CN116350835A - 一种生物止血海绵及其制备方法 - Google Patents
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Abstract
本发明属于功能高分子材料技术领域,具体涉及一种生物止血海绵及其制备方法。以改性琼脂糖作为高聚物的基本结构骨架,接枝多巴胺盐酸盐氧化自聚物和精氨酸‑FeⅢ复合物;所述改性琼脂糖为由一氯乙酸进行醚化反应后得到的琼脂糖。本发明在提高羧甲基琼脂糖制备效率的同时提供了兼具止血和抗菌性能的生物海绵,适用于体表可压迫出血和体内不可压迫性出血等多种出血模型。此外,该生物海绵重复吸液的特点可提高其使用率,应对短时医药物资缺乏情况。
Description
技术领域:
本发明属于功能高分子材料技术领域,具体涉及一种生物止血海绵及其制备方法。
背景技术:
不可控出血是创伤性损伤中的一个重要问题。目前的止血技术主要依赖于血液自身的凝固机制,其起效慢且形成的血凝块机械性能差。这种方法也不适用于患有先天性、疾病相关或药物引起的止血功能障碍的患者。传统的局部外伤止血材料可通过物理阻塞方式封堵出血部位。然而,其通常需要通过施压去除界面血液以起到止血作用,不适用于不可压迫性出血。新型生物高分子材料通过自身材料特征与优势可选择性地吸收血液中的水,导致血液浓缩,激活凝血因子,从而加速凝血,达到止血目的。此外,细菌易入侵受损皮肤,通常会导致组织损伤,特别是与金黄色葡萄球菌相关的皮肤伤口感染。因此,开发具有生物相容性、便携性、抗菌性、可操作性及可重复吸液止血作用的生物高分子材料,以满足现阶段大量且多样化的伤口需求在实际应用中具有重要意义。
琼脂糖是一种从海藻中提取的中性多糖,因其具有产量丰富、生物相容性好等优点,可作为构建生物高分子材料的主要来源。然而,相对较低的化学复杂性限制了琼脂糖在许多精细的化学和生物反应中的直接应用。引入官能团是改变琼脂糖理化性质的有效方法。对琼脂糖高分子链结构单元改造修饰羧甲基,可以使其很容易地与其它化学物质反应,从而引入新的功能。再经合理的分子设计对接,可拓宽琼脂糖的应用范围。
专利CN111303453A公开了一种多重敏感型水凝胶聚合物的制备方法和应用,其中的改性琼脂糖是通过碱化反应后加入一氯乙酸制备得到,该羧甲基修饰琼脂糖的制备方法效率低,制备时间长,羧甲基的取代度仅为0.26以上;而且该多重敏感型水凝胶聚合物采用离子交联的方式制备,其应用方向为制备药物保护、药物缓控及靶向传输给药材料,并未提及该羧甲基修饰琼脂糖在止血方面的应用。
发明内容:
本发明要解决的技术问题是现有生物材料的凝血性能较差、重复利用率低、不能满足现阶段大量且多样化的伤口需求。
为解决上述问题,本发明通过超声法制备,显著缩短羧甲基琼脂糖的制备时间及提高羧甲基取代度;在此基础上,接枝多巴胺盐酸盐氧化自聚物和精氨酸-FeⅢ复合物,得到了具有复合三维网络结构的海绵状生物材料,具备快速吸液、良好的抗菌性和生物相容性及可重复吸液的特点,具有广阔的市场前景。
为达到上述目的,本发明通过以下技术方案实现,一种生物止血海绵,以改性琼脂糖作为高聚物的基本结构骨架,接枝多巴胺盐酸盐氧化自聚物和精氨酸-FeⅢ复合物;所述改性琼脂糖为由一氯乙酸进行醚化反应后得到的琼脂糖。
进一步的,所述改性琼脂糖的制备方法如下:将琼脂糖与异丙醇溶液充分搅拌得悬浮液,向上述悬浮液中加入NaOH溶液,边搅拌边加入一氯乙酸进行醚化反应,升温至50~70℃保持反应0.5~3h,反应结束后用醇沉法析出改性琼脂糖,洗涤、干燥后即得。
进一步的,醚化反应时将反应体系置于超声波清洗器中并用水作振荡介质,调节输出功率为40~100W进行反应。
超声波对非均相反应的促进作用与超声波能产生“空腔效应”有关。这种效应在反应体系中形成了足以引发或加速反应的高能中心,且超声波也有利于反应物的充分混合,促进反应进行,该方法得到的羧甲基琼脂糖,其羧甲基取代度为0.52~0.74。
进一步的,所述琼脂糖与异丙醇溶液的质量体积比为1g:8~12mL;所述NaOH溶液的浓度为12.8~13.8M。
进一步的,所述NaOH溶液加入量为200~300mL/L。
进一步的,所述一氯乙酸按220~280g/L加入进行醚化反应。
上述生物止血海绵的制备方法如下:将羧甲基琼脂糖溶解于MES或磷酸缓冲体系中,分别加入1-乙基-(3-二甲基氨基丙基)碳二亚胺盐酸盐和N-羟基琥珀酰亚胺,混合溶液调节pH值为4.0~9.0,置于黑暗、冰浴环境中均匀搅拌1~4h,活化羧基;在室温条件下分别将多巴胺盐酸盐和精氨酸-FeⅢ复合物加入上述混合溶液中持续搅拌12~48h;产物透析3~5天后向其加入质量分数计8%~12%的5~20mM的AgNO3溶液,增强材料杀菌性,然后冻干,即得兼具重复吸液和抗菌性能的止血海绵。其中,羧甲基琼脂上的羧基与1-乙基-(3-二甲基氨基丙基)碳二亚胺盐酸盐反应生成中间体,N-羟基琥珀酰亚胺与中间体生成酯(加入这两种物质的目的为活化羧基)。精氨酸-FeⅢ复合物中FeⅢ可作为氧化剂并通过控制环境酸碱度将多巴胺盐酸盐氧化为聚多巴胺,同时利用聚多巴胺的二次修饰功能,将羧甲基琼脂糖上被活化的羧基与聚多巴胺的氨基发生偶联反应,精氨酸-FeⅢ复合物也可接枝于羧甲基琼脂糖,形成酰胺键作为化学交联点,形成的氢键可作为物理交联点,得到含多酰胺的交联紧密网络结构,增加分子间作用力,增强材料稳定性。此外,Ag+的加入可增强材料的杀菌性。
本发明制备的生物止血海绵以羧甲基琼脂糖作为高聚物的基本结构骨架,接枝了多巴胺盐酸盐氧化自聚物和精氨酸-FeⅢ复合物,具有粗糙、致密的孔洞结构,使其具备快速吸液性能,进而导致血液浓缩,激活凝血因子,达到快速止血作用,适用于体表可压迫出血和体内不可压迫性出血等多种出血模型;并且复合材料形成酰胺键作为化学交联点,形成的氢键可作为物理交联点,得到含多酰胺的交联紧密网络结构,增加分子间作用力,增强材料稳定性,从而可重复使用;其生物相容性好,并且Ag+的存在使得本发明的止血海绵还具有良好的抗菌性,可在伤口完成快速吸液止血后不必立即清创,延续止血效果且可显著降低伤口感染风险。
进一步的,所述羧甲基琼脂糖与1-乙基-(3-二甲基氨基丙基)碳二亚胺盐酸盐、N-羟基琥珀酰亚胺的质量比为1:0.25~1.5:0.15~1,为活化羧基的最适范围。
进一步的,所述羧甲基琼脂糖与多巴胺盐酸盐、精氨酸-FeⅢ复合物的质量比为1:0.2~1.5:0.1~0.3。此条件下得到的后续材料综合性能最佳。
本发明的有益效果如下:
(1)本发明对琼脂糖D-半乳糖结构单元上的羟基氢定向取代,引入羧甲基基团。采用超声波法,通过氯乙酸取代的方式,可以显著缩短羧甲基琼脂糖制备时间,提高羧甲基取代度。
(2)本发明以羧甲基琼脂糖作为高聚物的基本结构骨架。本发明制备的生物海绵具有粗糙、致密的孔洞结构,使其具备快速吸液性能,进而导致血液浓缩,激活凝血因子,达到快速止血作用,适用于体表可压迫出血和体内不可压迫性出血等多种出血模型。
(3)该生物海绵具有良好的抗菌性且生物相容性好,可在伤口完成快速吸液止血后不必立即清创,延续止血效果且可显著降低伤口感染风险。
(4)该生物海绵可重复吸液的特点可提高材料使用率,应对短时医药物资缺乏情况。
附图说明
图1为本发明实施例1-3中改性修饰后羧甲基琼脂糖的红外光谱图;
图2为本发明实施例3中制备的生物海绵重复吸液溶胀图;
图3为本发明实施例1、3中制备的生物海绵扫描电镜图;其中(a)为羧甲基琼脂糖冻干凝胶网络结构;(b)为CA-PDA-(Arg-FeⅢ)-Ag冻干海绵网络结构,附图3的目的是对比不同制备材料的网络结构,图中字符代表的参数不影响本领域技术人员对本发明的理解;
图4为本发明实施例3中制备的生物海绵、市售海绵敷料、市售超薄水胶体敷料、医用纱布体外动态全血凝血图;
图5为本发明(a)实施例3中制备的生物海绵、(b)市售海绵敷料、(c)市售超薄水胶体敷料、(d)医用纱布上血细胞粘附扫描电镜图。
图6为本发明实施例1-3中制备的生物材料体外抑菌效果透射电镜图;其中A为本发明制备材料对大肠杆菌的抑制作用((a)使用羧甲基琼脂糖凝胶材料,(b)使用CA-PDA-(Arg-FeⅢ)材料,(c)使用CA-PDA-(Arg-FeⅢ)-Ag材料);B为本发明制备材料对金黄色葡萄球菌的抑制作用((a)使用羧甲基琼脂糖凝胶材料,(b)使用CA-PDA-(Arg-FeⅢ)材料,(c)使用CA-PDA-(Arg-FeⅢ)-Ag材料)。
具体实施方式:
为使本发明实施例的目的、技术方案和优点更加清楚,下面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。
实施例1:
在室温条件下将5g琼脂糖悬浮于50mL异丙醇溶液中充分搅拌30min后,向上述悬浮液中加入12.5mL(与发明内容)的13.3MNaOH溶液,边搅拌边加入25g一氯乙酸进行30min醚化反应,将反应体系置于超声波清洗器中并用水作振荡介质,调节输出功率为40~100W,升温至50~70℃保持反应0.5~3h,反应结束后用醇沉法析出改性琼脂糖,洗涤、干燥后得改性羧甲基琼脂糖。通过计算得其羧甲基取代度为0.52~0.74。
实施例2:
室温条件下将5g琼脂糖悬浮于50mL异丙醇溶液中充分搅拌30min后,向上述悬浮液中加入12.5mL的13.3MNaOH溶液,边搅拌边加入25g一氯乙酸进行30min醚化反应,将反应体系置于超声波清洗器中并用水作振荡介质,调节输出功率为40~100W,升温至50~70℃保持反应0.5~3h,反应结束后用醇沉法析出改性琼脂糖,洗涤、干燥后得改性羧甲基琼脂糖。通过计算得其羧甲基取代度为0.52~0.74。
采用上述方法制备得到的羧甲基琼脂糖作为原料称取1.316g溶解于100mLMES缓冲液,分别加入1.917g1-乙基-(3-二甲基氨基丙基)碳二亚胺盐酸盐和1.151gN-羟基琥珀酰亚胺,混合溶液通过HCl和NaOH调节pH值为4.0~9.0,置于黑暗、冰浴环境中均匀搅拌3h。在室温条件下按与羧甲基琼脂糖质量比1:0.2~1.5:0.1~0.3加入多巴胺盐酸盐和精氨酸-FeⅢ复合物于上述混合溶液中持续搅拌12~48h。产物透析3~5天后冻干得产物。
实施例3:
选用实施例1或2制备的改性羧甲基琼脂糖或改性制备取代度为0.52~0.74的羧甲基琼脂糖原料溶解于100mLMES缓冲液,分别加入1.917g1-乙基-(3-二甲基氨基丙基)碳二亚胺盐酸盐和1.316gN-羟基琥珀酰亚胺,混合溶液通过HCl和NaOH调节pH值为4.0~9.0,置于黑暗、冰浴环境中均匀搅拌3h。在室温条件下按与羧甲基琼脂糖质量比1:0.2~1.5:0.1~0.3加入多巴胺盐酸盐和精氨酸-FeⅢ复合物于上述混合溶液中持续搅拌12~48h。产物透析3~5天后并向其加入质量分数计8%~12%的5~20mM的AgNO3溶液,冻干,即得兼具重复吸液和抗菌性能的止血海绵。
下面将实施例1-3进行性能实验验证。
实验1:傅里叶变换红外光谱测试及图谱分析
采用傅里叶变换红外光谱测定通过超声波法、经一氯乙酸取代修饰后的羧甲基琼脂糖的化学结构。使用红外光谱仪在4000-500cm-1范围内记录本发明修饰材料的FT-IR光谱。
测定结果如图1所示,修饰后的琼脂糖在1744cm-1波段处出现羧甲基的特征吸收峰,代表其已被成功引入到结构中。
实验2:本发明生物海绵及市售海绵敷料、市售超薄水胶体敷料、医用纱布瞬时吸液溶胀测定
在室温条件下对实施例3中制备的生物海绵、市售海绵敷料、市售超薄水胶体敷料、医用纱布进行溶胀实验。当达到预定时间(5s)时,用滤纸去除表层水。溶胀度计算公式如下:溶胀度(%)=(m湿重-m干重)/m干重×100%。
实施例3中制备的生物海绵瞬时(5s)溶胀度(2380±164%)显著大于市售海绵敷料(512±9%)、市售超薄水胶体敷料(22±3%)及医用纱布(159±6%)。
实验3:本发明生物海绵重复溶胀测定
在室温条件下对实施例3中制备的生物海绵进行重复溶胀实验。待测材料吸液溶胀后挤压至几乎无液体后再次吸液,用滤纸去除表层水,重复操作。溶胀度计算公式如下:溶胀度(%)=(m湿重-m干重)/m干重×100%。
结果如图2所示,对实施例3中制备的生物海绵按上述过程循环6次的溶胀度仍较高,为1778%±155%。
实验4:本发明生物海绵表面形貌
取实施例1和3制备的生物海绵切开充分暴露材料的内部结构,将其粘贴于导电银胶布并固定在金属样品支架上,喷金后经扫描电子显微镜(SEM)拍摄观察。
如图3所示,实施例1和3的表面形貌和多孔结构存在显著差异。与实施例1相比,实施例3的孔隙结构紧密,孔径更小。
实验5:本发明生物海绵体外凝血性能
采用动态全血凝血实验评价实施例3中制备的生物海绵、市售海绵敷料、市售超薄水胶体敷料、医用纱布的凝血能力,于540nm波长处测定血红蛋白溶液的吸光值(OD),血红蛋白溶液的吸光值越低,凝血速度越快。体外凝血指数(BCI)是描述血液凝固特性的参数,BCI值越低表示材料的凝血性能越好。BCI计算公式如下:BCI(%)=(OD样品组/OD对照组)×100%。
结果如图4所示,具有快速吸液能力的实施例3在各时间点的BCI均显著低于其它组,具有高效的促凝血效果。
实验6:本发明生物海绵粘附血细胞扫描电子显微镜形态学观察
通过观察血细胞在材料表面粘附和形态,进一步研究其止血机制,并以市售海绵敷料、市售超薄水胶体敷料、医用纱布为对照组。
将全血滴入待测材料,37℃放置15s后用DPBS洗涤测试材料3次,去除物理粘附的血细胞。用2.5%戊二醛固定2h后,依次用50%、60%、70%、80%、90%和100%乙醇溶液对测试材料中的血细胞进行脱水。用扫描电镜观察干燥后的标本。
实验结果如图5所示,实施例3表面有大量血细胞粘附,其呈不规则聚集状,血液凝固是机体止血机制的表现。血小板变得不规则,有多个方向的突起,证明此时的血小板处于激活状态,达到凝血的效果。市售海绵敷料、医用纱布上黏附少量呈凸起状的血小板。市售超薄水胶体敷料上没有观察到血细胞。
由实验2-6结果可知,实施例3具有互相连通粗糙多孔结构及高溶胀率,有利于快速吸收血液中的水和小分子物质,浓缩血液中颗粒较大形成分如红细胞、血小板等细胞,激活凝血因子,从而加速凝血。这些因素都使其具有良好的体外凝血效果。另外,实施例3中制备的生物海绵循环6次的溶胀度仍较高,证明实施例3具有优异重复吸液能力,可提高材料使用率。
实验7:本发明生物海绵抑菌性能评价
采用体外模型,吸取浓度为1.0*106CFU/mL的大肠杆菌、金黄色葡萄球菌悬液置于实施例1-3中,37℃环境下共同孵育后取等量与材料共孵育的细菌悬液与LB营养琼脂混合均匀,待凝固后倒置培养24h。观察大肠杆菌菌、金黄色葡萄球菌菌落生长情况,并拍照记录,观察实验结果。
由图6中透射电子显微镜(TEM)图像可知,与实施例1和2相比,制备过程加入AgNO3溶液的实施例3能够显著破坏菌体的生长,裂解细菌细胞壁,菌体裂解抑制率在90%以上。
以上所述仅为本发明的较佳实施例而已,并不用以限制本发明,凡在本发明的精神和原则之内,所作的任何修改、等同替换、改进等,均应包含在本发明的保护范围之内。
Claims (9)
1.一种生物止血海绵,其特征在于:以改性琼脂糖作为高聚物的基本结构骨架,接枝多巴胺盐酸盐氧化自聚物和精氨酸-FeⅢ复合物;所述改性琼脂糖为由一氯乙酸进行醚化反应后得到的琼脂糖。
2.如权利要求1所述的生物止血海绵,其特征在于所述改性琼脂糖的制备方法如下:将琼脂糖与异丙醇溶液充分搅拌得悬浮液,向上述悬浮液中加入NaOH溶液,边搅拌边加入一氯乙酸进行醚化反应,升温至50~70℃保持反应0.5~3h,反应结束后用醇沉法析出改性琼脂糖,洗涤、干燥后即得。
3.如权利要求2所述的生物止血海绵,其特征在于:醚化反应时将反应体系置于超声波清洗器中并用水作振荡介质,调节输出功率为40~100W进行反应。
4.如权利要求2或3所述的生物止血海绵,其特征在于:所述琼脂糖与异丙醇溶液的质量体积比为1g:8~12mL;所述NaOH溶液的浓度为12.8~13.8M。
5.如权利要求2或3所述的生物止血海绵,其特征在于:所述NaOH溶液加入量为200~300mL/L。
6.如权利要求2或3所述的生物止血海绵,其特征在于:所述一氯乙酸按320~480g/L加入进行醚化反应。
7.一种制备权利要求1中生物止血海绵的方法,其特征在于包括以下步骤:将羧甲基琼脂糖溶解于MES或磷酸缓冲体系中,分别加入1-乙基-(3-二甲基氨基丙基)碳二亚胺盐酸盐和N-羟基琥珀酰亚胺,混合溶液调节pH值为4.0~9.0,置于黑暗、冰浴环境中均匀搅拌1~4h;在室温条件下分别将多巴胺盐酸盐和精氨酸-FeⅢ复合物加入上述混合溶液中持续搅拌12~48h;产物透析3~5天后向其加入质量分数计8%~12%的5~20mM的AgNO3溶液,冻干,即得兼具重复吸液和抗菌性能的止血海绵。
8.如权利要求7所述的方法,其特征在于:所述羧甲基琼脂糖与1-乙基-(3-二甲基氨基丙基)碳二亚胺盐酸盐、N-羟基琥珀酰亚胺的质量比为1:0.25~1.5:0.15~1。
9.如权利要求7所述的方法,其特征在于:所述羧甲基琼脂糖与多巴胺盐酸盐、精氨酸-FeⅢ复合物的质量比为1:0.2~1.5:0.1~0.3。
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