CN113663208A - 一种七鳃鳗牙齿形状仿生的抗菌丝胶微针的制备及其生物应用 - Google Patents
一种七鳃鳗牙齿形状仿生的抗菌丝胶微针的制备及其生物应用 Download PDFInfo
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Abstract
本发明公开了一种七鳃鳗牙齿形状仿生的抗菌丝胶微针的制备方法,包括:(1)设计一种七鳃鳗牙齿形状仿生的微针模具,采用3D打印进行模具的打印;(2)将PDMS浇筑到模具表面,室温交联,得到PDMS微针模板;(3)将混合氧化锌纳米粒子的丝胶溶液加入PDMS模板中作为微针的主体成分;(4)离心,抽真空,重复进行三次;(5)加入PVA作为微针的基底,室温条件下自然干燥,去除模板得到抗菌丝胶微针。本发明制备的抗菌丝胶微针具有七鳃鳗牙齿仿生的形状,且保留了天然丝胶蛋白本身的良好生物相容性和生物可降解性,混合了氧化锌纳米粒子的微针兼具抗菌特性,可应用于细菌感染的创口修复。
Description
技术领域
本发明涉及生物医用材料领域,具体指一种七鳃鳗牙齿形状仿生的抗菌丝胶微针的制备方法,用于感染性皮肤创面修复。
背景技术
皮肤是人体最大的器官,具有保护机体、分泌代谢、调节体温、维持稳态、感受刺激等多种功能。在受到外伤、烧伤、糖尿病溃疡等因素影响时,皮肤完整性丧失,皮肤功能受损,会给患者身心造成伤害。虽然皮肤具有一定自愈能力,但大面积创伤愈合缓慢,并且在自愈过程中会形成瘢痕组织,难以修复具有功能的组织。同时皮肤损伤容易并发感染,使创口更难愈合,严重的会危及生命。因此,通常需要采用伤口敷料、人工真皮等皮肤替代物对感染性创面进行治疗。
丝胶蛋白是包裹在蚕茧表面的一种天然高分子黏性蛋白,主要由分子量为10-300kDa的多肽组成,包括丝氨酸、天冬氨酸、甘氨酸等多种氨基酸。丝胶是一种水溶性蛋白,同时具有优良的生物相容性、生物可降解、生物亲和性等特点,因此被制备成各种各样的生物活性材料,应用于生物医学的多种损伤修复和疾病诊疗中,在组织工程修复和药物载体的研究中备受关注,具有很大的发展前景。
微针是一种新兴的医疗技术,即通过微创方法将某些药物或小分子递送至人体内。根据微针的结构可将其分为空心微针和实心微针,其中实心微针包括不可溶性微针、可溶性微针、水凝胶微针等。微针的应用十分广泛,其主要应用于疫苗、癌症治疗、皮肤治疗、美容等领域。近年来随着生物医学的发展,一些具有生物活性的微针也被用于皮肤创面修复,微针较大的比表面积增加了它与伤口的接触面积,同时能缓慢释放活性物质,促进伤口愈合。
七鳃鳗是一种无颚的食腐动物,它有一个吸盘嘴巴,张开时呈圆形,其内壁长满了肉刺般锋利的小牙齿,口周边附生着细小的***状突起,称口触须,有吸附功能。当七鳃鳗进行捕食时,它就用具有向内倾斜角度的牙齿紧紧地扣住猎物,具有倾角的牙齿帮助它扣咬更紧,方便捕食。
基于以上,我们首次模仿七鳃鳗牙齿的特殊形状,设计了一种微针模具。它的特点是靠里面的一圈针比较短,刚好能够覆盖在皮肤创伤部位,起到支持和修复的作用,而靠外面的一圈针比较长而且仿生七鳃鳗的牙齿有一个向内倾斜的角度,利用向内的倾斜角度将创面向中间牵拉,有利于固定伤口从而促进创面修复。利用简单的模板法制备搭载氧化锌纳米粒子的丝胶微针,一方面外圈向内倾斜的针尖利于创面被动往中间牵拉有利于创面修复,另一方面微针逐渐溶解释放出的丝胶蛋白能够促进皮肤愈合,此外搭载的氧化锌纳米粒子具有抗菌作用,可用于感染性创面修复。
发明内容
本发明的目的在于针对感染性创面修复难愈合的问题,提供一种工艺简单、成本低廉、生物相容性良好、同时兼具抗菌和促修复功能的丝胶微针的制备方法,应用于感染性创面修复。
为达到上述目的,本发明提供的抗菌丝胶微针制备方法,所述制备方法包括以下步骤:
(1)利用SolidWorks软件设计七鳃鳗牙齿形状仿生的模型,利用3D打印得到微针阳性模具;
(2)将PDMS A液与B液按一定比例混合后浇筑到步骤(1)中得到的阳性模具上,室温固化交联得到PDMS微针阴性模板;
(3)称取一定质量蚕茧,高温碱提法提取丝胶蛋白,经离心、透析、冻干后得到天然丝胶蛋白固体;
(4)将步骤(3)中所得丝胶蛋白固体溶于水配制成一定浓度的丝胶蛋白溶液;
(5)将丝胶蛋白与氧化锌纳米粒子的混合溶液加入步骤(2)中得到的PDMS微针阴性模板中;
(6)将步骤(5)中的模板离心,真空抽干液体内的气泡,重复三次,加入PVA溶液填充模板作为微针的基底;
(7)将步骤(4)所得的微针置于室温自然干燥,去除PDMS模具即可得到完整的抗菌丝胶微针。
进一步地,所述步骤(1)中利用Solid Work设计的仿生模具特点包括:微针贴片呈圆形,其上分布若干长针和若干短针,其中短针位于圆形中间,长针分布于短针外周;长针长度为1.5-2.5mm,向内与贴片平面角度为0-90度;短针长度为0.5-1.5mm,与贴片平面角度为90度。
进一步地,所述步骤(1)中仿生微针模具的长针和短针的数量可依据实际需求进行调整。
进一步地,所述步骤(2)中选用的蚕茧为正常家蚕蚕茧品种(白玉,皓月等)或家蚕丝素缺失型突变品种(185Nd-s,140Nd-s等),购于中国农业科学院蚕业研究所。
进一步地,所述步骤(2)中PDMS的A液与B液的混合比例为8:1-20:1,即B液1mL对应A液8-20mL进行混合。
进一步地,所述步骤(4)中丝胶溶液浓度为10%-25%,即100mL水中溶解10-25g丝胶蛋白。
进一步地,所述步骤(5)中氧化锌纳米粒子的浓度为0-400μg/mL。
进一步地,所述步骤(6)中PVA的浓度为10%-30%,即100mL水中溶解10-30g PVA固体。
本发明提供了一种七鳃鳗牙齿形状仿生的抗菌丝胶微针的制备方法,该方法操作简单、成本较低、普遍适用、不需要特殊复杂仪器,可通过调整长针和短针的数量和角度改变微针的表观,同时可通过改变丝胶的浓度、氧化锌纳米粒子的浓度以及PVA的浓度调整微针的促修复和抗菌性能,可用于细菌感染性创面的修复,在生物医学领域具有广泛的应用前景。
附图说明
图1为本发明实施例中抗菌丝胶微针的表征展示图。
图2为本发明实施例中丝胶微针的表征展示图。
图3为本发明实施例中无倾角的丝胶微针的表征展示图。
图4为本发明实施例中丝胶微针的力学性能展示图。
图5为本发明实施例中抗菌丝胶微针的体外抗菌展示图。
图6为本发明实施例中抗菌丝胶微针的体内抗菌展示图。
图7为本发明实施例中抗菌丝胶微针的生物相容性展示图。
图8为本发明实施例中抗菌丝胶微针对普通皮肤创面修复大体观展示图。
图9为本发明实施例中抗菌丝胶微针对普通皮肤创面修复展示图。
图10为本发明实施例中抗菌丝胶微针对感染性皮肤创面修复展示图。
具体实施方案
为了使本发明的技术方案及优点更加清楚,以下结合附图及实施例,对本发明进行进一步的详细说明。此处所描述的具体实施例仅用以解释本发明,并不用于限定本发明。为了使公众对本发明有更好的了解,在下文对本发明的细节描述中详尽描述了一些特定的细节部分。
下面结合实施例对本发明做进一步的说明:
本发明中所用的蚕茧是家蚕蚕茧(白玉、皓月等)或丝素缺失型蚕茧(185Nd-s,140Nd-s等);其余所用试剂均为分析纯。
实施例1:抗菌丝胶微针的制备及表征
(1)利用SolidWorks软件设计七鳃鳗牙齿形状仿生的模型,利用3D打印得到阳性模具,模具特点为:微针贴片呈圆形,其上分布不同个数的长针和短针,长针长度为2.5mm,向内与贴片平面角度为60度,短针长度为1.5mm,与贴片平面角度为90度;
(2)将PDMS A液与B液按10:1体积比混合后浇筑到步骤(1)中得到的阳性模具上,室温固化交联得到PDMS微针阴性模板;
(3)将20g蚕茧洗净沥干,浸泡于400mL 0.02mol/L Na2CO3溶液中,在100℃,600rpm条件下搅拌加热反应1小时,冷却后3500rpm离心5分钟去除不溶性沉淀,取上层澄清溶液以3500Da透析袋在去离子水中透析2-3天,溶液以8000rpm离心10分钟去除不溶性沉淀,取上层澄清溶液于液氮中速冻后置于真空冷冻干燥机完全冻干,得到纯净的丝胶蛋白固体,溶于水中配成15%丝胶溶液;
(4)向丝胶溶液中加入氧化锌纳米粒子配成100μg/mL混悬液,将混悬液加入步骤(2)中的PDMS阴性模板中,以2000rpm离心5分钟,0.1kPa抽真空5分钟,并重复离心和抽真空3次;
(5)将20%PVA溶液加入丝胶混悬液上部填充PDMS模板作为微针的基底,室温自然干燥混合乳液;
(6)去除PDMS模板即可得到抗菌丝胶微针,对抗菌丝胶微针的形貌、SEM、荧光、EDS等进行表征检测。
结果如图1所示,A图为微针制备流程图;B图为3D打印的模具;C图为PDMS阴性模板图;D-E图为抗菌丝胶微针的大体观图,可见微针形状;F-G图为抗菌丝胶微针的荧光图,可见微针具有丝胶本身的荧光特性;H-I为抗菌丝胶微针的SEM图,可见长针长度为2.5mm,短针长度为1.5mm;J图为氧化锌纳米粒子的SEM图;K-L图中为丝胶微针和抗菌丝胶微针的针体SEM图,可见抗菌丝胶微针表面有氧化锌纳米粒子凸起;M图为丝胶微针和抗菌丝胶微针的EDS图,可见抗菌丝胶微针含有Zn元素。
实施例2:丝胶微针的制备及表征
(1)利用SolidWorks软件设计七鳃鳗牙齿形状仿生的模型,利用3D打印得到阳性模具,模具特点为:微针贴片呈圆形,其上分布不同个数的长针和短针,长针长度为2.5mm,向内与贴片平面角度为60度,短针长度为1.5mm,与贴片平面角度为90度;
(2)将PDMS A液与B液按10:1体积比混合后浇筑到步骤(1)中得到的阳性模具上,室温固化交联得到PDMS微针阴性模板;
(3)将20g蚕茧洗净沥干,浸泡于400mL 0.02mol/L Na2CO3溶液中,在100℃,600rpm条件下搅拌加热反应1小时,冷却后3500rpm离心5分钟去除不溶性沉淀,取上层澄清溶液以3500Da透析袋在去离子水中透析2-3天,溶液以8000rpm离心10分钟去除不溶性沉淀,取上层澄清溶液于液氮中速冻后置于真空冷冻干燥机完全冻干,得到纯净的丝胶蛋白固体,溶于水中配成15%丝胶溶液;
(4)将丝胶微针溶液加入步骤(2)中的PDMS阴性模板中,以2000rpm离心5分钟,0.1kPa抽真空5分钟,并重复离心和抽真空3次;
(5)将20%PVA溶液加入丝胶混悬液上部填充PDMS模板作为微针的基底,室温自然干燥混合乳液;
(6)去除PDMS模板即可得到抗菌丝胶微针,对丝胶微针的形貌、SEM、荧光等进行表征检测。
结果如图1所示,A图为丝胶微针的大体观,可见微针表观特征;B图为丝胶微针的压缩模量,表明丝胶微针的力学性能;C图为丝胶微针的SEM图,可见微针的细节特征;D图为丝胶微针的荧光图,可见丝胶微针具有荧光特性。
实施例3:无倾角的丝胶微针的制备及表征
(1)利用SolidWorks软件设计七鳃鳗牙齿形状仿生的模型,利用3D打印得到阳性模具,模具特点为:微针贴片呈圆形,其上分布不同个数的长针和短针,长针长度为2.5mm,向内与贴片平面角度为90度,短针长度为1.5mm,与贴片平面角度为90度;
(2)将PDMS A液与B液按10:1体积比混合后浇筑到步骤(1)中得到的阳性模具上,室温固化交联得到PDMS微针阴性模板;
(3)将20g蚕茧洗净沥干,浸泡于400mL 0.02mol/L Na2CO3溶液中,在100℃,600rpm条件下搅拌加热反应1小时,冷却后3500rpm离心5分钟去除不溶性沉淀,取上层澄清溶液以3500Da透析袋在去离子水中透析2-3天,溶液以8000rpm离心10分钟去除不溶性沉淀,取上层澄清溶液于液氮中速冻后置于真空冷冻干燥机完全冻干,得到纯净的丝胶蛋白固体,溶于水中配成15%丝胶溶液;
(4)将丝胶溶液加入步骤(2)中的PDMS阴性模板中,以2000rpm离心5分钟,0.1kPa抽真空5分钟,并重复离心和抽真空3次;
(5)将20%PVA溶液加入丝胶混悬液上部填充PDMS模板作为微针的基底,室温自然干燥混合乳液;
(6)去除PDMS模板即可得到无倾角的丝胶微针,对丝胶微针的形貌进行表征。
结果如图3所示,从左至右依次为3D打印的外圈无倾角的微针模具、PDMS阴性模板、微针大体观图,可见外圈无倾角的微针的表观特征。
实施例4:抗菌丝胶微针的力学性能
(1)体外力学性能:将抗菌丝胶微针置于压缩强度测试仪台面,传感探头自动压缩至微针断裂,记录所施加的力绘制压缩强度曲线图;
(2)体内力学性能:将抗菌丝胶微针扎于脱毛的小鼠背部,对背部组织进行台盼蓝染色和HE切片染色。
结果如图4所示,A图中压缩模量曲线图表明微针的强度可达6.4N,理论上能扎透皮肤;B图中小鼠皮肤台盼蓝染色可见扎出的针孔被染成蓝色:C图中HE切片结果表明微针能在小鼠皮肤扎出针孔。
实施例5:抗菌丝胶微针的体外抗菌作用
(1)将金黄色葡萄球菌和大肠杆菌配成浓度为0.5×108/mL的细菌悬液;
(2)取10μL上述菌液加入到190μL肉汤培养基中;
(3)将灭菌后的抗菌丝胶微针置于步骤(2)中的菌液中,使微针针尖与菌液充分接触,37℃孵育6小时;
(4)将菌液进行稀释并涂板,计数菌落个数。
结果如图5所示,OSM代表没有氧化锌纳米粒子的丝胶微针,OASM代表不同氧化锌纳米粒子浓度的丝胶微针,A图是实验步骤的示意图;B-C图为对金黄色葡萄球菌的体外抗菌作用,D-E图为对大肠杆菌的体外抗菌作用,结果表明含氧化锌纳米粒子的抗菌丝胶微针处理后菌落数明显减少,说明抗菌丝胶微针具有明显的体外抗菌作用。
实施例6:抗菌丝胶微针的体内抗菌作用
(1)将金黄色葡萄球菌配成浓度为0.5×108/mL的细菌悬液;
(2)在小鼠背部构建一个直径为10mm的圆形全皮层损伤模型,吸取10μL菌液涂于创口部位;
(3)将灭菌后的抗菌丝胶微针置于创口部位,使微针针尖与菌液充分接触;
(4)微针处理6小时后用无菌拭子收集创口处的液体,进行稀释并涂板,计数菌落个数。
结果如图6所示,OSM代表没有氧化锌纳米粒子的丝胶微针,OASM代表不同氧化锌纳米粒子浓度的丝胶微针,A图是实验步骤的示意图;B-C图为对金黄色葡萄球菌的体内抗菌作用,结果表明含氧化锌纳米粒子的抗菌丝胶微针处理后创口处菌落数明显减少,说明抗菌丝胶微针具有明显的体内抗菌作用。
实施例7:抗菌丝胶微针的生物相容性
(1)抗菌丝胶微针的血液相容性:将抗菌丝胶微针OASM和丝胶微针OSM溶解得到微针溶液,以PBS缓冲液作为阴性对照,0.2%Triton X 100溶液作为阳性对照;选取血常规正常的抗凝血标本,800rpm离心5分钟,弃上清,用PBS缓冲液洗涤红细胞2-3次,收集下层红细胞,配成2%红细胞悬液;将100μL不同的微针溶液和900μL红细胞悬液混合,于37℃摇床孵育4小时,8000rpm离心10分钟,收集上清;将收集的上清用酶标仪检测其545nm处的吸光度。
(2)抗菌丝胶微针的细胞相容性:将抗菌丝胶微针OASM和丝胶微针OSM溶解得到微针溶液,将不同的微针溶液与L929和HaCaT细胞共孵育24小时,采用CCK8检测细胞活力,Live/Dead进行活死细胞染色。
结果如图7所示,A图为血液相容性结果,表明抗菌丝胶微针不引起溶血反应;B图为L929和HaCat细胞的CCK8结果,C图为L929和HaCaT细胞的Live/Dead染色结果,结果表明抗菌丝胶微针具有良好的细胞相容性,不会引起细胞的死亡。
实施例8:抗菌丝胶微针对普通创面的修复作用
(1)在小鼠背部构建直径为10mm的圆形皮肤全层损伤创面模型;
(2)以未处理和基底组作为两个对照组,SM代表外圈无倾角的丝胶微针,OSM代表没有氧化锌纳米粒子的丝胶微针,OASM代表抗菌丝胶微针,皮耐克作为临床对照,将这些材料置于创面处,并用敷贴固定;
(3)记录处理后不同时间点创面的面积并计算伤口愈合率,在不同时间点取小鼠皮肤组织进行HE和马松染色。
结果如图8和图9所示,图8A-B为实验的流程图;8C-8D为不同时间点创面的大体观图和大体观模拟图,8D为创口愈合率统计结果,结果表明丝胶微针和抗菌丝胶微针具有更好的创面修复效果,即创口愈合得更快;图9A-9B是各组创口组织在第7、14、21天的HE和马松染色结果,图9C-F是第14和21天各组切片毛囊个数和瘢痕长度的统计结果,结果表明相较于对照组和皮耐克组,丝胶微针和抗菌丝胶微针处理组中新生毛囊更多,瘢痕长度更短,同时有倾角的微针效果更优于无倾角的微针,说明抗菌丝胶微针具有较好的促进创面愈合的作用。
实施例9:抗菌丝胶微针对金黄色葡萄球菌感染的创面的修复作用
(1)将金黄色葡萄球菌配成浓度为0.5×108/mL的细菌悬液;
(2)在小鼠背部构建一个直径为10mm的圆形全皮层损伤模型,吸取10μL菌液涂于创口部位;
(3)以未处理和基底组作为两个对照组,OSM代表没有氧化锌纳米粒子的丝胶微针,OASM代表抗菌丝胶微针,将这两种微针置于感染性创面处,并用敷贴固定;
(4)记录处理后不同时间点创面的面积并计算伤口愈合率,并在不同时间点取小鼠皮肤组织进行HE和马松染色。
结果如图10所示,A图是实验的流程图;B-C图是不同时间点各处理组小鼠创面的大体观和大体观的模拟图;D图是不同时间点的伤口愈合率;E图是各组处理后第14天和21天小鼠创面组织的HE和马松染色;F-I图是各组处理后第14天和第21天小鼠创面的毛囊个数和瘢痕长度的统计结果,以上结果共同表明抗菌丝胶微针具有抗菌作用,因此能在早期促进感染性创面的愈合,促进毛囊再生和血管再生,因此具有较好的促感染性创面修复的作用。
最后需申明的是,以上列举的仅为本发明的具体实施例,而本发明并不限于以上实施例,还可有许多变形,因此由本发明所公开的内容直接或联想到的所有变形,均应认为是本发明的保护范围。
Claims (6)
1.一种七鳃鳗牙齿形状仿生的抗菌丝胶微针,它由丝胶蛋白和氧化锌纳米粒子构成;微针整体呈圆形,其上分布若干长针和若干短针,其中短针分布于圆形中间,长针分布于短针外周;分布在外周的长针长度为1.5-2.5mm,向内与贴片平面角度为0-90度,分布在中间的短针长度为0.5-1.5mm,与贴片平面角度为90度。
2.根据权利要求1所述的抗菌丝胶微针,其制备方法包括:
(1)利用SolidWorks软件设计七鳃鳗牙齿形状仿生的模型,利用3D打印得到树脂材质的模具;
(2)将PDMS A液与B液按一定比例混合后浇筑到步骤(1)中得到的模具上,室温自然交联得到PDMS微针模板;
(3)将丝胶和氧化锌纳米粒子的混合溶液加入步骤(2)中得到的PDMS微针模板中;
(4)将步骤(3)中的模板离心,真空抽干液体内的气泡,重复三次,加入PVA溶液填充模板作为微针的基底;
(5)将步骤(4)所得的微针置于室温自然干燥,去除PDMS模板即可得到丝胶微针。
3.根据权利要求2所述的制备方法,其特征在于:所述步骤(2)中PDMS的A液与B液的混合比例为8:1-20:1。
4.根据权利要求2所述的制备方法,其特征在于:所述步骤(3)中丝胶溶液的浓度为10%-25%,氧化锌纳米粒子的浓度为0-400μg/mL。
5.根据权利要求2所述的制备方法,其特征在于:所述步骤(4)中PVA的浓度为10%-30%。
6.一种七鳃鳗牙齿形状仿生的抗菌丝胶微针的应用,其特征在于:丝胶微针作为感染性创面修复材料的应用。
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