CN116785491A - 一种多孔复合止血海绵及其制备方法 - Google Patents
一种多孔复合止血海绵及其制备方法 Download PDFInfo
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- CN116785491A CN116785491A CN202310501099.2A CN202310501099A CN116785491A CN 116785491 A CN116785491 A CN 116785491A CN 202310501099 A CN202310501099 A CN 202310501099A CN 116785491 A CN116785491 A CN 116785491A
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- Prior art keywords
- hemostatic sponge
- porous
- hemostatic
- silk fibroin
- dopamine hydrochloride
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Abstract
本发明提供了一种多孔复合止血海绵及其制备方法,主要包括丝素蛋白、海藻酸钠、盐酸多巴胺和交联剂;其具有多孔微观结构,孔隙率在45‑65%,所述微观多孔直径为20‑150μm左右。所述止血海绵的制备方法,是由丝素蛋白、海藻酸钠、盐酸多巴胺和交联剂通过简单的“一锅法”混合均匀,再经钙离子交联而成;所制备的复合止血海绵具有良好止血特性,能够吸收大量的血液,同时通过增强对红细胞、血小板的粘附、聚集、激活来实现快速止血,特别适用于对穿透性伤口和小而狭窄的伤口进行止血。本发明制备止血海绵的工艺简单、反应条件温和,易于操作和控制,生产成本低,在创伤止血领域具有广阔的应用前景。
Description
技术领域
本发明属于生物材料技术领域,尤其涉及一种多孔复合止血海绵及其制备方法。
背景技术
在战场、交通事故和手术等紧急情况下,过度失血仍然是患者死亡的主要原因。全球超过30%的创伤死亡是由不可控制的出血造成的,其中一半以上发生在获得急救护理之前。机体的自然凝血过程可以将血液转化为稳定的、不溶性的纤维蛋白来完成止血。但在没有止血装置和止血剂的情况下是无法及时完成止血的。
早在几千年前,人类就试图通过使用各种外用药剂来止血。埃及人用蜡、油脂和大麦的混合物来止血;美洲原住民将兽皮内部的刮痕与热沙和鹰绒混合在一起作为局部止血剂。1905年Morawitz首次将纤维蛋白粉末用于伤口愈合,开启早期的止血理论开始逐步成型。1944年Cronkite和Tidrick分别独立发表了将纤维蛋白原和凝血酶混合制得纤维蛋白胶的成果。由此,止血材料的性能和止血机制开始被广泛地研究。
目前,止血材料主要通过以下四个方面发挥止血作用。第一类是载药止血材料(如凝血酶、纤维蛋白胶、钙离子等),通过直接激活或参与凝血系统,达到止血的目的。TachoComb1是一种外用纤维蛋白密封剂,由人纤维蛋白原、牛凝血酶和抑肽酶包裹在马胶原海绵上,是各种手术中进行组织粘连/闭合的最常见的商业产品之一。但使用牛凝血酶和抑肽酶可能引起严重甚至致命的过敏反应,因为反复使用后机体会产生抗体。为了克服这些副作用,下一代TachoComb1已使用人凝血酶取代牛凝血酶。然而,使用所制备的纤维蛋白胶治疗的患者可能仍面临感染传播的风险,因为使用的是汇集的人血。此外,虽然胶凝得很快,但它在生物表面的粘合强度很低凝血酶,且价格昂贵。第二类止血材料是通过物理或化学因素(如孔隙率、比表面积和液体吸收率等)来止血。如沸石粉,对水分具有极强的物理吸附作用,并可以通过加热的方式将吸附的水分脱去。然而它在试剂应用过程中往往会引起异常排斥反应,甚至会产生严重的放热反应,导致皮肤灼伤。第三类止血材料通过强粘附力封闭血管止血。组织粘合剂主要包括生物蛋白和化学合成两大类。生物蛋白类是一种以白蛋白为基础的市售生物胶,可以迅速的在出血位点形成不可溶性纤维蛋白凝块而封堵出血血管,但是白蛋白产品通常具有潜在的免疫原性。另一类化学合成类,例如α-氰基丙烯酸酯组织胶,其结构中的异氰酸酯结构对含有羟基或氨基的物质具有极高的亲和能力,从而成为一类人工合成的反应型粘合止血剂。但这类止血材料的残留物可能会导致血管栓塞,降解过程中释放出的氰和甲醛等有毒物质也会导致注射部位周边产生炎症和组织坏死,并且对使用条件要求高。第四类是复合类止血材料,通过将上述两种或两种以上止血因子结合在一起达到止血目的。为了解决单一材料可能存在的某些性能缺陷或是应用上的局限,近年来研宄人员通过复合策略对已有的止血材料进行改性。与单一止血材料相比,复合止血材料综合了多种材料的优点,有利于提升材料的止血效率。
鉴于现有的止血材料存在的缺陷和局限性,有必要研究新的方法制备具有较高孔隙率和吸水率,能够快速吸收伤口表面多余血液,达到快速有效止血,促进创面凝血的新产品。CN113350566A公开了一种医用海绵止血材料,所述海绵止血材料包含以下成分:改性海藻酸钠、聚乙烯醇、丝素蛋白、羟丙基淀粉、双乙酰酒石酸单双甘油酯、山梨糖醇、四氧化三铁纳米颗粒。该止血材料虽然具有较好的止血效果,但是需要对天然材料进行过度改性,而天然材料过度改性后生物相容性较差,不够安全,不利于实际应用;并且,制备工艺较复杂,由于所用材料较多,其成本也相对较高。
发明内容
针对现有技术存在的上述不足,本发明旨在提供一种多孔复合止血海绵,解决现有止血材料生物相容性较差,安全性较低的问题。
进一步,本发明还提供所述多孔复合止血海绵的制备方法,解决现在制备工艺复杂、成本相对较高的问题。
进一步,本发明还解决现有止血材料止血效率较低的问题。
为了解决上述问题,本发明采用了如下技术方案:
(同权利要求,暂时省略)
相比现有技术,本发明具有如下有益效果:
1、本发明多孔复合止血海绵,成份简单,综合海藻酸钠、丝素蛋白和多巴胺的优点,具有良好的生物相容性、可降解性和无毒性。其形成的具有多孔结构的复合止血海绵,孔隙率在45-65%,使之能够吸收大量血液,加上具有良好生物相容性有效成份,可通过促进红细胞和血小板的粘附、聚集、激活实现快速止血,提升止血效率。其分级多孔结构还非常有利于气体渗透和对伤口渗出液的吸收。
2、本发明中,丝素蛋白用于提高凝血活性,缩短出血时间;海藻酸钠通过离子交换释放钙离子,激活与止血作用相关的内源性和外源性凝血过程;同时,富含儿茶酚的多巴胺在生理pH条件下的正电性可促进凝血;交联剂为聚乙二醇二缩水甘油醚,采用此种交联剂可以增加丝素蛋白的柔韧性,避免止血海绵发生断裂,造成止血海绵清除困难的问题。
3、本发明采用一锅法制备,制备工艺简单,其原材料来源丰富,因此具有较低的使用成本,在创伤止血领域具有广阔的应用前景。
附图说明
图1为实施例1~3、对照例1制备的多孔止血海绵的微观形貌图;
图2为实施例1~3、对照例1制备的多孔止血海绵的宏观形貌图;
图3为实施例1压缩后的多孔止血海绵吸水恢复原有形状的宏观示意图;
图4为实施例1~3、对照例1制备的多孔止血海绵的体外凝血时间图;
图5为实施例1~3、对照例1制备的多孔止血海绵的体外凝血宏观图。
具体实施方式
下面结合实施例对本发明作进一步的详细说明。实施例中所用试剂未特别说明均市售可得。
一、本发明提供一种多孔复合止血海绵
参见图1,一种多孔复合止血海绵,主要包括丝素蛋白、海藻酸钠、盐酸多巴胺和交联剂;其具有多孔微观结构,孔隙率在45-65%,所述微观多孔直径为20-150μm左右。止血材料的分级多孔结构非常有利于气体渗透和伤口渗出液的吸收,因此这些材料可以作为理想的止血敷料来止血。其中,所述丝素蛋白、海藻酸钠、盐酸多巴胺和交联剂按如下质量比配伍。
具体实施例如表1:
表1、丝素蛋白、海藻酸钠、盐酸多巴胺和交联剂用量配伍(单位,克)
实施例 | 丝素蛋白 | 海藻酸钠 | 盐酸多巴胺 | 交联剂 |
实施例1 | 2 | 2 | 0.2 | 0.8 |
实施例2 | 2 | 2 | 0.5 | 0.8 |
实施例3 | 2 | 2 | 1 | 0.8 |
二、一种多孔复合止血海绵的制备方法
包括如下步骤:
1)将浓缩的丝素蛋白溶液溶于去离子水中,机械搅拌均匀,制成质量分数为2wt%~10wt%的丝素蛋白溶液;
2)将海藻酸粉末钠溶于去离子水中,机械搅拌至完全溶解,制成质量分数为2wt%~10wt%海藻酸钠溶液;
3)将步骤1)和2)制得的溶液按体积比1~5:1~5混合,机械搅拌均匀;
4)将交联剂加入到步骤3)制得混合溶液中,搅拌均匀;所述交联剂与步骤3)所得混合溶液质量比为0.1~1:1;
5)将一定质量的盐酸多巴胺加入到步骤4)制得的混合溶液中,盐酸多巴胺的加入量为加入盐酸多巴胺后溶液总质量的0.1~1wt%,搅拌均匀后进行冷冻干燥;
6)将步骤5)制得的冷冻干燥样品置于氯化钙溶液中1~12h,用去离子水洗去样品表面的未结合的钙离子,再次进行冷冻干燥。
所述步骤1)中质量分数为2wt%~10wt%(例如可以是2wt%、3wt%、4wt%、5wt%、7wt%或10wt%)。
所述步骤2)质量分数为2wt%~10wt%(例如可以是2wt%、3wt%、4wt%、5wt%、7wt%或10wt%)。
所述步骤3)中丝素蛋白和海藻酸钠的体积比为1~5:1~5(例如可以是1:1、1:2、1:3、1:4、2:1、2:2、2:3、2:4、3:3或4:4)。
所述步骤4)中交联剂与步骤3)中所得混合溶液质量比为0.1~1:1(例如可以是0.1:1、0.2:1、0.3:1、0.5:1、0.7:1或1:1),交联反应时间为0.5~4h(例如可以是0.5h、1h、2h、3h或4h)。
所述步骤5)中的盐酸多巴胺的加入量为加入盐酸多巴胺后溶液总质量的0.1~1wt%,(例如可以是0.1wt%、0.2wt%、0.3wt%、0.5wt%、0.7wt%或1wt%),交联反应时间为4~36h,例如可以是4h,8h,12h,16h,20h,24h或36h;冷冻干燥时间为24~72h,例如24h,36h,48h,60h或72h。
所述步骤6)中的氯化钙质量分数为1~10wt%,例如1%、2%、3%、5%、7%或10%。
三、实施例
实施例1:一种多孔止血海绵的制备方法,包括如下步骤:
精确称取4g海藻酸钠粉末溶于96ml去离子水中配置成质量分数为4wt%的溶液;
将浓缩丝素溶液稀释为质量分数为4wt%的溶液;
将海藻酸钠溶液与丝素蛋白溶液等体积混合搅拌2h;
在上述混合溶液中加入与混合溶液质量比为0.8:1的聚乙二醇二缩水甘油醚(PEG-DE),充分搅拌45min;
再加入适量盐酸多巴胺,盐酸多巴胺的加入量为加入盐酸多巴胺后溶液总质量的0.2wt%,搅拌4h使其氧化为聚多巴胺;搅拌完成后,取上述混合凝胶液适量倒入模具中,在4℃温度条件放置4h消除气泡后置于-20℃预冻24h,再真空冷冻干燥48h。
最后,将冻干样品置于质量分数5%的氯化钙溶液中交联12h,用纯水洗涤三次,置于-20℃预冻24h,再次真空冷冻干燥48h,得到多孔止血海绵。其微观结构如图1所示。
其中,丝素蛋白溶液可以采用商用产品,也可以自制获得。
一种丝素蛋白溶液的制备方法,具体包括:
1)将清水洗净、晾干的蚕茧以浴比1:50置于质量分数为0.5%的碳酸钠溶液中,在99℃的恒温水浴锅中脱胶2h,得到脱胶丝素蛋白纤维。
2)将丝素蛋白纤维用蒸馏水彻底冲洗干净后在37℃恒温箱中烘干;然后以浴比1:10置于摩尔比为1:2:8的氯化钙-乙醇-水三元溶液中83℃盐解反应1~2h,直至丝素蛋白纤维完全溶解。
3)将溶解的丝素蛋白溶液以4000r/min离心20min取上清液,装入透析带(MWCO8000-14000)中透析3d,每隔12h置换一次去离子水;并将透析完成后的丝素蛋白溶液以4000rpm/min离心20min,去掉沉淀物,得到的透明丝素蛋白溶液的上清液浓缩后储存在4℃备用。使用时,可通过干燥并称量1mL纯化的丝素蛋白溶液来确定丝素蛋白溶液浓度。
实施例2~3、对照例1
采用与实施例1相同的制备方法,只是盐酸多巴胺加入量有所不同,具体如表2所示。
表2
二、性能检测
1、实施例1~3和对照例1中的多孔止血海绵的微观形貌如图1所示。由此可见,其均为多孔结构,分级多孔结构非常有利于气体渗透和对伤口渗出液的吸收。
2、多孔止血海绵的宏观形貌如图2和图3所示。图2中所示止血海绵从左到右依次是对照例1(SA/SF)、实施例1(SA/SF/DA2)、实施例2(SA/SF/DA5)和实施例3(SA/SF/DA10)。从图2中可以看出,随着多巴胺含量的增加,得到止血海绵的颜色逐渐加深,表面逐渐粗糙。从图3可以看到止血海绵在压缩后通过吸水溶胀可以恢复到原来的形状,因此可适用于小而狭窄的伤口。
3、采用试管法测定其全血凝血时间,测定方法如下:
1)将待测样品裁剪成相同大小(0.5×0.5×0.5cm3)放入若干个洁净的15mL试管中,置于37℃水浴中恒温5min。
2)依次迅速将1ml抗凝兔血,200ul的氯化钙(0.2mol/L)溶液加入上述试管中,开始计时,每30s倾斜离心管30°进行观察,直至试管缓慢倒置血液不流动,记录凝血时间。
结果如图4所示,不加任何样品的凝血时间为空白对照。从图中可以看到与空白对照(control)相比,实施例1~3和对照例1的凝血时间都缩短了。而实施例与对照例相比凝血时间更短,且随着多巴胺含量的增加,凝血时间减少。这说明多巴胺的存在加速了血液凝固时间。
图5为实施例1~3、对照例1制备的多孔止血海绵的体外凝血宏观图。由图4也可看出,随着多巴胺含量的增加,凝血效果逐渐增强。
综上,本发明多孔止血海绵综合了海藻酸钠、丝素蛋白、多巴胺的优点,具有良好的生物相容性、可降解性和无毒性,能够吸收大量血液,并通过促进红细胞和血小板的粘附、聚集、激活实现快速止血。
压缩的止血海绵在吸水溶胀后可以恢复到原来的形状,因此本发明也尤其适合于对穿透性伤口和小而狭窄的伤口止血。最后需要说明的是,以上实施例仅用以说明本发明的技术方案而非限制技术方案,本领域的普通技术人员应当理解,那些对本发明的技术方案进行修改或者等同替换,而不脱离本技术方案的宗旨和范围,均应涵盖在本发明的权利要求范围当中。
Claims (6)
1.一种多孔复合止血海绵,其特征在于,主要包括丝素蛋白、海藻酸钠、盐酸多巴胺和交联剂;其具有微观多孔结构,孔隙率在45-65%,所述微观多孔直径为20-150μm左右。
2.根据权利要求1所述多孔复合止血海绵,其特征在于,所述丝素蛋白、海藻酸钠、盐酸多巴胺和交联剂按如下质量比2~10:2~10:0.1~1:0.1~1配伍。
3.根据权利要求1所述多孔复合止血海绵的制备方法,其特征在于,具体包括:
1)将相同质量分数浓度、体积比为1~5:1~5的丝素蛋白溶液和海藻酸钠溶液混合均匀,得混合液;其中,相同质量分数浓度为2wt%~10wt%;
2)向步骤1)所得混合溶液加入交联剂并搅拌均匀,所述交联剂与上述混合液的质量比为0.1~1:1;
3)向步骤2)所得混合溶液中加入盐酸多巴胺,并搅拌均匀;其中,所述盐酸多巴胺的加入量为加入盐酸多巴胺后溶液总质量的0.1~1wt%。
4)将步骤3)所得溶液消除气泡后,冷冻干燥;然后置于氯化钙溶液中发生交联,用去离子水洗去样品表面未结合的钙离子,再次冷冻干燥,即得多孔止血海绵。
4.根据权利要求3所述多孔复合止血海绵的制备方法,其特征在于,所述交联剂为聚乙二醇二缩水甘油醚,乙二醇二缩水甘油醚。
5.根据权利要求3所述多孔复合止血海绵的制备方法,其特征在于,所述步骤4)中,氯化钙溶液的质量分数为1~10%;发生交联反应的时间为0.5~12h。
6.根据权利要求3所述多孔复合止血海绵的制备方法,其特征在于,所述步骤4)中冷冻干燥皆为-20℃预冻18~24h,再真空冷冻干燥36~54h。
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