CN116603097A - 一种自修复可注射水凝胶敷料及其制备方法 - Google Patents
一种自修复可注射水凝胶敷料及其制备方法 Download PDFInfo
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Abstract
本发明公开了一种自修复可注射水凝胶敷料及其制备方法,水凝胶敷料包括生物可降解聚合物、多酚化合物和活性药物,生物可降解聚合物与多酚化合物之间通过亚胺键、双硫键、硼酸酯键或酰腙键动态结合,活性药物包括具有光热效应的纳米材料、抗氧化药物、抗炎药物和促血管生成药物中的至少一种。该水凝胶敷料中引入动态键,使其具有自修复和可注射的性能,可适合于不同形状和面积的创口,使得水凝胶敷料具有较强的机械性能,在使用时可保持水凝胶敷料结构的完整性,延长使用寿命。
Description
技术领域
本发明属于水凝胶敷料技术领域,具体涉及一种自修复可注射水凝胶敷料及其制备方法。
背景技术
伤口按照愈合时间长短可分为急性伤口和慢性伤口,急性伤口能够在短时间内快速愈合,而慢性伤口通常指愈合速度慢,伤口超过1个月未能愈合,或者没有愈合倾向的难治性伤口,如:糖尿病足溃疡、静脉溃疡和压疮等。慢性伤口尽管成因不同,但都存在伤口持续感染,促炎因子、蛋白酶、ROS的水平过高和细胞功能障碍的共同特点。慢性伤口往往需要频繁换药、多次住院,对患者的健康和生活质量造成不良影响,并带来巨大的经济负担。慢性伤口的治疗是一个长期的联合治疗过程,标准治疗方法包括定期的伤口清创,减压治疗,血管灌注恢复,控制感染,局部使用敷料提供湿润的环境。传统敷料作为局部治疗慢性伤口的一种手段,通常用于清洁干燥的伤口,主要作用覆盖伤口并保持气体交换。
但是传统敷料的问题在于难以保持创面湿润,更换时由于对伤口渗出物的吸收会造成对伤口的粘附引起患者的疼痛并进一步造成伤口损伤。相较于传统敷料,具备先进功能的现代敷料具有更好的生物相容性,可降解性和保湿性,可以减轻疼痛并改善缺氧或无氧环境。现代敷料的特点是具有半渗透性和存在高吸收层,在伤口愈合过程中发挥积极作用。
水凝胶敷料作为临床中最常见的现代敷料之一,具有三维网络交联结构,含水量高,多孔结构能促进气体的充分交换,能为伤口提供湿润的环境。但普通水凝胶敷料只起到简单的物理隔离和创造湿润环境的作用,不具备治疗效果,并且和不规则形状伤口的贴合效果较差,日常运动产生的机械力会破坏水凝胶敷料网络结构的完整性,从而降低水凝胶敷料的治疗效果并且使用寿命大幅降低。因此开发具有多种生物学功能并适应伤口微环境的水凝胶敷料备受关注。
发明内容
针对现有技术中的上述不足,本发明提供了一种自修复可注射水凝胶敷料及其制备方法,该水凝胶敷料中引入动态键,使其具有自修复和可注射的性能,可适合于不同形状和面积的创口,使得水凝胶敷料具有较强的机械性能,在使用时可保持水凝胶敷料结构的完整性,延长使用寿命。
为实现上述目的,本发明解决其技术问题所采用的技术方案是:
一种自修复可注射水凝胶敷料,包括生物可降解聚合物、多酚化合物和活性药物,生物可降解聚合物与多酚化合物之间通过亚胺键、双硫键、硼酸酯键或酰腙键动态结合,活性药物包括具有光热效应的纳米材料、抗氧化药物、抗炎药物和促血管生成药物中的至少一种。
进一步地,生物可降解聚合物包括淀粉及其衍生物、壳聚糖及其衍生物、纤维素及其衍生物、明胶及其衍生物、海藻酸及其衍生物、透明质酸及其衍生物、肝糖及其衍生物和菊粉及其衍生物中的至少一种。
进一步地,多酚化合物包括咖啡酸、多巴、芦丁、藜芦醇、根皮素、根皮苷和单宁酸中的至少一种。
进一步地,具有光热效应的纳米材料包括金纳米棒、铜硫纳米颗粒、铜硒纳米颗粒、Nb2C MXene纳米片、Ti3C2MXene纳米片、W18O49纳米棒和普鲁士蓝纳米颗粒中的至少一种。
进一步地,光热效应的纳米材料的粒径为1-200nm。
进一步地,水凝胶敷料中生物可降解聚合物的质量占比为0.5-99.5%,多酚化合物的质量占比为0.5-99.5%,活性药物的质量占比为0.5-99.5%。
上述自修复可注射水凝胶敷料的制备方法,当生物可降解聚合物与多酚化合物通过硼酸酯键交联时,其制备方法包括以下步骤:
(1)将生物可降解聚合物和冰乙酸溶解于水中,制得生物可降解聚合物溶液,然后向其中滴加2,3-环氧丙基三甲基氯化铵水溶液,于加热条件下反应,然后离心,取上清液进行纯化、冻干,制得季铵化生物可降解聚合物;
(2)制备季铵化生物可降解聚合物溶液;将4-羧基-3-氨基苯硼酸、NHS和EDC溶解于DMSO中,制得羧基活化溶液,将季铵化生物可降解聚合物溶液和羧基活化溶液混合,调节混合溶液pH值为弱酸性后进行活化反应,然后透析、冻干,制得4-羧基-3-氟基苯硼酸季铵化生物可降解聚合物;
(3)将生物可降解聚合物溶解于PBS溶液中,制得生物可降解聚合物溶液,向其中添加NHS和EDC,活化羧基,然后向其中添加3-氨基苯硼酸进行接枝反应,然后透析、冻干,制得3-氨基苯硼酸生物可降解聚合物;
(4)将4-羧基-3-氟基苯硼酸生物可降解聚合物、3-氨基苯硼酸生物可降解聚合物和活性药物溶解,制得混合物溶液,将混合物溶液与多酚化合物溶液混合,搅拌,制得水凝胶敷料。
进一步地,步骤(1)中反应温度为50-60℃,反应时间为22-24h,离心转速为6000-7000rpm,离心时间为6-10min。
进一步地,步骤(2)中混合溶液pH值为5-6,活化反应温度为20-30℃,活化反应时间为3-5h。
进一步地,步骤(3)中PBS溶液的pH值为5-6,活化羧基反应时间为3-5h,接枝反应时间为44-50h。
本发明所产生的有益效果为:
1、本申请中通过动态键将生物可降解聚合物与多酚化合物进行动态交联,形成水凝胶敷料结构,该水凝胶敷料具有良好的自愈合性能,可延长其机械耐久性,增长其使用寿命,避免造成创口二次损伤;该水凝胶敷料可以以注射的形式进行使用,可根据患者创口的形状进行涂覆,提高对创口的覆盖效果。
2、该水凝胶敷料中还引入多酚化合物,多酚化合物自身具有较好的抗氧化性、抗菌性和抗炎性,可提高水凝胶敷料对创口的治疗效果,且多酚化合物接枝在水凝胶敷料基体中,可提高其稳定性,随着使用时间的增加逐渐释放,可提供缓释的治疗效果。
3、该水凝胶敷料中还引入活性药物,当活性药物为具有光热效应的纳米材料时,可利用其光热转换性能,提高水凝胶敷料的温度,使得创口处于微热环境中,促进新生血管的形成,从而促进慢性创口的愈合。
附图说明
图1为本发明水凝胶敷料的制备过程和治疗过程示意图;
图2为本发明水凝胶敷料自修复性能结果统计图;
图3为本发明水凝胶敷料注射性能效果图;
图4为本发明水凝胶敷料H2O2清除能力统计图;
图5为本发明水凝胶敷料·OH清除能力统计图;
图6为本发明水凝胶敷料·O2-清除能力统计图;
图7为本发明水凝胶敷料DPPH清除能力统计图;
图8为本发明水凝胶敷料ABTS+·清除能力统计图;
图9为本发明水凝胶敷料光热性能结果统计图;
图10为本发明水凝胶敷料抗炎性能结果统计图;
图11为本发明水凝胶敷料促进创口愈合效果图。
具体实施方式
为了使本发明的目的、技术方案及优点更加清楚明白,以下结合实施例,对本发明进行进一步详细说明。应当理解,此处所描述的具体实施例仅用以解释本发明,并不用于限定本发明,即所描述的实施例仅仅是本发明一部分实施例,而不是全部的实施例。
因此,以下对提供的本发明的实施例的详细描述并非旨在限制要求保护的本发明的范围,而是仅仅表示本发明的选定实施例。基于本发明的实施例,本领域技术人员在没有做出创造性劳动的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。
需要说明的是,术语“第一”和“第二”等之类的关系术语仅仅用来将一个实体或者操作与另一个实体或操作区分开来,而不一定要求或者暗示这些实体或操作之间存在任何这种实际的关系或者顺序。而且,术语“包括”、“包含”或者其任何其他变体意在涵盖非排他性的包含,从而使得包括一系列要素的过程、方法、物品或者设备不仅包括那些要素,而且还包括没有明确列出的其他要素,或者是还包括为这种过程、方法、物品或者设备所固有的要素。在没有更多限制的情况下,由语句“包括一个……”限定的要素,并不排除在包括要素的过程、方法、物品或者设备中还存在另外的相同要素。
下面结合实施例和附图对本发明的特征和性能作进一步的详细描述。
实施例1
一种自修复可注射水凝胶敷料,其制备方法包括以下步骤:
(1)将5g壳聚糖(CS)和0.9g冰乙酸先后加入到180mL水中,在磁力搅拌下使CS溶解,随后将6.7g 2,3-环氧丙基三甲基氯化铵(GTMAC)溶解于11.2mL水中,制得GTMAC溶液,然后将其逐滴加入到CS溶液中,并于55℃反应23h,反应完毕后在6500rpm条件下离心8min,取上清液用预冷的丙酮纯化三次,最后透析并冻干得到反应产物季铵化壳聚糖(QCS);
(2)将0.5g透明质酸(HA)溶解在pH为5.5的PBS中,制得HA溶液,然后将0.7g EDC和0.4g NHS加入到HA溶液中活化羧基4h,然后向溶液中加入0.2g 3-氨基苯硼酸并于25℃条件下反应48h,反应完成后,将产物透析并冻干,得到产物3-氨基苯硼酸透明质酸(HA-PBA);
(3)将0.3g QCS溶解在150mL PBS中,制备QCS溶液,随后将0.6g 4-羧基-3-氟基苯硼酸,1.2g NHS和2g EDC溶解在90mL DMSO中,并于25℃活化羧基4h,将两种溶液混合,并调节pH至5.5,在25℃条件下反应48h,反应完成后,将产物透析并冻干,得到产物4-羧基-3-氟基苯硼酸季铵化壳聚糖(QCSF);
(4)将1.1g聚乙烯基苯酚(PVP)超声分散于20mL水中,随后加入27.03mg FeCl3·6H2O并超声30min,将溶液转移到60℃水浴锅中加热搅拌30min,制得FeCl3·6H2O溶液;将42.2mg K4[Fe(CN)6]·3H2O加入到20mL水中超声分散5min,并将溶液转移到20mL注射器中,将K4[Fe(CN)6]·3H2O溶液以40mL/h的速度加入FeCl3·6H2O溶液中,随后在60℃水浴锅中继续反应1h,反应结束后,在12000rpm条件下离心10min,用丙酮和乙醇反复纯化五次,将产物真空烘干得到普鲁士蓝纳米颗粒(PBNPs);
(5)将3%w/v QCSF、2%w/vHA-PBA、0.1%w/v PBNPs溶解于水中,然后将溶液与5%w/v的单宁酸溶液混合,确保聚合物的浓度为4.5w/v%,搅拌至形成固体凝胶,得到以硼酸酯键交联形成的QHT@PBNPs水凝胶敷料。
实施例2
一种自修复可注射水凝胶敷料,其制备方法包括以下步骤:
(1)将5g壳聚糖(CS)和0.9g冰乙酸先后加入到180mL水中,在磁力搅拌下使CS溶解,随后将6.7g 2,3-环氧丙基三甲基氯化铵(GTMAC)溶解于11.2mL水中,制得GTMAC溶液,然后将其逐滴加入到CS溶液中,并于55℃反应23h,反应完毕后在6500rpm条件下离心8min,取上清液用预冷的丙酮纯化三次,最后透析并冻干得到反应产物季铵化壳聚糖(QCS);
(2)将0.5g透明质酸(HA)溶解在pH为5.5的PBS中,制得HA溶液,然后将0.7g EDC和0.4g NHS加入到HA溶液中活化羧基4h,然后向溶液中加入0.2g 3-氨基苯硼酸并于25℃条件下反应48h,反应完成后,将产物透析并冻干,得到产物3-氨基苯硼酸透明质酸(HA-PBA);
(3)将0.3g QCS溶解在150mL PBS中,制备QCS溶液,随后将0.6g 4-羧基-3-氟基苯硼酸,1.2g NHS和2g EDC溶解在90mL DMSO中,并于25℃活化羧基4h,将两种溶液混合,并调节pH至5.5,在25℃条件下反应48h,反应完成后,将产物透析并冻干,得到产物4-羧基-3-氟基苯硼酸季铵化壳聚糖(QCSF);
(4)将1.1g聚乙烯基苯酚(PVP)超声分散于20mL水中,随后加入27.03mg FeCl3·6H2O并超声30min,将溶液转移到60℃水浴锅中加热搅拌30min,制得FeCl3·6H2O溶液;将42.2mg K4[Fe(CN)6]·3H2O加入到20mL水中超声分散5min,并将溶液转移到20mL注射器中,将K4[Fe(CN)6]·3H2O溶液以40mL/h的速度加入FeCl3·6H2O溶液中,随后在60℃水浴锅中继续反应1h,反应结束后,在12000rpm条件下离心10min,用丙酮和乙醇反复纯化五次,将产物真空烘干得到普鲁士蓝纳米颗粒(PBNPs);
(5)将3%w/v QCSF、2%w/vHA-PBA、0.15%w/v PBNPs溶解于水中,然后将溶液与5%w/v的单宁酸溶液混合,确保聚合物的浓度为4.5w/v%,搅拌至形成固体凝胶,得到以硼酸酯键交联形成的QHT@PBNPs水凝胶敷料。
实施例3
一种自修复可注射水凝胶敷料,其制备方法包括以下步骤:
(1)将5g壳聚糖(CS)和0.9g冰乙酸先后加入到180mL水中,在磁力搅拌下使CS溶解,随后将6.7g 2,3-环氧丙基三甲基氯化铵(GTMAC)溶解于11.2mL水中,制得GTMAC溶液,然后将其逐滴加入到CS溶液中,并于55℃反应23h,反应完毕后在6500rpm条件下离心8min,取上清液用预冷的丙酮纯化三次,最后透析并冻干得到反应产物季铵化壳聚糖(QCS);
(2)将0.5g透明质酸(HA)溶解在pH为5.5的PBS中,制得HA溶液,然后将0.7g EDC和0.4g NHS加入到HA溶液中活化羧基4h,然后向溶液中加入0.2g 3-氨基苯硼酸并于25℃条件下反应48h,反应完成后,将产物透析并冻干,得到产物3-氨基苯硼酸透明质酸(HA-PBA);
(3)将0.3g QCS溶解在150mL PBS中,制备QCS溶液,随后将0.6g 4-羧基-3-氟基苯硼酸,1.2g NHS和2g EDC溶解在90mL DMSO中,并于25℃活化羧基4h,将两种溶液混合,并调节pH至5.5,在25℃条件下反应48h,反应完成后,将产物透析并冻干,得到产物4-羧基-3-氟基苯硼酸季铵化壳聚糖(QCSF);
(4)将1.1g聚乙烯基苯酚(PVP)超声分散于20mL水中,随后加入27.03mg FeCl3·6H2O并超声30min,将溶液转移到60℃水浴锅中加热搅拌30min,制得FeCl3·6H2O溶液;将42.2mg K4[Fe(CN)6]·3H2O加入到20mL水中超声分散5min,并将溶液转移到20mL注射器中,将K4[Fe(CN)6]·3H2O溶液以40mL/h的速度加入FeCl3·6H2O溶液中,随后在60℃水浴锅中继续反应1h,反应结束后,在12000rpm条件下离心10min,用丙酮和乙醇反复纯化五次,将产物真空烘干得到普鲁士蓝纳米颗粒(PBNPs);
(5)将3%w/v QCSF、2%w/vHA-PBA、0.3%w/v PBNPs溶解于水中,然后将溶液与5%w/v的单宁酸溶液混合,确保聚合物的浓度为4.5w/v%,搅拌至形成固体凝胶,得到以硼酸酯键交联形成的QHT@PBNPs水凝胶敷料。
实施例4
一种自修复可注射水凝胶敷料,其制备方法包括以下步骤:
(1)将5g壳聚糖(CS)和0.9g冰乙酸先后加入到180mL水中,在磁力搅拌下使CS溶解,随后将6.7g 2,3-环氧丙基三甲基氯化铵(GTMAC)溶解于11.2mL水中,制得GTMAC溶液,然后将其逐滴加入到CS溶液中,并于55℃反应23h,反应完毕后在6500rpm条件下离心8min,取上清液用预冷的丙酮纯化三次,最后透析并冻干得到反应产物季铵化壳聚糖(QCS);
(2)将0.5g透明质酸(HA)溶解在pH为5.5的PBS中,制得HA溶液,然后将1.08g高碘酸钠加入到HA溶液反应12h,反应完成后加入乙二醇终止反应,将产物透析并冻干,得到产物氧化透明质酸(OHA);
(3)将1.1g聚乙烯基苯酚(PVP)超声分散于20mL水中,随后加入27.03mg FeCl3·6H2O并超声30min,将溶液转移到60℃水浴锅中加热搅拌30min,制得FeCl3·6H2O溶液;将42.2mg K4[Fe(CN)6]·3H2O加入到20mL水中超声分散5min,并将溶液转移到20mL注射器中,将K4[Fe(CN)6]·3H2O溶液以40mL/h的速度加入FeCl3·6H2O溶液中,随后在60℃水浴锅中继续反应1h,反应结束后,在12000rpm条件下离心10min,用丙酮和乙醇反复纯化五次,将产物真空烘干得到普鲁士蓝纳米颗粒(PBNPs);
(4)将3%w/v QCS、6%w/vOHA、0.3%w/v PBNPs溶解于水中,然后将溶液与5%w/v的多巴溶液混合,搅拌至形成固体凝胶,得到以席夫碱键交联形成的QHT@PBNPs水凝胶敷料。
实施例5
一种自修复可注射水凝胶敷料,其制备方法包括以下步骤:
(1)将5g壳聚糖(CS)和0.9g冰乙酸先后加入到180mL水中,在磁力搅拌下使CS溶解,随后将6.7g 2,3-环氧丙基三甲基氯化铵(GTMAC)溶解于11.2mL水中,制得GTMAC溶液,然后将其逐滴加入到CS溶液中,并于55℃反应23h,反应完毕后在6500rpm条件下离心8min,取上清液用预冷的丙酮纯化三次,最后透析并冻干得到反应产物季铵化壳聚糖(QCS);(2)将0.5g透明质酸(HA)溶解在pH为5.5的PBS中,制得HA溶液,然后将0.7g EDC和0.4g NHS加入到HA溶液中活化羧基4h,然后向溶液中加入0.2g硒代胱胺并于25℃条件下反应48h,反应完成后,将产物透析并冻干,得到产物硒代胱胺透明质酸(HA-SeC);
(3)将1.1g聚乙烯基苯酚(PVP)超声分散于20mL水中,随后加入27.03mg FeCl3·6H2O并超声30min,将溶液转移到60℃水浴锅中加热搅拌30min,制得FeCl3·6H2O溶液;将42.2mg K4[Fe(CN)6]·3H2O加入到20mL水中超声分散5min,并将溶液转移到20mL注射器中,将K4[Fe(CN)6]·3H2O溶液以40mL/h的速度加入FeCl3·6H2O溶液中,随后在60℃水浴锅中继续反应1h,反应结束后,在12000rpm条件下离心10min,用丙酮和乙醇反复纯化五次,将产物真空烘干得到普鲁士蓝纳米颗粒(PBNPs);
(4)将3%w/v QCS、6%w/v HA-SeC、0.3%w/v PBNPs溶解于水中,然后将溶液与5%w/v的多巴溶液混合,搅拌至形成固体凝胶,得到以席夫碱键及双硒键交联形成的QHT@PBNPs水凝胶敷料。
试验例
图1为本发明水凝胶敷料的制备过程和治疗过程示意图;
以实施例1中的水凝胶敷料为例,实施例1的步骤(5)中未添加PBNPs制备得到的水凝胶敷料为QHT水凝胶敷料,添加了PBNPs制得的水凝胶敷料为QHT@PBNPs水凝胶敷料,测定水凝胶敷料的可注射性和系修复性能,测定水凝胶敷料的流变性能,具体见图2,图2中的a图为未添加PBNPs的水凝胶敷料的流变性能图,可以看出,在应变γ=1%时,水凝胶敷料的储能模量(G’)大于损耗模量(G”),水凝胶敷料处于凝胶状态;当应变为1300%时,G’降低,G”大于G’,说明水凝胶敷料已经被破坏;当施加应变恢复到1%时,G’和G”恢复到原来的值,说明水凝胶敷料的网络结构重构。经过3次重复实验,水凝胶敷料始终能在应变γ=1%时恢复凝胶状态,说明水凝胶敷料具有良好的自修复性能,b图为添加了PBNPs的水凝胶敷料的流变性能图,可以看出,PBNPs的加入并不影响QHT水凝胶敷料的自修复性;
将两份不同颜色的水凝胶敷料靠近使其接触,10min后用镊子将水凝胶敷料夹起,水凝胶敷料没有明显的裂痕,具体见图2中的c图,表明水凝胶敷料具有自修复性能。
对QHT水凝胶敷料和QHT@PBNPs水凝胶敷料进行剪切实验,测定水凝胶敷料的粘度;将水凝胶敷料加入注射器内,然后注射出“SWJTU”的字母,具体结果见图3,通过a图可以看出,随着剪切的进行,水凝胶敷料的粘度逐渐降低;通过b图可以看出,水凝胶敷料具有可注射性。
测定水凝胶敷料的RONS清除功能,具体操作如下:,
(1)采用Ti(SO4)2与H2O2的显色反应评估水凝胶敷料和PBNPs对H2O2的清除能力。首先配制0.1M的H2SO4溶液,将Ti(SO4)2加入到H2SO4中得到浓度为0.03M的硫酸钛溶液,将4mL浓度为1mM的H2O2溶液分别与200μL QHT水凝胶敷料、浓度为0.15mg/mL和0.3mg/mL的PBNPs、200μL QHT@PBNPs水凝胶敷料共同孵育。在不同的时间段,取100μL上清液于96孔板中,并加入30μLTi(SO4)2溶液,反应显色30min,之后,测量该溶液的紫外吸收光谱及在405nm处的吸光度以评估样品H2O2的清除性能。
(2)采用SA法对·OH的清除进行了实验。首先将200μL QHT水凝胶敷料、浓度为0.15mg/mL和0.3mg/mL的PBNPs、200μL QHT@PBNPs水凝胶敷料分别加入到1mL FeSO4(浓度为2mM)中,之后加入1mL H2O2(浓度为5mM)并静置10min,随后加入1mL SA(浓度为1.5mM)并将溶液在37℃避光孵育30min,随后测量混合溶液的紫外吸收光谱和在510nm处的吸光度,根据下列公式计算·OH的清除率:·OH清除率(%)=(Ac-As)/Ac×100%。Ac为只含有FeSO4、SA和H2O2的空白对照组在510nm的吸光度,As为实验组在510nm的吸光度。
(3)通过测试NBT的光还原抑制率评估水凝胶敷料和PBNPs对·O2-的清除能力。首先将200μL QHT水凝胶敷料、浓度为0.15mg/mL和0.3mg/mL的PBNPs、200μL QHT@PBNPs分别加入到1mL Met(浓度为12.5mM)中,随后向溶液中加入1mL NBT(浓度为75μM)和1mL核黄素(浓度为20μM),随后用紫外灯照射混合溶液15min,光照后,测量溶液的紫外吸收光谱和在560nm处的吸光度,通过下列公式计算·O2-的清除率:
·O2-清除率(%)=(A0-An)/(Ap-An)×100%
A0为实验组的吸光度,An为阴性对照组(含有核黄素、Met、NBT但处于黑暗环境中)在560nm处的吸光度,Ap为阳性对照组(含有核黄素、Met、NBT经过紫外照射)在560nm处的吸光度。
(4)DPPH清除实验的步骤如下:首先,配制0.1mM的DPPH乙醇溶液。将200μL QHT水凝胶、浓度为0.15mg/mL和0.3mg/mL的PBNPs、200μL QHT@PBNPs分别加入到3mL DPPH乙醇溶液中并在黑暗条件下孵育30min。孵育后,测量混合溶液的紫外吸收光谱和在517nm处的吸光度。通过下列公式计算DPPH的清除率:DPPH清除率(%)=(Ac-As)/Ac×100%
Ac为只含有DPPH乙醇溶液的空白对照组在517nm处的吸光度,As为实验组在517nm处的吸光度。
(5)ABTS+·清除实验的步骤如下:首先,2mL ABTS(浓度为7mM)和2mLK2S2O8(浓度为4.95mM)在室温下避光氧化12h,之后用PBS稀释溶液至浓度为原始的5%,将200μL QHT水凝胶敷料、浓度为0.15mg/mL和0.3mg/mL的PBNPs、200μL QHT@PBNPs分别加入到3mL ABTS+·溶液中避光孵育30min,测量混合溶液的紫外吸收光谱和在734nm处的吸光度。
通过下列公式计算ABTS·+的清除率:ABTS+·清除率(%)=(Ac-As)/Ac×100%Ac为只含有ABTS+·溶液的空白对照组在734nm处的吸光度,As为实验组在734nm处的吸光度。
具体测试结果见图4-8,图中PBNPs-1浓度为0.75mg/mL,PBNPs-2浓度为1.5mg/mL,QHT@PBNPs-1为QHT水凝胶敷料中添加了浓度为0.75mg/mL的PBNPs,QHT@PBNPs-2为QHT水凝胶敷料中添加了浓度为1.5mg/mL的PBNPs,如图4所示,在24h时,空白对照组H2O2的剩余量还有92.5%,PBNPs浓度为0.15mg/mL时,H2O2的剩余量有29.5%;浓度增加到0.3mg/mL时,H2O2的剩余量有11.6%,说明PBNPs对H2O2具有良好的清除能力,且对H2O2的清除与PBNPs的浓度相关。
如图5所示,PBNPs对·OH的清除率较弱,在浓度为0.15mg/mL和0.3mg/mL时,对·OH的清除率只有14.2%和17.0%。可能是因为PBNPs对·OH的清除能力受pH的影响,在pH为7.4的PBS溶液中下对·OH的清除能力较弱。相比之下QHT水凝胶敷料对·OH的清除率达到56.4%,QHT水凝胶敷料依靠水凝胶敷料中的单宁酸TA的电子转移实现对·OH的清除QHT@PBNPs-2水凝胶敷料对·OH的清除率达到了69.4%,实验结果说明QHT@PBNPs能够有效清除·OH。
由图6可知,PBNPs和QHT水凝胶敷料都表现出·O2-的清除能力,PBNPs在浓度为0.15mg/mL和0.3mg/mL时,对·O2-的清除率达到64.1%和74.6%,表明PBNPs对·O2-的清除与PBNPs的浓度存在依赖性;QHT水凝胶敷料对·O2-的清除率达到83.8%,依靠QHT水凝胶敷料中的单宁酸实现对·O2-的清除;QHT@PBNPs-2水凝胶敷料对·O2-达到了95.7%,表明PBNPs和QHT水凝胶敷料的联用能够有效清除·O2-。
如图7所示,PBNPs在浓度为0.15mg/mL和0.3mg/mL时,对DPPH的清除率达到51.3%和60.7%,表明PBNPs对DPPH的清除与PBNPs的浓度存在依赖性。相比之下,QHT水凝胶敷料对DPPH的清除率为89.1%,QHT@PBNPs水凝胶敷料DPPH的清除率为92%,表明QHT@PBNPs水凝胶敷料能有效清除DPPH。
由图8可知,PBNPs对ABTS+·的清除能力较差,在浓度为0.15mg/mL和0.3mg/mL时,对ABTS+·的清除率只有12.9%和22.9%。相比之下,QHT水凝胶敷料对ABTS+·的清除率达到了100%,表明了QHT水凝胶敷料对ABTS+·良好的清除能力,同样地,QHT@PBNPs组水凝胶敷料对ABTS+·的清除率也达到了100%。
测定水凝胶敷料的热转换性能,具体操作如下:采用808nm激光器对PBNPs和QHT@PBNPs水凝胶敷料在不同PBNPs浓度以及不同功率密度下进行光照,并用热成像仪记录其升温过程和升温图像,此外,通过激光器的3次开-关循环考察了QHT@PBNPs水凝胶敷料的光热稳定性。
具体测试结果见图9,图9中的a图为QHT水凝胶敷料和含有不同浓度PBNPs的QHT@PBNPs水凝胶敷料的温度变化统计图,如图a所示,不同PBNPs浓度(0.1、0.2、0.3mg/mL)的QHT@PBNPs水凝胶敷料在功率密度为0.5W/cm2的条件下,经过10min的光照,温度分别达到36.2、42.7、51.1℃;
b图为QHT@PBNPs0.1水凝胶敷料的在不同功率密度条件下的温度变化统计图,如图b所示,QHT@PBNPs0.1水凝胶敷料在0.25、0.5、0.75W/cm2的功率密度条件下经过10min的光照,温度分别达到33.3、37.5、47.8℃;
c图为在0.5W/cm2激光照射下,QHT@PBNPs0.1水凝胶敷料在3次激光器开-关循环过程中的温度变化统计图,表明QHT@PBNPs水凝胶敷料具有良好的光热稳定性;
d图为QHT水凝胶敷料和含有不同浓度PBNPs的QHT@PBNPs水凝胶敷料的热成像图;
e图为QHT@PBNPs0.1水凝胶敷料水凝胶敷料的热成像图,说明QHT@PBNPs0.1水凝胶敷料的升温与PBNPs的浓度,光照功率密度和光照时间相关。
测定水凝胶敷料的抗炎性能,实验共分为5组进行:LPS组、Control组、接枝苯硼酸的季铵化壳聚糖/单宁酸水凝胶敷料(QT)组、接枝苯硼酸的季铵化壳聚糖/透明质酸/单宁酸水凝胶敷料(QHT)组和QHT@PBNPs组。具体测试过程如下:首先,将Raw 264.7细胞吹打下来后以每孔1×105个细胞的密度接种到12孔板,用DMEM培养基(含10%FBS)孵育24h。之后,将培养基更换为含有1μg/mL的LPS的DMEM培养基(含10%FBS)继续孵育12h,空白对照组不加入LPS。12h后,弃去含有LPS的培养基,用无菌PBS清洗后分别加入含有5mg/mL的QT、QHT、QHT@PBNPs水凝胶敷料DMEM培养基继续孵育24h。随后,加入CD16/32抗体封闭非特异性蛋白15min,15min后弃去并用无菌PBS洗涤。用4%多聚甲醛固定细胞15min,15min后吸出多聚甲醛,用无菌PBS洗涤,加入破膜剂孵育30min。30min后吸出破膜剂,用无菌PBS洗涤,加入CD206-PE孵育30min,最后加入DAPI孵育15min。使用荧光显微镜观察Raw 264.7细胞的荧光染色情况。此外,通过ELISA检测了代表巨噬细胞极化的炎症相关因子IL-10、IL-6、TNF-α和TGF-β1的水平。细胞培养步骤同上,在水凝胶敷料溶液与Raw 264.7细胞共孵育24h后,收集细胞培养基,用于检测炎症因子。按照ELISA试剂盒的说明书步骤,检测IL-10、IL-6、TNF-α和TGF-β1的浓度。
具体测试结果见图10,图10中a图为IL-10含量统计图、b图为TGF-β1含量统计图、c图为TNF-α含量统计图、d图为IL-6含量统计图,可以看出,与LPS组比,QHT@PBNPs组的TNF-α、IL-6水平显著下降,而IL-10,TGF-β1水平上升,表明水凝胶敷料可以抑制促炎因子,促进抗炎因子的表达,QHT@PBNPs水凝胶敷料组具有最好的抗炎效果。
测定水凝胶敷料促进糖尿病大鼠伤口愈合情况,实验共分为5组进行:Control组、接枝苯硼酸的季铵化壳聚糖/单宁酸水凝胶敷料(QT)组、接枝苯硼酸的季铵化壳聚糖/透明质酸/单宁酸水凝胶敷料(QHT)组、QHT@PBNPs组和QHT@PBNPs水凝胶敷料光热(QHT@PBNPs+L)组。QHT@PBNPs+L组用808nm近红外激光器(0.5W/cm2)照射10min,温度保持在40℃,治疗的前5天每天光照一次,之后每两天光照一次。手术前对各组水凝胶敷料进行灭菌处理,手术时Control组不进行处理,其余组用400μL水凝胶敷料覆盖伤口。之后在每只大鼠伤口处覆盖3M透明敷料,用无菌纱布固定。手术完毕,对大鼠进行分笼饲养。间隔2-3天更换水凝胶敷料,在术后第0、3、7、10、14天,拍照记录伤口愈合情况。
具体见图11,通过图11可以看出,水凝胶敷料组能够促进糖尿病伤口的愈合,而QHT@PBNPs水凝胶敷料与轻度热刺激的结合能进一步加快糖尿病伤口的愈合。
Claims (10)
1.一种自修复可注射水凝胶敷料,其特征在于,包括生物可降解聚合物、多酚化合物和活性药物,所述生物可降解聚合物与所述多酚化合物之间通过亚胺键、双硫键、硼酸酯键或酰腙键动态结合,所述活性药物包括具有光热效应的纳米材料、抗氧化药物、抗炎药物和促血管生成药物中的至少一种。
2.根据权利要求1所述的自修复可注射水凝胶敷料,其特征在于,所述生物可降解聚合物包括淀粉及其衍生物、壳聚糖及其衍生物、纤维素及其衍生物、明胶及其衍生物、海藻酸及其衍生物、透明质酸及其衍生物、肝糖及其衍生物和菊粉及其衍生物中的至少一种。
3.根据权利要求1所述的自修复可注射水凝胶敷料,其特征在于,所述多酚化合物包括咖啡酸、多巴、芦丁、藜芦醇、根皮素、根皮苷和单宁酸中的至少一种。
4.根据权利要求1所述的自修复可注射水凝胶敷料,其特征在于,所述具有光热效应的纳米材料包括金纳米棒、铜硫纳米颗粒、铜硒纳米颗粒、Nb2CMXene纳米片、Ti3C2MXene纳米片、W18O49纳米棒和普鲁士蓝纳米颗粒中的至少一种。
5.根据权利要求4所述的自修复可注射水凝胶敷料,其特征在于,所述光热效应的纳米材料的粒径为1-200nm。
6.根据权利要求1所述的自修复可注射水凝胶敷料,其特征在于,所述水凝胶敷料中生物可降解聚合物的质量占比为0.5-99.5%,所述多酚化合物的质量占比为0.5-99.5%,所述活性药物的质量占比为0.5-99.5%。
7.权利要求1-6中任一项所述的自修复可注射水凝胶敷料的制备方法,其特征在于,当生物可降解聚合物与多酚化合物通过硼酸酯键交联时,其制备方法包括以下步骤:
(1)将生物可降解聚合物和冰乙酸溶解于水中,制得生物可降解聚合物溶液,然后向其中滴加2,3-环氧丙基三甲基氯化铵水溶液,于加热条件下反应,然后离心,取上清液进行纯化、冻干,制得季铵化生物可降解聚合物;
(2)制备季铵化生物可降解聚合物溶液;将4-羧基-3-氨基苯硼酸、NHS和EDC溶解于DMSO中,制得羧基活化溶液,将季铵化生物可降解聚合物溶液和羧基活化溶液混合,调节混合溶液pH值为弱酸性后进行活化反应,然后透析、冻干,制得4-羧基-3-氟基苯硼酸季铵化生物可降解聚合物;
(3)将生物可降解聚合物溶解于PBS溶液中,制得生物可降解聚合物溶液,向其中添加NHS和EDC,活化羧基,然后向其中添加3-氨基苯硼酸进行接枝反应,然后透析、冻干,制得3-氨基苯硼酸生物可降解聚合物;
(4)将4-羧基-3-氟基苯硼酸生物可降解聚合物、3-氨基苯硼酸生物可降解聚合物和活性药物溶解,制得混合物溶液,将混合物溶液与多酚化合物溶液混合,搅拌,制得水凝胶敷料。
8.权利要求7中所述的自修复可注射水凝胶敷料的制备方法,其特征在于,步骤(1)中反应温度为50-60℃,反应时间为6-48h,离心转速为6000-7000rpm,离心时间为6-30min。
9.权利要求7中所述的自修复可注射水凝胶敷料的制备方法,其特征在于,步骤(2)中混合溶液pH值为5-7,活化反应温度为20-40℃,活化反应时间为1-8h。
10.权利要求7中所述的自修复可注射水凝胶敷料的制备方法,其特征在于,步骤(3)中PBS溶液的pH值为5-7,活化羧基反应时间为1-8h,接枝反应时间为12-96h。
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