CN113730378B - 用于治疗创面的反蛋白石水凝胶微载体及其应用 - Google Patents
用于治疗创面的反蛋白石水凝胶微载体及其应用 Download PDFInfo
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- CN113730378B CN113730378B CN202111038997.6A CN202111038997A CN113730378B CN 113730378 B CN113730378 B CN 113730378B CN 202111038997 A CN202111038997 A CN 202111038997A CN 113730378 B CN113730378 B CN 113730378B
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Abstract
本发明涉及一种用于治疗创面的反蛋白石水凝胶微载体,其包括3.6~4.5wt%%环糊精、3~5wt%聚丙烯酸和3~5wt%琼脂,所述反蛋白石水凝胶微载体中具有平均粒径为100‑300nm的孔,所述孔中负载有维A酸。本发明的反蛋白石水凝胶微载体能够负载维A酸,并有助于维A酸改善创面瘢痕,具有使用方便,去瘢痕效果好的优势。
Description
技术领域
本发明属于生物医用材料领域,具体涉及一种用于治疗创面的反蛋白石水凝胶微载体。
背景技术
多年来,日常生活中突发性事故的急救治疗、医生对病人手术过程中的创伤止血、战争中受伤战士的救护止血手段大都是通过物理的压迫,如使用绷带、纱布、橡胶条等,但效果有限。在临床医学,在救治阶梯全链条的包扎止血需求,尤其是对于突发事件中的创面急性剧烈出血,由于突发出血环境的湿态多样性和动态复杂性,目前市售止血产品均不能达到快速有效止血同时可以抗菌的作用,极易发生失血性休克危及生命。目前市场上的止血材料主要包括“胶原蛋白类、氧化再生纤维素类、藻酸盐类、沸石类和壳聚糖类”等。疤痕组织的形成常发生在严重烧伤、皮肤外伤,或者是手术干预后的并发症之一。增生性疤痕主要由持续的真皮纤维化、不规则的胶原沉积和过度增生的增生性瘢痕成纤维细胞引起。疤痕组织的生成不仅影响美观,过多的疤痕组织还会影响关节的灵活运动。增生性疤痕的常规治疗可分为非侵入性治疗(如局部硅胶片和压力敷料)和侵入性治疗(如手术切除和激光切除)。但这些治疗方法存在疗效低、复发率高、疼痛过程等不良反应。如何有效防止疤痕的形成一直是临床医生和研究人员关注的问题。创面频繁地发生于日常生活和外科手术等,创面修复是全世界医疗卫生领域一个备受关注的问题。
维A酸是体内维生素A的代谢中间产物,主要影响骨的生长和促进上皮细胞增生、分化、角质溶解等代谢作用。其用于治疗寻常痤疮、银屑病、鱼鳞病、扁平苔癣、毛发红糠疹、毛囊角化病、鳞状细胞癌及黑色素瘤等疾病。但是,由于维A酸水溶性差,通常需要采用乳膏的形式给药。因此,如何克服维A酸水溶性差的缺点,提供一种新的载体用于维A酸的给药是一个新的研发方向。反蛋白石水凝胶因为其孔径和结构可控,成为药物载体领域的研发新热点。
中国专利申请CN112843220A公开了一种用于抑制疤痕生成的反蛋白石膜及其制备方法,该方法利用二氧化硅粒子与聚乳酸羟基乙酸共聚物通过负复制方法,制备得到具有规则且相互连通多孔结构的反蛋白石膜;在聚乳酸羟基乙酸共聚物的玻璃化温度下进行拉伸得到具有可调节图案的拉伸反蛋白石膜,通过真空负压的方法装载甲基丙烯酸酐化明胶和抗菌肽。
CN107655813B公开了一种基于反蛋白石结构水凝胶的心肌细胞检测方法及其应用,包括以下步骤:1)制备生物相容性的反蛋白石结构水凝胶;2)基于反蛋白石结构水凝胶心肌细胞的培养;3)心肌细胞的检测;4)数据的分析。该反蛋白石结构色水凝胶具备良好的生物相容性,细胞在其表面生长保持高活性和表型,反蛋白石结构水凝胶不仅为心肌细胞的生长提供载体,更重要的是为心肌细胞收缩力和跳动频率的检测提供稳定的光学传感信号,该检测方法不需要复杂的检测系统,具备直观性、高灵敏行、高效、不受外界条件影响的优势;该方法可应用于心脏药物的筛选、评估,通过加入药物后心肌细胞收缩力和跳动频率的改变进行筛选。
在本发明申请的前期研究中,发明了一种智能水凝胶,所述智能水凝胶包括抗菌活性成分、1.5~2.5wt%环糊精、3~5wt%聚丙烯酸、3~5wt%琼脂、适量pH调节剂和余量的去离子水。该智能水凝胶微具有温度敏感性,能够依据创伤部位的温度变化自动调整抗菌成分的释放速率。相关的研究成果已申请中国发明专利,申请号为202110349023.3。该发明专利申请的全部内容被引入到本发明申请的文本中并且作为说明书的一部分。本发明申请的内容是在该在先申请的基础上研发得到,本发明申请的发明出人意料的发现上述水凝胶虽然不能直接用于制备反蛋白石水凝胶微载体结构,但经过调整之后还可以制成反蛋白石水凝胶微载体结构并且用于负载维A酸,并且出人意料的发现该负载维A酸的反蛋白石水凝胶微载体能够减轻创面所导致的瘢痕。
发明内容
基于上述背景技术,本发明所要解决的技术问题在于提供用于治疗创面的反蛋白石水凝胶微载体。为了实现本发明的发明目的,拟采用如下技术方案:
本发明一方面涉及一种反蛋白石水凝胶微载体,其包括3.6~4.5wt%环糊精、3~5wt%聚丙烯酸和3~5wt%琼脂,所述反蛋白石水凝胶微载体中具有平均粒径为100-300nm的孔,所述孔中负载有维A酸。本发明通过调整环糊精的含量,有助于形成反蛋白石水凝胶微载体并有助于负载维A酸。
在本发明的一个优选实施方式中,所述反蛋白石水凝胶微载体为薄膜。本发明通过将反蛋白石水凝胶微载体设置为薄膜形态,可以直接用于创伤瘢痕部位的敷料。
本发明另一方面还涉及上述反蛋白石水凝胶微载体的制备方法,其制备步骤如下:
(1)制备二氧化硅胶体晶体模板;
(2)制备反蛋白石薄膜微载体;
(3)反蛋白石水凝胶微载体负载维A酸。
在本发明的一个优选实施方式中,所述二氧化硅胶体晶体模板的制备包括如下步骤:
选取平均直径为100-300纳米的二氧化硅粒子,悬浮于无水乙醇内,通过涡旋和超声使其分散于无水乙醇内,配置浓度为1-3%的二氧化硅分散液;将玻璃片垂直插入二氧化硅分散液内,静置于恒温恒湿箱内,随无水乙醇蒸发,二氧化硅粒子整齐排布于玻璃片表面,形成二氧化硅胶体晶体模板。
在本发明的一个优选实施方式中,所述反蛋白石薄膜微载体的制备包括如下步骤:
(1)在配制罐中加入去离子水,加入环糊精,搅拌均匀;
(2)将聚丙烯酸溶解于去离子水中,加入琼脂,加热到45-55℃,搅拌15~20min;
(3)将步骤(1)与步骤(2)所得的分散体混合,调节pH至6.5-7.5,加热到45-55℃得水凝胶分散液;
(4)将上述水凝胶分散液滴加在二氧化硅胶体晶体模板上形成薄膜,在45-55℃下保温0.5-2小时使其渗透二氧化硅粒子间隙,降至常温静止干燥1-2天;经过干燥后,将水凝胶分散液和二氧化硅粒子复合物从玻璃片上玻璃,滴加5-15%氢氟酸于复合物表面,分腐蚀二氧化硅胶体晶体模板,用纯水反复冲洗反蛋白石膜后干燥备用。
在本发明的一个优选实施方式中,所述反蛋白石水凝胶微载体负载维A酸的步骤包括:
将维A酸溶解于乙醇中形成溶液,将该溶液滴加到反蛋白石薄膜微载体表面,通过在反蛋白石薄膜微载体底面抽真空形成负压的方式将维A酸负载到反蛋白石水凝胶微载体中。
本发明另一方还涉及上述反蛋白石水凝胶微载体的应用,其应用于皮肤浅表损伤的快速修复。
本发明另一方还涉及上述反蛋白石水凝胶微载体的应用,其应用于创面瘢痕的修复。
有益效果
本发明的反蛋白石水凝胶微载体能够负载维A酸,并有助于维A酸改善创面瘢痕,具有使用方便,去瘢痕效果好的优势。
具体实施方式
为了进一步理解本发明,下面将结合本发明实施例,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。
如无特殊说明,本发明实施例中所涉及的试剂均为市售产品,均可以通过商业渠道购买获得。
实施例1:反蛋白石水凝胶微载体的制备
一种反蛋白石水凝胶微载体,制备步骤如下:
(1)制备二氧化硅胶体晶体模板:
选取平均直径为200纳米的二氧化硅粒子,悬浮于无水乙醇内,通过涡旋和超声使其充分分散于无水乙醇内,配置浓度为2%的二氧化硅分散液。将玻璃片垂直插入二氧化硅分散液内,静置于恒温恒湿箱内,调节箱内温度30摄氏度,湿度40%。随无水乙醇蒸发,二氧化硅粒子整齐排布于玻璃片表面,形成二氧化硅胶体晶体模板。
(2)制备反蛋白石薄膜微载体
首先,反蛋白石薄膜的配方如下:
环糊精 2g
聚丙烯酸 2g
琼脂 2g
pH调节剂 适量
去离子水 50g
其制备步骤如下:
1、在配制罐中加入配制总量一半的去离子水,加入环糊精,搅拌均匀;
2、将聚丙烯酸溶解于剩余的去离子水中,加入琼脂,加热到50℃,搅拌15~20min后;
3、将步骤1与步骤2所得的分散体混合,调节pH至7.0,加热到50℃得水凝胶分散液;
4、将上述水凝胶分散液滴加在二氧化硅胶体晶体模板上形成1mm厚的薄膜,在50℃下保温1小时使其充分渗透二氧化硅粒子间隙,降至常温静止干燥1天。经过干燥后,手动将水凝胶分散液和二氧化硅粒子复合物从玻璃片上玻璃,滴加10%氢氟酸于复合物表面,15分钟后充分腐蚀二氧化硅胶体晶体模板,用纯水反复冲洗反蛋白石膜后干燥备用。
(3)反蛋白石水凝胶微载体负载维A酸
将维A酸溶解于乙醇中形成5mg/mL溶液,将该溶液滴加到反蛋白石薄膜微载体表面,通过在反蛋白石薄膜微载体底面抽真空形成负压的方式将维A酸负载到反蛋白石水凝胶微载体中。
实施例2:创面瘢痕修复实验
方法:购买大耳白兔18只,雌雄不计,体重1.8-2.2kg,适应性喂养7天后,观察各白兔,进食水,均无明显异常,纳入实验用。瘢痕动物模型的建立:耳缘静脉注射浓度30g/L的戊巴比妥溶液进行麻醉,于兔耳腹侧沿长轴做直径为1cm的圆形创面,每耳2处,间隔大约3.0cm,完整切除全层皮肤,创面经21天皮化自然愈合形成增生性瘢痕硬块。未出现创面感染不愈或愈合不良,形成新生疤痕组织。
分组:选取18只兔子随机分为3组,分别是空白组、实验组和对照组,每组6只兔子,24个创面。其中空白组为不做任何干预处理的瘢痕模型兔子,实验组采用实施例1所制备的负载有维A酸的反蛋白石水凝胶薄膜微载体进行贴敷,水凝胶薄膜略大于创面,贴敷于兔耳新生疤痕贴表面并固定,每3天更换一次,在第13天进行评价,对照组为采用市售维A酸乳膏进行处理,每个创面每天涂抹一次。疗效评价:疗效评价采用如表1所示的温哥华瘢痕量表(vancouver scar scale,VSS)进行评定,分值越高,说明瘢痕越重。
表1:温哥华瘢痕量表评分标准
统计学处理:采用SPSS软件对数据进行统计学分析。结果采用x±SD表示,结果如表2所示。
表2:兔耳局部瘢痕干预前后VSS值比较
结果:评价3组瘢痕干预前VSS评分无差异。通过统计学分析重复测量方差分析发现,除了空白组降低不明显之外,而实验组和对照组的瘢痕经过干预后的VSS值明显降低,其中,实验组和对照组之间显著性差异明显,由此说明本发明的反蛋白石水凝胶微载体有助于维A酸改善创面瘢痕。
以上描述了本发明优选实施方式,然其并非用以限定本发明。本领域技术人员对在此公开的实施方案可进行并不偏离本发明范畴和精神的改进和变化。
Claims (4)
1.一种反蛋白石水凝胶微载体,其特征在于:包括3.6~4.5wt%wt%环糊精、3~5wt%聚丙烯酸和3~5wt%琼脂,所述反蛋白石水凝胶微载体中具有平均粒径为100-300nm的孔,所述孔中负载有维A酸;所述反蛋白石水凝胶微载体通过如下制备方法制备得到:
(1)制备二氧化硅胶体晶体模板:选取平均直径为100-300纳米的二氧化硅粒子,悬浮于无水乙醇内,通过涡旋和超声使其分散于无水乙醇内,配置浓度为1-3%的二氧化硅分散液;将玻璃片垂直插入二氧化硅分散液内,静置于恒温恒湿箱内,随无水乙醇蒸发,二氧化硅粒子整齐排布于玻璃片表面,形成二氧化硅胶体晶体模板;
(2)制备反蛋白石薄膜微载体:在配制罐中加入去离子水,加入环糊精,搅拌均匀;将聚丙烯酸溶解于去离子水中,加入琼脂,加热到45-55℃,搅拌15~20min;将步骤(1)与步骤(2)所得的分散体混合,调节pH至6.5-7.5,加热到45-55℃得水凝胶分散液;将上述水凝胶分散液滴加在二氧化硅胶体晶体模板上形成薄膜,在45-55℃下保温0.5-2小时使其渗透二氧化硅粒子间隙,降至常温静止干燥1-2天;经过干燥后,将水凝胶分散液和二氧化硅粒子复合物从玻璃片上剥离,滴加5-15%氢氟酸于复合物表面,分腐蚀二氧化硅胶体晶体模板,用纯水反复冲洗反蛋白石膜后干燥备用;
(3)反蛋白石水凝胶微载体负载维A酸:将维A酸溶解于乙醇中形成溶液,将该溶液滴加到反蛋白石薄膜微载体表面,通过在反蛋白石薄膜微载体底面抽真空形成负压的方式将维A酸负载到反蛋白石水凝胶微载体中。
2.根据权利要求1所述的水凝胶微载体,其中,所述反蛋白石水凝胶微载体为薄膜。
3.根据权利要求1或2所述的反蛋白石水凝胶微载体的应用,其应用于制备皮肤浅表损伤的快速修复制剂。
4.根据权利要求1或2所述的反蛋白石水凝胶微载体的应用,其应用于制备创面瘢痕的修复的制剂。
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