CN117398531A - 一种具有抗凝血-止血双功能的涂层改性留置针及其制备方法与应用 - Google Patents
一种具有抗凝血-止血双功能的涂层改性留置针及其制备方法与应用 Download PDFInfo
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Abstract
本发明公开一种具有抗凝血‑止血双功能的涂层改性留置针及其制备方法与应用,对于留置针导管内表面,利用多巴胺/聚乙烯亚胺在碱性Tris‑HCl溶液中的氧化自聚合在内表面沉积一层聚多巴胺/聚乙烯亚胺底漆;然后将含有催化剂的肝素溶液注射到留置针导管内部,利用肝素中的羧基与PDA/PEI底漆表面的氨基之间形成的共价相互作用和静电相互作用,制备了PDA/PEI‑Hep抗凝血涂层。对于留置针导管外表面,旋涂超支化聚合物黏合剂,然后再涂覆具有止血作用的羧甲基壳聚糖/醛基功能化透明质酸水凝胶,得到HBPA@CMCS/HA‑CHO止血涂层。本发明的技术方案可抵抗血小板的黏附和激活,很好地适用于OTGG模型。
Description
技术领域
本发明属于材料表面科学和留置针技术领域,具体涉及一种具有抗凝血-止血双功能的涂层改性留置针及其制备方法与应用。
背景技术
留置针是一种可植入的医疗器械,使用时将留置针导管和针芯一起穿刺入静脉血管内,当导管全部进入血管后,撤出针芯,仅将柔软的导管留置在血管内进行输液治疗。静脉留置针的使用能够显著减少反复静脉穿刺所造成的痛苦,并且便于临床用药和急、危重患者的抢救用药,可以减轻医务人员的工作量,因而在临床上得到了广泛应用。目前留置针的导管材料主要是特氟龙(FEP),这种生物惰性材料长时间植入血管会导致凝血发生甚至形成血栓造成留置针导管阻塞。临床上常采用稀释肝素溶液封管,但是同时会带来潜在的大出血风险,并且稀释作用会导致诸如口服糖耐量试验(OGTT)等临床测试结果的不准确。此外,留置针穿刺后的出血会增加疾病感染风险,对于血友病患者来说更加危险,甚至可能导致失血性休克。因此需要开发一种兼具抗凝血和止血功能的新型留置针来解决这些问题。
发明内容
本发明的目的在于针对现有技术的不足,提供一种具有抗凝血-止血双功能的涂层改性留置针及其制备方法与应用,首先通过氧化自聚合反应在留置针导管内表面设置PDA/PEI底漆,然后再接枝肝素大分子,形成PDA/PEI-Hep抗凝血涂层;用HBPA黏合剂修饰留置针导管的外表面,然后涂覆CMCS/HA-CHO水凝胶形成HBPA@CMCS/HA-CHO止血涂层,两步涂层修饰策略可以保持留置针一定时间内良好畅通的同时实现拔针止血效果。
本发明的技术目的通过下述技术方案予以实现。
一种具有抗凝血-止血双功能的涂层改性留置针的制备方法,包括如下:
在留置针导管内表面通过多巴胺/聚乙烯亚胺溶液的自聚合反应形成PDA/PEI底层(即聚多巴胺/聚乙烯亚胺底漆或底层),再将含有EDC/NHS的肝素溶液注入经处理的留置针导管内,通过共价相互作用和/或静电相互作用在PDA/PEI底层表面接枝肝素大分子涂层;
通过旋涂法将HBPA黏合剂(超支化聚合物黏合剂)涂覆于留置针导管外表面,形成HBPA底层;再通过旋涂法将具有止血作用的CMCS/HA-CHO水凝胶(羧甲基壳聚糖/醛基功能化透明质酸水凝胶)涂覆留置针导管外表面,以将羧甲基壳聚糖/醛基功能化透明质酸(CMCS/HA-CHO)水凝胶固定在HBPA底漆表面。
依据上述制备方法得到的留置针,在内表面上设置聚多巴胺/聚乙烯亚胺底层,在聚多巴胺/聚乙烯亚胺底层表面上接枝肝素涂层,在外表面上设置超支化聚合物黏合剂底层,在超支化聚合物黏合剂底层上设置羧甲基壳聚糖/醛基功能化透明质酸水凝胶层。
在本发明的技术方案中,将盐酸多巴胺和聚乙烯亚胺溶解于pH=8.5的Tris水溶液中,然后将上述溶液注入留置针的导管内,35—37摄氏度下反应12—24小时,以形成聚多巴胺/聚乙烯亚胺底层,之后用去离子水干净冲洗5次,真空干燥待用,多巴胺和聚乙烯亚胺的质量比为2:(1—1.2)。
在本发明的技术方案中,将肝素、EDC和NHS均匀分散于MES溶液(pH=5.5)中配置肝素溶液,然后将上述溶液注入留置针的导管内,室温20—30摄氏度下反应12-24小时,以在聚多巴胺/聚乙烯亚胺底层表面接枝肝素大分子涂层;然后用去离子水干净冲洗5次,真空干燥待用;肝素、EDC和NHS的质量比为(3—3.2):3:1。
在本发明的技术方案中,羧甲基壳聚糖和醛基功能化透明质酸的质量比为(1—1.2):2,将含有两者的水溶液混合均匀,旋涂在超支化聚合物黏合剂层表面,两者通过希夫碱反应形成水凝胶,以将羧甲基壳聚糖/醛基功能化透明质酸水凝胶固定在超支化聚合物黏合剂表面,在留置针导管外表面得到HBPA@CMCS/HA-CHO止血涂层。
依据本发明的方法制备的留置针内表面设置PDA/PEI-Hep抗凝血涂层,外表面设置HBPA@CMCS/HA-CHO止血涂层,且能够在OGTT模型中具有良好的应用前景。
与现有技术相比,本发明的留置针在导管内表面和外表面分别设置了PDA/PEI-Hep抗凝血涂层和HBPA@CMCS/HA-CHO止血涂层,赋予留置针导管植入血管后一段时间内的抗凝血作用,并在拔针时实现良好的止血效果。该涂层改性制备方法简易,可以使普通留置针兼具抗凝血-止血双重功能,具有广泛的应用前景。
附图说明
图1是本发明的双功能留置针的内外表面涂层修饰流程图。
图2是本发明的双功能留置针的内表面涂层的XPS谱图。
图3是本发明的双功能留置针的内表面涂层的静态水接触角测试图。
图4是本发明中CMCS、HA、HA-CHO和CMCS/HA-CHO的FTIR光谱图。
图5是本发明中CMCS/HA-CHO水凝胶形成的试管倒置试验图。
图6是本发明的双功能留置针的表面形貌SEM和化学组成EDS图。
图7是本发明的双功能留置针的内外表面涂层的血细胞黏附图。
图8是本发明的双功能留置针的内外表面涂层孵化的新鲜兔血的活化部分凝血活酶时间(APTT)和凝血酶原时间(PT)的测试结果图。
图9是本发明的双功能留置针的内外表面涂层的溶血率测试结果图。
图10是本发明的双功能留置针的内外表面涂层的细胞毒性测试结果图。
图11是本发明的双功能留置针在兔耳缘静脉模型中的抗凝血-止血效果图。
图12是本发明的双功能留置针在正常大鼠和糖尿病大鼠口服糖耐量试验(OGTT)模型中的应用效果图。
具体实施方式
下面结合具体实施例对本发明的技术方案做进一步的详细说明。
如附图1所示,本发明中的抗凝血-止血双功能的涂层改性留置针的制备按照下述步骤进行:
步骤(1),将盐酸多巴胺(4mg/mL)和聚乙烯亚胺(2mg/mL)溶解于pH=8.5的Tris-HCl水溶液中,然后将上述溶液注入留置针导管内,37℃下反应24小时,然后用去离子水干净冲洗3次,真空干燥待用。
步骤(2),将肝素(25mg/mL)、EDC(24mg/mL)、NHS(8mg/mL)溶解于MES溶液(pH=5.5)中配置肝素溶液,然后将上述溶液注入经步骤(1)处理的留置针导管内,室温下反应24小时,然后用去离子水干净冲洗5次,真空干燥待用。
步骤(3),通过旋涂法将HBPA涂覆于经步骤(2)处理后的留置针导管外表面。
步骤(4),将等体积的CMCS(5w/v%,0.05g CMCS均匀分散在1ml水中)和合成的HA-CHO(10w/v%,0.1g HA-CHO均匀分散在1ml水中)混合均匀,然后立即旋涂在HBPA表面,HA-CHO和CMCS通过希夫碱反应形成水凝胶,室温20—25摄氏度干燥后在留置针导管外表面得到HBPA@CMCS/HA-CHO止血涂层。
上述步骤使用的超支化聚合物黏合剂HBPA的合成,按照下述步骤进行并可具体参考文献(Water-Triggered Hyperbranched Polymer Universal Adhesives:From StrongUnderwater Adhesion to Rapid Sealing Hemostasis,Adv.Mater.2019,1905761):用天平分别称取2.64g季戊四醇四丙烯酸酯、3.00g聚乙二醇二丙烯酸酯、6.50g盐酸多巴胺,将其溶于40ml的二甲基亚砜中,然后在搅拌下向其中逐滴加入三乙胺,将溶液的pH调到8左右。然后将上述溶液置于80℃的油浴中避光反应4h。反应产物经纯化处理后即可获得超支化聚合物黏合剂HBPA,密封保存供进一步使用,如下化学式所示的基本原理。
上述步骤使用的醛基功能化透明质酸HA-CHO的合成,按照下述步骤进行并可具体参考文献(Coadministration of an Adhesive Conductive Hydrogel Patch andanInjectable Hydrogel to Treat Myocardial Infarction,ACSAppl.Mater.Interfaces 2020,12,2039-2048):首先,将3.0g的透明质酸(Mw=50kDa)溶于300mL去离子水中,然后,加入16.5mL 0.25M的高碘酸钠溶液,室温下反应3h。随后,加入60mL的乙二醇,搅拌1h终止反应。反应结束后在去离子水中透析3天,透析液经冷冻干燥后获得HA-CHO产物,密封保存供进一步使用。
为了证明PDA/PEI底漆和PDA/PEI-Hep抗凝血涂层在留置针导管内表面的成功制备。在FEP薄膜上进行上述步骤的操作,模拟留置针导管的内表面涂层修饰。利用X射线光电子能谱(XPS)表征了PDA/PEI底漆和PDA/PEI-Hep涂层的形成。如附图2中a所示,纯FEP基质(黑色曲线)只在685.9和288.4eV处出现了F1s和C1s两个特征峰(含量比为2:1);PDA/PEI-coated FEP(红色曲线)在528.6和396.4eV处出现了两个新峰,这对应着PDA/PEI中的O1s和N1s的结合能,证明了PDA/PEI底漆在FEP基底表面的成功制备。更进一步的,PDA/PEI-Hep-coated FEP(蓝色曲线)表面出现了S 2p的165.4eV特征峰(图2中b对应元素S),这来自于肝素大分子的-SO3 -基团,证明了肝素涂层在PDA/PEI底漆表面的成功接枝。N 1s高分辨光谱(图2中c对应元素N)证明了含氨基的PDA/PEI与肝素大分子之间的酰胺共价键和静电相互作用。PDA/PEI底漆的N1s高分辨光谱在398.8eV和396.4eV出现了两个拟合峰,分别对应C-NH3 +/C-N+质子化胺成分和-C-N-骨架结构。接枝肝素后,PDA/PEI-Hep涂层中C-NH3 +/C-N+峰强度明显减弱,并且转移到了更高结合能的400.5eV处,这表面了肝素分子中的SO3 -/COO-阴离子与C-NH3 +/C-N+质子化胺形成了静电相互作用。此外,PDA/PEI-Hep涂层的N1s高分辨光谱中在398.4eV处出现了新的拟合峰,这是EDC/NHS催化下肝素的-COO-和PDA/PEI底漆表面-NH2形成的-CO-NH-共价键。这些结果表明,肝素涂层在PDA/PEI底漆表面通过共价键和静电相互作用协同作用稳定固定。
通过静态水接触角测试评价了FEP基质在内表面涂层改性后的疏水性-亲水性变化(附图3)。纯FEP为疏水表面,其水接触角为107.1±0.8°;沉积PDA/PEI底漆水接触角减少到了56.0±1.6°。进一步接枝肝素后,PDA/PEI-Hep-coated FEP表面的接触角降低至11.9±1.1°,具有极佳的亲水性。水接触角的变化源于PDA/PEI和PDA/PEI-Hep涂层的亲水性,这进一步证明了PDA/PEI-Hep涂层在FEP表面的成功制备。
利用FTIR证明了HA-CHO和CMCS/HA-CHO水凝胶的成功制备。如附图4所示,相比HA的FTIR谱图,HA-CHO在1734.2cm-1处出现了弱的醛基C=O峰,表明了HA的成功氧化。此外,CMCS/HA-CHO在1635.3cm-1处的吸收振动峰是酰胺带与席夫碱键重叠形成的宽峰,证明了席夫碱水凝胶的形成。如附图5所示,试管倒置实验也证明CMCS/HA-CHO混合后在约150s后形成水凝胶。
利用扫描电镜(SEM)原位观察了涂层改性的双功能留置针的表面形貌,并利用能量色散X射线光谱(EDS)表征了涂层的元素分布。如附图6所示,HBPA@CMCS/HA-CHO薄膜均匀地包裹在留置针外导管表面形成光滑的外涂层,低的表面粗糙度可以保证留置针穿刺过程中低的摩擦力,减少患者的疼痛。留置针导管内表面沉积PDA/PEI-Hep涂层后也保持宏观的均匀。此外,EDS化学映射显示改性留置针导管的外表面出现了HBPA@CMCS/HA-CHO涂层包含的C、O、N等元素,而留置针导管的F元素则因为涂层的覆盖而无法采集。留置针导管内表面的EDS能谱主要则采集了FEP基底的C、F元素,PDA/PEI-Hep涂层中的N、O元素也以较少的比例出现。结果证明了PDA/PEI-Hep涂层和HBPA@CMCS/HA-CHO涂层分别在留置针导管内表面和外表面的成功制备。
血小板粘附的数量和激活活性是评价生物材料表面血液相容性的主要指标,红细胞聚集也是凝血过程中的关键步骤。为了评价涂层与血细胞的相互作用,将FEP、PDA/PEI-coated FEP、PDA/PEI-Hep-coated FEP和CMCS/HA-CHO浸泡在肝素化的新鲜血液中孵化1小时,用PBS干净冲洗后用2.5%的戊二醛溶液固定,干燥后用SEM观察血细胞的黏附情况。如附图7所示,FEP薄膜黏附了大量的血小板,并且这些黏附的血小板呈现为树突状,表示已经处于活化状态。PDA/PEI-coated FEP表面则黏附了更多的活化状态血小板,这可能是因为PDA/PEI阳离子表面与带负电的血小板细胞膜具有静电相互作用,导致了更差的血液相容性。而PDA/PEI-Hep-coated FEP几乎可以完全排斥血小板粘附,并且极少数黏附的血小板呈现正常状态的椭圆形,没有被表面激活。结果证明PDA/PEI-Hep涂层不仅可以抵抗血小板的黏附,还避免了血小板的活化,赋予了FEP良好的抗凝血性能。在生理状态下,静电排斥作用抑制了红细胞的聚集和粘附。而CMCS/HA-CHO接触血液后的固态-凝胶转变密集聚集了大量的红细胞。结果证明HBPA@CMCS/HA-CHO涂层具有一定的密封止血作用。
通过活化部分凝血酶时间(APTT)和凝血酶原时间(PT)测试来评估PDA/PEI-Hep抗凝涂层和HBPA@CMCS/HA-CHO止血涂层对机体正常凝血机制的影响。APTT和PT是凝血功能监测中最常用的两个参数,分别用于考察内源性凝血途径缺陷和外源性凝血途径缺陷。如附图8所示,FEP、PDA/PEI-coated FEP、PDA/PEI-Hep-coated FEP和HBPA@CMCS/HA-CHO-coated FEP孵化后的血液的APTT和PT在数值虽然略有不同,但是没有显著性差异,所有涂层孵化后的血液的APTT和PT都在正常参考范围内(阴影区域)。结果证明PDA/PEI-Hep涂层和HBPA@CMCS/HA-CHO涂层都是基于表面作用来实现抗凝效果和止血效果,并不会影响机体正常的凝血功能。这种基于表面而非整体的抗凝血-止血作用保证了涂层使用的安全性。
如附图9所示,红细胞孵育实验证明了PDA/PEI-coated FEP、PDA/PEI-Hep-coatedFEP和HBPA@CMCS/HA-CHO-coated FEP都具有可媲美FEP的极低的溶血率(<1%)。结果证明了这些涂层都具有良好的血液相容性。如附图10所示,采用MTT法测量了FEP、PDA/PEI-coated FEP、PDA/PEI-Hep-coated FEP和HBPA@CMCS/HA-CHO-coated FEP的浸提液对小鼠成纤维细胞(L929)的细胞毒性。这些涂层浸提液孵化处理后的L929细胞存活率分别为96.5±0.3%、89.4±2.4%、97.1±6.02%和98.0±0.18%。结果表明各种表面涂层均具有良好的细胞相容性。
如附图11所示,通过植入兔耳缘静脉后的连续采血实验和拔针止血实验评价了涂层改性双功能留置针的抗凝血-止血性能(n=5)。由于缺乏足够的血液相容性,未改性的留置针植入血管后30min内即发生了凝血堵塞,无法正常采血(附图11中a标记所示)。如附图11中b、c标记所示,涂层改性双功能留置针植入血管后具有良好的通畅性,可以在3小时内每间隔1小时连续采血4次,扩大了静脉留置针的临床应用范围。通过定量测量拔针后的出血量证明了涂层改性留置针的止血性能(n=5)。如附图11中d、f标记所示,裸露的留置针从兔耳缘静脉拔出后,伴随着明显的出血,其平均出血量为1850mg,最高出血量可达3084mg。而涂层改性留置针拔出静脉后没有任何的出血迹象发生(附图11中e标记所示)。结果证明涂层改性双功能留置针在体内具有良好的抗凝血-止血性能。
进一步评估了涂层改性双功能留置针在糖尿病大鼠和正常大鼠的口服糖耐量试验(OGTT)模型中的应用(n=3)。涂层改性双功能留置针植入股静脉后可以在0、1、2、3小时连续采血4次(附图12中a标记所示),成功监测糖尿病大鼠和正常大鼠的血糖浓度变化。利用血糖试纸测量了不同时刻留置针采集的血样的血糖浓度,绘制了血糖浓度变化曲线。血糖浓度曲线(附图12中b标记所示)表明,糖尿病大鼠在口服葡萄糖后3小时内血糖浓度不断升高,并且都保持在高血糖浓度水平;而正常大鼠在口服葡萄糖后3小时内血糖浓度先升高后降低,并且浓度远低于糖尿病组。结果证明,涂层改性双功能留置针可监测糖尿病大鼠和正常大鼠的血糖浓度变化,具有有效的区分度,在OGTT模型中具有良好的应用前景。
根据本发明内容进行工艺参数的调整,均可实现留置针的内外表面修饰,经测试表现出与本发明基本一致的性能。以上对本发明做了示例性的描述,应该说明的是,在不脱离本发明的核心的情况下,任何简单的变形、修改或者其他本领域技术人员能够不花费创造性劳动的等同替换均落入本发明的保护范围。
Claims (6)
1.一种具有抗凝血-止血双功能的涂层改性留置针的制备方法,其特征在于,
在留置针导管内表面通过多巴胺/聚乙烯亚胺溶液的自聚合反应形成聚多巴胺/聚乙烯亚胺底层,再将含有EDC/NHS的肝素溶液注入经处理的留置针导管内,通过共价相互作用和/或静电相互作用在聚多巴胺/聚乙烯亚胺底层表面接枝肝素大分子涂层;
通过旋涂法将超支化聚合物黏合剂涂覆于留置针导管外表面,形成超支化聚合物黏合剂底层;再通过旋涂法将具有止血作用的羧甲基壳聚糖/醛基功能化透明质酸水凝胶涂覆留置针导管外表面,以将羧甲基壳聚糖/醛基功能化透明质酸水凝胶固定在超支化聚合物黏合剂表面。
2.根据权利要求1所述的一种具有抗凝血-止血双功能的涂层改性留置针的制备方法,其特征在于,将盐酸多巴胺和聚乙烯亚胺溶解于pH=8.5的Tris水溶液中,然后将上述溶液注入留置针的导管内,35—37摄氏度下反应12—24小时,以形成聚多巴胺/聚乙烯亚胺底层,之后用去离子水干净冲洗5次,真空干燥待用,多巴胺和聚乙烯亚胺的质量比为2:(1—1.2)。
3.根据权利要求1所述的一种具有抗凝血-止血双功能的涂层改性留置针的制备方法,其特征在于,将肝素、EDC和NHS均匀分散于MES溶液(pH=5.5)中配置肝素溶液,然后将上述溶液注入留置针的导管内,室温20—30摄氏度下反应12-24小时,以在聚多巴胺/聚乙烯亚胺底层表面接枝肝素大分子涂层;然后用去离子水干净冲洗5次,真空干燥待用;肝素、EDC和NHS的质量比为(3—3.2):3:1。
4.根据权利要求1所述的一种具有抗凝血-止血双功能的涂层改性留置针的制备方法,其特征在于,羧甲基壳聚糖和醛基功能化透明质酸的质量比为(1—1.2):2,将含有两者的水溶液混合均匀,旋涂在超支化聚合物黏合剂层表面,两者通过希夫碱反应形成水凝胶,以将羧甲基壳聚糖/醛基功能化透明质酸水凝胶固定在超支化聚合物黏合剂表面,在留置针导管外表面得到HBPA@CMCS/HA-CHO止血涂层。
5.利用1—4之一所述的一种具有抗凝血-止血双功能的涂层改性留置针的制备方法,其特征在于,得到的留置针,其特征在于,在内表面上设置聚多巴胺/聚乙烯亚胺底层,在聚多巴胺/聚乙烯亚胺底层表面上接枝肝素涂层,在外表面上设置超支化聚合物黏合剂底层,在超支化聚合物黏合剂底层上设置羧甲基壳聚糖/醛基功能化透明质酸水凝胶层。
6.如权利要求5所述的留置针在口服糖耐量试验模型中的应用。
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