CN116999605A - 具有强粘附力、抗菌性及可降解性的止血粉的制备方法 - Google Patents
具有强粘附力、抗菌性及可降解性的止血粉的制备方法 Download PDFInfo
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- CN116999605A CN116999605A CN202310577777.3A CN202310577777A CN116999605A CN 116999605 A CN116999605 A CN 116999605A CN 202310577777 A CN202310577777 A CN 202310577777A CN 116999605 A CN116999605 A CN 116999605A
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- powder
- chitosan
- solution
- gelatin
- quaternized chitosan
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Abstract
具有强粘附、抗菌及可降解的快速止血粉末的制备方法，步骤如下：(1)将壳聚糖溶于冰乙酸溶液中，经季铵化反应，制得的季铵化壳聚糖粉末，溶于水，制得季铵化壳聚糖溶液。(2)将明胶粉末加入(1)步溶液中，得到季铵化壳聚糖/明胶混合液。(3)将含酚羟基溶液在加热条件下与(2)步溶液混合，并冷却干燥，制得快速止血粉。本发明止血粉具有强粘附性，优异的抗菌性，可降解性以及快速止血等特点。
Description
技术领域
本发明属于生物材料制备领域，具体涉及具有强粘附、抗菌及可降解的快速止血粉末及其制备方法。
背景技术
不可控的出血是外科手术中或遭受重大创伤后的一个严重问题，导致了全世界超过30％的创伤死亡，其中一半以上发生在急救之前。有效的止血可显著减轻痛苦，防止进一步损伤，促进伤口恢复并提高存活率。然而，现有的止血敷料(纱布、纸巾和止血带等)不能很好地止住创伤性静脉或动脉的出血，也无法控制不可压缩伤口出血，并且它们的湿粘附性较差，难以牢固地覆盖在伤口部位。氰基丙烯酸酯止血剂虽有较好的止血效果，但其固化时间长，且具有细胞毒性，不适于肝脏或股动脉出血。因此，需设计一种具有良好生物相容性且适用于各种出血伤口的的止血材料。
粉末止血剂可完美贴合不规则伤口和不可压缩伤口，并且可吸收伤口部位出血并形成物理屏障，是理想的止血材料。而现有的止血粉末大多使用的是合成高分子，粉末进入体内后降解速度慢，易形成血栓造成风险。理想的止血材料应该具备吸血能力强，生物相容性好，多功能化，生物降解性好等优点。目前，还未有一种止血材料可满足理想需求，制备出一种具有多功能的止血材料对生物医学领域具有重要意义。
发明内容
本发明的目的是提供具有强粘附、抗菌及可降解的快速止血粉末的制备方法，该方法制备的止血粉以天然高分子壳聚糖和明胶为主体，具有良好的生物相容性和多功能性，并且具有强粘附性和止血性能。
本发明首先提供如下技术方案：
具有强粘附、抗菌及可降解的快速止血粉末的制备方法，包括以下步骤：
步骤1：将壳聚糖溶解在冰乙酸溶液中，在55℃下与2，3环氧丙基三甲基氯化铵反应，通过季铵化反应在壳聚糖分子链上接枝季铵基团得到接枝度为40％的季铵化壳聚糖，然后透析，冷冻干燥得到季铵化壳聚糖粉末。将冷冻干燥后的季铵化壳聚糖粉末溶解于水中，搅拌均匀，得到季铵化壳聚糖溶液。
步骤2：将一定量的明胶粉末溶解于季铵化壳聚糖溶液中，继续搅拌，得到季铵化壳聚糖/明胶混合液。
步骤3：配制一定浓度的含酚羟基的化合物溶液，将其加入步骤2配制的季铵化壳聚糖/明胶混合液中，在加热条件下充分搅拌使三种组分混合均匀后，得到明胶/壳聚糖/多酚基水凝胶。
步骤4：将步骤3制备的明胶/壳聚糖/多酚基水凝胶进行冷冻干燥，并研磨至粉末，得到具有强粘附、抗菌及可降解的快速止血粉末。
进一步的，步骤3中所述含酚羟基的化合物为邻苯二酚、间苯二酚、对苯二酚、邻苯三酚、鞣花酸、儿茶素、胞苷、多巴胺、单宁酸、没食子酸、咖啡酸和表没食子儿茶素没食子酸酯，其浓度为10％～50wt.％。
进一步的，步骤1中所述季铵化壳聚糖溶液浓度为：3～30mg/mL。
进一步的，步骤2中所述明胶类型为：A型、B型、鱼明胶。
进一步的，步骤3中所述加热条件为60℃～80℃。
进一步的，步骤3中所述含酚羟基官能团有机物溶液与季铵化壳聚糖/明胶混合溶液按一定比例混合。
进一步的，步骤3中所述搅拌时间为30～60s。
本发明中所述的纯水为去离子水或蒸馏水。
本发明的有益效果是：
(1)本发明提供的止血水凝胶粉末依靠分子间物理相互作用和可逆动态化学键交联，制备方法简单，条件温和，便于大规模生产。
(2)本发明提供的止血粉末，在止血过程中可作为物理屏障并聚集血小板和血细胞，可缩短活化部分凝血活酶时间和凝血酶原时间，可激活内源性和外源性止血因子，加快凝血时间，起到快速止血的作用。止血时间在10秒内，能够对肠、肝脏、心脏、皮肤表面组织均进行快速止血。
(3)本发明提供的止血粉末具有广谱粘附性，可牢固粘附各种基材，如玻璃、钛片、骨片、猪皮、肝脏、心脏、胃等组织上，最高粘附强度可达80kPa。
(4)由于季铵化壳聚糖的引入，本发明提供的止血粉末还具有优异的抗菌性能，可以抑制伤口处有害微生物滋长，降低伤口感染风险。
(5)由于本发明制备的止血粉末依靠分子间相互作用交联成胶，因此本发明提供的止血粉末可重新成胶，方便保存，重新成胶时间短，且水凝胶可注射，可按需调控成胶时间及胶体浓度，应用范围广泛。
附图说明
图1A为本发明制备的所述粉末应用实施例1重新成胶前后黑白照片图。
图1B为本发明制备的所述粉末应用实施例1吸水能力示意图。
图2A为本发明制备的粉末应用实施例1粘附强度示意图。
图2B为本发明制备的粉末应用实施例1粘附黑白照片图。
图3A为本发明制备的粉末应用实施例1抗大肠杆菌效果黑白照片图。
图3B为本发明制备的粉末应用实施例1抗大肠肝菌率示意图。
图3C为本发明制备的粉末应用实施例1抗表皮葡萄球菌效果黑白照片图。
图3D为本发明制备的粉末应用实施例1抗表皮葡萄球菌率示意图。
图4为本发明制备的粉末应用实施例1止血效果示意图。
图5为本发明制备的粉末通过细胞相容性对季铵化壳聚糖量的筛选数据图
具体实施方式
为了使本发明的实验成果及有益特性更加清晰，以下结合实施例，对本发明实施例中的实验方案进行清楚地阐述。所描述的实施例仅是本发明一部分实施例，而不是全部的实施例，且所描述的具体实施例仅用以解释本发明。
实施例1
具有强粘附、抗菌及可降解的快速止血粉末的制备
步骤1：将壳聚糖溶解在冰乙酸溶液中，在55℃下与2，3环氧丙基三甲基氯化铵反应，通过季铵化反应在壳聚糖分子链上接枝季铵基团得到接枝度为40％的季铵化壳聚糖，然后透析，冷冻干燥得到季铵化壳聚糖粉末。将0.06g冷冻干燥后的季铵化壳聚糖粉末溶解于3mL水中，搅拌均匀，得到季铵化壳聚糖溶液。
步骤2：将1g明胶粉末溶解于季铵化壳聚糖溶液中，继续搅拌，得到季铵化壳聚糖/明胶混合液。
步骤3：配制0.2g/mL的单宁酸(TA)溶液，取1mL加入步骤2配制的季铵化壳聚糖/明胶混合液中，在60℃下充分搅拌使三种组分混合均匀后，得到明胶/壳聚糖/单宁酸水凝胶。
步骤4：将步骤3制备的明胶/壳聚糖/单宁酸水凝胶进行冷冻干燥，并研磨至粉末，得到目标止血粉。该目标止血粉可在10s内止血，对猪皮粘附力为32±5KPa,对大肠杆菌抗菌率为98.41％，对表皮葡萄球菌抗菌率为97.35％。
实施例2
步骤1：将壳聚糖溶解在冰乙酸溶液中，在55℃下与2，3环氧丙基三甲基氯化铵反应，通过季铵化反应在壳聚糖分子链上接枝季铵基团得到接枝度为40％的季铵化壳聚糖，然后透析，冷冻干燥得到季铵化壳聚糖粉末。将0.06g冷冻干燥后的季铵化壳聚糖粉末溶解于3mL水中，搅拌均匀，得到季铵化壳聚糖溶液。
步骤2：将0.5g的明胶粉末溶解于季铵化壳聚糖溶液中，继续搅拌，得到季铵化壳聚糖/明胶混合液。
步骤3：配制0.1g/mL的多巴胺(DA)溶液，取1mL加入步骤2配制的季铵化壳聚糖/明胶混合液中，在60℃下充分搅拌使三种组分混合均匀后，得到明胶/壳聚糖/多巴胺水凝胶。
步骤4：将步骤3制备的明胶/壳聚糖/多巴胺水凝胶进行冷冻干燥，并研磨至粉末，得到目标止血粉。该目标止血粉可在12s内止血，对猪皮粘附力为27±3KPa,对大肠杆菌抗菌率为97.09％，对表皮葡萄球菌抗菌率为96.83％。
实施例3
步骤1：将壳聚糖溶解在冰乙酸溶液中，在55℃下与2，3环氧丙基三甲基氯化铵反应，通过季铵化反应在壳聚糖分子链上接枝季铵基团得到接枝度为40％的季铵化壳聚糖，然后透析，冷冻干燥得到季铵化壳聚糖粉末。将0.06g冷冻干燥后的季铵化壳聚糖粉末溶解于3mL水中，搅拌均匀，得到季铵化壳聚糖溶液。
步骤2：将1g的明胶粉末溶解于季铵化壳聚糖溶液中，继续搅拌，得到季铵化壳聚糖/明胶混合液。
步骤3：配制0.1g/mL的没食子酸(GA)溶液，取1mL加入步骤2配制的季铵化壳聚糖/明胶混合液中，在60℃下充分搅拌使三种组分混合均匀后，得到明胶/壳聚糖/没食子酸水凝胶。
步骤4：将步骤3制备的明胶/壳聚糖/没食子酸水凝胶进行冷冻干燥，并研磨至粉末，得到目标止血粉。该目标止血粉可在10s内止血，对猪皮粘附力为31±4KPa,对大肠杆菌抗菌率为95.35％，对表皮葡萄球菌抗菌率为92.33％。
实施例4
步骤1：将壳聚糖溶解在冰乙酸溶液中，在55℃下与2，3环氧丙基三甲基氯化铵反应，通过季铵化反应在壳聚糖分子链上接枝季铵基团得到接枝度为40％的季铵化壳聚糖，然后透析，冷冻干燥得到季铵化壳聚糖粉末。将0.06g冷冻干燥后的季铵化壳聚糖粉末溶解于3mL水中，搅拌均匀，得到季铵化壳聚糖溶液。
步骤2：将0.8g的明胶粉末溶解于季铵化壳聚糖溶液中，继续搅拌，得到季铵化壳聚糖/明胶混合液。
步骤3：配制0.2g/mL的表没食子儿茶素没食子酸酯(EGCG)溶液，取1mL加入步骤2配制的季铵化壳聚糖/明胶混合液中，在60℃下充分搅拌使三种组分混合均匀后，得到明胶/壳聚糖/表没食子儿茶素没食子酸酯水凝胶。
步骤4：将步骤3制备的明胶/壳聚糖/表没食子儿茶素没食子酸酯水凝胶进行冷冻干燥，并研磨至粉末，得到目标止血粉。该目标止血粉可在10s内止血，对猪皮粘附力为37±3KPa,对大肠杆菌抗菌率为99.65％，对表皮葡萄球菌抗菌率为94.44％。
实施例5
步骤1：将壳聚糖溶解在冰乙酸溶液中，在55℃下与2，3环氧丙基三甲基氯化铵反应，通过季铵化反应在壳聚糖分子链上接枝季铵基团得到接枝度为40％的季铵化壳聚糖，然后透析，冷冻干燥得到季铵化壳聚糖粉末。将0.06g冷冻干燥后的季铵化壳聚糖粉末溶解于3mL水中，搅拌均匀，得到季铵化壳聚糖溶液。
步骤2：将1g的明胶粉末溶解于季铵化壳聚糖溶液中，继续搅拌，得到季铵化壳聚糖/明胶混合液。
步骤3：配制0.2g/mL的咖啡酸(CA)溶液，取1mL加入步骤2配制的季铵化壳聚糖/明胶混合液中，在60℃下充分搅拌使三种组分混合均匀后，得到明胶/壳聚糖/咖啡酸水凝胶。
步骤4：将步骤3制备的明胶/壳聚糖/咖啡酸水凝胶进行冷冻干燥，并研磨至粉末，得到目标止血粉。该目标止血粉可在10s内止血，对猪皮粘附力为26±5KPa,对大肠杆菌抗菌率为93.6％，对表皮葡萄球菌抗菌率为92.62％。
由于季铵基团带正电，在体系中引入过多正电会引起细胞毒性，因此我们对壳聚糖浓度进行了筛选，最终确定向体系中引入0.06g季铵化壳聚糖。
Claims (7)
1.具有强粘附、抗菌及可降解的快速止血粉末的制备方法，其特征在于，包括以下步骤：
步骤1：将壳聚糖溶解在冰乙酸溶液中，通过季铵化反应在壳聚糖分子链上接枝季铵基团，然后透析，冷冻干燥得到季铵化壳聚糖粉末，将冷冻干燥后的季铵化壳聚糖粉末溶解于水中，搅拌均匀，得到季铵化壳聚糖溶液；
步骤2：将一定重量的明胶粉末溶解于季铵化壳聚糖溶液中，继续搅拌，得到季铵化壳聚糖/明胶混合液；
步骤3：配制一定浓度的含酚羟基的化合物溶液，将其加入步骤2配制的季铵化壳聚糖/明胶混合液中，在加热条件下充分搅拌使三种组分混合均匀后，得到明胶/壳聚糖/多酚基水凝胶。
步骤4：将步骤3制备的明胶/壳聚糖/多酚基水凝胶进行冷冻干燥，并研磨至粉末，得到具有强粘附、抗菌及可降解的快速止血粉末。
2.根据权利要求1所述的具有强粘附、抗菌及可降解的快速止血粉末的制备方法，其特征在于，所述步骤1中将壳聚糖溶解在冰乙酸溶液中，在55℃下与2，3环氧丙基三甲基氯化铵进行季铵化反应，季铵化壳聚糖溶液浓度为：3～30mg/mL。
3.根据权利要求1所述的具有强粘附、抗菌及可降解的快速止血粉末的制备方法，其特征在于，所述步骤2中明胶类型为：A型、B型、鱼明胶。
4.根据权利要求1所述的具有强粘附、抗菌及可降解的快速止血粉末的制备方法，其特征在于，所述步骤3中的含酚羟基的化合物为邻苯二酚、间苯二酚、对苯二酚、邻苯三酚、鞣花酸、儿茶素、胞苷、多巴胺、单宁酸、没食子酸、咖啡酸和表没食子儿茶素没食子酸酯，其浓度为10％～50wt.％。
5.根据权利要求1所述的具有强粘附、抗菌及可降解的快速止血粉末的制备方法，其特征在于，所述步骤3中加热条件为60℃～80℃。
6.根据权利要求1所述的具有强粘附、抗菌及可降解的快速止血粉末的制备方法，其特征在于，所述步骤3中含酚羟基官能团有机物溶液与季铵化壳聚糖/明胶混合溶液按一定比例混合。
7.根据权利要求1所述的具有强粘附、抗菌及可降解的快速止血粉末的制备方法，其特征在于，所述步骤3中搅拌时间为30～60s。
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