CN115105622B - 多功能创伤敷料及其制备方法与应用 - Google Patents
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- CN115105622B CN115105622B CN202210806025.5A CN202210806025A CN115105622B CN 115105622 B CN115105622 B CN 115105622B CN 202210806025 A CN202210806025 A CN 202210806025A CN 115105622 B CN115105622 B CN 115105622B
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- wound dressing
- polylactic acid
- collagen
- wound
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Abstract
本发明属于生物医药领域,具体涉及一种创伤敷料及其制备方法与应用。该创伤敷料的组分包括利多卡因、胶原蛋白、海藻酸盐和聚乳酸,具体制备方法为:提取难溶性胶原纤维,制得胶原蛋白海绵体;采用所述海藻酸钠和所述利多卡因制备海藻酸钠凝胶球;将海藻酸钠凝胶球加入胶原蛋白海绵体中,制得复合海绵;采用静电纺丝技术制备聚乳酸纳米纤维膜,得到聚乳酸静电纺丝纤维层;将复合海绵与聚乳酸静电纺丝纤维层复合,制得创伤敷料。该创伤敷料具备止血镇痛、抑菌、吸收渗液、促愈合的效果,同时具有良好的透气性、生物相容性和机械性能等特征,可以为细胞的增殖、迁移等提供一个适宜的环境。
Description
技术领域
本发明属于生物医药领域,具体涉及一种创伤敷料及其制备方法与应用。
背景技术
因疾病、交通事故、火灾、***等引起的皮肤组织是常见的临床问题。皮肤作为人体最大的器官,在维持体内平衡和防止微生物入侵方面起着重要作用。皮肤创伤修复是一个复杂的生物过程,创面敷料发挥至关重要的作用。与传统敷料相比,现代敷料具备三点优势:(1)现代敷料有利于溶解和清除坏死组织和纤维蛋白,并发挥清创作用;(2)有利于保持伤口局部相对恒定的温度和湿度,为伤口提供类似于人体内部环境的条件;(3)现代敷料避免了因瘢痕造成的新肉芽组织的再损伤,并可以促进细胞增殖、分化和上皮细胞迁移;在隔离细菌方面和预防交叉感染方面,现代敷料发挥了重要作用。
理想的敷料应具有以下几个功能:减少伤口的水分和体液的流失;抵御细菌的攻击,防止感染;维持、促进肉芽和上皮组织的正常增殖和生长,促进恢复;不留疤痕,不会产生变形;柔软并且具有一定的机械强度;透气、透湿、有一定的保湿性。遗憾的是,目前临床上使用的创面敷料几乎没有满足理想皮肤创面敷料的全部要求,在复杂、深度创伤的治疗中往往存在缺陷和不足。
近年来,单功能敷料已经得到了广泛地研究和应用。基于水胶体和水凝胶之类的敷料,可以为创面提供一个潮湿的环境,加快修复和防止感染,但其吸收渗液的能力有限;生物可降解聚合物敷料通过负载银离子可以有效防止感染,透明质酸、壳聚糖可以促进血肿愈合和止血。虽然这些治疗方法得到了临床的认可,疗效也得到了证实,但其成本仍然很高,并可能出现排斥、感染、过敏等不良反应。一般来说,这些方法的主要缺点是启动愈合过程的能力有限,不能进一步刺激重建阶段。因此,如何开发具有高生物活性和生物安全性的伤口敷料是现代再生医学领域皮肤再生的关键问题。
静电纺丝技术是医用敷料制备的主流技术之一。无论是聚乳酸和聚氨酯等人工合成材料,还是壳聚糖、海藻酸钠、胶原蛋白等各种天然材料,都已经可以通过静电纺丝制作不同类型的医用敷料,并且取得了一定的修复效果。但是单一的由静电纺丝制备而成的敷料在创面修复过程中,不可避免的会导致感染,从而导致创面修复失败。单功能敷料往往难以满足慢性创面的治疗需求。
基于此,本专利通过静电纺丝技术制备聚乳酸纳米纤维层,并将其与利用胶原蛋白和海藻酸钠凝胶球所制成的可载药海绵体进行复合,制备一种新型非对称性多功能敷料。该敷料具备止血镇痛、抑菌、吸收渗液、促愈合的效果,同时具有良好的透气性、生物相容性和机械性能等特征,可以为细胞的增殖、迁移等提供一个适宜的环境。
公开号为CN106620811A的发明专利公开了一种采用静电纺丝法制备纳米纤维敷料的方法,该专利以利多卡因和胶原蛋白原料,通过静电纺丝技术制备纳米纤维敷料,但该专利与本专利制备方法并不相同,且未提及在难溶性胶原纤维中加入载药海藻酸钠凝胶球这一关键特征。
发明内容
本发明的目的之一在于提供一种创伤敷料的制备方法。
为实现上述目的,本发明采取以下技术方案:
一种创伤敷料的制备方法,所述创伤敷料的组分包括利多卡因、胶原蛋白、海藻酸盐和聚乳酸,所述方法具体包括以下步骤:
S1:提取难溶性胶原纤维,制得胶原蛋白海绵体;
S2:采用所述海藻酸盐和所述利多卡因制备载利多卡因的海藻酸盐凝胶球;
S3:将S2制得的海藻酸盐凝胶球加入S1制得的胶原蛋白海绵体中,制得复合海绵;
S4:采用静电纺丝技术制备聚乳酸纳米纤维膜,得到聚乳酸静电纺丝纤维层;
S5:将S3所得复合海绵与S4所得聚乳酸静电纺丝纤维层复合,得到创伤敷料。
聚乳酸(PLA)是一种用途广泛、生物可吸收、生物可降解的新型高分子材料,具有良好的生物相容性。利用静电纺丝技术制备出来的聚乳酸纤维具有良好的透气性和比表面积大的优点,其纳微结构可以在一定程度上具备抗菌能力,可有效阻隔微生物的入侵,在创伤敷料领域具有巨大的应用潜能。
胶原蛋白是皮肤天然细胞外基质的主要成分,可以为细胞的繁殖和迁移等提供一个合适环境,是较为理想的敷料制备的材料。与可溶性胶原相比,难溶性胶原纤维(ICFs)存在许多天然的分子共价交联和分子排列,具备更好的力学性能和稳定性,更适用于创面敷料的制备。然而单一的胶原蛋白敷料存在稳定性差、吸收渗液能力较差等问题,在临床使用时需要特别注意控制感染,因此更适合将其制成复合敷料应用于临床。
海藻酸盐是从藻类生物中分离得到的一类天然线性高分子化合物,其凝血性能优异,所制备的创面敷料具有能使伤口快速止血、无毒,良好的透气性,吸收渗出物能力强,不易黏附皮肤,减轻换药痛苦等优点。同时,海藻酸盐可作为输送药物的载体而广泛应用于组织工程及创面修复领域中。单一的海藻酸盐过强的吸湿性可能会导致创面脱水,更换敷料时就可能导致伤口的再损伤,因此干燥或有硬痂的创面不宜应用。且海藻酸盐敷料自身没有黏附性,需要搭配其他材料复合之后才能投入临床使用。
进一步,所述聚乳酸的质量分数为8%。
进一步,所述海藻酸盐包括海藻酸钠、海藻酸钾和/或海藻酸铵;所述聚乳酸还可以是聚乙醇酸、聚乳酸-乙醇酸共聚物、聚己内酯和/或聚乙二醇。
进一步,所述难溶性胶原纤维来源于牛皮、牛跟腱、鱼皮和/或猪。
进一步,S1具体为:将牛皮真皮层经过碱分散、酸膨胀及高压脱纤处理后得到胶原松弛纤维凝胶,随后进行如下操作:
(1)溶液配制:4%NaOH溶液、10%AgNO3、0.5mol/L醋酸,0.2mol/L Na2HPO4/NaOH;
(2)用4%NaOH溶液中和样品液pH值至6.8-7.0,用pH计测量pH值,使胶原纤维从溶液中析出;
(3)用大量去离子水对析出的胶原纤维进行充分洗涤,去除盐分,纱布过滤;10%AgNO3溶液检测,无白色沉淀即可,得到粗提纯胶原;
(4)在胶原纤维加入0.5mol/L醋酸(固液比为1:100),加入1%蛋白酶(胶原纤维干重),室温下磁力搅拌36h;
(5)在浆液中加入NaCl晶体至1mol/L,4℃静置过夜;离心,弃上清,在沉淀中加入适量去离子水,调节pH(4mol/L NaOH)至7.0左右,4℃静置过夜;
(6)离心,弃上清,在沉淀中加入0.5mol/L醋酸,4℃磁力搅拌过夜;匀浆后调节pH(0.2mol/L Na2HPO4/NaOH)至7.2左右,4℃静置过夜;
(7)离心,弃上清,将沉淀通过离心用去离子水清洗3次;
(8)加入适量0.5mol/L醋酸均匀混合,装入截留分子量为8kDa的透析袋中透析72h,通过10%的AgNO3溶液检测透析程度;离心;
(9)冷冻干燥后真空封装,4℃保存。
进一步,上述离心条件均为:4℃,8000r/min,10min。
进一步,S2具体为:用去离子水配置2%海藻酸钠溶液,均匀溶解后加入1%(w/v)利多卡因,磁力搅拌,制备均质溶液;将海藻酸钠和利多卡因的混合溶液用注射器缓慢滴加在搅拌的5%CaCl2溶液中,在磁力搅拌器上温和搅拌30min,老化海藻酸钠凝胶球,去离子水多次洗涤。
进一步,所述载利多卡因的海藻酸钠凝胶球的直径为2mm,且凝胶球表面凹凸不平,内部呈现颗粒状。
进一步,S4所述聚乳酸纳米纤维膜采用静电纺丝装置制备,所述静电纺丝装置由高压发生器、喷射丝头以及收集器三部分组成;本专利所用的电纺丝材料是经过处理后具有高分子量和高纯度的PLA,所述PLA的溶剂为六氟异丙醇溶液。
进一步,S4中静电纺丝参数为:推进速度0.002mm/s,电压25.25kV,针头长度30mm(25G),注射器与收集器的距离25cm。
本发明的目的之二在于提供一种采用上述制备方法制备的创伤敷料,该创伤敷料兼具止血镇痛、抑菌、吸收渗液、促进愈合等多种功效,同时具有良好的透气性、生物相容性和机械性能等特征,能为细胞的增殖、迁移等提供适宜的环境。
为实现上述目的,本发明采取以下技术方案:
一种采用上述制备方法制备的创伤敷料。
进一步,所述创伤敷料的复合海绵层具有多孔结构,其孔隙率为60~90%,其孔径大小为10~300μm;所述创伤敷料的聚乳酸静电纺丝纤维层的孔隙率为50%~80%,其孔径大小为1.0~1.3μm。
复合海绵的多孔结构和高孔隙率为在止血使用过程中的快速吸湿效率及吸附聚集血小板等提供了良好的三维空间结构。而聚乳酸静电纺丝纤维层虽然孔径较小,但高比表面积使其孔隙率较高,为创面提供了透气性良好的修复环境。
进一步,所述复合海绵的溶胀率为3500%,所述聚乳酸静电纺丝纤维层的溶胀率为500%,复合海绵良好的溶胀性赋予其对创面渗出物有较好的吸收能力。
进一步,所述复合海绵的保水率为2121.8%±31.2%,平均接触角为98.1°±1.7°;所述聚乳酸静电纺丝纤维层的保水率为61.0%±10.0%,平均接触角为120.5°±2.6°。由此可见,本专利制备的创伤敷料具备良好的保水性,可以保持创面的湿润,避免创面过分脱水。
进一步,所述创伤敷料的PLA纳米纤维层粗细均匀,表面光滑,且具有较强的空间结构,十分适合细胞的繁殖和迁移。
进一步,所述创伤敷料的复合海绵层具有多孔结构,且内部分层明显,可知复合海绵的比表面积大,内部具有较好的空间结构。
本发明的目的之三在于提供一种用所述创伤敷料对伤口进行保湿的方法。
为实现上述目的,本发明采取以下技术方案:
用所述创伤敷料对伤口进行保湿的方法,用所述创伤敷料对伤口进行保湿,所述创伤敷料为伤口创造微湿、微酸和低氧环境,促进细胞增殖、分化和上皮细胞迁移。
本发明的目的之四在于提供一种用所述创伤敷料吸附创口渗液的方法。
为实现上述目的,本发明采取以下技术方案:
用所述创伤敷料吸附创口渗液的方法,用所述创伤敷料对创口渗液进行吸附,减少伤口水分和体液的流失的同时,抑制细菌生长。
本发明的有益之处在于:
1.本专利通过静电纺丝技术制备了PLA纳米纤维,探索并优化其制备条件,以此制备出的PLA纳米纤维直径主要分布于1.0μm~1.3μm,结构规整,粗细均匀,表面光滑,具有良好的空间特性;
2.本专利制备的载药复合海绵孔隙率能达到80%以上,溶胀率能达到3000%以上,保水性极强,同时在凝血性能方面也比医用纱布优越,表明该多功能敷料具备作为创伤敷料的基本要求;
3.本专利将冷冻干燥制备的胶原蛋白/海藻酸钠海绵与静电纺丝制备的聚乳酸纳米纤维二者结合,创新性地设计并构建了一种新型的复合创伤敷料,该敷料具有止血镇痛、抑菌、吸收渗液、促愈合的效果,同时具有良好的透气性、生物相容性和机械性能等特征,可以为细胞的增殖、迁移等提供一个适宜的环境。
4.本专利在难溶性胶原纤维中加入载药的海藻酸钠凝胶球,使其集止血、镇痛、吸收渗液等多种功能于一体。
附图说明
图1为新型敷料的结构示意图;
图2为静态水接触角测定示意图;
图3为纺上PLA纳米纤维膜的复合海绵;
图4为胶原的FTIR谱图;
图5为麦克林胶原DSC图;
图6为难溶性胶原DSC图;
图7为PLA的FTIR光谱图;
图8为8%PLA实验组的电镜图,其中8-A和8-a为1号纤维电镜图;8-B和8-b为2号纤维电镜图;8-C和8-c为3号纤维电镜图;
图9为10%PLA实验组的电镜图,其中10-D和10-d为4号纤维电镜图;10-E和10-e为5号纤维电镜图;
图10为12%PLA实验组的电镜图,其中10-F和10-f为6号纤维电镜图;10-G和10-g为7号纤维电镜图;10-H和10-h为8号纤维电镜图;
图11为8种电纺丝直径分布图,图11-A~图11-H分别为1-8号纤维的直径分布图;
图12为PLA静态水接触角;
图13为凝胶球的形貌图,其中,图13-A为凝胶球的形态结构;图13-B为显微镜下的凝胶球;
图14为多功能敷料形貌图,其中,图14-A和图14-B为PLA纳米纤维的形貌图;图14-C和图14-D为复合海绵的形貌图;
图15为PLA和复合海绵的孔隙率结果;
图16为PLA和复合海绵的溶胀率结果;
图17为PLA和复合海绵的保水率结果;
图18为PLA和复合海绵的静态水接触角;
图19为体外凝血测试,其中,图19-A表示滴加血液后各材料的凝血情况,图19-B表示去离子水清洗后各材料的凝血情况;
图20为血红蛋白含量图。
具体实施方式
所举实施例是为了更好地对本发明进行说明,但并不是本发明的内容仅局限于所举实施例。所以熟悉本领域的技术人员根据上述发明内容对实施方案进行非本质的改进和调整所获得的技术方案,仍属于本发明的保护范围。
表1和表2为实施例部分涉及的主要仪器和试剂。
表1.试剂名称、厂家及作用
表2.仪器名称、厂家及作用
设备 | 公司 | 作用 |
磁力搅拌器 | 上海尚普仪器 | 搅拌 |
鼓风干燥机 | 上海慧泰仪器 | 干燥 |
紫外分光光度计 | 上海佑科仪器 | 测定吸光度 |
冰箱 | 中国海尔公司 | 冷冻 |
静电纺丝机 | 大连鼎通科技 | 纺丝 |
大型离心机 | Thermo Fisher Scientific | 离心 |
多歧管低温真空干燥机 | 北京博医康仪器 | 冻干 |
pH计 | 绍兴艾科仪器 | 测量pH |
电子天平 | Toledo公司 | 称量 |
超纯水*** | Thermo Fisher Scientific | 纯化水 |
场发射扫描电镜 | 日本日立 | 形貌观察 |
差示扫描量热仪 | 美国TA | 热性能表征 |
红外光谱仪 | 美国Nicolet | 结构表征 |
倒置生物显微镜 | 日本尼康 | 形貌观察 |
实施例1.难溶性胶原纤维
1.难溶性胶原纤维的提取:
将牛皮真皮层经过碱分散、酸膨胀及高压脱纤处理后得到胶原松弛纤维凝胶,牛皮纤维凝胶的质量为84.85g,随后进行如下操作:
(1)溶液配制:4%NaOH溶液、10%AgNO3、0.5mol/L醋酸,0.2mol/L Na2HPO4/NaOH;
(2)用4%NaOH溶液中和样品液pH值至6.8-7.0,用pH计测量pH值,使胶原纤维从溶液中析出;
(3)用大量去离子水对析出的胶原纤维进行充分洗涤,去除盐分,纱布过滤;10%AgNO3溶液检测,无白色沉淀即可,得到粗提纯胶原11.52g;
(4)在胶原纤维加入0.5mol/L醋酸1152mL(固液比为1:100),加入0.16g蛋白酶(1:0.01),室温下磁力搅拌36h;
(5)在浆液中加入67.32g NaCl晶体至1mol/L,4℃静置过夜;离心(8000r/min,10min,4℃,下同),弃上清,在沉淀中加入适量去离子水,调节pH(4mol/L NaOH)至7.0左右,4℃静置过夜;
(6)离心,弃上清,在沉淀中加入800mL 0.5mol/L醋酸,4℃磁力搅拌过夜;匀浆后调节pH(0.2mol/L Na2HPO4/NaOH)至7.2左右,4℃静置过夜;
(7)离心,弃上清,将沉淀通过离心用去离子水清洗3次;
(8)加入适量0.5mol/L醋酸均匀混合,装入截留分子量为8kDa的透析袋中透析72h,通过10%的AgNO3溶液检测透析程度;离心(8000r/min,10min,4℃);
(9)冷冻干燥后真空封装,4℃保存。
2.难溶性胶原纤维的结构和性能分析
(1)傅里叶红外光谱(FTIR)分析:将5mg~10mg胶原样品与溴化钾混合并置于玛瑙研钵研细,压制成均匀透明的溴化钾片,用傅里叶变红外光谱仪进行测试,扫描波数范围为400cm-1~4000cm-1,分辨率为4cm-1。
傅里叶变换红外光谱可以反映胶原的二级构象,为了更好的表征实验室制备的难溶性胶原的结构,将其与从上海麦克林公司购买的胶原蛋白(简称麦克林胶原)进行了FTIR光谱分析比较,如图4所示。构象完整的胶原蛋白具有特殊的三螺旋结构,在FTIR光谱中可以通过其的特征酰胺键来表征。通常,3200-3500cm-1的强吸收是由于酰胺A带的N-H基团的伸缩振动(氢键)峰,在2934cm-1附近的弱吸收主要是酰胺B带的C-N基团伸缩振动引起的特征吸收峰。酰胺I带通常在1631cm-1左右,主要由C=O基团的伸缩振动引起,而酰胺II带出现在1529cm-1左右由C-N伸缩振动耦合和N-H弯曲振动引起。由于胶原多肽的甘氨酸和特征氨基酸羟脯氨酸和脯氨酸含量高,且形成独特的(Gly-Pro-Hyp)序列,这使得胶原多肽在1000-1400cm-1光谱范围内具有其他蛋白质所没有的红外光谱特征。如图4所示,与麦克林胶原类似,自提的难溶性胶原出现了上述提及的特征性吸收峰(酰胺A带:3289cm-1vs3270cm-1,酰胺B带:2934cm-1vs2934cm-1,酰胺I带:1629cm-1vs1631cm-1,酰胺II带:1543cm- 1vs1529cm-1,酰胺Ⅲ带:1285cm-1vs1243cm-1)。结果显示两种胶原蛋白样品的特征峰是在相似的波数处得到的,表明制备的难溶性胶原具有胶原的结构特征。
(2)差示扫描量热仪(DSC)
称取干燥至恒重的样品3mg~5mg,置于DSC测试坩埚中,以空白坩埚为参比,以N2为保护气体,升温速率设置为5℃·min-1,温度范围为0~120℃。
将麦克林胶原与自制的难溶性胶原进行DSC对比,如图5-6所示。由图5可知麦克林胶原的吸收峰出现在70℃左右,而难溶性胶原的吸收峰出现在107℃左右,表明难溶性胶原具有较高的热稳定性,在实际应用时不会轻易变性。DSC曲线中峰面积的大小代表吸热或放热焓值的大小,难溶性胶原的曲线在102℃~115℃处出现一个较窄而深的吸热峰。难溶性胶原是天然胶原蛋白的聚集体,包含许多胶原蛋白天然的空间结构,其分子间由化学键相互连接,形成一个网状结构,在受热时分子链段不易发生移动。
实施例2.PLA纳米纤维膜
1.PLA纳米纤维膜的制备
静电纺丝装置由高压发生器、喷射丝头以及收集器三部分组成。
本实验所用的电纺丝材料是经过处理后具有高分子量和高纯度的PLA。为了探究在何种条件下电纺出来的PLA纤维丝形态最好,根据以往的经验用六氟异丙醇溶液配制了质量分数分别为8%、10%和12%的PLA溶液。同时根据电压、推进速度、针头的长度以及注射器和收集器之间的距离,设定了8个实验组,具体8个实验组的参数设定如表3所示。8%PLA设定了三个实验组,10%PLA设定了2个实验组,12%PLA设定了3个实验组,具体参数的设定均是依据纺丝时具体情况下择最优条件设定。
表3.静电纺丝实验参数优化设计方案
2.PLA纳米纤维层的结构和性能分析
(1)傅里叶红外光谱(FTIR):分析方法与实施例1中的方法一致。
图7为PLA的FTIR光谱图,从图中可以清楚地看出羰基、羧基等的峰形,特征吸收峰的归属见表4,结果表明实验中合成的PLA的结构与文献报道一致。
表4.聚乳酸红外光谱分析
峰位置(cm-1) | 分析 | 结论 |
2994.88 | C-H伸缩振动峰 | 含有-CH3基团 |
2942.97 | C-H伸缩振动峰 | 含有-CH3基团 |
1745.97 | C=O伸缩振动峰 | 含有-C=O基团 |
1452.10,1381.01 | C-H弯曲振动峰 | 含有-CH3基团 |
1266.83,1182.06,1127.93 | C-O反对称伸缩振动峰 | 含有O-C=O基团 |
1079.56,1045.28 | C-O的对称伸缩振动峰 | 含有O-C=O基团 |
(2)表面形貌观察:用扫描电镜对静电纺丝支架形貌进行观察,并采集放大倍数为2000倍和10000倍的图片。
将8个实验组所制备的8种PLA电纺丝纤维命名为1-8号纤维,分别进行电镜观察,图8为聚乳酸质量分数8%时所设定的3个实验组实验得到的电纺纤维电镜图,图9为质量分数10%时所设定的2个实验组实验得到的电纺纤维电镜图,图10为质量分数10%时所设定的3个实验组实验得到的电纺纤维电镜图。其中,图8-A,8-B,8-C,9-D,9-E,10-F,10-G,10-H分别为对照实验组1-8在电镜下放大2000倍的图像,图8-a,8-b,8-c,9-d,9-e,10-f,10-g,10-h分别为对照实验组1-8在电镜下放大10000倍的图像。
由图8可知,当聚乳酸浓度为8%时,在3种不同实验条件下所得到的纤维出现长且均匀连续的纤维结构,纤维排布有序且形成网状结构,纤维粗细均匀。1号和2号纤维表面光滑,3号纤维表面出现许多细小的凹槽。
由图9可知,当聚乳酸浓度为10%时,在2种不同实验条件下所得到的纤维形态差别较大,4号纤维结构更加规整,出现长且均匀连续的纤维结构,纤维排布有序且形成网状结构,粗细均匀。但5号纤维排布显得杂乱,纤维粗细也不均匀,纤维之间出现交联现象。但两组纤维表面都比较光滑。
由图10可知,当聚乳酸浓度为12%时,在3种不同实验条件下所得到的纤维形态差别较大,8号纤维看起来结构更加规整,出现长且均匀连续的纤维结构,纤维排布有序且形成网状结构,粗细均匀,但中间出现了很多细小的杂纤维丝。6号和7号纤维排布显得杂乱,纤维粗细也不均匀,纤维之间出现交联现象,纤维之间也没有出现较为有序的空间结构。但3组纤维表面都比较光滑。
综上所述,2号纤维具有最好的空间特性,纤维最为规整。
(3)统计纳米纤维的直径:根据扫描电镜图,通过Image J软件随机测量至少60根纳米纤维的直径并记录每次测量的具体数值。使用Origin 2018软件生成了描述直径分布的直方图,并采用高斯曲线进行拟合。
进一步,我们对扫描电镜图片中纤维直径进行半定量统计分析。如图11所示,与10%PLA组(图11-D和图11-E)和12%PLA组(图11-F、图11-G和图11-H相比,8%PLA组(图11-A、图11-B和图11-C)的纤维直径的直径较小,且均一性较好。在8%PLA组中,2号纤维的直径分布峰最狭窄和尖锐(主要分布于1.0μm~1.3μm),1号次之(主要分布于0.9μm~1.5μm),3号的直径分布峰最宽和平缓(主要分布于1.3~1.7μm)。
综上所述,在静电纺丝中,纤维直径受注射器与收集器之间的距离、电场和溶液的流速特性(电导率、浓度和粘度)的影响。2号纤维粗细均匀,在8种纤维中直径分布最集中,纤维直径小,在纤维直径分布上其具有最好特性。因此,静电纺丝条件优选为:质量分数8%PLA,推进速度0.002mm/s,电压25.25kV,针头长度30mm,注射器与收集器的距离25cm。
(4)静态水接触角测定:在25℃下,将PLA电纺膜粘贴于载玻片上,并置于接触角测定仪的载物台上,用微量注射器将蒸馏水滴加到薄膜材料的表面上,在静态水接触角测定仪的显微镜下读数并拍照,每个样品在不同的位置测定3次并计算其平均值,测量的示意图见图2。
利用8%的PLA纺丝液,在推进速度0.002mm/s,电压25.25kV,针头长度30mm,注射器与收集器的距离25cm的条件下制备具有最好性能的PLA纳米纤维,将该纳米纤维进行静态水接触角的测定,测量3次得到的结果如图12所示。3次得到的PLA纳米纤维层的平均接触角(120.5°±2.6°),均大于90°,说明纳米纤维层的亲水性较差。
实施例3.含镇痛药物的复合海绵
1.含镇痛药物的复合海绵的制备
(1)用去离子水配置2%海藻酸钠溶液,均匀溶解后加入1%(w/v)利多卡因,磁力搅拌,制备均质溶液;将海藻酸钠和利多卡因的混合溶液用注射器缓慢滴加在搅拌的5%CaCl2溶液中,在磁力搅拌器上温和搅拌30min,老化海藻酸钠凝胶球,去离子水多次洗涤。
(2)制备2%胶原纤维(0.5mol/L醋酸)溶液,缓慢加入海藻酸钠凝胶球,均匀后加入模具中,冷冻干燥制备复合海绵。
2.含镇痛药物的复合海绵表征
(1)表面形貌观察:
①.载药海藻酸钠凝胶球的表面形貌观察与分析:制备的载药凝胶球的直径大约为2mm,如图13-A所示;在显微镜下放大10倍观察到凝胶球表面凹凸不平,内部呈现颗粒状,如图13-B所示。
②.多功能敷料的表面形貌观察与分析
对复合上PLA纳米纤维膜的载药复合海绵得到的多功能敷料进行形貌观察,如图14所示。图14-A和14-B分别是上层PLA纳米纤维层在电镜放大10000倍和30000倍的图像,可以看到PLA纳米纤维粗细较为均匀,且具有较强的空间结构,纤维表面光滑,所以该纤维层十分适合细胞的繁殖和迁移。
图14-C和14-D分别是含镇痛药的复合海绵表层和内部的形貌图,可以看出复合海绵具有多孔结构,且内部分层明显,可知复合海绵的比表面积大,内部具有较好的空间结构。在内部图中可以隐约看到圆形的颗粒,推测其为凝胶球。
(2)孔隙率的测定:
在20℃的条件下,取25mL的容量瓶加无水乙醇至刻度线,称重,记其为m1,取一定量的复合海绵,称重记为m0,将样品浸没于乙醇中,使无水乙醇充盈海绵的孔隙之中,封口并静置24h,再将容量瓶中刻度线以上的无水乙醇吸去,称重记为m2,将浸满无水乙醇的海绵取出,称量剩余无水乙醇和容量瓶的总质量记为m3。不同比例的混合海绵的孔隙率K可按公式(1)计算:
结果:对3组PLA纳米纤维和3组复合海绵进行孔隙率的测定,测定结果如图15所示。复合海绵的孔隙率显著高于PLA静电纺丝层(p0.05),达80%以上,其多孔结构和高孔隙率为在止血使用过程中的快速吸湿效率及吸附聚集血小板等提供了良好的三维空间结构。并且PLA层的孔隙率也达到60%以上,这是由于PLA纤维层内部是由直径1.0μm~1.3μm的纤维交错排列构成,虽孔径较小,但高比表面积使其孔隙率较高,为创面提供一个良好的透气性。
(3)溶胀率的测定:
取一定量的复合海绵称重记为m0,将试验敷料浸入去离子水中;膨胀2h后,取出敷料,轻轻拭去黏附在表面的水分;然后立即称重。根据下面的公式(2)计算溶胀度(DS):
公式(2)中,m0和mw是浸泡前和浸泡后的敷料重量。
结果:对3组PLA纳米纤维和3组复合海绵进行溶胀率的测定,测定结果如图16所示。复合海绵的溶胀率为3500%,而PLA纳米纤维层的溶胀率较低约为500%,两者的溶胀性能有显著性差异(p<0.01)。结果表明,复合海绵良好的溶胀性赋予其对创面渗出物有较好的吸收能力。
(4)保水性测定:
将样品浸没于去离子水中2h后,后将其置于离心管内,在管底填充滤纸以吸收离心所脱去的水分,离心条件:1200rpm,15min,离心结束后测湿重W2并记录,再将材料置于烘箱中烘干至恒重并记录其质量W3,根据公式(3)计算其保水率:
结果:3组PLA纳米纤维和3组复合海绵进行保水率的测定结果如图17所示。PLA纳米纤维层的保水率为61.0%±10.0%,复合海绵的保水率为2121.8%±31.2%,两者的保水率有显著性差异(p<0.01),这结果与溶胀率的研究结果一致。理想的医用敷料需要具有一定的保水性,以保持创面的湿润,避免创面过分脱水。
(5)静态水接触角测定:方法与实施例2一致。
亲水性是评价伤口敷料的一个重要标准,因为它影响细胞粘附、增殖和吸收渗出物的能力。PLA纳米纤维和复合海绵的水接触角如图18所示。
PLA纳米纤维层的平均接触角为120.5°±2.6°,复合海绵的平均接触角为98.1°±1.7°,两者的亲水性有显著性差异(p<0.01)。
上述测试指标综合表明,复合海绵为一种典型的非对称结构,外层PLA纤维为疏水层,孔径小、孔隙率较高,可以防水,防止环境污染物附着的能力,具有一定的抑菌能力,同时具有良好的透气性;内层多孔海绵为亲水层,孔径大、孔隙高,具有优异的溶胀性、保水性,可以有效地吸收创面渗出液,同时为创面创造较为湿润的生长环境,促进创面愈合。
(6)体外凝血试验:
将复合海绵和医用纱布(作为对照)切成直径约10mm的圆形样本。首先,将100μL血液(含10%柠檬酸钠)滴于每个样品表面,37℃浸润5min,然后用50mL蒸馏水轻轻冲洗,以除去未凝结的红细胞。使用血红蛋白检测液,对每个样本进行血块定量测定。通过紫外分光光度计在540nm波长下测量每个样品的吸光度。血红蛋白含量按公式(4)计算:
血红蛋白含量(g/L)=(OD-OD0)×367.7 (4)
公式(4)中,OD0表示空白吸光度值,OD表示被测样品的吸光度值。
结果:通过体外全血终凝实验来评价复合海绵的凝血性能。如图19所示,与医用纱布和PLA微/纳米纤维层相比,复合海绵的凝血性能较好;血红蛋白含量测试结果如图20所示,其与宏观观察结果一致。
实施例4.复合海绵与PLA纳米纤维膜复合
将已经制备好的复合海绵与PLA纳米纤维膜进行复合,制备最终的多功能敷料,将复合海绵放置于纺丝机的收集台上,让其进行纺丝,复合海绵会被纺上一层PLA纳米纤维膜,纺丝过后复合海绵如图3所示。
Claims (7)
1.一种创伤敷料,其特征在于,所述创伤敷料的组分包括利多卡因、胶原蛋白、海藻酸钠和聚乳酸,所述创伤敷料的制备方法包括以下步骤:
S1:提取难溶性胶原纤维:
1)将牛皮真皮层经过碱分散、酸膨胀及高压脱纤处理后得到胶原松弛纤维凝胶;
2)用4% NaOH溶液中和样品液pH值至6.8-7.0,使胶原纤维从溶液中析出;
3)用去离子水对析出的胶原纤维进行充分洗涤,去除盐分,纱布过滤,得到粗提纯胶原;
4)在胶原纤维加入0.5mol/L醋酸、1%蛋白酶,室温下磁力搅拌36h,得浆液;
5)在浆液中加入NaCl晶体至1mol/L,4°C静置过夜;离心,弃上清,在沉淀中加入去离子水,采用4mol/L NaOH调节pH为7.0,4°C静置过夜;离心,弃上清,在沉淀中加入0.5mol/L醋酸,4°C磁力搅拌过夜;匀浆后采用0.2mol/L Na2HPO4/NaOH调节pH为7.2,4°C静置过夜;离心,弃上清,将沉淀通过离心用去离子水清洗3次;
6)步骤5)所得沉淀中加入0.5mol/L醋酸均匀混合,装入截留分子量为8kDa的透析袋中透析72h,离心,冷冻干燥即得;
S2:采用所述海藻酸钠和所述利多卡因制备载利多卡因的海藻酸钠凝胶球;
S3:将S2制得的海藻酸钠凝胶球加入S1制得的难溶性胶原纤维溶液中,制得复合海绵;
S4:采用静电纺丝技术制备聚乳酸纳米纤维膜,得到聚乳酸静电纺丝纤维层;
S5:将S3所得复合海绵与S4所得聚乳酸静电纺丝纤维层复合,得到创伤敷料;
所述聚乳酸的质量分数为8%;所述S4中静电纺丝参数为:推进速度0.002mm/s,电压25.25kV,针头长度30mm,注射器与收集器的距离25cm。
2.根据权利要求1所述的创伤敷料,其特征在于,所述海藻酸钠还可以是海藻酸钾和/或海藻酸铵;所述聚乳酸还可以是聚乙醇酸、聚乳酸-乙醇酸共聚物、聚己内酯和/或聚乙二醇。
3.根据权利要求1所述的创伤敷料,其特征在于,所述创伤敷料的复合海绵层具有多孔结构,其孔隙率为60%~90%,其孔径大小为10~300μm;所述创伤敷料的聚乳酸静电纺丝纤维层的孔隙率为50%~80%,其孔径大小为1.0~1.3μm。
4.根据权利要求1所述的创伤敷料,其特征在于,所述复合海绵的溶胀率为3500%,所述聚乳酸静电纺丝纤维层的溶胀率为500%。
5.根据权利要求1所述的创伤敷料,其特征在于,所述复合海绵的保水率为2121.8%±31.2%,平均接触角为98.1°±1.7°;所述聚乳酸静电纺丝纤维层的保水率为61.0%±10.0%,平均接触角为120.5°±2.6°。
6.权利要求1所述的创伤敷料在制备用于伤口保湿的产品中的应用,其特征在于,用所述创伤敷料对伤口进行保湿,所述创伤敷料为伤口创造微湿、微酸和低氧环境,促进细胞增殖、分化和上皮细胞迁移。
7.权利要求1所述的创伤敷料在制备用于吸附创口渗液的产品中的应用,其特征在于,用所述创伤敷料对创口渗液进行吸附,减少伤口水分和体液的流失的同时,抑制细菌生长。
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