CN111317855B - 促进糖尿病溃疡创面愈合的三维复合海绵状结构体及方法 - Google Patents
促进糖尿病溃疡创面愈合的三维复合海绵状结构体及方法 Download PDFInfo
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- CN111317855B CN111317855B CN202010125425.0A CN202010125425A CN111317855B CN 111317855 B CN111317855 B CN 111317855B CN 202010125425 A CN202010125425 A CN 202010125425A CN 111317855 B CN111317855 B CN 111317855B
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Abstract
本发明公开了一种促进糖尿病溃疡创面愈合的三维复合海绵状结构体,包括:由靠近溃疡创面向外的方向上依次设置有A层海绵状结构、B层海绵状结构和C层海绵状结构,其中,A层海绵状结构包含负载细胞生长因子的肝素‑泊洛沙姆聚合物凝胶,B层海绵状结构包含负载纳米银的壳聚糖及其衍生物的凝胶,C层海绵状结构包含脱细胞真皮支架。本发明还公开了促进促进糖尿病溃疡创面愈合的三维复合海绵状结构体的制备方法。本发明的三维复合海绵状结构体是一个有机的整体系统,各组分通过相互协同作用,产生优势互补效果,实现糖尿病溃疡创面的安全高效愈合作用。
Description
技术领域
本发明属于生物医药技术领域,涉及一种促进糖尿病溃疡创面愈合的三维复合海绵状结构体,还涉及其制备方法。
背景技术
糖尿病是一组以高血糖为特征的代谢性疾病。高血糖则是由于胰岛素分泌缺陷或其生物作用受损,或两者兼有引起。糖尿病时长期存在的高血糖,导致各种组织,特别是眼、肾、心脏、血管、神经的慢性损害、功能障碍。
糖尿病患者的血糖长期处在一个高负荷的状态,不利于伤口的愈合,所以糖尿病患者特别容易出现皮肤的溃疡。
糖尿病溃疡创面愈合不良的主要问题出在局部的感染和组织血液灌注不良,两者互为因果的关系。糖尿病患者皮肤一旦溃疡,很容易感染细菌,导致糖尿病溃疡创面不容易愈合,严重影响糖尿病患者的生活质量。
目前针对于糖尿病溃疡的治疗方法主要是减轻压力和保护溃疡。即使是糖尿病溃疡最佳的创面护理也不能完全避免损伤、缺血或感染。深达皮下组织的溃疡应得到及时的制剂治疗,但尚未见到任何能够快速有效促进糖尿病溃疡创面愈合的制剂报道。因此针对目前缺乏有效促进糖尿病溃疡创面愈合制剂的瓶颈,开发有利于促进糖尿病溃疡创面高效愈合的制剂对于提升糖尿病患者的生活质量具有十分重大的意义。
发明内容
本发明的一个目的是解决至少上述问题和/或缺陷,并提供至少后面将说明的优点。
为了克服目前缺乏有效促进糖尿病溃疡创面愈合制剂的瓶颈,缩短糖尿病溃疡创面愈合时间,本发明的目的在于提供一种促进糖尿病溃疡创面愈合的三维复合海绵,本发明还有一个目的是提供一种促进糖尿病溃疡创面愈合的三维复合海绵状结构体。
本发明另有一个目的是提供一种促进糖尿病溃疡创面愈合的三维复合海绵状结构体的制备方法。
为此,本发明提供的技术方案为:
一种促进糖尿病溃疡创面愈合的三维复合海绵状结构体,由靠近溃疡创面向外的方向上依次设置有A层海绵状结构、B层海绵状结构和C层海绵状结构,其中,所述A层海绵状结构包含负载细胞生长因子的肝素-泊洛沙姆聚合物凝胶,所述B层海绵状结构包含负载纳米银的壳聚糖及其衍生物的凝胶,所述C层海绵状结构包含脱细胞真皮支架。
优选的是,所述的促进糖尿病溃疡创面愈合的三维复合海绵状结构体中,所述A层海绵状结构中细胞生长因子的质量百分含量为0.001%~0.1%,所述B层海绵状结构中纳米银的质量百分含量为0.0001%~0.01%。
优选的是,所述的促进糖尿病溃疡创面愈合的三维复合海绵状结构体中,所述A层海绵状结构中细胞生长因子的质量百分含量为0.005%~0.01%,所述B层海绵状结构中纳米银的质量百分含量为0.001%~0.005%。
优选的是,所述的促进糖尿病溃疡创面愈合的三维复合海绵状结构体中,所述C层海绵状结构还包括表皮干细胞,所述表皮干细胞铺满所述脱细胞真皮支架表面积的80%以上。
优选的是,所述的促进糖尿病溃疡创面愈合的三维复合海绵状结构体中,所述细胞生长因子选自转化生长因子、胰岛素样生长因子、角质细胞生长因子、成纤维细胞生长因子、表皮生长因子、血管内皮生长因子、神经生长因子中的任意一种或几种;
所述壳聚糖衍生物包括N-三甲基壳聚糖、N-马来酰化壳聚糖、羧甲基壳聚糖、N,O-羧甲基壳聚糖和羟丙基壳聚糖中的任意一种或几种。
优选的是,所述的促进糖尿病溃疡创面愈合的三维复合海绵状结构体中,所述细胞生长因子为血管内皮生长因子和表皮生长因子。
一种所述的促进糖尿病溃疡创面愈合的三维复合海绵状结构体的制备方法,包括如下步骤:
步骤一、取肝素-泊洛沙姆聚合物凝胶和细胞生长因子混匀,于模具中进行第一冷冻干燥,并制备得到A层海绵状结构;
步骤二、取壳聚糖及其衍生物粉末分散于与硝酸中进行氨基质子化反应,之后加入1,2-丙二醇混匀,再加入硝酸银,混匀,于模具中进行第二冷冻干燥,并制备得到B层海绵状结构;
步骤三、取脱细胞真皮支架在液氮中进行粉碎,于模具中进行第三冷冻干燥,并制备得到C层海绵状结构;
步骤四、将步骤一中得到的A层海绵状结构、步骤二中得到的B层海绵状结构和步骤三中的C层海绵状结构按照A-B-C的次序依次叠放在一起,灭菌后得到三维复合海绵状结构体。
优选的是,所述的促进糖尿病溃疡创面愈合的三维复合海绵状结构体的制备方法中,进行所述第一冷冻干燥的具体方法包括:首先于温度-20~-30℃下冷冻3~4小时,之后于温度-35~-75℃冷冻干燥24~48h,冷冻干燥时的真空度小于10Pa,然后于体积比80~90%的乙醇溶液熏蒸和紫外线下交联1~3h,最后再次于温度-35~-75℃冷冻干燥24~48h,冷冻干燥时的真空度小于10Pa;
进行所述第二冷冻干燥的具体方法包括:首先于温度-35~-45℃下冷冻3~4小时,之后于温度-45~-85℃冷冻干燥24~48h,冷冻干燥时的真空度小于10Pa,然后于体积比80~90%的乙醇溶液熏蒸和紫外线下交联3~5h,最后再次于温度-35~-75℃冷冻干燥24~48h,冷冻干燥时的真空度小于10Pa;
进行所述第三冷冻干燥的具体方法包括:首先于温度-30~-40℃下冷冻3~4小时,之后于温度-40~-80℃冷冻干燥24~48h,冷冻干燥时的真空度小于10Pa,然后于体积比80~90%的乙醇溶液熏蒸和紫外线下交联1~3h,最后再次于温度-35~-75℃冷冻干燥24~48h,冷冻干燥时的真空度小于10Pa。
优选的是,所述的促进糖尿病溃疡创面愈合的三维复合海绵状结构体的制备方法中,步骤一、步骤二和步骤三中,首先将模具内表面加热至50~60℃,之后再将组分加入到模具中,并于50~60rpm下振动25~35min后,之后进行冷冻干燥。
优选的是,所述的促进糖尿病溃疡创面愈合的三维复合海绵状结构体的制备方法中,步骤一、步骤二和步骤三中,制备海绵状结构时,各组分还分别加入有保湿剂、稳定剂、抑菌剂和pH调节剂。
本发明至少包括以下有益效果:
本发明克服糖尿病溃疡治疗的缺乏有效制剂的限制性瓶颈,在促进溃疡创面愈合同时还具备以下优点:(1)病人可以自行贴敷,简便易行;(2)具有较好的防止血栓和防止疤痕形成的作用;(3)可以吸收溃疡面的渗出液,发挥局部长效作用。(4)具有抑菌功能,防止细菌感染。(5)溃疡面愈合速度快。
本发明的促进糖尿病溃疡创面愈合的三维复合海绵是一个有机的整体系统,各组分通过相互协同作用,产生优势互补效果,实现糖尿病溃疡创面的安全高效愈合作用。
本发明的其它优点、目标和特征将部分通过下面的说明体现,部分还将通过对本发明的研究和实践而为本领域的技术人员所理解。
具体实施方式
下面对本发明做进一步的详细说明,以令本领域技术人员参照说明书文字能够据以实施。
应当理解,本文所使用的诸如“具有”、“包含”以及“包括”术语并不配出一个或多个其它元件或其组合的存在或添加。
本发明提供一种促进糖尿病溃疡创面愈合的三维复合海绵状结构体,由靠近溃疡创面向外的方向上依次设置有A层海绵状结构、B层海绵状结构和C层海绵状结构,其中,所述A层海绵状结构包含负载细胞生长因子的肝素-泊洛沙姆聚合物凝胶,所述B层海绵状结构包含负载纳米银的壳聚糖及其衍生物的凝胶,所述C层海绵状结构包含脱细胞真皮支架。
申请人发现,糖尿病溃疡产生大量渗出液,影响创面微血管重建和肉芽组织再生,容易造成创面的感染。而海绵状制剂具有良好的吸水性,适用于有渗出液的创面。肝素-泊洛沙姆聚合物制备的海绵遇水后形成水凝胶,不仅具有很好的相变温度,可以在常温下保持液态,在人体温度下形成半固体凝胶,不仅有利于肝素高亲和性的细胞因子类药物的缓释,形成长效制剂,还具有较好的防止血栓和防止疤痕形成的作用。纳米银具有杀菌作用,但不能直接与细胞因子联合应用,否则影响细胞因子的生物学活性。皮肤脱细胞支架保留了原皮肤组织的细胞基质,为皮肤再生提供很好的营养基础。但皮肤脱细胞支架单独应用的效果不佳,主要是缺乏血氧的供应,不能保持创面微血管重建和持续促进肉芽组织再生。
本发明人经过大量实验研究,创新性地将肝素-泊洛沙姆聚合物、纳米银、脱细胞真皮支架和细胞生长因子等多个治疗因素有机组合,制备了一种促进糖尿病溃疡创面愈合的三维复合海绵状结构体,发挥各组分优势互补效果,同时避免相互抵触的副作用,极大缩短了糖尿病溃疡创面愈合时间。
在上述方案中,作为优选,所述A层海绵状结构中细胞生长因子的质量百分含量为0.001%~0.1%,所述B层海绵状结构纳米银的质量百分含量为0.0001%~0.01%。更优选的是,所述A层海绵状结构中细胞生长因子的质量百分含量为0.005%~0.01%,所述B层海绵状结构中纳米银的质量百分含量为0.001%~0.005%。
在本发明的其中一个实施例中,作为优选,所述C层海绵状结构还包括表皮干细胞,所述表皮干细胞铺满所述脱细胞真皮支架表面积的80%以上。
在本发明的其中一些实施例中,作为优选,,所述细胞生长因子选自转化生长因子、胰岛素样生长因子、角质细胞生长因子、成纤维细胞生长因子、表皮生长因子、血管内皮生长因子、神经生长因子中的任意一种或几种;
所述壳聚糖衍生物包括N-三甲基壳聚糖、N-马来酰化壳聚糖、羧甲基壳聚糖、N,O-羧甲基壳聚糖和羟丙基壳聚糖中的任意一种或几种。
在本发明的其中一些实施例中,作为优选,,所述细胞生长因子为血管内皮生长因子和表皮生长因子。
本发明还提供一种所述的促进糖尿病溃疡创面愈合的三维复合海绵状结构体的制备方法,包括如下步骤:
步骤一、取肝素-泊洛沙姆聚合物凝胶和细胞生长因子混匀,于模具中进行第一冷冻干燥,并制备得到A层海绵状结构;
步骤二、取壳聚糖及其衍生物粉末分散于与硝酸中进行氨基质子化反应,之后加入1,2-丙二醇混匀,再加入硝酸银,混匀,于模具中进行第二冷冻干燥,并制备得到B层海绵状结构;
步骤三、取脱细胞真皮支架在液氮中进行粉碎,于模具中进行第三冷冻干燥,并制备得到C层海绵状结构;
步骤四、将步骤一中得到的A层海绵状结构、步骤二中得到的B层海绵状结构和步骤三中的C层海绵状结构按照A-B-C的次序依次叠放在一起,灭菌后得到三维复合海绵状结构体。
在上述方案中,作为优选,进行所述第一冷冻干燥的具体方法包括:首先于温度-20~-30℃下冷冻3~4小时,之后于温度-35~-75℃冷冻干燥24~48h,冷冻干燥时的真空度小于10Pa,然后于体积比80~90%的乙醇溶液熏蒸和紫外线下交联1~3h,最后再次于温度-35~-75℃冷冻干燥24~48h,冷冻干燥时的真空度小于10Pa;
进行所述第二冷冻干燥的具体方法包括:首先于温度-35~-45℃下冷冻3~4小时,之后于温度-45~-85℃冷冻干燥24~48h,冷冻干燥时的真空度小于10Pa,然后于体积比80~90%的乙醇溶液熏蒸和紫外线下交联3~5h,最后再次于温度-35~-75℃冷冻干燥24~48h,冷冻干燥时的真空度小于10Pa;
进行所述第三冷冻干燥的具体方法包括:首先于温度-30~-40℃下冷冻3~4小时,之后于温度-40~-80℃冷冻干燥24~48h,冷冻干燥时的真空度小于10Pa,然后于体积比80~90%的乙醇溶液熏蒸和紫外线下交联1~3h,最后再次于温度-35~-75℃冷冻干燥24~48h,冷冻干燥时的真空度小于10Pa。本发明针对不同特性的材料设置不同的冷冻干燥工艺,使其各自形成表观密度小、孔隙率高的海绵状结构,同时结合乙醇溶液熏蒸和紫外线交联,进一步使得形成的海绵状结构的比表面积最大化,且该制备方法制备得到的海绵状结构具有缓释性能,提高了对糖尿病溃疡创面的愈合。
在上述方案中,作为优选,步骤一、步骤二和步骤三中,首先将模具内表面加热至50~60℃,之后再将组分加入到模具中,并于50~60rpm下振动25~35min后,之后进行冷冻干燥。使各组分充分混匀处于发起状态后,在对其进行冷冻干燥,能使得各组分的性能保持在最优异的状态,增强本发明的效果。
在本发明的其中一个实施例中,作为优选,步骤一、步骤二和步骤三中,制备海绵状结构时,各组分还分别加入有保湿剂、稳定剂、抑菌剂和pH调节剂。
在本发明的其中一个实施例中,本发明的一种促进糖尿病溃疡创面愈合的三维复合海绵是由A-B-C三层组合而成,A层紧密贴合糖尿病溃疡面,是由负载细胞生长因子的肝素-泊洛沙姆聚合物凝胶组成,B层是由负载纳米银的壳聚糖及其衍生物凝胶组成,C层是由脱细胞真皮支架组成。
上述的A层中肝素-泊洛沙姆聚合物凝胶中细胞生长因子的质量百分含量为0.001%~0.1%,优选的细胞生长因子的质量百分含量为0.005%~0.01%。
上述的细胞生长因子选自:转化生长因子、胰岛素样生长因子、角质细胞生长因子、成纤维细胞生长因子、表皮生长因子、血管内皮生长因子、神经生长因子中的一种或几种组合,优选的细胞生长因子为血管内皮生长因子和表皮生长因子。
上述B层壳聚糖凝胶中的纳米银的质量百分含量为0.0001%~0.01%,优选的纳米银的质量百分含量为0.001%~0.005%。
上述C层的脱细胞真皮支架是指通过化学和生化方法获得的同种或异种来源的皮肤真皮基质。
上述C层的脱细胞真皮支架中进一步加入表皮干细胞。
上述B层中的壳聚糖及其衍生物包括:壳聚糖、N-三甲基壳聚糖、N-马来酰化壳聚糖、羧甲基壳聚糖、N,O-羧甲基壳聚糖、羟丙基壳聚糖的一种或几种。
一种促进糖尿病溃疡创面愈合的三维复合海绵状结构体的制备方法如下:
(1)肝素-泊洛沙姆聚合物用2倍体积的水溶解,形成肝素-泊洛沙姆聚合物凝胶,加入细胞生长因子混匀,于模具中冷冻干燥,制备得到A层海绵状结构;
(2)壳聚糖粉末分散于与其氨基等当量的硝酸中进行氨基质子化反应,完全溶解后加入与硝酸等质量的1,2-丙二醇混匀,加入硝酸银,充分搅拌获得均匀溶液,于模具中冷冻干燥,制备得到B层海绵状结构;
(3)采用化学和生化方法制备得到脱细胞真皮支架,在液氮中进行粉碎,于模具中冷冻干燥,制备得到C层海绵状结构;
(4)将(1)的A层海绵状结构、(2)的B层海绵状结构和(3)的C层海绵状结构按照A-B-C的次序叠放在一起,边缘切齐,无菌密封包装,得到三维复合海绵状结构体。
上述的C层海绵状结构中进一步加入表皮干细胞。
上述的三维复合海绵状结构体中进一步加入药学领域公知的保湿剂、稳定剂、抑菌剂、pH调节剂。
为使本领域技术人员更好地理解本发明的技术方案,现提供如下的实施例进行说明:
实施例1一种促进糖尿病溃疡创面愈合的三维复合海绵状结构体
实验组1-10:按照表1的三维复合海绵状结构体实验组的组成,量取各组分,按照以下步骤制备三维复合海绵状结构体:
(1)肝素-泊洛沙姆聚合物用2倍体积的水溶解,形成肝素-泊洛沙姆聚合物凝胶,加入细胞生长因子混匀,于模具中进行冷冻干燥,制备得到A层海绵状结构;
(2)壳聚糖粉末分散于与其氨基等当量的硝酸中进行氨基质子化反应,完全溶解后加入与硝酸等质量的1,2-丙二醇混匀,加入硝酸银,充分搅拌获得均匀溶液,于模具中进行冷冻干燥,制备得到B层海绵状结构;
(3)采用化学和生化方法制备得到脱细胞真皮支架,在液氮中进行粉碎,于模具中进行冷冻干燥,制备得到C层海绵状结构;
(4)将(1)的A层海绵状结构、(2)的B层海绵状结构和(3)的C层海绵状结构按照A-B-C的次序叠放在一起,边缘切齐,无菌密封包装,得到三维复合海绵状结构体。(理论上各层厚度比例对药效没有影响)
对照组:按照表1的三维复合海绵对照组的组成,参照实验组1-10的制备方法进行。
实验组11:按照表1的三维复合海绵状结构体实验组的组成,量取各组分,按照以下步骤制备三维复合海绵状结构体:
(1)肝素-泊洛沙姆聚合物用2倍体积的水溶解,形成肝素-泊洛沙姆聚合物凝胶,加入细胞生长因子混匀,于模具中进行第一冷冻干燥,制备得到A层海绵状结构;进行所述第一冷冻干燥的具体方法包括:首先于温度-20℃下冷冻3小时,之后于温度-35℃冷冻干燥24h,冷冻干燥时的真空度小于10Pa,然后于体积比80%的乙醇溶液熏蒸和紫外线下交联1h,最后再次于温度-35℃冷冻干燥24h,冷冻干燥时的真空度小于10Pa;
(2)壳聚糖粉末分散于与其氨基等当量的硝酸中进行氨基质子化反应,完全溶解后加入与硝酸等质量的1,2-丙二醇混匀,加入硝酸银,充分搅拌获得均匀溶液,于模具中进行第二冷冻干燥,制备得到B层海绵状结构;
进行所述第二冷冻干燥的具体方法包括:首先于温度-35℃下冷冻3小时,之后于温度-45℃冷冻干燥24h,冷冻干燥时的真空度小于10Pa,然后于体积比80%的乙醇溶液熏蒸和紫外线下交联3h,最后再次于温度-35℃冷冻干燥24h,冷冻干燥时的真空度小于10Pa;
(3)采用化学和生化方法制备得到脱细胞真皮支架,在液氮中进行粉碎,于模具中进行第三冷冻干燥,制备得到C层海绵状结构;进行所述第三冷冻干燥的具体方法包括:首先于温度-30℃下冷冻3小时,之后于温度-40℃冷冻干燥24h,冷冻干燥时的真空度小于10Pa,然后于体积比80%的乙醇溶液熏蒸和紫外线下交联1h,最后再次于温度-35℃冷冻干燥24h,冷冻干燥时的真空度小于10Pa。
在上述步骤(1)、(2)和(3)中,首先将模具内表面加热至50℃,之后再将组分加入到模具中,并于50rpm下振动25min后,之后进行冷冻干燥。
(4)将(1)的A层海绵状结构、(2)的B层海绵状结构和(3)的C层海绵状结构按照A-B-C的次序叠放在一起,边缘切齐,无菌密封包装,得到三维复合海绵状结构体。
实验组12:按照表1的三维复合海绵状结构体实验组的组成,量取各组分,按照以下步骤制备三维复合海绵状结构体:
(1)肝素-泊洛沙姆聚合物用2倍体积的水溶解,形成肝素-泊洛沙姆聚合物凝胶,加入细胞生长因子混匀,于模具中进行第一冷冻干燥,制备得到A层海绵状结构;进行所述第一冷冻干燥的具体方法包括:首先于温度-30℃下冷冻4小时,之后于温度-75℃冷冻干燥48h,冷冻干燥时的真空度小于10Pa,然后于体积比90%的乙醇溶液熏蒸和紫外线下交联3h,最后再次于温度-35~-75℃冷冻干燥48h,冷冻干燥时的真空度小于10Pa;
(2)壳聚糖粉末分散于与其氨基等当量的硝酸中进行氨基质子化反应,完全溶解后加入与硝酸等质量的1,2-丙二醇混匀,加入硝酸银,充分搅拌获得均匀溶液,于模具中进行第二冷冻干燥,制备得到B层海绵状结构;
进行所述第二冷冻干燥的具体方法包括:首先于温度-45℃下冷冻4小时,之后于温度-85℃冷冻干燥48h,冷冻干燥时的真空度小于10Pa,然后于体积比90%的乙醇溶液熏蒸和紫外线下交联5h,最后再次于温度-75℃冷冻干燥48h,冷冻干燥时的真空度小于10Pa;
(3)采用化学和生化方法制备得到脱细胞真皮支架,在液氮中进行粉碎,于模具中进行第三冷冻干燥,制备得到C层海绵状结构;进行所述第三冷冻干燥的具体方法包括:首先于温度-40℃下冷冻4小时,之后于温度-80℃冷冻干燥48h,冷冻干燥时的真空度小于10Pa,然后于体积比90%的乙醇溶液熏蒸和紫外线下交联3h,最后再次于温度-75℃冷冻干燥48h,冷冻干燥时的真空度小于10Pa。
在上述步骤(1)、(2)和(3)中,首先将模具内表面加热至60℃,之后再将组分加入到模具中,并于60rpm下振动25~35min后,之后进行冷冻干燥。
(4)将(1)的A层海绵状结构、(2)的B层海绵状结构和(3)的C层海绵状结构按照A-B-C的次序叠放在一起,边缘切齐,无菌密封包装,得到三维复合海绵状结构体。
实验组13:按照表1的三维复合海绵状结构体实验组的组成,量取各组分,按照以下步骤制备三维复合海绵状结构体:
(1)肝素-泊洛沙姆聚合物用2倍体积的水溶解,形成肝素-泊洛沙姆聚合物凝胶,加入细胞生长因子混匀,于模具中进行第一冷冻干燥,制备得到A层海绵状结构;进行所述第一冷冻干燥的具体方法包括:首先于温度-25℃下冷冻3.5小时,之后于温度-55℃冷冻干燥36h,冷冻干燥时的真空度小于10Pa,然后于体积比85%的乙醇溶液熏蒸和紫外线下交联2h,最后再次于温度-55℃冷冻干燥36h,冷冻干燥时的真空度小于10Pa;
(2)壳聚糖粉末分散于与其氨基等当量的硝酸中进行氨基质子化反应,完全溶解后加入与硝酸等质量的1,2-丙二醇混匀,加入硝酸银,充分搅拌获得均匀溶液,于模具中进行第二冷冻干燥,制备得到B层海绵状结构;
进行所述第二冷冻干燥的具体方法包括:首先于温度-40℃下冷冻3.5小时,之后于温度-65℃冷冻干燥36h,冷冻干燥时的真空度小于10Pa,然后于体积比85%的乙醇溶液熏蒸和紫外线下交联4h,最后再次于温度-55℃冷冻干燥36h,冷冻干燥时的真空度小于10Pa;
(3)采用化学和生化方法制备得到脱细胞真皮支架,在液氮中进行粉碎,于模具中进行第三冷冻干燥,制备得到C层海绵状结构;进行所述第三冷冻干燥的具体方法包括:首先于温度-35℃下冷冻3.5小时,之后于温度-60℃冷冻干燥36h,冷冻干燥时的真空度小于10Pa,然后于体积比85%的乙醇溶液熏蒸和紫外线下交联2h,最后再次于温度-55℃冷冻干燥36h,冷冻干燥时的真空度小于10Pa。
在上述步骤(1)、(2)和(3)中,首先将模具内表面加热至55℃,之后再将组分加入到模具中,并于55rpm下振动30min后,之后进行冷冻干燥。
(4)将(1)的A层海绵状结构、(2)的B层海绵状结构和(3)的C层海绵状结构按照A-B-C的次序叠放在一起,边缘切齐,无菌密封包装,得到三维复合海绵状结构体。
表1三维复合海绵实验组和对照组的组成
注:“/”代表该项组分空缺;“*”代表该项组分被新组分替换;EGF:表皮生长因子;VEGF:血管内皮生长因子;bFGF:碱性成纤维细胞因子;TGF:转化生长因子。
实施例2三维复合海绵的动物模型应用效果评价
(1)糖尿病溃疡模型动物
依据文献,建立糖尿病溃疡模型动物,方法简述为:选择Wistar大鼠,经链脲佐菌素诱导产生糖尿病,监测其空腹血糖、体质量、饮水量、尿量等指标,建模成功后将大鼠背部切除一圆形区域全层皮肤组织,形成糖尿病溃疡模型动物。
(2)应用效果评价
将糖尿病溃疡模型动物随机分成25个小组,每组5只,糖尿病溃疡面贴敷三维复合海绵。经过两周治疗,从糖尿病溃疡创面的愈合情况进行观察,根据愈合进程和疤痕渗血等副作用给予定性评价(“+”代表愈合进程快且疤痕渗血等副作用少,“-”代表愈合进程慢且疤痕渗血等副作用明显),根据综合治疗效果给予定量评价,评分从1到10共分10个等级,数值越高表示三维复合海绵状结构体对于糖尿病溃疡的治疗效果越好。
实验结果:以上各组的三维复合海绵效果评价结果见表2
表2三维复合海绵用于糖尿病溃疡的治疗效果评价
组别 | 愈合进程评价 | 综合效果评分 |
实验组1 | + | 6.9 |
实验组2 | + | 6.8 |
实验组3 | + | 7.2 |
实验组4 | + | 7.1 |
实验组5 | + | 7.4 |
实验组6 | + | 7.2 |
实验组7 | ++ | 8.0 |
实验组8 | ++ | 8.4 |
实验组9 | +++ | 8.9 |
实验组10 | ++++ | 9.4 |
实验组11 | ++++ | 9.4 |
实验组11 | ++++ | 9.1 |
实验组11 | ++++ | 9.2 |
对照组1 | -- | 4.8 |
对照组2 | - | 5.4 |
对照组3 | -- | 4.2 |
对照组4 | --- | 2.1 |
对照组5 | --- | 2.4 |
对照组6 | --- | 2.8 |
对照组7 | - | 5.5 |
对照组8 | - | 5.0 |
对照组9 | --- | 2.7 |
对照组10 | -- | 4.9 |
对照组11 | --- | 2.2 |
对照组12 | --- | 2.0 |
从表2数据可见,各个实验组的创面愈合较快,治疗效果评分较高,验证了实验组三维复合海绵状结构体对糖尿病溃疡的具有良好的愈合效果。对照组的创面愈合较慢并伴有疤痕出血等问题,治疗效果评分明显劣于实验组,表明对照组的组分和组合对糖尿病溃疡的愈合效果差。糖尿病溃疡模型动物实验结果表明,本发明三维复合海绵状结构体各组分对糖尿病溃疡的愈合具有良好的协同起效优势。
这里说明的模块数量和处理规模是用来简化本发明的说明的。对本发明的促进糖尿病溃疡创面愈合的三维复合海绵状结构体及方法的应用、修改和变化对本领域的技术人员来说是显而易见的。
尽管本发明的实施方案已公开如上,但其并不仅仅限于说明书和实施方式中所列运用,它完全可以被适用于各种适合本发明的领域,对于熟悉本领域的人员而言,可容易地实现另外的修改,因此在不背离权利要求及等同范围所限定的一般概念下,本发明并不限于特定的细节。
Claims (3)
1.一种促进糖尿病溃疡创面愈合的三维复合海绵状结构体的制备方法,其特征在于,包括如下步骤:
步骤一、取肝素-泊洛沙姆聚合物凝胶和细胞生长因子混匀,于模具中进行第一冷冻干燥,并制备得到A层海绵状结构;
步骤二、取壳聚糖及其衍生物粉末分散于硝酸中进行氨基质子化反应,之后加入1,2-丙二醇混匀,再加入硝酸银,混匀,于模具中进行第二冷冻干燥,并制备得到B层海绵状结构;
步骤三、取脱细胞真皮支架在液氮中进行粉碎,于模具中进行第三冷冻干燥,并制备得到C层海绵状结构;
步骤四、将步骤一中得到的A层海绵状结构、步骤二中得到的B层海绵状结构和步骤三中的C层海绵状结构按照A-B-C的次序依次叠放在一起,灭菌后得到三维复合海绵状结构体;
进行所述第一冷冻干燥的具体方法包括:首先于温度-20~-30℃下冷冻3~4小时,之后于温度-35~-75℃冷冻干燥24~48 h,冷冻干燥时的真空度小于10Pa,然后于体积比80~90%的乙醇溶液熏蒸和紫外线下交联1~3h,最后再次于温度-35~-75℃冷冻干燥24~48 h,冷冻干燥时的真空度小于10Pa;
进行所述第二冷冻干燥的具体方法包括:首先于温度-35~-45℃下冷冻3~4小时,之后于温度-45~-85℃冷冻干燥24~48 h,冷冻干燥时的真空度小于10Pa,然后于体积比80~90%的乙醇溶液熏蒸和紫外线下交联3~5 h,最后再次于温度-35~-75℃冷冻干燥24~48 h,冷冻干燥时的真空度小于10Pa;
进行所述第三冷冻干燥的具体方法包括:首先于温度-30~-40℃下冷冻3~4小时,之后于温度-40~-80℃冷冻干燥24~48 h,冷冻干燥时的真空度小于10 Pa,然后于体积比80~90%的乙醇溶液熏蒸和紫外线下交联1~3h,最后再次于温度-35~-75℃冷冻干燥24~48 h,冷冻干燥时的真空度小于10Pa;
所述促进糖尿病溃疡创面愈合的三维复合海绵状结构体由靠近溃疡创面向外的方向上依次设置有A层海绵状结构、B层海绵状结构和C层海绵状结构,其中,所述A层海绵状结构包含负载细胞生长因子的肝素-泊洛沙姆聚合物凝胶,所述B层海绵状结构包含负载纳米银的壳聚糖及其衍生物的凝胶,所述C层海绵状结构包含脱细胞真皮支架和表皮干细胞,所述表皮干细胞铺满所述脱细胞真皮支架表面积的80%以上;所述细胞生长因子选自转化生长因子、胰岛素样生长因子、角质细胞生长因子、表皮生长因子、血管内皮生长因子、神经生长因子中的任意一种或几种;所述壳聚糖衍生物包括N-三甲基壳聚糖、N-马来酰化壳聚糖、羧甲基壳聚糖、N,O-羧甲基壳聚糖和羟丙基壳聚糖中的任意一种或几种;所述A层海绵状结构中细胞生长因子的质量百分含量为0.001%~0.1%,所述B层海绵状结构中纳米银的质量百分含量为0.0001%~0.01%。
2. 如权利要求1所述的促进糖尿病溃疡创面愈合的三维复合海绵状结构体的制备方法,其特征在于,步骤一、步骤二和步骤三中,首先将模具内表面加热至50~60℃,之后再将组分加入到模具中,并于50~60 rpm下振动25~35min后,之后进行冷冻干燥。
3.如权利要求1所述的促进糖尿病溃疡创面愈合的三维复合海绵状结构体的制备方法,其特征在于,步骤一、步骤二和步骤三中,制备海绵状结构时,各组分还分别加入有保湿剂、稳定剂、抑菌剂和pH调节剂。
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