CN116474180A - 一种术后防粘连医用贴片及其制备方法与应用 - Google Patents
一种术后防粘连医用贴片及其制备方法与应用 Download PDFInfo
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Abstract
本发明公开了一种术后防粘连医用贴片及其制备方法与应用。通过将双键共聚物聚乙二醇二丙烯酸酯(PEGDA)、聚甲基丙烯酰胺左旋多巴‑co‑N,N‑二甲基丙烯酰胺(DCL)和黄原胶(XG)溶解共混,随后在光引发下聚合成胶并干燥得到黏附下层PDX;旋涂制备聚氨酯膜(PUF)并包埋疏水光引发剂,通过表面聚合生长得到聚甲基丙烯酸酯磺酸甜菜碱(PSBMA)两性离子聚合物修饰的聚氨酯膜(PSF);采用聚氨酯乳液扩散缠结的方式将PDX和PSF组装干燥,最终制得一种术后防粘连医用贴片。本发明制得的贴片能够快速、稳固地黏附贴合于组织受损处,规避手术缝合所带来的不便,同时能避免术后组织修复的过程中因局部纤维化发生粘连,还可以清除活性氧缓解局部炎症,促进组织正常修复生长。
Description
技术领域
本发明属于功能复合材料领域,具体涉及一种术后防粘连医用贴片及其制备方法与应用,该贴片可快速、稳固地黏附贴合组织受损处并防止发生术后粘连,清除活性氧缓解局部炎症。
背景技术
组织粘连是一种严重地术后并发症,病人在接受该手术后,软组织损伤处周围的力学刺激会激活成纤维细胞,诱导组织纤维化形成组织粘连,罹患腹壁组织粘连的概率高达90%,其结果不仅会诱发剧烈的疼痛,严重者甚至会造成死亡。其中,腹腔内组织粘连病变诱发小肠梗阻病症的概率超过了12%。当前用于解决术后组织粘连问题的方法主要包括药物治疗和屏障隔离两种。通过局部或全身注射阿司匹林、地塞米松、肝素、抑肽酶、抗生素链激酶等药物能够有助于减少纤维蛋白的增生并增强其分解,从而实现减少组织感染防止粘连的形成。但是,这些药物在体内会很快渗漏,导致持续驻留的时间非常短,在预防腹壁粘连上的实际效果似乎并不能令人满意。商用的聚丙烯补片往往会导致伤口愈合效果不佳,而且还会诱发机体组织出现强烈的免疫炎症反应,导致实际使用效果并不理想。商用的聚乳酸薄膜在使用过程中一旦不慎接触到潮湿的非病变组织表面就很容易发生吸附,大大限制了手术操作的灵活性。
水凝胶材料具有类似细胞外基质的可调三维网络结构,水凝胶内部含水量丰富,不仅能保持伤口湿润,方便组织代谢、促进伤口修复,而且一般还具有较为良好的生物相容性,能够避免引起严重的免疫炎症反应,因此正受到国内外科研人员的广泛研究。Ruiz-Esparza等报道了一种基于PEO和SiO2纳米颗粒复合物的可喷洒的单溶液衍生水凝胶,用于预防术后组织粘连。然而,该复合水凝胶材料在其组分中不具有组织黏附官能团结构,导致该水凝胶材料在光滑组织表面上的稳定结合性受到影响。因此,在水凝胶材料的设计思路上不仅要使其表面能够预防术后腹壁组织的粘连问题,同时还需要水凝胶材料本身能够稳定、可靠的黏附在受损组织处,不会因肠道蠕动、呼吸运动等正常生理活动的干扰而掉落失效。
动物腹膜组织表面高度水合的卵磷脂成分能够为腹腔和肠道之间提供良好的润滑作用,可有效防止腔内组织界面之间发生粘连,使得肠道可以正常蠕动,确保生命代谢活动不受影响。受到动物腹膜组织的启发,本发明提出设计了一种术后防粘连医用贴片(DJP),贴片表面聚氨酯层上原位生长的PSBMA聚合物刷的水合作用能够改善组织损伤处的润滑条件减轻机械刺激,防止因纤维化而发生粘连,贴片底层吸收EDC/NHS溶液后能够快速凝胶化并且能够快速、稳固地黏附贴合于组织受损处,避免复杂的手术缝合过程,其功能黏附分子DCL上的儿茶酚结构还能清除活性氧缓解局部炎症。
发明内容
本发明公开一种术后防粘连医用贴片的制备方法和应用效果。本发明合成了新型功能黏附共聚物聚甲基丙烯酰胺左旋多巴-co-N,N-二甲基丙烯酰胺(DCL)、双键封端的聚乙二醇二丙烯酸酯(PEGDA),通过将DCL、PEGDA和黄原胶(XG)共混后引发聚合制备水凝胶并将干燥后得到黏附下层PDX。(2)通过在水性聚氨酯(PU)乳液中预先包埋疏水光引发剂制备出聚氨酯膜(PUF)并采用原位聚合生长的方式得到两性离子聚合物聚甲基丙烯酸酯磺酸甜菜碱(PSBMA)表面改性的聚氨酯膜(PSF)。(3)在PU乳液渗透缠结的作用下,将PDX和PSF进行组装,最终获得术后防粘连医用贴片(DJP)。DJP在密封干燥条件下可长期保存,通过EDC/NHS溶液则可介导左旋多巴结构在组织缺损处实现快速、稳固的黏附效果,避免了繁杂的手术缝合过程;同时,DJP表层生长的水合两性离子聚合物润滑涂层能够有效防止组织之间发生纤维化粘连,清除活性氧缓解局部炎症,促进组织正常修复生长。
为实现上述目的,本发明采用如下技术方案:
本发明合成出了一种新型的功能黏附共聚物DCL,通过将PEGDA、DCL和XG溶解共混后的前驱体溶液在光引发下聚合成胶并干燥得到黏附下层PDX;旋涂制备PUF并包埋疏水光引发剂,通过表面聚合生长的方式得到PSBMA两性离子聚合物修饰的聚氨酯膜PSF;采用聚氨酯乳液扩散缠结的方式将PDX和PSF组装干燥,最终获得术后防粘连医用贴片,用于快速、稳定的黏附贴合在组织受损处并防止术后组织修复过程中发生粘连病变,同时清除活性氧缓解局部炎症。
该功能复合材料的制备方法包括以下步骤:
(1)量取480mL去离子水到圆底烧瓶中边搅拌边抽真空,排出水中溶解的空气直至水中不再产生气泡为止,然后称取12.1g Na2B4O7·10H2O和5g Na2CO3溶于体系中,并通过针头鼓入N230分钟进一步确保溶液体系中不再有多余的氧气,加入3.12g称量好的左旋多巴(Levodopa)在N2氛围保护下充分溶解。待溶解完成后,在0℃条件下,30分钟内继续边搅拌边逐滴向反应体系中加入50%(v/v)10ml丙烯酰氯-四氢呋喃溶液。接下来,在N2氛围保护下继续向反应体系中加入9g Na2CO3,保持pH=9左右常温下搅拌反应24小时。其反应过程如(a)所示:
(2)向H2O:DMSO体积比为15:35的50mL复合溶剂中鼓入氮气30分钟,确保尽可能多的除去溶剂体系中的空气。然后,再称取40mg AIBN引发剂和388mg LevodopaMA单体至复合溶剂中搅拌直至完全溶解(需在N2氛围保护下进行)。最后,量取2.08mL N,N-二甲基丙烯酰胺液体至反应体系中,保持60℃ N2氛围保护下连续搅拌反应5小时。其反应过程如(b)所示:
(3)称取20g 35000Da PEG粉末分散到100mL CH2Cl2中连续搅拌至透明均匀状态,再量取243μL丙烯酰氯至100mL PEG的有机溶液体系中均匀混合,最后量取160μL三乙胺缚酸剂至反应体系中促进酰氯和羟基之间的酯化反应正向进行,常温下连续搅拌反应24小时。其反应过程如(c)所示
(4)将266.5mg DCL和4mg黄原胶分散于1mL去离子水中磁子搅拌溶解获得透明溶液A。再将4mg I2959和266.5mg PEGDA分散于0.6mL去离子水中,完全溶解后获得溶液B。将A、B溶液混合均匀后注入模具中光交联聚合成成胶并干燥,获得黏附下层PDX。
(5)将固含量为60wt%的水性聚氨酯乳液用无水乙醇稀释到10wt%备用。稀释后的聚氨酯乳液滴加到单晶硅衬底上反复旋涂20次,待溶剂挥发后干燥,获得聚氨酯膜(PUF)。将制备好的PUF在10wt%的二苯甲酮-乙醇溶液中预包埋5分钟并干燥。然后,将原位包埋引发剂的PUF在30wt%SBMA单体水溶液中浸泡20分钟,并原位光引发聚合1小时,获得PSBMA聚合物刷修饰的聚氨酯薄膜PSF(即润滑上层PSF)。
(6)向黏附下层PDX上滴加10wt%聚氨酯乳液滴,然后将润滑上层PSF按压至黏附下层PDX上组装并干燥,最终获得术后防粘连医用贴片DJP。
本发明的优点在于:
(1)本发明制得的术后防粘连医用贴片DJP本身即为干燥状态,在密封干燥环境下可以长期保存,只需要预先配置好0.064μM EDC/NHS溶液即可方便医生手术期间使用,具有良好的便利性。
(2)本发明制得的术后防粘连医用贴片DJP水化后能够恢复凝胶状态,材料具有良好的拉伸力学韧性和拉伸循环耐疲劳性,可适宜运动组织处的力学要求。
(3)本发明制得的术后防粘连医用贴片DJP的黏附下层含有左旋多巴结构,能够在0.064μM EDC/NHS溶液的介导下先后通过儿茶酚作用和酰胺化反应实现了对组织快速、稳固的黏附贴合,避免了复杂的手术缝合过程,有利于临床使用。
(4)本发明制得的术后防粘连医用贴片DJP中的功能黏附分子DCL上具有丰富的儿茶酚结构,具有良好的抗氧化作用,有利于清除组织内的活性氧缓解局部炎症反应,这对于受损组织的恢复具有促进作用。
(5)受到动物腹膜组织的启发,在术后防粘连医用贴片DJP表层生长了一层PSBMA两性离子聚合物润滑层,其水合效应可以有效阻止组织成纤维化的侵袭,避免发生术后粘连病变。
附图说明
图1是实施例1中丙烯酰胺左旋多巴(LevodopaMA)核磁氢谱图。
图2是实施例2中聚丙烯酰胺左旋多巴-co-N,N-二甲基丙烯酰胺共聚物(DCL)核磁氢谱图。
图3是实施例3中聚乙二醇二丙烯酸酯(PEGDA)核磁氢谱图。
图4是实施例5中PSF傅里叶红外光谱图。
图5是实施例5中PSF表面水接触角图。
图6是实施例6制得的DJP水化后拉伸应力-应变测试图。
图7是实施例6制得的DJP水化后循环拉伸测试图。
图8是实施例6制得的DJP在EDC/NHS溶液介导下的组织黏附性能图。
图9是实施例6制得的DJP的抗氧化试验结果图。
图10是实施例6制得的DJP的表面润滑性能图。
图11是实施例6制得的DJP的防止术后组织粘连图。
具体实施方式
以下结合附图对本发明的具体实施方式进行详细说明。应当理解的是,此处所描述的具体实施方式仅用于说明和解释本发明,并不用于限制本发明。
除有定义外,以下实施例中所用的技术术语具有与本发明创造所属领域技术人员普遍理解的相同含义。以下实施例中所用的试验试剂,如无特殊说明,均为常规生化试剂;所述实验方法,如无特殊说明,均为常规方法。
实施例1
在本实施例中提供了丙烯酰胺左旋多巴(LevodopaMA)的详细合成过程,其步骤如下:
首先,量取480mL去离子水到圆底烧瓶中边搅拌边抽真空,排出水中溶解的空气直至水中不再产生气泡为止,然后称取12.1g Na2B4O7·10H2O和5g Na2CO3溶于体系中,并通过针头鼓入N230分钟进一步确保溶液体系中不再有多余的氧气,加入3.12g称量好的左旋多巴(Levodopa)在N2氛围保护下充分溶解。待溶解完成后,在0℃条件下,30分钟内继续边搅拌边逐滴向反应体系中加入50%(v/v)10ml丙烯酰氯-四氢呋喃溶液。接下来,在N2氛围保护下继续向反应体系中加入9g Na2CO3,保持pH=9左右常温下搅拌反应24小时。待反应结束后,向反应混合物中逐渐加入浓盐酸调节pH=2,直至溶液中不再产生气泡,然后用乙酸乙酯反复萃取溶液三次用无水MgSO4对有机溶液进行干燥,最后通过旋转蒸发对产物进行浓缩后再用正己烷沉淀,获得双键修饰后的LevodopaMA单体。如图1所示,核磁氢谱表明成功合成出LevodopaMA单体。
实施例2
在本实施例中提供了聚丙烯酰胺左旋多巴-co-N,N-二甲基丙烯酰胺共聚物(DCL)的详细合成过程,其步骤如下:
首先,向H2O:DMSO体积比为15:35的50mL复合溶剂中鼓入氮气30分钟,确保尽可能多的除去溶剂体系中的空气。然后,再称取40mg AIBN引发剂和388mg LevodopaMA单体至复合溶剂中搅拌直至完全溶解(需在N2氛围保护下进行)。最后,量取2.08mL N,N-二甲基丙烯酰胺液体至反应体系中,保持60℃ N2氛围保护下连续搅拌反应5小时。待反应时间结束后,将产物用透析袋透析三天去除掉未反应的小分子以及低聚物,冻干后得到DCL。如图2所示,核磁氢谱表明合成出DCL共聚物。
实施例3
在本实施例中提供了聚乙二醇二丙烯酸酯(PEGDA)的详细合成过程,其步骤如下:
将首先,称取20g 35000Da PEG粉末分散到100mL CH2Cl2中连续搅拌至透明均匀状态,然后量取243μL丙烯酰氯加到100mL PEG的有机溶液体系中均匀混合,最后再量取160μL三乙胺缚酸剂至反应体系中促进酰氯和羟基之间的酯化反应正向进行,常温下连续搅拌反应24小时。待反应结束后,首先向反应混合物中加入30mL浓度为2M K2CO3水溶液剧烈搅拌30分钟;然后再加入100mL饱和NaCl溶液促进有机相和水相分相,分离出有机相并用CH2Cl2对水相反复萃取三次,确保有足够的PEGDA产物转移到了CH2Cl2中(用无水MgSO4进行干燥);最后,通过旋转蒸发除去有机溶剂得到两端封端的聚乙二醇二丙烯酸酯(PEGDA)。如图3所示,核磁氢谱表明成功合成出PEGDA共聚物。
实施例4
在本实施例中提供了黏附下层PDX的详细制备过程,其步骤如下:
首先,将266.5mg DCL和4mg黄原胶分散于1mL去离子水中磁子搅拌溶解获得透明溶液A。再将4mg I2959和266.5mg PEGDA分散于0.6mL去离子水中,完全溶解后获得溶液B。将A、B溶液混合均匀后注入到长方形聚四氟乙烯模具中,在365nm紫外光下照射5分钟交联聚合成PDX水凝胶,保持水凝胶在模具中的状态,放入通风橱中彻底干燥,获得干燥的PDX。
实施例5
在本实施例中提供了润滑上层PSF的详细制备过程,其步骤如下:
首先,将固含量为60wt%浓度的水性聚氨酯乳液用无水乙醇稀释到10wt%浓度的聚氨酯乳液。然后,将10wt%聚氨酯乳液滴加到单晶硅衬底上铺展开并在800rpm转速下旋涂,待溶剂挥发后干燥,按照上述操作重复旋涂20次获得聚氨酯薄膜(PUF)。将制备好的PUF在10wt%浓度的二苯甲酮-乙醇溶液中浸泡5分钟,再用无水乙醇清洗表面并在N2流下风干,获得表层原位包埋疏水引发剂二苯甲酮的PUF。然后,将原位包埋引发剂的PUF在30wt%SBMA单体水溶液中浸泡20分钟,在365nm紫外光下照射1小时原位聚合生长PSBMA润滑涂层,获得PSBMA聚合物刷修饰的聚氨酯薄膜PSF。如图4所示,傅里叶红外光谱表明PSF表面具有PSBMA聚合物润滑层。如图5所示,水接触角测试表明PSF表明具有良好的亲水性。
实施例6
在本实施例中提供了术后防粘连医用贴片DJP的详细制备过程,其步骤如下:
在实施例4制备的PDX贴片上滴加10wt%聚氨酯乳液并在500rpm转速下旋涂铺开,然后将实施例5制备的PSF按压至PDX上组装并干燥。在干燥过程中,滴加的聚氨酯分子分别向PSF层和PDX层扩散缠结,促进PSF和PDX结合,最后成功制得术后防粘连医用贴片DJP。
试验例1
本试验例提供了实施例6制得的术后防粘连医用贴片DJP水化后的拉伸力学试验,其测试步骤如下:
首先将DJP水化恢复凝胶状态后夹持在万能力学试验机(传感器量程为20kg)适配的夹具上,调整力学试验机夹具位置保持上下夹具间刚好夹持住材料的状态,在100mm/min的速率下进行单轴拉伸直至材料发生断裂后停止。将DJP水凝胶按照同样的上样方式夹持在力学试验机上并保持刚好夹持住材料的状态,同样在100mm/min的速率下将样品拉伸至400%应变处,按照100mm/min的速率返回初始状态,循环拉伸11次。如图6所示,拉伸应力-应变测试结果表明材料具有良好柔韧性。如图7所示,循环拉伸测试结果表明材料具有良好的耐疲劳性。
试验例2
本试验例提供了实施例6制得的术后防粘连医用贴片DJP在EDC/NHS溶液介导下的180°组织黏附性剥离试验,其测试步骤如下:
首先,在猪皮表面喷洒预先配置好的0.064μM EDC/NHS溶液,使猪皮组织表面润湿,然后将实施例7中制备的DJP术后防粘连医用贴片贴到猪皮组织上并用100g砝码按压5分钟,使得在DJP和猪皮组织的界面处形成黏附(预留出5-10mm位置方便夹具夹持),待其恢复凝胶状态后进行测试。使用质构仪适配的上下夹具分别夹持住DJP凝胶和猪皮组织上预留出的位置,启动质构仪并保持在100mm/min速率下进行180°界面剥离试验测试。如图8所示,DJP在EDC/NHS溶液介导下具有良好的界面黏附韧性。
试验例3
本试验例提供了实施例6制得的术后防粘连医用贴片DJP的抗氧化性,其测试步骤如下:
将2mL DPPH(0.1mM)乙醇溶液和0.8mL DJP浸提液(3mg/mL)共混摇匀并将最终体积定容到4mL,在37℃的黑暗环境下孵育30分钟。其中,设置不加DPPH的组为阴性对照组(Sham组),不加DJP浸提液的组为阳性对照组(Control组)。如图9所示,DPPH和DJP浸提物共孵育30分钟后DPPH溶液的紫色褪去,表明材料具有良好的抗氧化作用。
试验例4
本试验例提供了实施例6制得的术后防粘连医用贴片DJP的摩擦试验,其测试步骤如下:
采用摩擦试验机在球-面模式下对材料的润滑性能进行了测试。把直径为8mm的Si3N4球固定在仪器上方的夹具上,把材料(PUF、PSF和DJP)用双面胶粘在玻璃片上后固定在仪器下方载物台上。在参数振幅为3mm,摩擦时间为300秒,频率为1Hz,正压力为3N条件下,测试摩擦系数的变化情况。所有的摩擦学测试均在室温和相对湿度为40-50%的条件下进行。在摩擦试验开始时,将去离子水滴入Si3N4球和材料的接触区,根据记录的CoF值评估材料的水合润滑性能。如图10所示,表面改性后DJP材料具有良好的润滑性。
试验例5
本试验例提供了实施例6制得的术后防粘连医用贴片DJP的SD大鼠腹腔内防粘连试验作为测试预防组织粘连的动物模型,其测试步骤如下:
将成年雄性SD大鼠(200-250g)随机分为阳性对照组(Control组)和DJP组。在进行术前,腹腔注射1%戊巴比妥钠(40mg/kg)麻醉大鼠。待药效发挥后,剃去腹部绒毛露出表皮并消毒。在SD大鼠腹部中线处用手术刀切出一个4cm长切口,打开腹部并露出盲肠。随后用无菌纱布刮擦盲肠直至渗血,用手术刀在腹壁上渗血盲肠对应处造出1.5cm×1.5cm的缺损。Control组在缺损处注射1mL PBS缓冲液即可。DJP组则是先在腹壁损伤处喷洒预配的0.064μM EDC/NHS溶液,然后将DJP黏附下层贴合至伤口处按压1分钟即可实现吸水贴合黏附。最后以外科丝线逐层缝合腹部和皮肤饲养14天,然后打开腹腔观察组织粘连情况。所有环节均严格按照专业外科医生和无菌原则进行。如图11所示,14天后打开SD大鼠腹腔进行观察,DJP成功防止了术后组织粘连。
Claims (10)
1.一种术后防粘连医用贴片,包括:
黏附下层PDX;以及
润滑上层PSF;
其中:
黏附下层PDX与润滑上层PSF通过PU乳液渗透粘合,经干燥后,完成组装。
2.一种根据权利要求1所述的术后防粘连医用贴片的制备方法,包括:
(1)制备黏附下层PDX:将DCL、XG混合后溶于去离子水中,得到溶液A;再将I2959和PEGDA分散于去离子水中,得到溶液B;AB溶液混匀后注入模具中,经干燥后,即得黏附下层PDX;
(2)制备润滑上层PSF:通过多次旋涂PU溶液制得PUF薄膜;随后将PUF薄膜在BP中预包埋后干燥处理,再置入SBMA中浸泡,经原位光引发聚合后,即得润滑上层PSF;
(3)制备术后防粘连医用贴片:PDX上滴加PU乳液后旋涂铺开,将PSF按压至PDX上组装并干燥,即得一种术后防粘连医用贴片DJP。
3.根据权利要求2所述的制备方法,其中:
步骤(1)所述溶液A中DCL、XG、去离子水的质量比为266.5:4:1;所述溶液B中I2959、PEGDA、去离子水的质量比为4:266.5:0.6。
4.根据权利要求2所述的制备方法,其中:
步骤(1)所述DCL由如下方法制得:
①在pH=9的缓冲体系下,丙烯酰氯和左旋多巴经酰胺化反应,合成丙烯酰胺左旋多巴单体;
②将丙烯酰胺左旋多巴单体和N,N-二甲基丙烯酰胺共聚,得到DCL。
5.根据权利要求2所述的制备方法,其中:
步骤(1)所述PEGDA由如下方法制得:
丙烯酰氯和35000Da聚乙二醇进行酯化反应,合成PEGDA。
6.根据权利要求2所述的制备方法,其中:
步骤(2)所述PU溶液的质量浓度10%,旋涂次数为20次。
7.根据权利要求1所述的制备方法,其中:
步骤(2)所述BP的质量浓度为10%,所述预包埋出时间为5min。
8.根据权利要求1所述的制备方法,其中:
步骤(2)所述SBMA溶液的质量浓度为30%,所述浸泡时间为20min,所述原位光引发聚合时间为1h。
9.一种根据权利要求2~8任一所述的制备方法制得的术后防粘连医用贴片。
10.一种根据权利要求1或9所述术后防粘连医用贴片的应用,包括:
在0.064μMEDC/NHS溶液介导下,将贴片的黏附下层PDX贴合至伤口处,按压1min。
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