CN116462863B - 一种含载Mg2+单宁酸微粒子的没食子酸接枝壳聚糖水凝胶及制备方法和应用 - Google Patents
一种含载Mg2+单宁酸微粒子的没食子酸接枝壳聚糖水凝胶及制备方法和应用 Download PDFInfo
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Abstract
本发明涉及口腔种植体周围炎技术领域，具体为一种含载Mg2+单宁酸微粒子的没食子酸接枝壳聚糖水凝胶及制备方法和应用，其制备方法包括：1）没食子酸接枝壳聚糖（CS‑GA）的制备；2）载Mg2+单宁酸微粒子（TAMP‑Mg2+）的制备；3）含有H2O2的CS‑GA溶液、含有HRP的TAMP‑Mg2+溶液混合，形成CS‑GA/TAMP‑Mg2+水凝胶。该水凝胶制备工艺简单，具有原位成型、可注射的特点，其CS‑GA、单宁酸、Mg2+组分的组合配合近红外光的照射赋予了其良好的抗菌、抗炎、抗氧化、促进骨再生的性能，在种植体周围炎的预防和治疗方面有较好的应用前景。
Description
技术领域
本发明涉及口腔种植体周围炎技术领域，特别是涉及一种含载Mg2+单宁酸微粒子的没食子酸接枝壳聚糖水凝胶、制备方法和用途。
背景技术
口腔种植技术是治疗牙列缺损及牙列缺失的有效方法，但种植体周围炎显著影响了其成功率。若不及时干预，种植体修复可能会失败。目前，临床上预防和治疗种植体周围炎的常规方法包括机械清创术、局部抗生素治疗、激光治疗、手术等。但是这些方法治疗结果不理想。例如，龈下刮治术和喷砂术高度依赖于操作者的技术；抗生素的频繁使用容易引起耐药性；激光治疗会损害种植体的表面结构；手术治疗会带来创伤且费用相对较高。因此，迫切需要开发一种简单、安全、有效的药物来治疗种植体周围炎。
种植体周围炎是一种以种植体周围软组织炎症和牙槽骨进行性吸收为特征的炎性疾病，其具体发病机制为粘附在种植体表面的细菌的某些代谢物和自身抗原，可能会刺激宿主的免疫应答，募集大量炎症细胞，促使炎症细胞因子、活性氧等的上调，从而直接或间接激活破骨细胞，抑制成骨细胞，导致种植体周围软硬组织破坏，最终可致种植体松动脱落。鉴于此，控制致病菌，减少促炎细胞因子、活性氧等的产生，抑制牙槽骨吸收，促进新骨形成可能是预防和治疗种植体周围炎的有效策略。因此,有必要寻找一种抗菌、抗炎、抗氧化、促成骨的多功能方法预防和治疗种植体周围炎。
近红外（NIR）光响应药物由于近红外光的高组织透明度及其外部精确控制能力而表现出优越的多功能性。CN202210223326.5中制备了这样一种由介孔普鲁士蓝(MPB)纳米粒子和沸石咪唑骨架-8(ZIF-8)纳米粒子组成的复合结构的NIR光响应药物，此药物以水溶液或PBS溶液、或与水凝胶、软膏混合后加辅以不同参数的近红外光照射应用于牙周炎或种植体周围炎，拟发挥其抗生物膜和促骨再生的作用；但基于其给药方式考虑其在应用部位的粘附和保持时间有限，且在抗炎、抗氧化方面的功能有待提高。因此研发多功能NIR光响应药物的同时需要使用合适的支架生物材料作为NIR光响应药物的递送载体以增强粘附性、延长其在应用部位的作用时间。近期在软、硬组织工程中广泛应用的可注射粘附性水凝胶可能是一种合适的支架生物材料的选择。其制备和使用简单，可调节的组成、微结构、机械性能和降解速率使其可作为载体受控递送各种治疗药物至体内，特别是其可以填充任何形状不规则的伤口，在湿态环境中有优良粘附性能，还可作为屏障防止细菌感染,诚然可将其作为药物的载体用于狭窄、湿润、易被细菌侵入的种植体周围袋。
综上，研发一种全新的含有多功能性能的NIR光响应药物的粘性可注射性水凝胶用于种植体周围炎的预防和治疗具有较好的前景和应用价值。
发明内容
本发明的目的是提供一种含载Mg2+单宁酸微粒子的没食子酸接枝壳聚糖水凝胶及制备方法和应用。
为了解决上述技术问题，本申请提供了如下技术方案：
一种含载Mg2+单宁酸微粒子的没食子酸接枝壳聚糖水凝胶的制备方法，包括以下步骤：
（1）通过碳二亚胺和1-羟基苯并三氮唑介导将没食子酸接枝到壳聚糖分子链上，得到没食子酸接枝壳聚糖（CS-GA）共聚物；
（2）将氨水、乙醇与去离子水混合，室温下搅拌；然后向反应物加入单宁酸水溶液，搅拌，然后加入氯化镁，继续搅拌；然后通过离心洗涤分离形成的固体产物；最后收集固体产物，冷冻干燥得到载Mg2+单宁酸微粒子（TAMP-Mg2+）；
（3）将CS-GA溶于去离子水并加入H2O2配制成含H2O2的CS-GA溶液；将TAMP-Mg2+溶于去离子水并加入辣根过氧化物酶（HRP）配制成含HRP的TAMP-Mg2+溶液；再将含有H2O2的CS-GA溶液、含有HRP的TAMP-Mg2+溶液混合，形成含载Mg2+单宁酸微粒子的没食子酸接枝壳聚糖（CS-GA/TAMP-Mg2+）水凝胶。
其中，所述步骤（1）具体为：在氮气保护下，按壳聚糖重复单元和1-羟基苯并三唑的摩尔比为1:1的比例将壳聚糖与1-羟基苯并三唑混合溶解于去离子水中, 搅拌过夜直至形成透明溶液；再向得到的溶液中加入与壳聚糖重复单元的摩尔比为1:1~5的没食子酸；待没食子酸充分溶解后边搅拌边逐滴加入1-(3-二甲氨基丙基)-3-乙基碳二亚胺的乙醇溶液，反应12~36小时后向反应产物中滴加 0.1mol/L盐酸至体系澄清，再将其透析72小时并真空冷冻干燥，得到CS-GA共聚物。其中，1-(3-二甲氨基丙基)-3-乙基碳二亚胺与没食子酸摩尔的质量比为1:1。
其中，所述步骤（2）具体为：将2 mL氨水、40 mL乙醇与90 mL去离子水混合，室温下搅拌0.5 h；然后向上述反应物加入10ml含4g单宁酸的水溶液，搅拌12 h，然后加入氯化镁，继续搅拌12~36h；然后通过离心洗涤分离形成的固体产物；最后收集固体产物，冷冻干燥得到TAMP-Mg2+。其中，所述氯化镁与单宁酸的摩尔质量比为1：1~30。
其中，所述步骤（3）中，将CS-GA溶于去离子水并加入H2O2配制成含0.025-0.1 wt %H2O2的浓度为1%~4%的CS-GA溶液。将TAMP-Mg2+溶于去离子水并加入辣根过氧化物酶HRP配制成含0.005-0.1 mg/mL HRP的浓度为1~5mg/mL的TAMP- Mg2+溶液。再将等体积的含有H2O2的CS-GA溶液、含有HRP的TAMP-Mg2+溶液混合，形成CS-GA/TAMP-Mg2+水凝胶。
采用本发明上述制备方法制得的含载Mg2+单宁酸微粒子的没食子酸接枝壳聚糖水凝胶可用于制备种植体周围炎相关药物。
与现有技术相比，本发明的含载Mg2+单宁酸微粒子的没食子酸接枝壳聚糖水凝胶及制备方法和应用至少具有以下有益效果：
（1）本发明制得了一种近红外光可控的具有抗菌、抗氧化、抗炎、促成骨性能的强粘性可原位注射的水凝胶，通过在种植体周围袋注入此水凝胶，同时适时的进行近红外光治疗，从而控制致病菌，减少种植体周围局部活性氧、促炎细胞因子等的产生，抑制牙槽骨吸收，促进新骨形成，实现对种植体周围炎预防和治疗。
（2）本发明通过HRP/H2O2介导的氧化交联反应，CS-GA/TAMP-Mg2+水凝胶可以溶液的形式注射进入种植体周围袋后快速交联形成凝胶，此种水凝胶成型方式使CS-GA/TAMP-Mg2+水凝胶可以微创的方式良好的匹配狭窄、形状不规则的种植体周围袋以及其他任意形状的病损部位；另外，该水凝胶优良的粘附性能可使其在注射后具有良好的稳定性，从而延长其在种植体周围袋中的作用时间的同时达到良好的封闭效果，减少给药次数，改善了患者的治疗舒适度，提高治疗果。
（3）本发明制得的CS-GA/TAMP-Mg2+水凝胶具有良好的生物安全性，且没食子酸接枝壳聚糖、单宁酸、Mg2+这些组分的组合赋予了该水凝胶良好的抗菌、抗炎、抗氧化、促进骨再生的性能，避免了通过负载抗菌、抗炎药物获得多功能性的传统水凝胶材料引起的耐药性、成本高等的缺点。
（4）本发明将TAMP-Mg2+加入CS-GA凝胶赋予了其光热治疗和光动力治疗（释放Mg2 +）的作用：一方面，光热治疗可以协同抗菌，有效杀灭局部细菌，去除种植体周围的病变组织；另一方面，轻度光热治疗可促进炎症状态的组织再生，再配合近红外光调控Mg2+的释放，调节炎症反应，促进骨组织再生。因此，在临床应用时，可以根据病变的位置、进展阶段等选择适当功率的808nm近红外光照射适当的时间，精准作用于病变部位，更为高效的治疗种植体周围炎。
（5）本发明制备的CS-GA/TAMP-Mg2+粘性可注射水凝胶中双组分的原材料来源广泛，组分制备工艺简单，流程易控，反应条件温和，具有规模化生产、进一步实际应用的潜力。
（6）与CN202210223326.5相比，本发明的药物为可注射粘性水凝胶剂型，具有原位成型、强粘附的特点，可以更好地填充种植体周围袋/牙周袋，且能起到封闭作用，使给药方式更微创的同时延长给药时间。
下面结合附图对本发明的含载Mg2+单宁酸微粒子的没食子酸接枝壳聚糖水凝胶及制备方法和应用作进一步说明。
附图说明
图1为实施例1制备的TAMP-Mg2+的扫描电子显微镜图。
图2为实施例2~4的条件下CS-GA/TAMP-Mg2+水凝胶在0.5W/cm2近红外光照射下的温度变化。
图3为实施例3制备的CS-GA/TAMP-Mg2+ 2水凝胶在不同功率近红外光下温度变化。
图4为实施例2~4的条件下制备的水凝胶的粘接强度统计图。
图5为实施例2~4的条件下制备的水凝胶与P.g.共培养10min、2h后的抗菌效果。
图6为实施例3制备的CS-GA/TAMP-Mg2+ 2水凝胶在有、无NIR照射下水凝胶对P.g.的抗菌效果。
具体实施方式
实施例1 制备CS-GA和TAMP-Mg2+
（1）在氮气保护下，将1.85 mmol壳聚糖与1.85 mmol1-羟基苯并三唑混合溶解于30ml去离子水中，搅拌过夜直至形成透明溶液；再向得到的溶液中加入3.7mmol没食子酸；待没食子酸充分溶解后边搅拌边逐滴加入含3.7 mmol1-(3-二甲氨基丙基)-3-乙基碳二亚胺的2.0 mL乙醇溶液，反应24小时后向反应产物中滴加 0.1mol / L 盐酸至体系澄清，再将其透析72小时并真空冷冻干燥，得到CS-GA共聚物。
（2）将氨水(2 mL)和乙醇(40 mL)与去离子水(90 mL)混合，室温下搅拌0.5 h。然后向上述反应物加入10ml含4g单宁酸的水溶液，搅拌12 h，然后加入与单宁酸摩尔质量比1：10的氯化镁，继续搅拌24h。然后通过离心洗涤程序分离形成的固体产物。最后收集固体产物，在-80℃下冷冻干燥得到TAMP-Mg2+。
使用扫描电子显微镜对该粒子的形貌进行研究，图1显示该粒子呈短棒状结构。
实施例2 制备CS-GA/TAMP-Mg2+ 1水凝胶
将实施例1中制备的CS-GA溶于去离子水并加入H2O2配制成含0.025wt% H2O2的浓度为2%的CS-GA溶液；将实例1中制备的TAMP-Mg2+溶于去离子水并加入辣根过氧化物酶（HRP）配制成含0.02 mg/mL HRP的浓度为1mg/mL的TAMP-Mg2+溶液；再将等体积的含有H2O2的CS-GA溶液、含有HRP的TAMP-Mg2+溶液混合，即可在31.67±0.6895s形成CS-GA/TAMP-Mg2+1水凝胶。
实施例3 制备CS-GA/TAMP-Mg2+ 2水凝胶。
将实施例1中制备的CS-GA溶于去离子水并加入H2O2配制成含0.025wt % H2O2的浓度为2%的CS-GA溶液；将实例1中制备的TAMP-Mg2+溶于去离子水并加入辣根过氧化物酶（HRP）配制成含0.02mg/mL HRP的浓度为2mg/mL的TAMP-Mg2+溶液；再将等体积的含有H2O2的CS-GA溶液、含有HRP的TAMP-Mg2+溶液混合，即可在50.39±1.123 s形成CS-GA/TAMP-Mg2+ 2水凝胶。
实施例4 制备CS-GA/TAMP-Mg2+ 3水凝胶。
将实施例1中制备的CS-GA溶于去离子水并加入H2O2配制成含0.025wt % H2O2的浓度为2%的CS-GA溶液；将实例1中制备的TAMP-Mg2+溶于去离子水并加入辣根过氧化物酶（HRP）配制成含0.02mg/mL HRP的浓度为3mg/mL的TAMP-Mg2+溶液；再将等体积的含有H2O2的CS-GA溶液、含有HRP的TAMP-Mg2+溶液混合，即可在130.8±3.135 s形成CS-GA/TAMP-Mg2+ 3水凝胶。
实施例5 CS-GA/TAMP-Mg2+水凝胶的光热性能
将实施例2~4制备好的1.0mL各组水凝胶放入1×1×4.5cm的石英比色管中，在0.5W/cm2功率设置下，用808 nm近红外激光照射10min，使用红外热像仪每隔30s测试凝胶样品的温度。
还研究了不同功率密度(0.5、0.75、和1.0 W/cm2)的808 nm激光辐照下实施例3制备的水凝胶温度变化的影响。图2-3为不同组水凝胶的升温效果图，结果示随着TAMP-Mg2+浓度的升高和近红外光功率的升高，CS-GA/TAMP-Mg2+水凝胶所能到达的温度也越高。
实施例6 CS-GA/TAMP-Mg2+水凝胶的粘接性能
将猪牙龈、钛片切成1×1厘米的小块，将组织和钛片分别粘在两个载玻片上，然后移取25μL含有H2O2的CS-GA溶液、含有HRP的TAMP-Mg2+溶液分别涂布于牙龈、钛片表面，然后将两者附在一起使水凝胶发生交联反应，后将样品放置在力学测试仪拉伸夹头之间检测粘接强度。图4为实施例2~4水凝胶的粘接强度统计图，结果显示实施例2~4中制备的水凝胶的粘接强度分别为：63.96±13.88KPa、66.44±13.83KPa、64±12.02KPa。
实施例7 CS-GA/TAMP-Mg2+水凝胶对牙龈卟啉单胞菌（P.g.）的抗菌性
将10μL 107 CFU mL–1的P.g.菌悬液加到实施例2~4中制备的水凝胶表面后共培养10min、2 h后，每孔加入灭菌培养基1 mL，充分接触后，吸10μL加入另一孔，再加入灭菌培养基1 mL，继续培养12 ~ 24 h。用微孔板分析仪测定悬液在600 nm处的吸光度。结果如图5所示，显示实施例2~4中制备的水凝胶对P.g.有一定的抗菌效果，随着作用时间的延长，抗菌效果增加。
将10μL 107 CFU mL–1的P.g.菌悬液加到实施例3中制备的水凝胶表面后有或无NIR照射10min后共培养2 h后，每孔加入灭菌培养基1 mL，充分接触后，吸10μL加入另一孔，再加入灭菌培养基1 mL，继续培养12~24 h。用微孔板分析仪测定悬液在600 nm处的吸光度。结果如图6所示，显示NIR照射可以提高实施例3中制备的水凝胶对P.g.的抗菌效果。
综上所述，本发明制得的多功能可注射粘性CS-GA/TAMP-Mg2+水凝胶可在不同功率的808nm近红外光照射不同的时间的情况下产生不同的作用。而且，该水凝胶可精确的作用于种植体周围炎的病变部位，为高效地治疗种植体周围炎提供了一种有潜力的方法；且此种水凝胶也适用于其他类似的需抗菌、抗炎的病变部位。
以上所述的实施例仅仅是对本发明的优选实施方式进行描述，并非对本发明的范围进行限定，在不脱离本发明设计精神的前提下，本领域普通技术人员对本发明的技术方案作出的各种变形和改进，均应落入本发明权利要求书确定的保护范围内。
Claims (5)
1.一种含载Mg2+单宁酸微粒子的没食子酸接枝壳聚糖水凝胶的制备方法，其特征在于，包括以下步骤：
（1）在氮气保护下，按壳聚糖重复单元和1-羟基苯并三氮唑的摩尔比为1:1的比例将壳聚糖与1-羟基苯并三氮唑混合溶解于去离子水中, 搅拌过夜直至形成透明溶液；再向得到的溶液中加入与壳聚糖重复单元的摩尔比为1:1~5的没食子酸；待没食子酸充分溶解后边搅拌边逐滴加入1-(3-二甲氨基丙基)-3-乙基碳二亚胺的乙醇溶液，反应12~36小时后向反应产物中滴加0.1mol/L盐酸至体系澄清，再将其透析72小时并真空冷冻干燥，得到没食子酸接枝壳聚糖共聚物；
（2）将2 mL氨水、40 mL乙醇与90 mL去离子水混合，室温下搅拌0.5 h；然后向上述反应物加入10ml含4g单宁酸的水溶液，搅拌12 h，然后加入氯化镁，继续搅拌12~36h；然后通过离心洗涤分离形成的固体产物；最后收集固体产物，冷冻干燥得到载Mg2+单宁酸微粒子；
（3）将没食子酸接枝壳聚糖溶于去离子水并加入H2O2配制成含0.025-0.1 wt % H2O2的浓度为1%~4%的没食子酸接枝壳聚糖溶液；将载Mg2+单宁酸微粒子溶于去离子水并加入辣根过氧化物酶配制成含0.005-0.1 mg/mL 辣根过氧化物酶的浓度为1~5mg/mL的载Mg2+单宁酸微粒子溶液；将等体积的含有H2O2的没食子酸接枝壳聚糖溶液、含有辣根过氧化物酶的载Mg2+单宁酸微粒子溶液混合，形成含载Mg2+单宁酸微粒子的没食子酸接枝壳聚糖水凝胶。
2.根据权利要求1所述的含载Mg2+单宁酸微粒子的没食子酸接枝壳聚糖水凝胶的制备方法，其特征在于：1-(3-二甲氨基丙基)-3-乙基碳二亚胺与没食子酸摩尔的质量比为1:1。
3.根据权利要求1所述的含载Mg2+单宁酸微粒子的没食子酸接枝壳聚糖水凝胶的制备方法，其特征在于：所述氯化镁与单宁酸的摩尔质量比为1：1~30。
4.权利要求1-3任一所述制备方法制得的含载Mg2+单宁酸微粒子的没食子酸接枝壳聚糖水凝胶。
5.权利要求4所述含载Mg2+单宁酸微粒子的没食子酸接枝壳聚糖水凝胶在制备种植体周围炎相关药物中的应用。
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