CN109513036B - 一种受体温诱导可自动关闭抗菌功能的胶原蛋白材料 - Google Patents

一种受体温诱导可自动关闭抗菌功能的胶原蛋白材料 Download PDF

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CN109513036B
CN109513036B CN201910027923.9A CN201910027923A CN109513036B CN 109513036 B CN109513036 B CN 109513036B CN 201910027923 A CN201910027923 A CN 201910027923A CN 109513036 B CN109513036 B CN 109513036B
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陈意
杨高夫
侯德隆
严孙贤
王忠辉
曾琦
范浩军
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Sichuan University
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Abstract

本发明公开了一种受体温诱导可自动关闭抗菌功能的胶原蛋白材料。该材料的表面共价接枝有N‑异丙基丙烯酰胺‑黄樟素嵌段共聚物链，其特点在于：（1）疏水黄樟素链段以微嵌段方式均匀分布于共聚物主链上；（2）聚（N‑异丙基丙烯酰胺）间隔链段具有足够长度。在胶原器件的储存条件下（20℃以下），接枝的嵌段共聚物链完全伸展，黄樟素链段与细菌外层胞膜的接触几乎不受限制，其抗菌功能可正常发挥，保证胶原器件不受微生物侵蚀；一旦与活组织接触，嵌段共聚物链受生理温度（37℃）影响迅速塌缩，将有毒的黄樟素链段包裹在塌缩球中，以规避其毒副作用，天然胶原固有生物相容性可得以最大程度保留。上述智能材料在生物医用领域具有应用前景。

Description

一种受体温诱导可自动关闭抗菌功能的胶原蛋白材料
技术领域
本发明涉及一种受体温诱导可自动关闭抗菌功能的胶原蛋白材料，属于生物质材料领域。
背景技术
胶原结构独特、功能多样，与其他人工材料相比生物相容性优良，在当代医美、组织工程领域占有重要地位。然而，天然胶原极易受微生物侵蚀。因此，抗菌防腐是其作为医用材料高值利用的必要前提。
长期以来，通过外添加抗菌剂以提高胶原的抗菌防腐性被证明是一种行之有效的方法。然而，常用抗菌剂大多具有生理毒性。临床应用时，胶原器件所含抗菌剂直接暴露于活组织环境，可引发过敏、炎症、神经紊乱、甚至肾脏损伤等不良反应。因此，如何有效规避所含抗菌剂的毒副作用，成为了胶原基医用材料固有生物相容性得以充分利用的关键和难点。
发明内容
本发明的目的是为了克服现有技术存在的缺点和不足，提供一种受体温诱导可自动关闭抗菌功能的胶原蛋白材料，其特征在于该材料的制备工艺步骤和条件如下，以下所用物料的份数均为重量份数：
（1）将表面活性剂26-50份，水200-400份混合均匀形成稳定的胶束溶液，再加入N-异丙基丙烯酰胺80-162份、黄樟素10-16份，密封、循环冷冻-解冻除氧，在氮气氛围中，持续搅拌30-60分钟至溶液稳定，随后加入引发剂0.8-1.6份，在持续搅拌和氮气保护下，20-25℃反应6-8小时，最后加入含N-羟基琥珀酰亚胺活性酯的巯基类封端剂3-7份，反应1-2小时，反应结束后，将以上混合物倒入沉淀剂中，沉淀经反复洗涤、真空干燥即得N-羟基琥珀酰亚胺活性酯单封端的N-异丙基丙烯酰胺-黄樟素嵌段共聚物；
（2）将N-羟基琥珀酰亚胺活性酯单封端的N-异丙基丙烯酰胺-黄樟素嵌段共聚物80-140份溶于120-200份水中，搅拌20-40分钟充分溶解后，将胶原蛋白材料100-200份浸没其中，室温轻轻搅拌反应36-48小时，反应结束后，将接枝改性的胶原蛋白材料用水反复冲洗，即得受体温诱导可自动关闭抗菌功能的胶原蛋白材料。
以上方法中步骤（1）所述表面活性剂为十二烷基硫酸钠、十六烷基三甲基溴化铵、十四烷基二甲基乙基溴化铵、十六烷基三甲基氯化铵中的一种或多种。
以上方法中步骤（1）所述引发剂为过硫酸钾、过硫酸铵、硫酸亚铁、四甲基乙二胺、四甲基丙二胺中的一种或多种。
以上方法中步骤（1）所述含N-羟基琥珀酰亚胺活性酯的巯基类封端剂为2-巯基乙酸N-羟基琥珀酰亚胺酯、3-巯基丙酸N-羟基琥珀酰亚胺酯、4-巯基丁酸N-羟基琥珀酰亚胺酯中的一种或多种。
以上方法中步骤（1）所述沉淀剂为正己烷、环己烷、环戊烷、正庚烷、乙醚、石油醚中的一种或多种。
以上方法中步骤（2）所述胶原蛋白材料为胶原蛋白手术缝合线、胶原蛋白敷料、胶原蛋白止血剂、胶原蛋白手术卫生棉条、胶原蛋白人造血管、胶原蛋白角膜、胶原蛋白膜材料中的一种或多种。
本发明与现有技术相比，具有以下积极效果：
（1）本发明通过胶束共聚技术合成N-异丙基丙烯酰胺-黄樟素嵌段共聚物，黄樟素链段不仅均匀分布于共聚物主链上，聚（N-异丙基丙烯酰胺）间隔链段还具有足够长度。在低临界溶解温度以下，共聚物完全伸展，黄樟素链段充分暴露于外界环境，可与细菌细胞外膜（黄樟素靶标）正常接触，发挥抗菌功能；当温度上升至低临界溶解温度以上时，共聚物塌缩成球，由于黄樟素链段的疏水缔合速度更快，缔合滞后的具有足够长度的聚（N-异丙基丙烯酰胺）间隔链段可将先缔合的抗菌内核包裹，形成径向异质球，阻断抗菌内核与外界环境的接触，屏蔽其抗菌活性；
（2）上述嵌段共聚物的末端含N-羟基琥珀酰亚胺活性酯，可在温和条件下自发与胶原伯胺基反应。因此，在接枝改性过程中，不会破坏天然胶原自身三股螺旋结构，胶原材料固有生物学功能可最大程度保留；
（3）医用胶原器件通常储存于20℃以下的水介质中，此时的N-异丙基丙烯酰胺-黄樟素嵌段共聚物链应处于伸展状态（LCST约为32℃），黄樟素侧基与细菌外层胞膜的接触几乎不受限制，其抗菌功能可正常发挥，保证胶原器件不受微生物侵蚀。临床应用时，胶原器件一旦与活组织接触，这些共聚物链受生理温度影响将迅速塌缩，有毒黄樟素侧基适时隐藏，以规避其毒副作用。因此，储存液与活组织间自然温差为黄樟素侧基的暴露与自动隐藏创造了条件，该过程无需任何物理或化学干涉即可进行，胶原基材的储存稳定性和使用安全性可望获得“自适应”协调。
附图说明
图1为本发明所涉及的N-羟基琥珀酰亚胺活性酯单封端的N-异丙基丙烯酰胺-黄樟素嵌段共聚物结构示意图。
图2为本发明所涉及的改性胶原材料“自适应”抗菌功能原理图。
具体实施方式
下面通过实施例对本发明进行具体的描述，只用于对本发明进行进一步说明，不能理解为对本发明保护范围的限定，该领域的技术工程师可根据上述发明的内容对本发明作出一些非本质的改进和调整。
实施例1：
（1）将十六烷基三甲基氯化铵30份，水200份混合均匀形成稳定的胶束溶液，再加入N-异丙基丙烯酰胺80份，黄樟素10份溶解于其中，密封、循环冷冻-解冻除氧，在氮气氛围中，持续搅拌30分钟至溶液稳定，随后加入过硫酸钾0.8份、四甲基乙二胺0.8份，在持续搅拌和氮气保护下，25℃反应6小时，最后加入4-巯基丁酸N-羟基琥珀酰亚胺酯3份，反应2小时，反应结束后，将以上混合物倒入正己烷中，沉淀经反复洗涤、真空干燥即得N-羟基琥珀酰亚胺活性酯单封端的N-异丙基丙烯酰胺-黄樟素嵌段共聚物；
（2）将N-羟基琥珀酰亚胺活性酯单封端的N-异丙基丙烯酰胺-黄樟素嵌段共聚物80份溶于120份水中，搅拌20分钟充分溶解后，将胶原蛋白手术卫生棉条100份浸没其中，室温轻轻搅拌反应36小时，反应结束后，将接枝改性的胶原蛋白手术卫生棉条用水反复冲洗，即得可受体温诱导自动关闭抗菌功能的胶原蛋白手术卫生棉条。
配制浓度为106 CFU大肠杆菌菌液并预热至25℃，取0.5mL菌液置于N-异丙基丙烯酰胺-黄樟素嵌段共聚物接枝的胶原蛋白手术卫生棉条表面，放入25℃的恒温振荡箱中培养24h。用2mL磷酸盐缓冲溶液冲洗卫生棉条表面收集菌体，取此混合液100μL涂布平板，于37℃恒温培养箱中培养12h，与空白组对比计算抑菌率为99.8%；
配制浓度为106 CFU大肠杆菌菌液并预热至37℃，取0.5mL菌液置于N-异丙基丙烯酰胺-黄樟素嵌段共聚物接枝的胶原蛋白手术卫生棉条表面，放入37℃的恒温振荡箱中培养24h。用2mL磷酸盐缓冲溶液冲洗卫生棉条表面收集菌体，取此混合液100μL涂布平板，于37℃恒温培养箱中培养12h，与空白组对比计算抑菌率为4.2%；
实施例1所制备的N-异丙基丙烯酰胺-黄樟素嵌段共聚物接枝的胶原蛋白手术卫生棉条在共聚物的低临界溶解温度以下时，抗菌活性强，而在其低临界溶解温度以上时，抗菌功能被关闭，其生理毒性随之屏蔽。
实施例2：
（1）将十二烷基硫酸钠28份，水300份混合均匀形成稳定的胶束溶液，再加入N-异丙基丙烯酰胺90份，黄樟素15份溶解于其中，密封、循环冷冻-解冻除氧，在氮气氛围中，持续搅拌60分钟至溶液稳定，随后加入过硫酸铵0.9份，在持续搅拌和氮气保护下，22℃反应8小时，最后加入3-巯基丙酸N-羟基琥珀酰亚胺酯3份，反应1小时，反应结束后，将以上混合物倒入石油醚中，沉淀经反复洗涤、真空干燥即得N-羟基琥珀酰亚胺活性酯单封端的N-异丙基丙烯酰胺-黄樟素嵌段共聚物；
（2）将N-羟基琥珀酰亚胺活性酯单封端的N-异丙基丙烯酰胺-黄樟素嵌段共聚物100份溶于160份水中，搅拌30分钟充分溶解后，将胶原蛋白敷料150份浸没其中，室温轻轻搅拌反应42小时，反应结束后，将接枝改性的胶原蛋白敷料用水反复冲洗，即得可受体温诱导自动关闭抗菌功能的胶原蛋白敷料。
配制浓度为106 CFU大肠杆菌菌液并预热至25℃，取0.5mL菌液置于N-异丙基丙烯酰胺-黄樟素嵌段共聚物接枝胶原蛋白敷料的表面，放入25℃的恒温振荡箱中培养24h。用2mL磷酸盐缓冲溶液冲洗胶原蛋白敷料表面收集菌体，取此混合液100μL涂布平板，于37℃恒温培养箱中培养12h，与空白组对比计算抑菌率为99.2%；
配制浓度为106 CFU大肠杆菌菌液并预热至37℃，取0.5mL菌液置于N-异丙基丙烯酰胺-黄樟素嵌段共聚物接枝胶原蛋白敷料的表面，放入37℃的恒温振荡箱中培养24h。用2mL磷酸盐缓冲溶液冲洗胶原蛋白敷料表面收集菌体，取此混合液100μL涂布平板，于37℃恒温培养箱中培养12h，与空白组对比计算抑菌率为3.9%；
实施例2所制备的N-异丙基丙烯酰胺-黄樟素嵌段共聚物接枝的胶原蛋白敷料在共聚物的低临界溶解温度以下时，抗菌活性强，而在其低临界溶解温度以上时，抗菌功能被关闭，其生理毒性随之屏蔽。

Claims (1)

1.一种受体温诱导可自动关闭抗菌功能的胶原蛋白材料，其特征在于该材料的制备工艺步骤和条件如下，以下所用物料的份数均为重量份数：
(1.1)将表面活性剂26-50份，水200-400份混合均匀形成稳定的胶束溶液，再加入N-异丙基丙烯酰胺80-162份、黄樟素10-16份，密封、循环冷冻-解冻除氧，在氮气氛围中，持续搅拌30-60分钟至溶液稳定，随后加入引发剂0.8-1.6份，在持续搅拌和氮气保护下，20-25℃反应6-8小时，最后加入含N-羟基琥珀酰亚胺活性酯的巯基类封端剂3-7份，反应1-2小时，反应结束后，将以上混合物倒入沉淀剂中，沉淀经反复洗涤、真空干燥即得N-羟基琥珀酰亚胺活性酯单封端的N-异丙基丙烯酰胺-黄樟素嵌段共聚物；
(1.2)将N-羟基琥珀酰亚胺活性酯单封端的N-异丙基丙烯酰胺-黄樟素嵌段共聚物80-140份溶于120-200份水中，搅拌20-40分钟充分溶解后，将胶原蛋白材料100-200份浸没其中，室温轻轻搅拌反应36-48小时，反应结束后，将接枝改性的胶原蛋白材料用水反复冲洗，即得受体温诱导可自动关闭抗菌功能的胶原蛋白材料；
步骤(1.1)所述表面活性剂为十二烷基硫酸钠、十六烷基三甲基溴化铵、十四烷基二甲基乙基溴化铵、十六烷基三甲基氯化铵中的一种或多种；
步骤(1.1)所述引发剂为过硫酸钾、过硫酸铵、硫酸亚铁、四甲基乙二胺、四甲基丙二胺中的一种或多种；
步骤(1.1)所述含N-羟基琥珀酰亚胺活性酯的巯基类封端剂为2-巯基乙酸N-羟基琥珀酰亚胺酯、3-巯基丙酸N-羟基琥珀酰亚胺酯、4-巯基丁酸N-羟基琥珀酰亚胺酯中的一种或多种；
步骤(1.1)所述沉淀剂为正己烷、环己烷、环戊烷、正庚烷、乙醚、石油醚中的一种或多种；
步骤(1.2)所述胶原蛋白材料为胶原蛋白手术缝合线、胶原蛋白敷料、胶原蛋白止血剂、胶原蛋白手术卫生棉条、胶原蛋白人造血管、胶原蛋白角膜、胶原蛋白膜材料中的一种或多种。
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