CN110522947A - 一种4d-壳聚糖温敏凝胶制备方法 - Google Patents

一种4d-壳聚糖温敏凝胶制备方法 Download PDF

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CN110522947A
CN110522947A CN201910871003.5A CN201910871003A CN110522947A CN 110522947 A CN110522947 A CN 110522947A CN 201910871003 A CN201910871003 A CN 201910871003A CN 110522947 A CN110522947 A CN 110522947A
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chitosan
sensitive gel
thermo
aqueous solution
sodium
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CN110522947B (zh
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徐文华
董妍涵
张丽霞
樊雨乔
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Qingdao University
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Qingdao University
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Priority to CN201910871003.5A priority Critical patent/CN110522947B/zh
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Priority to AU2020100879A priority patent/AU2020100879A4/en
Priority to ZA2020/03401A priority patent/ZA202003401B/en
Priority to RU2020124839A priority patent/RU2805920C2/ru
Priority to NL2026161A priority patent/NL2026161B1/en
Priority to US16/984,626 priority patent/US20210079170A1/en
Priority to NZ766841A priority patent/NZ766841A/en
Priority to GB2012940.9A priority patent/GB2589682A/en
Priority to JP2020138653A priority patent/JP2021045537A/ja
Priority to CA3091199A priority patent/CA3091199A1/en
Priority to CH01085/20A priority patent/CH716648A2/de
Priority to DE102020123424.4A priority patent/DE102020123424A1/de
Priority to BE20205640A priority patent/BE1027544B9/de
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Abstract

本发明属于医用材料生产制备技术领域，涉及一种4D‑壳聚糖温敏凝胶制备方法，首先将壳聚糖溶于乙酸水溶液中，采用4D生物打印机打印壳聚糖温敏凝胶，抽除溶剂后冷冻干燥，得到冷冻干燥的壳聚糖，然后用超纯水和β‑甘油磷酸钠制备β‑甘油磷酸钠水溶液，再用超纯水配制的羧甲基壳聚糖水溶液和β‑甘油磷酸钠水溶液加入羧甲基壳聚糖水溶液中并混合均匀制备混合液，最后冷冻干燥的壳聚糖与混合液交联得到4D‑壳聚糖温敏凝胶；其原理科学可靠，解决了传统壳聚糖温敏凝胶孔径大小不一的问题，提高了角膜缘干细胞的包载效率和能力，在角膜损伤修复领域具有重要的理论意义和广阔的应用前景，为临床医学上修复角膜碱烧伤患者提供帮助。

Description

一种4D-壳聚糖温敏凝胶制备方法
技术领域：
本发明属于医用材料生产制备技术领域，涉及一种4D-壳聚糖温敏凝胶制备方法，基于4D打印技术制备用于修复碱烧伤的壳聚糖温敏凝胶。
背景技术：
角膜损伤种类繁多，其中化学损伤在临床上治疗难度较大。角膜碱烧伤是较为严重的化学性损伤，可导致角膜上皮坏死、脱落，角结膜融解穿孔及睑球粘连等，同时伴随大量的新生毛细血管的生成，严重可致角膜盲的形成。目前临床上主要以角膜移植或羊膜移植来治疗，但是前者面临着供体缺乏和免疫排斥两大问题；后者作为一种基底膜，在严重角膜损伤如碱烧伤后，易被损伤组织中聚积的胶原酶降解导致自溶，患者即使多次移植效果仍不佳，所以如何修复角膜上皮缺损及减少角膜新生血管和瘢痕的形成是临床亟待解决的难题。
组织工程方法制备的生物凝胶转载角膜缘干细胞对角膜损伤的修复有一定的效果，但是由于电镜扫描凝胶表面呈现不规则的网状结构，孔径大小不一，直接影响角膜缘干细胞的包载效率。例如：中国专利201610837528.3公开的一种替米考星包合物壳聚糖温敏凝胶的制备方法包括以下步骤：(1)称取壳聚糖溶于0.1mol/L盐酸中，充分搅拌至完全溶解，得浓度为10-20mg/mL壳聚糖溶液，将甘油磷酸钠溶于去离子水中，得浓度为0.2-1.0g/mL甘油磷酸钠溶液，将甘油磷酸钠溶液滴加至壳聚糖溶液中混合，调节混合溶液pH至7.1-7.4，然后将混合溶液于4℃搅拌均匀，得壳聚糖温敏凝胶；(2)称取HP-β-CD于研钵中，按照水与HP-β-CD质量比2-5:1的比例称取水将其溶解，按照HP-β-CD与替米考星质量比2:1的比例称取替米考星于研钵中，在20℃温度下混合研磨30min，得到白色粉状物，过80目筛，即得替米考星包合物；(3)将步骤(1)中得到的壳聚糖温敏凝胶加入锥形瓶中，称取步骤(2)得到的替米考星包合物于锥形瓶中，常温下于磁力搅拌器搅拌均匀，即得替米考星包合物温敏凝胶，所述替米考星包合物温敏凝胶中替米考星药物的质量分数为9.9％-10％，替米考星包合物温敏凝胶在4℃保存。
2013年2月25号，在美国加州举办的TED 2013大会上，来自美国麻省理工学院的斯凯拉·蒂比茨展示了4D打印技术，并且是通过一个完整的实验向与会者展示的，并借助实验加以阐述。所谓的4D打印，准确地说是一种能够自动变形的材料，只需特定条件(如温度、湿度等)，不需要连接任何复杂的机电设备，就能按照产品设计自动折叠成相应的形状。4D打印是一种通过3D打印机，打印用变形材料的技术。4D打印技术已经被引入凝胶制备技术领域：中国专利201810208715.4公开的一种可编程变形的强韧水凝胶的4D打印方法包括以下步骤：(1)将丙烯酰胺和丙烯酸混合溶液加入温度引发剂及促引发剂后，置于保温箱中保温，得到聚(丙烯酸-co-丙烯酰胺)共聚物溶液；(2)将丙烯酸和N-异丙基丙烯酰胺混合溶液加入温度引发剂及促引发剂后，置于保温箱中保温，得到聚(丙烯酸-co-N-异丙基丙烯酰胺)共聚物溶液；(3)将聚(丙烯酸-co-丙烯酰胺)共聚物溶液与聚(丙烯酸-co-N-异丙基丙烯酰胺)共聚物溶液混合，得到两种比例的聚(丙烯酸-co-丙烯酰胺)与聚(丙烯酸-co-N-异丙基丙烯酰胺)混合的溶液，其中，聚(丙烯酸-co-N-异丙基丙烯酰胺)组分偏高的作为盐敏材料来驱动变形，而另一种作为聚(丙烯酸-co-丙烯酰胺)溶液与盐敏混合溶液的粘结剂；(4)使用3D打印平台，将聚(丙烯酸-co-丙烯酰胺)以及聚(丙烯酸-co-丙烯酰胺)与聚(丙烯酸-co-N-异丙基丙烯酰胺)混合溶液按照预先设置的打印参数分别挤出到玻璃基板上形成特定的形状结构；(5)将打印得到的形状结构放入恒温箱中的三价铁离子溶液中进行交联，然后将浸泡过铁离子溶液后的凝胶再放入恒温箱中的去离子水溶液中进一步交联得到平衡态凝胶结构；(6)将平衡态凝胶结构放入浓盐水中变形得到预先设计的形状结构；中国专利201810280579.X公开的一种温度驱动可编程4D打印智能材料的制备方法的步骤如下：一、高密度值4D智能温敏型水凝胶材料的制备a)高密度值4D智能温敏型水凝胶的原始材料的组成：以N-异丙基丙烯酰胺作单体，XLG型合成硅酸镁锂作交联剂，过硫酸钾作引发剂，N,N,N’,N’-四甲基乙二胺作催化剂，纳米木浆纤维素作增强相，单体、引发剂和催化剂之间的摩尔比为100:0.370:0.638；纳米木浆纤维素的浓度为3-5mg/mL，交联剂质量分数为3-3.5wt.％；b)配料：按照a中所述的配料比称取原始材料，在冰水浴条件下将纳米木浆纤维素搅拌30-40分钟，随后超声处理10-15分钟；随后加入XLG型合成硅酸镁锂，搅拌60-65分钟；然后加入N-异丙基丙烯酰胺并搅拌120-130分钟；最后依次加入过硫酸钾和N,N,N’,N’-四甲基乙二胺，搅拌5-6分钟；c)将b中混合均匀后的材料注入组合模具中，刮平后将模具密封密封，并置于25-27℃环境下静置24-26小时成型；二、温度驱动可编程4D打印智能材料的合成a)低密度值4D智能温敏型水凝胶的原始材料的组成：以N-异丙基丙烯酰胺作单体，XLG型合成硅酸镁锂作交联剂，过硫酸钾作引发剂，N,N,N’,N’-四甲基乙二胺作催化剂，纳米木浆纤维素作增强相，单体、引发剂和催化剂之间的摩尔比为100:0.370:0.638；纳米木浆纤维素的浓度为0-2mg/mL，交联剂质量分数为3-3.5wt.％；b)配料：按照a中所述的配料比称取原始材料，在冰水浴条件下将纳米木浆纤维素搅拌30-40分钟，随后超声处理10-15分钟；随后加入XLG型合成硅酸镁锂，搅拌60-65分钟；然后加入N-异丙基丙烯酰胺并搅拌120-130分钟；最后依次加入过硫酸钾和N,N,N’,N’-四甲基乙二胺，搅拌5-6分钟；c)将b中混合均匀后的低密度值4D智能温敏型水凝胶材料注入组合模具中，置于高密度值4D智能温敏型水凝胶的上方，刮平后将模具密封，并置于25-27℃环境下静置24-26小时成型，至此成功制备出了温度驱动可编程4D打印智能材料；中国专利201910141257.1公开的一种4D打印自愈合水凝胶材料的制备方法按以下步骤进行：一、合成CD-丙烯酰胺：将侧基被氨基取代的环糊精类物质溶解于弱碱性溶液中并将溶液的pH值用碱性无机物调节为8-10，再加入酸酐类物质，在40-80℃的条件下搅拌4-8h，再将溶液中的水分蒸发掉90-95％，再加入有机溶剂Ⅰ洗涤，离心分离，收集沉淀，真空干燥，得到CD-丙烯酰胺；其中步骤一中的侧基被氨基取代的环糊精类物质为6-氨基-a-CD、3-氨基-a-CD或6-氨基-β-CD；二、合成偶氮丙烯酰胺：将偶氮苯类物质和胺类物质溶于有机溶剂Ⅱ中，然后升温至20-50℃，加入酸酐类物质，得到混合溶液；再将混合溶液在60-65℃的条件下搅拌3-5h，过滤，除去沉淀，将滤液减压浓缩，再用有机溶剂Ⅲ重结晶，得到偶氮丙烯酰胺；其中偶氮苯类物质为对氨基偶氮苯或聚酰亚胺偶氮苯；胺类物质为三羟乙基胺或三乙胺；三、自由基聚合合成凝胶：将可自由基聚合的单体、步骤一得到的CD-丙烯酰胺、步骤二得到的偶氮丙烯酰胺和增强链刚性的单体加入有机溶剂Ⅳ中，搅拌均匀后，加热到60-80℃加入引发剂，在60-80℃的条件下搅拌反应15-20h后，停止搅拌，接着在60-65℃的条件下保温1-5h，得到4D打印自愈合水凝胶材料；其中可自由基聚合的单体为丙烯酸、丙烯酰胺或丙烯酸甲酯；增强链刚性的单体为N-乙烯基咔唑或苯乙烯。因此，研发一种4D-壳聚糖温敏凝胶制备方法，以提高对角膜缘干细胞的包载效率，具有很高的社会意义及实用价值。
发明内容：
本发明的目的在于克服现有技术存在的缺点，研发设计一种4D-壳聚糖温敏凝胶制备方法，制备能够有效提高角膜缘干细胞包载效率，促进碱烧伤角膜上皮重建的4D-壳聚糖温敏凝胶。
为了实现上述目的，本发明涉及的4D-壳聚糖温敏凝胶制备方法的工艺过程包括以下步骤：
(1)在室温条件下，称取壳聚糖溶于乙酸水溶液中，搅拌至壳聚糖完全溶解，得到壳聚糖溶液，采用4D生物打印机按照设定的打印参数将壳聚糖溶液打印成孔径为50-100μm的壳聚糖温敏凝胶，并使壳聚糖温敏凝胶形成设定的形状结构，抽除溶剂后冷冻干燥，得到冷冻干燥的壳聚糖；
(2)在60-70℃的水浴锅中加入超纯水和β-甘油磷酸钠，待β-甘油磷酸钠溶解后，自然冷却至室温，得到β-甘油磷酸钠水溶液；
(3)在室温条件下用超纯水配制羧甲基壳聚糖水溶液，将步骤(2)得到的β-甘油磷酸钠水溶液逐滴加入羧甲基壳聚糖水溶液中并混合均匀，得到混合液；
(4)将步骤(1)得到的冷冻干燥的壳聚糖与步骤(3)得到的混合液交联1-2分钟，得到孔径大小均一的4D-壳聚糖温敏凝胶。
本发明步骤(1)涉及的乙酸水溶液的摩尔浓度为0.2Mol/L，壳聚糖溶液的质量百分比浓度为2.2-6.7％；步骤(2)得到的β-甘油磷酸钠水溶液的质量百分比浓度为6-8％；步骤(3)配制的羧甲基壳聚糖水溶液的质量百分比浓度为2.2-6.7％；步骤(4)制备的4D-壳聚糖温敏凝胶中壳聚糖、羧甲基壳聚糖和β-甘油磷酸钠的重量百分比分别为：10-30％、10-30％和60-80％。
本发明制备的4D-壳聚糖温敏凝胶能够在4-15℃的无菌环境中保存6-12个月。
本发明制备的4D-壳聚糖温敏凝胶包载角膜缘干细胞后贴敷于碱烧伤的角膜表面，释放角膜缘干细胞对创面进行修复和治疗。
本发明与现有技术相比，将4D生物打印技术应用于壳聚糖温敏凝胶的制备，制备的孔径大小一致的壳聚糖温敏凝胶作为角膜缘干细胞的移植载体，能够有效提高对角膜缘干细胞的包载效率，促进碱烧伤角膜上皮的重建；其原理科学可靠，解决了传统壳聚糖温敏凝胶孔径大小不一的问题，提高了角膜缘干细胞的包载效率和能力，在角膜损伤修复领域具有重要的理论意义和广阔的应用前景，为临床医学上修复角膜碱烧伤患者提供帮助。
附图说明：
图1为本发明实施例1步骤(1)涉及的壳聚糖的结构示意图。
图2为本发明实施例1步骤(4)涉及的4D-壳聚糖温敏凝胶的结构示意图。
图3为本发明实施例2涉及的40倍镜下4D-壳聚糖温敏凝胶包载角膜缘干细胞的状态示意图。
图4为本发明实施例2涉及的10倍镜下4D-壳聚糖温敏凝胶包载角膜缘干细胞的状态示意图。
图5为本发明实施例3涉及的传统温敏凝胶包载角膜缘干细胞和4D-壳聚糖温敏凝胶包载角膜缘干细胞治疗兔子角膜碱烧伤的效果对比示意图。
具体实施方式：
下面通过实施例并结合附图对本发明作进一步说明。
实施例1：
本实施例涉及的4D-壳聚糖温敏凝胶制备方法包括以下步骤：
(1)在室温条件下，称取壳聚糖溶于摩尔浓度为0.2Mol/L的乙酸水溶液中，搅拌12小时至壳聚糖完全溶解，得到质量百分比浓度为4.4％的壳聚糖溶液，采用UN-4DBI-C01型4D生物打印机按照打印参数：孔间距为600μm，层厚为100μm，平台温度为-25℃，打印速度为15mm/s，喷嘴直径为0.3mm，出料量为0.1g/min，将壳聚糖溶液打印成孔径为50-100μm的圆形壳聚糖温敏凝胶，抽除溶剂后冷冻干燥，得到冷冻干燥的壳聚糖，如图1所示；
(2)在65℃的水浴锅中加入超纯水和β-甘油磷酸钠，待β-甘油磷酸钠溶解后，自然冷却至室温，得到质量百分比浓度为7％的β-甘油磷酸钠水溶液；
(3)在室温条件下用超纯水配制质量百分比浓度为4.4％的羧甲基壳聚糖水溶液，将步骤(2)得到的β-甘油磷酸钠水溶液逐滴加入羧甲基壳聚糖水溶液中并混合均匀，得到混合液；
(4)将步骤(1)得到的冷冻干燥的壳聚糖与步骤(3)得到的混合液交联1-2分钟，得到如图2所示的孔径大小均一的4D-壳聚糖温敏凝胶，4D-壳聚糖温敏凝胶中壳聚糖、羧甲基壳聚糖和β-甘油磷酸钠的重量百分比分别为：18％、18％和64％。
实施例2：
本实施例涉及实施例1制备的4D-壳聚糖温敏凝胶包载角膜缘干细胞的过程：
(1)将4D-壳聚糖温敏凝胶放入细胞培养皿中充分浸润，得到待包载的4D-壳聚糖温敏凝胶；
(2)分离培养角膜缘干细胞并加入步骤(1)得到的待包载的4D-壳聚糖温敏凝胶中，继续培养；
(3)培养24h后分别在显微镜40倍镜和10倍镜下观察4D-壳聚糖温敏凝胶包载角膜缘干细胞的状态，如图3和图4所示。
实施例3：
本实施例涉及4D-壳聚糖温敏凝胶与传统温敏凝胶包载角膜缘干细胞治疗兔子角膜碱烧伤效果的对比试验：
(1)将活体兔子的眼角膜进行碱烧伤，得到碱烧伤动物模型；
(2)利用传统温敏凝胶包载角膜缘干细胞对步骤(1)得到的碱烧伤动物模型进行治疗，得到传统温敏凝胶治疗模型；
(3)利用实施例1制备的4D-壳聚糖温敏凝胶包载角膜缘干细胞对步骤(1)得到的碱烧伤动物模型进行治疗，得到4D-壳聚糖温敏凝胶治疗模型；
(4)治疗28天后分别观察二者的治疗效果，如图5所示，碱烧伤手术后，随着时间的推移，各分组角膜损伤面积(图中白色区域)都逐渐减少，其中，4D-壳聚糖温敏凝胶治疗组的修复效果明显优于传统温敏凝胶治疗组和不修复组的修复效果。

Claims (7)

1.一种4D-壳聚糖温敏凝胶制备方法，其特征在于工艺包括以下步骤：
(1)在室温条件下，称取壳聚糖溶于乙酸水溶液中，搅拌至壳聚糖完全溶解，得到壳聚糖溶液，采用4D生物打印机按照设定的打印参数将壳聚糖溶液打印成孔径为50-100μm的壳聚糖温敏凝胶，并使壳聚糖温敏凝胶形成设定的形状结构，抽除溶剂后冷冻干燥，得到冷冻干燥的壳聚糖；
(2)在60-70℃的水浴锅中加入超纯水和β-甘油磷酸钠，待β-甘油磷酸钠溶解后，自然冷却至室温，得到β-甘油磷酸钠水溶液；
(3)在室温条件下用超纯水配制羧甲基壳聚糖水溶液，将步骤(2)得到的β-甘油磷酸钠水溶液逐滴加入羧甲基壳聚糖水溶液中并混合均匀，得到混合液；
(4)将步骤(1)得到的冷冻干燥的壳聚糖与步骤(3)得到的混合液交联1-2分钟，得到孔径大小均一的4D-壳聚糖温敏凝胶。
2.根据权利要求1所述的4D-壳聚糖温敏凝胶制备方法，其特征在于步骤(1)涉及的乙酸水溶液的摩尔浓度为0.2Mol/L，壳聚糖溶液的质量百分比浓度为2.2-6.7％。
3.根据权利要求1所述的4D-壳聚糖温敏凝胶制备方法，其特征在于步骤(2)得到的β-甘油磷酸钠水溶液的质量百分比浓度为6-8％。
4.根据权利要求1所述的4D-壳聚糖温敏凝胶制备方法，其特征在于步骤(3)配制的羧甲基壳聚糖水溶液的质量百分比浓度为2.2-6.7％。
5.根据权利要求1所述的4D-壳聚糖温敏凝胶制备方法，其特征在于步骤(4)制备的4D-壳聚糖温敏凝胶中壳聚糖、羧甲基壳聚糖和β-甘油磷酸钠的重量百分比分别为：10-30％、10-30％和60-80％。
6.根据权利要求1-5所述的4D-壳聚糖温敏凝胶制备方法，其特征在于4D-壳聚糖温敏凝胶能够在4-15℃的无菌环境中保存6-12个月。
7.根据权利要求1-5所述的4D-壳聚糖温敏凝胶制备方法，其特征在于4D-壳聚糖温敏凝胶包载角膜缘干细胞后贴敷于碱烧伤的角膜表面，释放角膜缘干细胞对创面进行修复和治疗。
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