散到石墨烯量子点溶液中,经过震荡、离心、清洗后获得多孔硅/石墨烯量子点复合颗粒;
步骤二,制备多孔硅/石墨烯量子点复合载药颗粒:
将多孔硅/石墨烯量子点复合颗粒分散至浓度为0.5-5mg/mL的多肽药物溶液中,经过震荡、离心、清洗后获得负载药物分子的多孔硅/石墨烯量子点复合载药颗粒。
前述的一种多孔硅石墨烯量子点复合载药颗粒的制备方法,含羧基的碳材料为L-谷氨酸粉末,将L-谷氨酸粉末采用150-200℃高温加热100-150分钟,会得到具有蓝色荧光特性的石墨烯量子点溶液。
前述的一种多孔硅石墨烯量子点复合载药颗粒的制备方法,将柠檬酸钠粉末高温加热的条件采用150-250℃高温下加热30-60分钟,会得到具有蓝色荧光特性的石墨烯量子点溶液。
前述的一种多孔硅石墨烯量子点复合载药颗粒的制备方法,多肽药物溶液为浓度为0.5-5mg/mL的胰岛素溶液,浓度为0.5-5mg/mL的表皮生长因子溶液,或浓度各为0.5-5mg/mL的胰岛素和表皮生长因子的混合溶液。
一种多孔硅石墨烯量子点复合载药颗粒伤口敷料,包括:高分子伤口敷料作为柔性载体,包覆在高分子伤口敷料上的多孔硅/石墨烯量子点复合载药颗粒。
前述的一种多孔硅石墨烯量子点复合载药颗粒伤口敷料,高分子伤口敷料包括:壳聚糖伤口敷料,羧甲基壳聚糖伤口敷料,羟丙基壳聚糖伤口敷料。
一种多孔硅石墨烯量子点复合载药颗粒伤口敷料的制备方法,包括如下步骤:
步骤一,制备多孔硅/石墨烯量子点复合颗粒:
1)将单晶硅片经表面洗涤预处理后经过电化学刻蚀、电化学剥离、弱氧化活化后得到具有荧光特性的多孔硅颗粒;
2)将L-谷氨酸粉末在高温下加热,加入适量去离子水稀释,获得具有荧光特性的石墨烯量子点溶液;
3)将多孔硅颗粒分散到石墨烯量子点溶液中,经过震荡、离心、清洗后获得多孔硅/石墨烯量子点复合颗粒;
步骤二,制备多孔硅/石墨烯量子点复合载药颗粒:
将多孔硅/石墨烯量子点复合颗粒分散至浓度为0.5-5mg/mL的多肽药物溶液中,经过震荡、离心、清洗后获得负载药物分子的多孔硅/石墨烯量子点复合载药颗粒;
步骤三,制备包覆多孔硅/石墨烯量子点复合载药颗粒的伤口敷料:
将多孔硅/石墨烯量子点复合载药颗粒分散到高分子敷料原料中,并加入体积浓度为0.1-0.3%的硅烷化偶联剂,再将混合均匀的溶液涂覆在聚氨酯薄膜表面,待壳聚糖凝胶形成后,获得包覆多孔硅/石墨烯量子点复合载药颗粒的伤口敷料。
前述的一种多孔硅石墨烯量子点复合载药颗粒伤口敷料的制备方法,高分子敷料原料包括:壳聚糖,羧甲基壳聚糖或羟丙基壳聚糖。
前述的一种多孔硅石墨烯量子点复合载药颗粒伤口敷料的制备方法,硅烷化偶联剂包括:γ-(2.3环氧丙氧)丙基三甲氧基硅烷,1,2-二(三乙氧基甲硅烷基)乙烷,4,4’二(三乙氧基甲硅烷)-1,1’联苯,双[3-(三甲氧基甲硅烷基)丙基]胺。
一种多孔硅石墨烯量子点复合载药颗粒伤口敷料的用途,多孔硅石墨烯量子点复合载药颗粒伤口敷料用于伤口治疗:适用于糖尿病患者伤口,疾病伤口。
本发明的有益之处在于:
本发明的多孔硅颗粒、石墨烯量子点及天然高分子材料,相比于其他量子点和荧光染料具有无毒、生物相容性好等特点;
本发明的多孔硅颗粒/石墨烯量子点复合载药颗粒利用多孔硅的孔道负载特性和石墨烯量子点的药物分子吸附能力构建了高效的药物递送材料,可实现多肽类药物的高效负载,同时实现胰岛素、表皮生长因子的氧化刺激响应性释放,避免了多肽类药物的酶催化降解,增加其药效和有效期;缩短治疗周期,敷料后一天伤口面积即明显减小,减轻患者痛苦;
本发明的多孔硅颗粒/石墨烯量子点复合载药颗粒对糖尿病伤口活性氧所产生的荧光颜色变化肉眼可见,实现了对糖尿病伤口活性氧的可视化监控及糖尿病伤口的反馈性治疗,无需复杂的信号传输设备,实用,方便;
本发明的多孔硅/石墨烯量子点复合载药颗粒和高分子伤口敷料对伤口部位表皮细胞增殖具有良好的协同促进作用;本发明的多孔硅/石墨烯量子点复合载药颗粒和包覆多孔硅/石墨烯量子点复合载药颗粒的高分子伤口敷料对伤口部位表皮细胞迁移具有促进作用;二者联合使用,能够加快伤口愈合;
本发明采用柔性的天然高分子凝胶作为多孔硅颗粒/石墨烯量子点复合载药颗粒的载体,制作成兼具诊疗效果的智能伤口敷料;
本发明有望突破糖尿病伤口难治愈的临床难题,便于糖尿病伤口患者的的自我健康管理和个性化诊疗。
附图说明
图1是本发明中多孔硅、多孔硅/石墨烯量子点复合颗粒对表皮生长因子和胰岛素的负载率随时间变化的示意图;
图2是本发明中多孔硅/石墨烯量子点复合载药颗粒在溶液体系中对表皮生长因子和胰岛素的释放率随时间变化的示意图;
图3是本发明中对多孔硅/石墨烯量子点复合载药颗粒进行荧光性能测试时,颗粒在梯度浓度的过氧化氢溶液中反应10小时后,多孔硅/石墨烯量子点复合载药颗粒的荧光光谱的示意图;
图4是本发明中对多孔硅/石墨烯量子点复合载药颗粒进行荧光性能测试时,颗粒在梯度浓度的过氧化氢溶液中反应10小时后,颗粒的荧光图像的红色通道图像和蓝色通道图像;
图5是本发明中对多孔硅/石墨烯量子点复合载药颗粒进行的多肽保护效果的测试时,在基质金属蛋白酶(MMP-2)存在时,多孔硅/石墨烯量子点复合载药体系及药物溶液体系中,表皮生长因子和胰岛素浓度随时间变化的示意图;
图6是本发明中对多孔硅/石墨烯量子点复合载药颗粒和包覆多孔硅/石墨烯量子点复合载药颗粒的高分子伤口敷料进行对伤口部位表皮细胞增殖的促进作用的的测试结果示意图;
图7是本发明中对多孔硅/石墨烯量子点复合载药颗粒和包覆多孔硅/石墨烯量子点复合载药颗粒的高分子伤口敷料进行对伤口部位表皮细胞迁移的促进作用的的测试结果示意图;
图8是本发明中多孔硅/石墨烯量子点复合载药颗粒和包覆多孔硅/石墨烯量子点复合载药颗粒的高分子伤口敷料促进糖尿病伤口愈合效果的示意图;
图9是本发明中包覆多孔硅/石墨烯量子点复合载药颗粒的高分子伤口敷料在糖尿病伤口表面荧光图像的的红色通道图像变化的示意图。
具体实施方式
以下结合附图和具体实施例对本发明作具体的介绍。
按照如下步骤制造一种多孔硅/石墨烯量子点复合载药颗粒,过程包括:制备多孔硅/石墨烯量子点复合颗粒,再制备多孔硅/石墨烯量子点复合载药颗粒。
一,多孔硅/石墨烯量子点复合颗粒的制备过程如下:
(1)将单晶硅片经表面洗涤预处理后经过电化学刻蚀、电化学剥离、弱氧化活化后得到具有荧光特性多孔硅颗粒;
电化学刻蚀的具体过程为:将P型掺硼硅片作为单晶硅片固定在电解池中,电解液为有机溶剂和氢氟酸,阳极为硅片,阴极为铂电极,进行电化学刻蚀,得到多孔硅层;
电化学剥离的具体过程为:降低氢氟酸的质量浓度进行电化学剥离,多孔硅薄膜脱离硅基底;将得到的多孔硅薄膜置于乙醇中超声处理,获得微米级多孔硅颗粒;
弱氧化活化的具体过程为:将多孔硅颗粒浸泡于PBS缓冲液中,浸泡后离心、清洗,得到具有荧光特性的多孔硅颗粒。
作为一种实施例,可以通过如下步骤得到一种具有红色荧光的多孔硅颗粒:
多孔硅颗粒的电化学制备具体步骤为:将P型掺硼硅片固定在电解池中,按体积比为1:4的比例加入有机溶剂乙醇和质量浓度为40%的氢氟酸作为电解液,以硅片为阳极,铂电极为阴极,以电流密度为77mA·cm-1进行恒电流电解10min,得到多孔硅层;改变刻蚀液氢氟酸的质量浓度为3.3%继续刻蚀,刻蚀电流密度为22mA·cm-1,进行恒电流刻蚀,3min后多孔硅薄膜脱离硅基底;将得到的多孔硅薄膜置于乙醇中超声处理10min,获得微米级多孔硅颗粒。
多孔硅颗粒的弱氧化活化体步骤为:将多孔硅颗粒浸泡于pH为7.42的PBS缓冲液中,12小时后离心并用去离子水清洗,得到具有红色荧光的多孔硅颗粒。
需要说明的是:用单晶硅片制作具有红色荧光特性多孔硅颗粒的方法在专利名称“一种多孔硅颗粒在伤口pH可视化监测中的应用”,授权公告号:CN 106245106 B,在此不再赘述。需要说明的是不同的生产方法和制备的条件可以生产出不同颜色荧光特性的多孔硅颗粒,在此不一一举例,但所有颜色的荧光特性的多孔硅颗粒,只要是应用在载药颗粒上都在本发明的保护范围之内。
(2)通过溶液化学法,将含羧基的碳材料在高温下加热,加入去离子水稀释,获得具有荧光特性的石墨烯量子点溶液。
作为一种实施例,将L-谷氨酸粉末高温加热的条件采用150-200℃高温下加热100-150分钟,会得到具有蓝色荧光特性的石墨烯量子点溶液。
作为一种实施例,将柠檬酸钠粉末高温加热的条件采用150-250℃高温下加热30-60分钟,会得到具有蓝色荧光特性的石墨烯量子点溶液。
在此需要说明的是:不同的制备条件可以生产出不同颜色荧光特性的石墨烯量子点溶液,在此不一一举例,但所有颜色的荧光特性的石墨烯量子点溶液,只要是应用在载药颗粒上都在本发明的保护范围之内。
(3)将多孔硅颗粒分散到石墨烯量子点溶液中,混合震荡3-6小时,经过离心、清洗后获得多孔硅/石墨烯量子点复合颗粒。
二,多孔硅/石墨烯量子点复合载药颗粒的制备过程如下,
将多孔硅/石墨烯量子点复合颗粒分散至浓度各为0.5mg/mL的胰岛素和表皮生长因子的混合溶液中,混合震荡3-6小时,经过离心、清洗后获得负载药物分子的多孔硅/石墨烯量子点复合载药材料。需要说明的是:采用浓度各为0.5mg/mL的胰岛素和表皮生长因子的混合溶液只是一种实施例,多肽类药物还包括单组分浓度为0.5-5mg/mL的胰岛素或单组分浓度为0.5-5mg/mL的表皮生长因子。
包覆多孔硅/石墨烯量子点复合载药颗粒的高分子伤口敷料的制作过程包括:
(1)配制壳聚糖水溶液,壳聚糖质量浓度为1-3%,并加入体积浓度为0.1-0.3%的γ-(2.3环氧丙氧)丙基三甲氧基硅烷作为交联剂;需要说明的是:壳聚糖选用为高分子敷料原料,γ-(2.3环氧丙氧)丙基三甲氧基硅烷选用为交联剂只是一种实施例,高分子敷料原料还包括:羧甲基壳聚糖,羟丙基壳聚糖;交联剂还包括:γ-(2,3-环氧丙氧基)丙基三甲氧基硅烷,1,2-二(三乙氧基甲硅烷基)乙烷,4,4’二(三乙氧基甲硅烷)-1,1’联苯,双[3-(三甲氧基甲硅烷基)丙基]胺。
(2)将多孔硅/石墨烯量子点复合载药颗粒分散到壳聚糖溶液中,取50μL溶液均匀涂覆在尺寸为0.5cm×0.5cm的粘性的聚氨酯薄膜表面,室温下放置6小时,待壳聚糖凝胶形成后,获得具有双色荧光和药物缓释性质的多孔硅/石墨烯量子点复合载药颗粒伤口敷料。
多孔硅/石墨烯量子点复合载药颗粒伤口敷料的用途是伤口治疗,包括糖尿病患者伤口、慢性疾病伤口的治疗。
包覆多孔硅/石墨烯量子点复合载药颗粒的高分子伤口敷料应用于糖尿病伤口的诊疗方法如下:
将包覆多孔硅/石墨烯量子点复合载药颗粒的高分子伤口敷料贴敷于糖尿病患者伤口表面,每隔24h拍照记录伤口尺寸,同时,每隔24h在紫外手电筒照射下观察并拍照记录敷料荧光变色情况,一旦敷料荧光颜色由红色完全变为蓝色则说明,药物已经完全释放,需要立即更换新的敷料。其中,双层荧光波段为400-600nm和600-800nm。
实验一,对多孔硅/石墨烯量子点复合颗粒的药物负载和药物缓释性能,具体测试过程如下,
1-1,对获得的多孔硅/石墨烯量子点复合颗粒进行载药效率测试;
具体过程包括:使用与多肽药物对应的定量检测试剂盒,对药物溶液装载前及不同时间点上清液中的药物含量进行定量检测,并计算载入颗粒中的药物质量与装载前药物总质量的比值作为药物的负载率,绘制药物负载效率随负载时间变化的负载动力学曲线。图1是本发明中多孔硅、多孔硅/石墨烯量子点复合颗粒对表皮生长因子和胰岛素的负载率随时间变化的示意图。(实验数据见表1、表2)
表1.多孔硅、多孔硅/石墨烯量子点颗粒对表皮生长因子的负载率
表2.多孔硅、多孔硅/石墨烯量子点颗粒对胰岛素的负载率
结果分析:由图1可知,与单组分的多孔硅颗粒相比,多孔硅/石墨烯量子点复合颗粒对胰岛素和表皮生长因子具有更强的负载效率,药物负载率显著提升。
1-2,对获得的多孔硅/石墨烯量子点复合颗粒进行药物缓释动力学测试;
具体过程包括:配制含梯度过氧化氢浓度的缓冲溶液,将多孔硅/石墨烯量子点复合载药颗粒浸泡于各个溶液中,置于37℃水浴中反应,使用与多肽药物对应的定量检测试剂盒,对颗粒溶液反应前及不同反应时间点上清液中的药物含量进行定量检测,并计算释放到溶液中的药物质量与载入颗粒中的药物质量的比值作为药物的负载率,绘制药物释放率随时间变化的释放动力学曲线。图2是本发明中多孔硅/石墨烯量子点复合载药颗粒在溶液体系中对表皮生长因子和胰岛素的释放率随时间变化的示意图。(实验数据见表3、表4)
表3.多孔硅、多孔硅/石墨烯量子点载药颗粒对表皮生长因子的释放率
表4.多孔硅、多孔硅/石墨烯量子点载药颗粒对胰岛素的释放率
结果分析:由图2可知,与单组分的多孔硅颗粒相比,多孔硅/石墨烯量子点复合颗粒对胰岛素和表皮生长因子具有更优的缓释效果。
实验二,对获得的多孔硅/石墨烯量子点复合颗粒进行荧光性能测试;
具体过程包括:配制含梯度过氧化氢浓度的缓冲溶液,将多孔硅/石墨烯量子点复合载药颗粒浸泡于各个溶液中,置于37℃水浴中反应,使用紫外光作为激发光源,使用荧光光谱仪记录颗粒的荧光光谱,颗粒的双色荧光动力学曲线随环境中不同的过氧化氢浓度显示出明显差异。
实验结果:图3是本发明本发明对多孔硅/石墨烯量子点复合载药颗粒进行荧光性能测试时,颗粒在梯度浓度的过氧化氢溶液中反应10小时后,多孔硅/石墨烯量子点复合载药颗粒的荧光光谱的示意图。图4是本发明对多孔硅/石墨烯量子点复合载药颗粒进行荧光性能测试时,颗粒在梯度浓度的过氧化氢溶液中反应10小时后,颗粒的荧光图像的红色通道图像和蓝色通道图像。
结果分析:由图3和图4的结果可知,反应10小时后,体系中过氧化氢浓度越高,颗粒荧光光谱中碳硅双峰比值也越高,荧光图像中红色通道越弱,蓝色通道越强,说明多孔硅/石墨烯量子点复合颗粒的比率荧光性质可用于判断体系中过氧化氢的浓度。
实验三,对多孔硅/石墨烯量子点复合载药颗粒在基质金属蛋白酶媒介中对多肽类药物的保护作用进行测试;
测试方法为:在含有浓度为5μg/mL的基质金属蛋白酶(MMP-2)的PBS缓冲溶液中,测试含有多孔硅/石墨烯量子点复合载药颗粒的溶液中胰岛素和表皮生长因子的浓度随时间的变化情况,与直接将等量的胰岛素和表皮生长因子加入MMP-2溶液后的药物浓度变化情况进行对比。
实验结果:实验数据见表5、表6;
表5.MMP媒介中表皮生长因子浓度数据(归一化)
表6.MMP媒介中胰岛素浓度数据(归一化)
图5是本发明对多孔硅/石墨烯量子点复合载药颗粒进行的多肽保护效果的测试时,在基质金属蛋白酶(MMP-2)存在时,多孔硅/石墨烯量子点复合载药体系及药物溶液体系中,表皮生长因子和胰岛素浓度随时间变化的示意图。
结果分析:根据图5的结果可知,直接加入胰岛素和表皮生长因子会被MMP-2快速降解导致药物浓度迅速下降,而多孔硅/石墨烯量子点复合载药颗粒溶液中药物浓度缓慢上升,说明多孔硅/石墨烯量子点复合载药颗粒可以通过药物的缓释有效保护多肽类药物被蛋白酶的降解作用。
实验四,测试多孔硅/石墨烯量子点复合载药颗粒和包覆多孔硅/石墨烯量子点复合载药颗粒的高分子伤口敷料对伤口部位表皮细胞增殖的促进作用;
具体过程包括:使用小鼠胚胎成纤维细胞(NIH3T3)作为模型细胞,测试与载药材料共培养后NIH3T3细胞的增殖数量。细胞活性测试方法为:在细胞培养瓶中分别培养NIH3T3细胞至贴壁后,用胰酶将细胞消化并传入96孔板中,每孔约104个细胞将孔板置于37℃、5%CO2的培养箱内过夜培养使其完全贴壁,去除上清液,向孔中分别加入100μL含有1mg/mL不同载药材料的DMEM培养基,每个浓度设置5个复孔,无添加材料的培养基作为对照组。将孔板置于培养箱中继续培养24h和48h后,去除上清,向每个孔中加入100μLCellTiterGlo试剂,静置10min后使用酶标仪检测每个孔的生物发光信号并计算细胞存活率。
实验结果:图6是本发明对多孔硅/石墨烯量子点复合载药颗粒和包覆多孔硅/石墨烯量子点复合载药颗粒的高分子伤口敷料进行对伤口部位表皮细胞增殖的促进作用的的测试结果示意图。
结果分析:根据图6的结果可知,与NIH3T3细胞共培养48小时后,单组分的壳聚糖使细胞数量增加41%,多孔硅/石墨烯量子点复合载药颗粒使细胞数量增加58%,而两者结合后包覆多孔硅/石墨烯量子点复合载药颗粒的高分子伤口敷料促进细胞数量增加77%,证明了多孔硅/石墨烯量子点复合载药颗粒与壳聚糖对于成纤维细胞的增殖具有良好的协同促进作用。
实验五,测试多孔硅/石墨烯量子点复合载药颗粒和包覆多孔硅/石墨烯量子点复合载药颗粒的高分子伤口敷料对伤口部位表皮细胞迁移具有促进作用。
促进作用通过细胞划痕实验进行验证;
实验的具体过程包括:将培养的NIH3T3细胞传入6孔板中,每个孔约加入5×105个细胞,将孔板置于37℃、5%CO2的培养箱内过夜培养后使其融合率达到第二天用10μL移液枪头垂直与细胞平面在细胞层上进行划痕使用无菌PBS冲洗细胞3次,洗去不贴壁的细胞,然后更换新鲜无血清培养基。将细胞放入培养箱中继续培养。在培养的0,6,12,24,48小时取出孔板,显微镜下观察并拍照记录划痕处的细胞图像,使用ImageJ软件打开图片,随机划取6条水平线,并计算划痕的平均宽度。
实验结果:实验数据见表7,图7是本发明对多孔硅/石墨烯量子点复合载药颗粒和包覆多孔硅/石墨烯量子点复合载药颗粒的高分子伤口敷料进行对伤口部位表皮细胞迁移的促进作用的的测试结果示意图。
表7.细胞划痕宽度数据(归一化)
结果分析:根据图7的结果可知,与对照组相比,壳聚糖对于划痕部位NIH3T3细胞的迁移有一定的促进效果,多孔硅/石墨烯量子点复合载药颗粒也可以显著的促进细胞迁移,而两者结合后,包覆多孔硅/石墨烯量子点复合载药颗粒的高分子伤口敷料对细胞迁移的促进作用更加明显。
实验五,在糖尿病大鼠伤口模型上对高分子伤口敷料的伤口诊疗效果进行测试;
实验方法为:将9只糖尿病大鼠随机分为三组,通过肌肉注射速眠新II麻醉剂使大鼠麻醉,使用剃毛机进行背部剃毛并用75%乙醇消毒。用剪刀在每只大鼠背部剪开直径为1cm左右的圆形伤口,深至筋膜。第一组对照组大鼠伤口不进行处理,第二组壳聚糖对照组大鼠伤口部位贴上仅含有壳聚糖的聚氨酯薄膜,第三组实验组大鼠伤口部位贴敷包覆多孔硅/石墨烯量子点复合载药颗粒的高分子伤口敷料。每只大鼠单独饲养,每隔24h拍照记录每只大鼠的伤口尺寸,并且贴有智能绷带的实验组大鼠伤口每天在紫外手电筒照射下观察,并拍照记录敷料荧光变色情况,一旦敷料荧光颜色由红色完全变为蓝色则说明药物已经完全释放,需立即更换新的敷料。
实验结果:
实验数据见表8,图8是本发明中多孔硅/石墨烯量子点复合载药颗粒和包覆多孔硅/石墨烯量子点复合载药颗粒的高分子伤口敷料促进糖尿病伤口愈合效果的示意图。
图9是本发明中包覆多孔硅/石墨烯量子点复合载药颗粒的高分子伤口敷料在糖尿病伤口表面荧光图像的的红色通道图像变化的示意图。
表8.糖尿病大鼠伤口面积数据(归一化)
结果分析:根据图8的结果可知,无处理的对照组在伤口造模的5天内没有明显自愈的趋势,仅贴敷壳聚糖的伤口,与不做处理的对照组相比伤口愈合的趋势略明显,5天后伤口面积减小至85%左右,说明壳聚糖做为无毒的天然高分子材料对糖尿病伤口有一定的辅助治疗作用;而贴敷包覆多孔硅/石墨烯量子点复合载药颗粒的高分子伤口敷料的伤口,伤口面积减小速率明显更快,在5天之内伤口面积持续减小,5天后伤口已经愈合50%,说明包覆多孔硅/石墨烯量子点复合载药颗粒的高分子伤口敷料对糖尿病伤口有良好的治疗效果。
根据图9的结果可知,在贴敷料一天后敷料的荧光颜色完全由红色完全消失,并且在第一天伤口明显愈合,说明在第一天的时间内伤口部位活性氧处于高水平,伴随着高分子敷料中多孔硅的氧化降解和药物的释放,因此促进伤口愈合的作用明显,随后更换新的敷料后的4天时间内,伤口严重程度降低,薄膜荧光颜色缓慢由红色转变为蓝色,随着颗粒的降解药物逐渐释放及伤口的逐渐愈合。在伤口愈合过程中,智能绷带荧光颜色的变化程度与治疗效果表现出一定的协同性。
本发明利用生物无毒性的多孔硅/石墨烯量子点复合载药颗粒中多孔硅的孔道负载特性和石墨烯量子点的药物分子吸附能力构建了高效的药物递送材料,多孔硅/石墨烯量子点对药物的负载避免了多肽类药物胰岛素、表皮生长因子的酶催化降解作用。将多孔硅/石墨烯量子点复合载药颗粒包覆在生物无毒性的柔性天然高分子凝胶上,制作成兼具诊疗效果的智能伤口敷料,利用多孔硅/石墨烯量子点的双色荧光对活性氧浓度的敏感性,实现对糖尿病伤口活性氧的可视化监控,并利用多孔硅孔道降解的氧化敏感性,实现了氧化刺激响应性的药物释放。多孔硅/石墨烯量子点复合载药颗粒与高分子凝胶的协同作用,能够加快伤口愈合,本发明有望突破糖尿病伤口难治愈的临床难题,便于糖尿病伤口患者的的自我健康管理和个性化诊疗。
以上显示和描述了本发明的基本原理、主要特征和优点。本行业的技术人员应该了解,上述实施例不以任何形式限制本发明,凡采用等同替换或等效变换的方式所获得的技术方案,均落在本发明的保护范围内。
Claims (10)
1.一种多孔硅石墨烯量子点复合载药颗粒的制备方法,其特征在于,包括:
步骤一,制备多孔硅/石墨烯量子点复合颗粒:
1)将单晶硅片经表面洗涤预处理后经过电化学刻蚀、电化学剥离、弱氧化活化后得到具有荧光特性的多孔硅颗粒;
2)将含羧基的碳材料在高温下加热,加入去离子水稀释,获得具有荧光特性的石墨烯量子点溶液;
3)将多孔硅颗粒分散到石墨烯量子点溶液中,经过震荡、离心、清洗后获得多孔硅/石墨烯量子点复合颗粒;
步骤二,制备多孔硅/石墨烯量子点复合载药颗粒:
将多孔硅/石墨烯量子点复合颗粒分散至浓度为0.5-5mg/mL的多肽药物溶液中,经过震荡、离心、清洗后获得负载药物分子的多孔硅/石墨烯量子点复合载药颗粒。
2.根据权利要求1所述的一种多孔硅石墨烯量子点复合载药颗粒的制备方法,其特征在于,所述含羧基的碳材料为L-谷氨酸粉末,将L-谷氨酸粉末采用150-200℃高温加热100-150分钟,会得到具有蓝色荧光特性的石墨烯量子点溶液。
3.根据权利要求1所述的一种多孔硅石墨烯量子点复合载药颗粒的制备方法,其特征在于,将柠檬酸钠粉末高温加热的条件采用150-250℃高温下加热30-60分钟,会得到具有蓝色荧光特性的石墨烯量子点溶液。
4.根据权利要求1所述的一种多孔硅石墨烯量子点复合载药颗粒的制备方法,其特征在于,所述多肽药物溶液为浓度为0.5-5mg/mL的胰岛素溶液,浓度为0.5-5mg/mL的表皮生长因子溶液,或浓度各为0.5-5mg/mL的胰岛素和表皮生长因子的混合溶液。
5.一种多孔硅石墨烯量子点复合载药颗粒伤口敷料,其特征在于,包括:高分子伤口敷料作为柔性载体,包覆在所述高分子伤口敷料上的多孔硅/石墨烯量子点复合载药颗粒。
6.根据权利要求5所述的一种多孔硅石墨烯量子点复合载药颗粒伤口敷料,其特征在于,所述高分子伤口敷料包括:壳聚糖伤口敷料,羧甲基壳聚糖伤口敷料,羟丙基壳聚糖伤口敷料。
7.一种多孔硅石墨烯量子点复合载药颗粒伤口敷料的制备方法,其特征在于,包括如下步骤:
步骤一,制备多孔硅/石墨烯量子点复合颗粒:
1)将单晶硅片经表面洗涤预处理后经过电化学刻蚀、电化学剥离、弱氧化活化后得到具有荧光特性的多孔硅颗粒;
2)将L-谷氨酸粉末在高温下加热,加入适量去离子水稀释,获得具有荧光特性的石墨烯量子点溶液;
3)将多孔硅颗粒分散到石墨烯量子点溶液中,经过震荡、离心、清洗后获得多孔硅/石墨烯量子点复合颗粒;
步骤二,制备多孔硅/石墨烯量子点复合载药颗粒:
将多孔硅/石墨烯量子点复合颗粒分散至浓度为0.5-5mg/mL的多肽药物溶液中,经过震荡、离心、清洗后获得负载药物分子的多孔硅/石墨烯量子点复合载药颗粒;
步骤三,制备包覆多孔硅/石墨烯量子点复合载药颗粒的伤口敷料:
将多孔硅/石墨烯量子点复合载药颗粒分散到高分子敷料原料中,并加入体积浓度为0.1-0.3%的硅烷化偶联剂,再将混合均匀的溶液涂覆在聚氨酯薄膜表面,待壳聚糖凝胶形成后,获得包覆多孔硅/石墨烯量子点复合载药颗粒的伤口敷料。
8.根据权利要求7所述的一种多孔硅石墨烯量子点复合载药颗粒伤口敷料的制备方法,其特征在于,所述高分子敷料原料包括:壳聚糖,羧甲基壳聚糖或羟丙基壳聚糖。
9.根据权利要求7所述的一种多孔硅石墨烯量子点复合载药颗粒伤口敷料的制备方法,其特征在于,所述硅烷化偶联剂包括:γ-(2.3环氧丙氧)丙基三甲氧基硅烷,1,2-二(三乙氧基甲硅烷基)乙烷,4,4’二(三乙氧基甲硅烷)-1,1’联苯,双[3-(三甲氧基甲硅烷基)丙基]胺。
10.一种多孔硅石墨烯量子点复合载药颗粒伤口敷料的用途,其特征在于,多孔硅石墨烯量子点复合载药颗粒伤口敷料用于伤口治疗:适用于糖尿病患者伤口,疾病伤口。
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