CN116694089B - 一种用于抑制瘢痕的水凝胶及其制备方法和应用 - Google Patents
一种用于抑制瘢痕的水凝胶及其制备方法和应用 Download PDFInfo
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Abstract
本发明涉及一种用于抑制瘢痕的水凝胶,涉及生物医学工程技术领域。该水凝胶包括水凝胶基料、光热材料、YAP信号抑制剂、光引发剂,水凝胶基料的工作浓度为0.1‑0.3g/ml,光热材料的工作浓度为0.00015‑0.00025g/ml,YAP信号抑制剂的工作浓度为0.00025‑0.00035g/ml,光引发剂的工作浓度为0.000025‑0.00025g/ml。该水凝胶采用光热材料、YAP信号抑制剂作为原料,使该水凝胶具有在伤口愈合的过程中抑制瘢痕生成,并且抗伤口感染的优势。
Description
技术领域
本发明涉及生物医学工程技术领域,特别是涉及一种用于抑制瘢痕的水凝胶及其制备方法和应用。
背景技术
伤口愈合是一个复杂的过程,涉及炎症、纤维增生、新生血管形成、胶原沉积、上皮形成和伤口收缩。在愈合过程中,任何一个阶段出现问题则会造成慢性伤口形成,增加细菌感染的风险,且造成瘢痕化愈合。健康个体的正常愈合过程以最佳速度发生,但在慢性伤口中通常会延迟甚至完全受损。而对于糖尿病患者来说,伤口愈合不良是一个主要的临床问题。现有的伤口护理中杀死细菌的办法大部分为使用抗生素,抗生素可以有效抑制和杀死大多数细菌,但是如果长期使用抗生素,则会产生细菌耐药性,从而加剧健康问题。不仅如此,慢性伤口愈合过程中非常容易造成细菌感染,且往往伴随着瘢痕形成。
发明内容
针对上述问题,本发明提供一种用于抑制瘢痕的水凝胶,该水凝胶采用光热材料、YAP信号抑制剂作为原料,使该水凝胶具有在伤口愈合的过程中抑制瘢痕生成,并且抗伤口感染的优势。
为了达到上述目的,本发明提供了一种用于抑制瘢痕的水凝胶,该水凝胶包括水凝胶基料、光热材料、YAP信号抑制剂、光引发剂,所述水凝胶基料的工作浓度为0.1-0.3g/ml,所述光热材料的工作浓度为0.00015-0.00025g/ml,所述YAP信号抑制剂的工作浓度为0.00025-0.00035g/ml,所述光引发剂的工作浓度为0.000025-0.00025g/ml。
所述工作浓度为上述成分在使用时能够达到预期效果的浓度,可以理解的,本领域技术人员在配制上述水凝胶时,可以配制浓度更高的母液或者储备液,待使用时再稀释,所述母液或者储备液及其浓度均在本发明的保护范围之内。
光热疗法(PTT)是一种微创和局部治疗方式,越来越多地用于临床伤口护理中,PTT在通过近红外(NIR)激光照射下具有很高的光热转换效率,而NIR可以穿透组织,同时对周围区域的损害最小。与抗生素不同,PTT利用近红外激光产生的热量来抑制细菌生长并破坏生物膜,进而防止细菌耐药性的发展。采用上述原料,能够使水凝胶在伤口愈合过程中抑制瘢痕的生成,同时还能通过光热疗法在伤口治疗过程中杀死伤口细菌,防止细菌感染。
在其中一个实施例中,所述光热材料为铋烯。
铋烯是一种光热材料,在近红外的照射下可迅速升温,通过其光热性在伤口治疗过程中杀死伤口细菌,防止伤口愈合过程中的细菌感染;并且通过控制铋烯材料的量和近红外照射时长能够控制伤口处升温温度,避免升温过快过高灼伤皮肤组织。
在其中一个实施例中,所述YAP信号抑制剂为维替伯芬。
维替伯芬是一种YAP信号抑制剂,可以通过在伤口愈合过程中抑制YAP信号通路减少通路下游因子的表达,以减少伤口中瘢痕相关蛋白,最终实现无瘢痕愈合。
在其中一个实施例中,所述水凝胶基料包括以下原料中的至少1种:甲基丙烯酰化丝素蛋白,甲基丙烯酰化明胶,甲基丙烯酰化透明质酸,甲基丙烯酰化海藻酸钠,甲基丙烯酰化葡聚糖,或甲基丙烯酰化壳聚糖。
在其中一个实施例中,所述光引发剂为:苯基(2,4,6-三甲基苯甲酰基)磷酸锂盐。
本发明还提供了所述水凝胶的制备方法,包括以下步骤:将水凝胶基料、光引发剂、光热材料和YAP信号抑制剂混合,即得。
本发明还提供了一种微针,该微针包括可溶性材料和所述水凝胶,所述可溶性材料为:葡聚糖。
上述可溶性材料能制备遇水快速溶解的基底,从而使制备得到的微针的针尖和基底是遇水可分离的。当操作者使用该微针给患者治疗时,基底与皮肤刺破后的体液相遇,溶解,针尖顺势脱离,并留存在患者体内,包埋在针尖内部的药物在针尖内部的药物随后通过扩散作用释放到周围组织发挥作用,实现功能性药物的留存和缓释。可以理解的,本领域技术人员可通过改变针尖的长度来控制针尖到达的深度。与表层敷贴给药的方式相比,上述微针给药的深度更大,能起到更好的治疗效果。
在其中一个实施例中,所述葡聚糖由质量百分比为20-30%的葡聚糖溶液提供。
在其中一个实施例中,所述葡聚糖溶液与所述水凝胶的体积比为(200-300μl):(80-100ul)。
本发明还提供了所述微针的制备方法,包括以下步骤:
制备针尖:将水凝胶加入微针模具,真空脱泡,进行针尖干燥浓缩,光照固化,得到针尖;
制备基底:将可溶性材料加入微针模具,真空脱泡,进行基底干燥浓缩,形成基底,脱模,得到微针。
通过上述方法能够将所述水凝胶制成针尖,将可溶性材料制成基底,并将针尖和基底连接起来,形成针尖可分离的微针。
在其中一个实施例中,所述制备针尖步骤中,所述针尖干燥浓缩的温度为0-37℃,所述基底干燥浓缩的温度为22-28℃。
本发明还提供了所述微针在制备愈合伤口药物中的应用。
与现有技术相比,本发明具有以下有益效果:
本发明的一种用于抑制瘢痕的水凝胶及其制备方法和应用,该水凝胶采用光热材料、YAP信号抑制剂作为原料,使该水凝胶具有在伤口愈合的过程中抑制瘢痕生成,并且抗伤口感染的优势。该微针可达到促进伤口愈合,减轻伤口感染风险,以及无瘢痕愈合,药物成分深部组织递送,局部缓释递送的优势。
附图说明
图1为实施例5中功率2W/cm2的NIR照射下微针的升温温度测定结果图;
图2为实施例5中功率1W/cm2的NIR照射下微针的升温温度测定结果图,其中1为MN,2为20μgBi@MN,3为30μgBi@MN,4为40μgBi@MN,5为50μgBi@MN;
图3为实施例5中功率2W/cm2的NIR激光照射下的热成像图;
图4为实施例7中针对金黄葡萄球菌和大肠杆菌的治疗效果结果图;
图5为实施例8中对体外3T3细胞的生物相容性实验的结果图;
图6为实施例9中体内创面应用验证实验的结果图;
图7为实施例10中HE染色试验的结果图;
图8为实施例11中Massson染色试验的结果图。
具体实施方式
为了便于理解本发明,下面将参照相关附图对本发明进行更全面的描述。附图中给出了本发明的较佳实施例。但是,本发明可以以许多不同的形式来实现,并不限于本文所描述的实施例。相反地,提供这些实施例的目的是使对本发明的公开内容的理解更加透彻全面。
除非另有定义,本文所使用的所有的技术和科学术语与属于本发明的技术领域的技术人员通常理解的含义相同。本文中在本发明的说明书中所使用的术语只是为了描述具体的实施例的目的,不是旨在于限制本发明。
来源:
维替伯芬(购自MedChemExpress),苯基(2,4,6-三甲基苯甲酰基)磷酸锂盐溶液(购自Macklin Biochemical Co.,Ltd.(中国上海)),铋烯(深圳瀚光科技有限公司,纯度100%)。
本实施例所用试剂、材料、设备如无特殊说明,均为市售来源;试验方法如无特殊说明,均为本领域的常规试验方法。
实施例1
一种微针,其制备方法如下所示。
一、制备水凝胶。
将水凝胶基料、光引发剂、光热材料混合,得到水凝胶。
在本实施例中,水凝胶基料为甲基丙烯酰化丝素蛋白,光热材料为铋烯,光引发剂为浓度为0.002g/ml的苯基(2,4,6-三甲基苯甲酰基)磷酸锂盐溶液(LAP);添加量为:20μg铋烯、50μL苯基(2,4,6-三甲基苯甲酰基)磷酸锂盐溶液;在水凝胶中,铋烯、苯基(2,4,6-三甲基苯甲酰基)磷酸锂盐的工作浓度之比为2:1。本实施例中,甲基丙烯酰化丝素蛋白在水凝胶中的工作浓度为0.3g/ml,铋烯在水凝胶中的工作浓度为0.0002g/ml,苯基(2,4,6-三甲基苯甲酰基)磷酸锂盐在水凝胶中的工作浓度为0.0001g/ml。
在本实施例中,甲基丙烯酰化丝素蛋白由蚕茧制备得到,具体制备方法如下:称取50g去除蚕蛹的蚕茧,在1L 0.05M Na2CO3(5.3g)溶液中于100℃分2次煮沸30min,并用蒸馏水洗涤多次。然后,将脱胶后的丝素蛋白(SF)在60℃烘箱中烘干。将20g脱胶SF溶解在100mL9.3M的溴化锂(LiBr)溶液(加0.48g NaOH)中,在60℃下搅拌1小时,脱胶SF完全溶解后,加入1mL浓盐酸,溶液离心10000rpm 5min,然后通过miracloth(神奇滤布)过滤。并加入12mL甲基丙烯酸缩水甘油酯,混合,在60℃下以1000rpm搅拌8h。反应完毕,溶液离心10000rpm5min,然后通过miracloth(神奇滤布)过滤,用蒸馏水使用透析膜(12-14kDa)透析3-5天除去盐。溶液在-80℃下冻干,得到甲基丙烯酰化丝素蛋白。
二、制备针尖。
将含有铋烯的水凝胶,使用移液枪吸取80-100ul,滴入微针模具中,真空脱泡,在4℃下干燥浓缩;将浓缩过后的微针模具中的针尖上部溶液去除干净,用405nm光照引发针尖水凝胶聚合,得到针尖。
三、制备基底。
采用质量百分比为30%的葡聚糖溶液制备基底,该葡聚糖溶液的用量为200-300μl,将葡聚糖溶液加入针尖聚合后的微针模具,真空脱泡,常温(约25℃)干燥浓缩,形成基底,脱模,得到20ugBi@MN微针,该微针的针尖和基底遇水可分离。
在本实施例中,微针模具采用硫化硅橡胶制备得到,微针阵列为8×8方形排列,微针针尖为四棱锥型,高800微米,四棱锥底边长200微米,针距200微米。
将本实施例制备得到的20ugBi@MN微针,按压至创面表面,使用808激光器照射创面5min,5min后取下微针,此时微针的针尖已经滞留于皮肤组织中,取下的是微针的可分离背衬。
实施例2
一种微针,其制备方法和实施例1基本相同,不同点在于水凝胶中铋烯的工作浓度为300μg/ml(即0.0003g/ml),得到30ugBi@MN微针。
实施例3
一种微针,其制备方法和实施例1基本相同,不同点在于水凝胶中铋烯的工作浓度为400μg/ml(即0.0004g/ml),得到40ugBi@MN微针。
实施例4
一种微针,其制备方法和实施例1基本相同,不同点在于水凝胶中铋烯的工作浓度为500μg/ml(即0.0005g/ml),得到50ugBi@MN微针。
实施例5
光热性能测试。
对上述各实施例制备得到的微针进行光热性能测试,测试方法:通过1W/cm2的NIR或2W/cm2的NIR激光对微针定时照射5min,同时使用红外热成像相机对照射过程中微针的升温温度进行记录,从而选择出所用微针需装载铋烯的浓度和升到所需温度所需要的NIR功率。
测试结果如图1、图2、图3所示,其中图1为功率2W/cm2的NIR照射下微针的升温温度测定结果图,图2为功率1W/cm2的NIR照射下微针的升温温度测定结果图,图3为2W/cm2的NIR激光照射下的热成像图。根据图1-图3,可看出实施例1制备得到的20μgBi@MN微针和2W/cm2的NIR,其结合使用得到的升温温度用于杀灭细菌是效果最好的。
实施例6
一种用于抑制瘢痕的微针,其制备方法如下所示。
一、制备水凝胶。
将水凝胶基料、光引发剂、光热材料和YAP信号抑制剂混合,得到水凝胶。
在本实施例中,水凝胶基料为甲基丙烯酰化丝素蛋白,光热材料为铋烯,YAP信号抑制剂为维替伯芬,光引发剂为浓度为0.002g/ml的苯基(2,4,6-三甲基苯甲酰基)磷酸锂盐溶液(LAP);添加量为:20μg铋烯、30μL维替伯芬、50μL苯基(2,4,6-三甲基苯甲酰基)磷酸锂盐溶液;在水凝胶中,铋烯、维替伯芬、苯基(2,4,6-三甲基苯甲酰基)磷酸锂盐的工作浓度之比为2:3:1。本实施例中,甲基丙烯酰化丝素蛋白在水凝胶中的工作浓度为0.3g/ml,铋烯在水凝胶中的工作浓度为0.0002g/ml,维替伯芬在水凝胶中的工作浓度为0.0003g/ml,苯基(2,4,6-三甲基苯甲酰基)磷酸锂盐在水凝胶中的工作浓度为0.0001g/ml。
二、制备针尖。
将含有铋烯和维替伯芬的水凝胶,使用移液枪吸取80-100ul,滴入微针模具中,真空脱泡,在4℃下干燥浓缩;将浓缩过后的微针模具中的针尖上部溶液去除干净,用405nm光照引发针尖水凝胶聚合,得到针尖。
三、制备基底。
采用质量百分比为30%的葡聚糖溶液制备基底,该葡聚糖溶液的用量为200-300μl,将葡聚糖溶液加入针尖聚合后的微针模具,真空脱泡,常温(约25℃)干燥浓缩,形成基底,脱模,得到Bi/Ver@MN微针,该微针的针尖和基底遇水可分离。
在本实施例中,微针模具采用硫化硅橡胶制备得到,微针阵列为8×8方形排列,微针针尖为四棱锥型,高800微米,四棱锥底边长200微米,针距200微米。
将本实施例制备得到的Bi/Ver@MN微针,按压至创面表面,使用808激光器照射创面5min,5min后取下微针,此时微针的针尖已经滞留于皮肤组织中,取下的是微针的可分离背衬。
实施例7
治疗效果验证。
采用实施例1(20μgBi@MN)、实施例6(Bi/Ver@MN)制备得到的微针,以及不含铋烯和维替伯芬的微针(MN,制备方法和实施例1相同,不同点在于未加入铋烯),对金黄葡萄球菌和大肠杆菌,在有无近红外光照射下的治疗效果进行测试。
测试方法:将所用微针置于24孔板中,分别将金黄葡萄球菌和大肠杆菌溶液滴在所制备的微针上,使用2W/cm2的NIR激光照射微针5min,后加入细菌培养基对照射过后的细菌置于细菌培养箱中进行孵育培养4h-8h,然后将孵育后的细菌溶液按照浓度梯度稀释,分别涂布于细菌选择培养板中,置于细菌培养箱中孵育8h后对细菌平板拍照对菌落计数统计。
测试结果如图4所示,由上至下,第1、2排为金黄葡萄球菌,第3、4排为大肠杆菌,可以看出,实施例1、实施例6制备得到的微针,在2W/cm2的NIR激光照射后,对于金黄葡萄球菌和大肠杆菌的杀灭效果非常显著。
实施例8
对体外3T3细胞的验证。
采用实施例1(20μgBi@MN)、实施例6(Bi/Ver@MN)制备得到的微针,以及不含铋烯和维替伯芬的微针(MN,制备方法和实施例1相同,不同点在于未加入铋烯),对体外3T3细胞的24h增殖实验。
测试方法:以5000个细胞每孔的细胞密度将3T3细胞接种于96孔板中,并在37℃和5%CO2环境下培养24h。分别将MN、20μgBi@MN和Bi/Ver@MN在紫外线下照射1h进行灭菌。再将其浸入10mL DMEM培养基中进行浸提液的提取,然后在37℃,5%CO2培养箱中放置24h以获得浸提液。随后将3T3细胞在浸提液中培养24和48h,每孔用PBS洗涤3次后,将细胞与含有10%CCK-8试剂的DMEM培养基一起在37℃下孵育1h,最后使用酶标仪测量细胞在450nm的波长处的光密度以测试不同微针对3T3细胞的毒性,以此来评估所制备的微针的生物相容性。
测试结果如图5所示,可见实施例6(Bi/Ver@MN)制备得到的微针,其生物相容性较好。
实施例9
体内创面应用验证。
采用实施例1(20μgBi@MN)、实施例6(Bi/Ver@MN)制备得到的微针应用于体内创面,并对其修复结果进行拍照观察。
测试方法:对小鼠腹腔注射进行麻醉,随后对背部毛发进行修剪,碘伏消毒后,用手术剪在小鼠背部造成2个直径10mm的圆形创面。每个创面滴加100μL S.aureus细菌悬液(1×106CFU mL-1)并感染24h。感染后每个创面用手指压入所制备微针以完全覆盖伤口区域,对于需要利用NIR治疗的组中,用激光密度为2W/cm2的NIR激光照射伤口5min。在第0、3、7、10、30和90天获取创面图像并统计创面面积。
测试结果如图6所示,可看出Bi/Ver@MN/NIR组小鼠的愈合速度是本实施例中最快的。
实施例10
HE染色试验。
将上述体内创面应用验证中的伤口组织进行HE染色。
HE染色结果如图7所示,可看出Bi/Ver@MN/NIR组小鼠的伤口组织愈合后,没有生产瘢痕。
实施例11
Massson染色试验。
将上述体内创面应用验证中的伤口组织进行Massson染色。
Massson染色结果如图8所示,可看出Bi/Ver@MN/NIR组小鼠的伤口组织愈合后,没有生产瘢痕。
以上所述实施例的各技术特征可以进行任意的组合,为使描述简洁,未对上述实施例中的各个技术特征所有可能的组合都进行描述,然而,只要这些技术特征的组合不存在矛盾,都应当认为是本说明书记载的范围。
以上所述实施例仅表达了本发明的几种实施方式,其描述较为具体和详细,但并不能因此而理解为对发明专利范围的限制。应当指出的是,对于本领域的普通技术人员来说,在不脱离本发明构思的前提下,还可以做出若干变形和改进,这些都属于本发明的保护范围。因此,本发明专利的保护范围应以所附权利要求为准。
Claims (6)
1.一种用于抑制瘢痕的水凝胶,其特征在于,该水凝胶包括水凝胶基料、光热材料、YAP信号抑制剂、光引发剂,所述水凝胶基料的工作浓度为0.1-0.3g/ml,所述光热材料的工作浓度为0.00015-0.00025g/ml,所述YAP信号抑制剂的工作浓度为0.00025-0.00035g/ml,所述光引发剂的工作浓度为0.000025-0.00025g/ml;
所述光热材料为铋烯;所述YAP信号抑制剂为维替伯芬;所述水凝胶基料包括以下原料中的至少1种:甲基丙烯酰化丝素蛋白,甲基丙烯酰化明胶,甲基丙烯酰化透明质酸,甲基丙烯酰化海藻酸钠,甲基丙烯酰化葡聚糖,或甲基丙烯酰化壳聚糖;所述光引发剂为:苯基(2,4,6-三甲基苯甲酰基)磷酸锂盐。
2.权利要求1所述水凝胶的制备方法,其特征在于,包括以下步骤:将水凝胶基料、光引发剂、光热材料和YAP信号抑制剂混合,即得。
3.一种微针,其特征在于,该微针包括可溶性材料和权利要求1所述的水凝胶,所述可溶性材料为:葡聚糖。
4.权利要求3所述微针的制备方法,其特征在于,包括以下步骤:
制备针尖:将水凝胶加入微针模具,真空脱泡,进行针尖干燥浓缩,光照固化,得到针尖;
制备基底:将可溶性材料加入微针模具,真空脱泡,进行基底干燥浓缩,形成基底,脱模,得到微针。
5.根据权利要求4所述的制备方法,其特征在于,所述制备针尖步骤中,所述针尖干燥浓缩的温度为0-37℃,所述基底干燥浓缩的温度为22-28℃。
6.权利要求3所述的微针在制备愈合伤口药物中的应用。
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