CN116617439A - 一种壳聚糖复合止血敷料及其制造方法 - Google Patents
一种壳聚糖复合止血敷料及其制造方法 Download PDFInfo
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- CN116617439A CN116617439A CN202310650816.8A CN202310650816A CN116617439A CN 116617439 A CN116617439 A CN 116617439A CN 202310650816 A CN202310650816 A CN 202310650816A CN 116617439 A CN116617439 A CN 116617439A
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- chitosan
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- hemostatic dressing
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- 229920001661 Chitosan Polymers 0.000 title claims abstract description 87
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- 239000004372 Polyvinyl alcohol Substances 0.000 claims description 10
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 claims description 10
- 239000000203 mixture Substances 0.000 claims description 10
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- PZZHMLOHNYWKIK-UHFFFAOYSA-N eddha Chemical compound C=1C=CC=C(O)C=1C(C(=O)O)NCCNC(C(O)=O)C1=CC=CC=C1O PZZHMLOHNYWKIK-UHFFFAOYSA-N 0.000 claims description 7
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- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 description 1
- 229910052782 aluminium Inorganic materials 0.000 description 1
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- HNPSIPDUKPIQMN-UHFFFAOYSA-N dioxosilane;oxo(oxoalumanyloxy)alumane Chemical compound O=[Si]=O.O=[Al]O[Al]=O HNPSIPDUKPIQMN-UHFFFAOYSA-N 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
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- FCBUKWWQSZQDDI-UHFFFAOYSA-N rhamnolipid Chemical compound CCCCCCCC(CC(O)=O)OC(=O)CC(CCCCCCC)OC1OC(C)C(O)C(O)C1OC1C(O)C(O)C(O)C(C)O1 FCBUKWWQSZQDDI-UHFFFAOYSA-N 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
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Classifications
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- Health & Medical Sciences (AREA)
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- Engineering & Computer Science (AREA)
- Hematology (AREA)
- Surgery (AREA)
- Inorganic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Dispersion Chemistry (AREA)
- Materials For Medical Uses (AREA)
Abstract
本申请提供了一种壳聚糖复合止血敷料,其由X射线可探测基线的壳聚糖基布和壳聚糖海绵部分组成。本申请的海绵部分可以提供良好的止血性能,X射线可探测基线的壳聚糖基布通过静电纺丝沉积制备,可以有效避免止血材料的体内的遗漏或残留;通过在纺丝液中加入适合的盐成分和表面活性剂成分,有效提高了X射线可探测基线的壳聚糖基布和壳聚糖海绵部分的粘结强度。
Description
技术领域
本申请属于医用材料领域,具体地,本申请提供了一种壳聚糖复合止血敷料及其制造方法。
背景技术
止血是紧急医疗救治的一个重要步骤,病人手术治疗、日常生活中出现突发性创伤时,均需进行快速止血。在恶劣的战争环境和复杂突发事件的战、创伤急救治疗时,实现快速有效的止血尤为重要。目前市场上出售和使用的止血产品从作用机制上大致可分为三类:第一类通过材料的物理或化学作用,吸收伤口附近血液中的水分,使伤口处血液的凝血成分浓缩、聚集,从而加速凝血,或材料通过表面电荷与细胞之间的静电作用,提高红细胞或血小板的粘附和聚集能力,如明胶止血海绵、止血颗粒/粉等;第二类是利用材料对组织的粘着力直接封闭创面,从而实现止血,如聚氨酯止血敷贴等;第三类是直接或间接提供止血活性物质与血液有效成分进行反应,启动或提高内源性和外源性凝血途径,进而加速凝血,如凝血酶等。
由于急救止血的突发性和救治环境条件的不确定,常规止血材料还存在止血后清创的麻烦,如各类不可降解的止血颗粒/粉等。止血敷贴在手术过程遗留在体内的风险,在手术闭合后无法检查确认。因此发明一种可快速使用、生物安全性好、无残留、可在体外进行射线检测的止血材料是临床亟需解决的问题。
此外,传统止血材料对于III类或IV类出血(VIBe出血分级III级:非中心性动脉或静脉严重出血,10-50ml/minVIBe出血分级IV级:中心性动脉或静脉严重出血,大于50ml/min)以及严重出血的伤口时效果不加。医生在处置过程中往往要使用或提前打开包装浪费大量止血材料,而且加剧手术操作者的紧张情绪。
发明内容
一方面,本申请提供了一种壳聚糖复合止血敷料,其由X射线可探测基线的壳聚糖基布和壳聚糖海绵部分组成。
进一步地,所述壳聚糖海绵为壳聚糖、甲壳素和明胶形成的壳聚糖海绵。
进一步地,所述壳聚糖海绵的通过包括以下步骤的方法制备:将500-800g精制壳聚糖溶于8-15kg质量浓度为1-4%的醋酸中制成壳聚糖溶液;将20-60g明胶加入400-500g纯化水,在水浴中配制成明胶溶液;将明胶溶液加入壳聚糖溶液中,并再加入甲壳素200-300g,在水浴中搅拌均匀,得到混悬液。
进一步地,所述壳聚糖海绵的通过包括以下步骤的方法制备:将700g壳聚糖溶于10kg质量浓度为2%的醋酸中制成壳聚糖溶液;将50g明胶加入450g纯化水,在80℃水浴中配制成10%质量浓度的明胶溶液500g;将明胶溶液加入壳聚糖溶液中,并再加入甲壳素250g,在50℃水浴中搅拌均匀,得到混悬液。
进一步地,所述甲壳素的制备方法为:将1kg壳聚糖,加入5kg乙酸酐及15kg甲醇配制的溶液中,在70℃温度条件下反应15小时后,使用质量浓度为25%的KOH溶液处理5小时,水洗烘干得到精制甲壳素。
进一步地,所述X射线可探测基线的壳聚糖基布中含有银离子成分。
进一步地,所述X射线可探测基线的壳聚糖基布通过包括以下步骤的方法制备:将含10-20%质量浓度聚乙烯醇,0.4%-0.8%质量浓度氯化钠和0.1%-0.5%质量浓度表面活性剂的水溶液和2-6%质量浓度的壳聚糖乳酸溶液混合后加入乙醇,搅拌均匀后加入聚乙烯醇质量3-5%的硝酸银,避光搅拌,配成纺丝液;将纺丝液静电纺丝沉积于基布上。
进一步地,所述X射线可探测基线的壳聚糖基布通过包括以下步骤的方法制备:将750g含15%质量浓度聚乙烯醇,0.6%质量浓度氯化钠和0.1%质量浓度EDDHA的水溶液和180g5%质量浓度的壳聚糖乳酸溶液混合后加入120g乙醇,搅拌均匀后加入硝酸银4.5g,避光搅拌48h,配成纺丝液;将纺丝液静电纺丝沉积于无纺布基布上。
另一方面,本申请提供了上述壳聚糖复合止血敷料在制备手术用止血材料中的应用。
另一方面,本申请提供了上述壳聚糖复合止血敷料在制备外伤急救用止血材料中的应用。
本申请还要求保护上述材料的对应制备方法。
如无特殊说明,本申请的浓度为质量浓度,即w/w浓度。
本申请辅料的使用方法:
1.打开包装、取出敷料
2.可根据伤口大小切割成适用形状
3.放置止血敷料,完整覆盖整个出血位置
4.施加均匀压力,保证紧密贴合,达到止血效果
5.必要时施加纱布或绷带固定
6.止血后(24小时内)用水冲洗湿润去除止血敷料
7.关闭手术,包扎伤口。
有益效果:
本发明以壳聚糖为主要原料制备,在保持壳聚糖自身生物相容性的基础上,进一步通过乙酰化反应制得甲壳素,添加明胶配制混悬液,经冻干工艺制备多孔、疏松的止血材料层,使用过程中,壳聚糖能够激活凝血过程中一些环节。壳聚糖的氨基带正电荷与神经细胞表现含负电荷的氨基酸残基受体相互作用促进凝血过程。壳聚糖与患处血小板凝聚,刺激血小板加速凝固过程。复合射线可探测基线的壳聚糖纺织布,避免手术过程中止血材料留在体内的风险。产品在人体内短时间不降解,使用过程中无脱落物,止血后去除方便,无残留。本发明采用的制备方法,工艺简便、操作便捷,可用于大规模工业生产。
附图说明
图1为止血辅料产品外观示意图a;
图2为止血辅料产品外观示意图b;
图3为止血实验典型状况图a;
图4为止血实验典型状况图b。
具体实施方式
下面结合具体实施例详述本发明。以下实施例仅做展示用,本发明的保护范围由权利要求限定,不局限于以下实施例。
实施例1含X射线可探测基线的壳聚糖基布的制备
配制纺丝液
将750g 15%质量浓度的聚乙烯醇水溶液和180g 5%质量浓度的壳聚糖乳酸溶液混合后加入120g乙醇,搅拌均匀后加入硝酸银4.5g(聚乙烯醇质量的4%),避光搅拌48h,配成纺丝液。
静电纺丝
静电纺丝过程使用铝箔接收,电压为18 kV,泵推进速度为2 mL/h,接收距离为15cm,温度为22 ℃,制成直径为0.8μm的微米带,其中银纳米颗粒的粒径为5-60nm。静电纺丝使用通力微纳TL-Pro静电纺丝机。将静电纺丝置沉积于无纺布膏药基布上(江苏广益医用敷料有限公司)制成含X射线可探测基线的壳聚糖基布。
实施例2 多糖混悬液的制备
精制壳聚糖
将1.5kg壳聚糖原料放入10kg质量浓度为50%的KOH溶液中,在100℃温度条件下反应4小时后,水洗烘干得到脱乙酰度95%的精制壳聚糖。
精制甲壳素
将1kg精制壳聚糖,加入5kg乙酸酐及15kg甲醇配制的溶液中,在70℃温度条件下反应15小时后,使用质量浓度为25%的KOH溶液处理5小时,水洗烘干得到精制甲壳素。
配制混悬液
将700g精制壳聚糖溶于10kg质量浓度为2%的醋酸中制成壳聚糖溶液;将50g明胶加入450g纯化水,在80℃水浴中配制成10%质量浓度的明胶溶液500g;将明胶溶液加入壳聚糖溶液中,并再加入精制甲壳素250g,在50℃水浴中搅拌均匀,得到混悬液。
实施例3 止血辅料的制备
将实施例1中制备的可探测基线的壳聚糖基布放入成型模具中,将其在模具底部平整铺垫,将实施例2制备混悬液注入模具后(120mL/dm2),模具放入-50℃中冷冻10小时后,放入-20℃脱玻3小时,在-45℃,真空度为30pa的条件下冻干5小时成型,获得复合敷料。将成型后的复合敷料放入5%质量浓度的的NaOH溶液中浸泡3小时,清洗至中性后再次冻干,获得复合止血敷料。经辐射灭菌处理后得到终产品。
实施例4 粘结强度的检测及其改进
使用实施例2中的混悬液所制备壳聚糖海绵,将壳聚糖海绵与贴合面压紧后即开始测试(不加专门固化时间,结合面积20mm×20mm,Instron 5567 材料试验机,拉开速度4mm/min),以最大载荷除以面积来计算粘结强度,实验结合对象包括实施例1中制备的可探测基线的壳聚糖基布、猪皮;每个实验平行重复三次。经过检测实施例2中的混悬液所制备的壳聚糖海绵与猪皮的粘结强度28.17±1.22KPa,结合实际贴附人体皮肤验证,基本满足牢固贴附皮肤的粘度要求;但与实施例1中制备的可探测基线的壳聚糖基布的粘结强度仅为10.44±1.58 KPa,即使让混悬液在基布上凝固1小时,粘结强度仅为17KPa左右(凝固过程导致粘结强度难以准确测定,只能根据多次检测来大约推测),推测这也是实施例3中的产品在取用,贴附过程中经常出现基布与海绵分离的情况的原因。
为解决此问题,申请人尝试在可行的范围内改变实施例2混悬液中的壳聚糖、明胶、甲壳素比例以及实施例1中静电纺丝的中PVA和壳聚糖用量等参数,均未能显著改善粘结强度。推测粘结强度的问题与壳聚糖海绵/纺丝自身的性质以及银离子的存在相关。
基于上述情况,申请人尝试了在静电纺丝液中加入盐氯化钠以提升纤维直径,或者加入表面活性剂EDTA、EDDHA和鼠李糖脂来改变表面张力以改善纤维的光滑和均匀度。具体配方和效果如表1所示(所示配方为在纺丝过程允许可行的范围内的代表性配方,更多的筛选配方由于篇幅问题没有展示)。
表1静电纺丝液的改进效果
结果表明:0.3%的EDTA以及0.1%和0.3%的EDDHA都能在一定程度上提高粘结强度,但提高的程度仍然不足以改善产品的使用效果。我们进一步尝试了两者的结合。结果见表2。
表2静电纺丝液进一步的改进效果
结果表明:0.6%质量浓度的氯化钠+0.1%质量浓度的EDDHA和0.8%质量浓度的氯化钠+0.1%质量浓度的EDDHA,考虑到强度略高和盐浓度较高可能影响纺丝(1%时成丝性能即受到显著影响),选用“含15%质量浓度的聚乙烯醇,0.6%质量浓度的氯化钠和0.1%质量浓度的EDDHA水溶液”用于改进实施例1中的纺丝液。
实施例4 新西兰兔股动脉止血实验
选取25只健康新西兰兔,雌雄各半,随机分为5组,每组5只新西兰兔,分组依次是空白对照组、加压纱布包扎组、聚氨酯敷料(美德舒N)、沸石止血粉(上海企晟)、实施例3和实施例4中改进的止血辅料。将新西兰兔麻醉后固定于手术台上,去毛后露出一侧股动脉,横向切开一半,令其自由喷血8s,然后根据分组进行相应处理,记录止血时间、失血量和90分钟死亡率。结果如表3所示:
表3 新西兰兔股动脉止血试验结果
Claims (10)
1.一种壳聚糖复合止血敷料,其特征在于,其由X射线可探测基线的壳聚糖基布和壳聚糖海绵部分组成。
2.根据权利要求1所述的壳聚糖复合止血敷料,其中所述壳聚糖海绵为壳聚糖、甲壳素和明胶形成的壳聚糖海绵。
3.根据权利要求2所述的壳聚糖复合止血敷料,其中所述壳聚糖海绵的通过包括以下步骤的方法制备:将500-800g精制壳聚糖溶于8-15kg质量浓度为1-4%的醋酸中制成壳聚糖溶液;将20-60g明胶加入400-500g纯化水,在水浴中配制成明胶溶液;将明胶溶液加入壳聚糖溶液中,并再加入甲壳素200-300g,在水浴中搅拌均匀,得到混悬液。
4.根据权利要求3所述的壳聚糖复合止血敷料,其中所述壳聚糖海绵的通过包括以下步骤的方法制备:将700g壳聚糖溶于10kg质量浓度为2%的醋酸中制成壳聚糖溶液;将50g明胶加入450g纯化水,在80℃水浴中配制成10%质量浓度的明胶溶液500g;将明胶溶液加入壳聚糖溶液中,并再加入甲壳素250g,在50℃水浴中搅拌均匀,得到混悬液。
5.根据权利要求3或4所述的壳聚糖复合止血敷料,其中所述甲壳素的制备方法为:将1kg壳聚糖,加入5kg乙酸酐及15kg甲醇配制的溶液中,在70℃温度条件下反应15小时后,使用质量浓度为25%的KOH溶液处理5小时,水洗烘干得到精制甲壳素。
6.根据权利要求1-5任一项所述的壳聚糖复合止血敷料,其中所述X射线可探测基线的壳聚糖基布中含有银离子成分。
7.根据权利要求6所述的壳聚糖复合止血敷料,其中所述X射线可探测基线的壳聚糖基布通过包括以下步骤的方法制备:将含10-20%质量浓度聚乙烯醇,0.4%-0.8%质量浓度氯化钠和0.1%-0.5%质量浓度表面活性剂的水溶液和2-6%质量浓度的壳聚糖乳酸溶液混合后加入乙醇,搅拌均匀后加入聚乙烯醇质量3-5%的硝酸银,避光搅拌,配成纺丝液;将纺丝液静电纺丝沉积于基布上。
8.根据权利要求7所述的壳聚糖复合止血敷料,其中所述X射线可探测基线的壳聚糖基布通过包括以下步骤的方法制备:将750g含15%质量浓度聚乙烯醇,0.6%质量浓度氯化钠和0.1%质量浓度EDDHA的水溶液和180g 5%质量浓度的壳聚糖乳酸溶液混合后加入120g乙醇,搅拌均匀后加入硝酸银4.5g,避光搅拌48h,配成纺丝液;将纺丝液静电纺丝沉积于无纺布基布上。
9.根据权利要求1-8任一项所述的壳聚糖复合止血敷料在制备手术用止血材料中的应用。
10.根据权利要求1-8任一项所述的壳聚糖复合止血敷料在制备外伤急救用止血材料中的应用。
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KR101700107B1 (ko) * | 2016-03-15 | 2017-01-26 | 주식회사 엔도비전 | 키토산 기반의 지혈 드레싱재 및 그 제조방법 |
CN106757785A (zh) * | 2016-11-30 | 2017-05-31 | 齐鲁工业大学 | 一种载银壳聚糖/聚乙烯醇微米带及其制备方法与应用 |
CN113289050A (zh) * | 2021-05-14 | 2021-08-24 | 宁波市第一医院 | 一种止血海绵及其制备方法 |
CN115154642A (zh) * | 2022-07-05 | 2022-10-11 | 福州大学 | 一种仿生非对称海绵敷料及其制备方法 |
CN115177778A (zh) * | 2022-07-25 | 2022-10-14 | 滨州医学院 | 一种复合型伤口敷料、制备方法及应用 |
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