CN115581796A - 一种缓释bmsc的光响应抗菌水凝胶的制备方法 - Google Patents
一种缓释bmsc的光响应抗菌水凝胶的制备方法 Download PDFInfo
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Abstract
本发明公开了一种缓释BMSC的光响应性抗菌水凝胶的制备方法,该水凝胶以十二烷基壳聚糖与联吡啶钌交联后,再将骨髓间充质干细胞附着于交联所得水凝胶表面,等待细胞的自动附着即得,在无光线情况下,本发明的水凝胶将伤口封闭形成屏障,发挥天然抑菌作用,防止外来细菌入侵。同时作为一种3D的水凝胶材料可以缓慢释放BMSC,由于BMSC自身的归巢作用,靶向损伤部位进行修复,并且BMSC释放的生长因子等物质具有优良的抗炎作用和促进新生血管生成的作用,可快速修复受损部位。同时,在光照条件下,水凝胶光致脱落后的RuB2A发挥了抗菌作用,并伴随着水凝胶的降解反应。
Description
技术领域
本发明属于生物技术领域,具体涉及一种缓释BMSC的光响应性抗菌水凝胶的制备方法。
背景技术
口腔疾病是全球最普遍的疾病之一。其中,口腔粘膜疾病为一系列由炎症性坏死组织脱落引起,从而影响口腔粘膜及软组织的病症,包括以复发性口疮为代表的口腔粘膜溃疡性病变,严重影响患者的生活质量。口腔溃疡的成因是复杂的,比如口腔微生物群失衡,糖尿病引起的并发症。然而,一方面口腔溃疡的种类众多,致病的确切因素尚不明确,另一方面受口腔的动态环境影响,有效的治疗方法很少。目前市场常见的治疗口腔溃疡的产品是以透明质酸作为水凝胶或漱口液,与其他具有愈合舒缓特性的物质组合而成的。传统的制剂容易伴随着舌头搅动和唾液吞咽,在口腔保留的时间较短。由于光动力疗法(PTD)具有广谱抗菌作用和促进伤口愈合的潜力,PTD对局部和表层感染的治疗效果良好,十分适合用于治疗口腔溃疡。最近的研究表明光敏剂吲哚菁绿介导的PDT治疗可以加速大鼠口腔内的创伤性口腔溃疡愈合。
伤口愈合会经历止血,炎症,增殖和伤口组织结构重塑的连续过程,涉及到多种细胞和各种生物过程。因此能够快速止血且抗菌抗炎的伤口敷料对于伤口愈合和促进肉芽组织生成十分重要。如今,已经开发了多种止血材料,比如聚乙二醇、壳聚糖、纳米粘土。另外,炎症反应往往伴随着止血过程,抗氧化、抗菌、调节免疫和血管生成都可以起到抗炎作用。有趣的是,水凝胶在多项研究中被证明有良好的生物相容性,可用于止血、抗菌和药物递送,并且由于其粘附力低,可以避免从伤口去除时引起患者继发性疼痛。此外,炎症反应会影响组织结构再生,并且由各种细胞因子和生长因子调节。在伤口愈合过程中,减少促炎细胞因子的增加(白细胞介素-6)和促进血小板内皮细胞的增殖(CD31)会减少病理性疼痛,加速伤口愈合。如CN111494702B公开了一种抗菌水凝胶及其制备方法与应用,水凝胶由甲基丙烯酸化壳聚糖和抗菌微球制成,所述抗菌微球为负载有纳米银的海藻酸钠微球,将纳米银负载到海藻酸钠微球中,实现了纳米银的缓慢释放。同时,将负载纳米银的海藻酸钠微球加入甲基丙烯酸化壳聚糖水凝胶中形成含微球的抗菌水凝胶,大大提高了材料的抗菌性能和降低了纳米银的细胞毒性,使纳米银的释放周期长达10天以上。该抗菌水凝胶安全无毒,抗菌性能好,表现出合适的溶胀和降解行为,具有优异的生物相容性和力学性能,可生物降解和生物吸收,还具有可注射性和止血功能,但该水凝胶在促进伤口愈合方面效果不显著,且难以适用于口腔伤口。又如CN108367100A公开了一种制备水凝胶的方法,包括将聚合物溶液与光引发剂混合,然后用可见光照射混合物以生成水凝胶,所述聚合物可以为壳聚糖,所述光引发剂是在用可见光照射时产生自由基物质以使聚合物链交联的任何合适的化合物或化合物的混合物。一种类型的光引发剂是钌(II)化合物和过硫酸钠、过硫酸铵或过硫酸钾的组合。钌(II)化合物的一个例子是三(2,2-联吡啶基)-二氯钌(II)六水合物。但该水凝胶在促进伤口愈合方面效果不显著。
现有技术中,以水凝胶做医用敷料的技术多未考虑口腔环境的因素,口腔始终处于潮湿、黑暗的环境中,口腔内有很多微生物,因此口腔内的伤口修复不同于皮肤表面的伤口。口腔黏膜创面修复材料必须具有一定的粘附性和抗菌性,此外,还要考虑材料本身的毒性,以及进入胃肠道的降解性和生物相容性问题,因此这给用于治疗口腔黏膜缺损、促进伤口修复的功能性水凝胶制备提出了技术挑战。
发明内容
本发明基于通过外源光进行光化学操纵的功能聚合物在材料科学中具有巨大的前景,本发明采用壳聚糖和光交联剂联吡啶钌合成光响应性水凝胶,在可见光照射后吡啶醛基团脱落,此时的联吡啶钌在潮湿环境中发挥杀菌作用。聚合物系统对材料特性(如储能模量和孔隙率)提供更大的时空控制,以及在生物医学应用中调节药物递送曲线和细胞功能。因此,这种光响应水凝胶可视为一种良好的干细胞呈递系统,在黑暗条件下,该材料无杀灭作用,其3D结构有利于负载骨髓间充质干细胞(BMSC)的生长和缓释,这种能够呈递BMSC的光响应性抗菌水凝胶在口腔黏膜创面修复中具有广阔的应用前景。为达到上述目的,本发明采用如下发明构思:
本发明首先以壳聚糖(CS)为水凝胶的基础,用十二醛取代氨基得到十二烷基壳聚糖(DCS),原料摩尔比设定为1:0.4,以达到DCS的最佳止血性能。在氩气保护下Ru(bpy)2Cl2溶液于-80℃回流5h,然后用3-吡啶甲醛置换氯离子,分离蒸干并纯化得到棕红色固体,溶解在水中得到Ru(bipyridine)2(3-pyridinecarboxaldehyde)2,计为RuB2A2(B为2,2'-联吡啶,A为3-吡啶甲醛)。在酸性条件下,DCS与RuB2A2发生席夫碱交联反应,形成致密的网络状凝胶。DCS和RuB2A2交联形成的酰胺键大大提高了凝胶的性能。在光照下,3-吡啶甲醛脱落,DCS-RuB2A2水凝胶分解,DCS和RuB2A/RuB2独立作用。DCS的十二烷基锚定细菌外膜,然后释放的RuB2A/RuB2附着在细胞表面,引起细胞通透性改变,导致细胞成分逸出,干扰酶在细胞代谢中的作用。同时,RuB2A/RuB2破膜能对DNA造成损伤,从而起到杀菌作用。DCS-RuB2A2-BMSC用作治疗口腔黏膜缺损的敷料时,水凝胶首先附着于创面,DCS迅速止血并聚集血小板。在黑暗条件下,水凝胶缓慢释放BMSC,BMSC微环境中的细胞因子发挥抗炎作用,同时促进新血管的形成。待BMSC缓慢释放到创面环境后,用光源照射水凝胶发挥抗菌作用。
根据上述发明构思,本发明采用如下技术方案:
一种缓释BMSC的光响应抑菌性水凝胶是以十二烷基壳聚糖与联吡啶钌在黑暗条件下交联后,制得DCS-RuB2A2水凝胶,再将BMSC附着于DCS-RuB2A2水凝胶表面,等待细胞的自动附着,即得DCS-RuB2A2-BMSC水凝胶。
一种缓释BMSC的光响应抑菌性水凝胶的制备方法,包括如下步骤:
第一步制备RuB2A2
(1)将Ru(bpy)2Cl2溶解在水中,制得溶液A,在氩气保护下将溶液A在-80℃下回流反应5小时;
(2)将3-吡啶甲醛溶解在乙醇中,制得溶液B,然后将溶液B缓慢滴加到步骤(1)的回流反应中,并将反应回流过夜;
(3)反应结束后,旋出乙醇,冷却至室温,加入NH4PF6,用二氯甲烷(DCM)萃取,取下层有机相,硫酸镁干燥,过滤,蒸干溶剂,得棕红色固体;
(4)利用DCM:甲醇=6:1作为洗脱液进行硅胶色谱柱分离,去除过量的3-吡啶甲醛,收集纯橙红色溶液;
(5)蒸干溶剂,以甲醇为溶剂,通过氯离子交换柱,蒸干甲醇,最终产物为棕红色固体RuB2A2;所述RuB2A2中B为2,2'-联吡啶,A为3-吡啶甲醛;
第二步十二烷基取代壳聚糖
(6)将壳聚糖(CS)加入到乙酸水溶液中,室温下搅拌溶解,制得壳聚糖溶液;
(7)将十二醛溶解在乙醇中制得溶液C,然后将溶液C加入到壳聚糖溶液中,不断搅拌直至溶解,制得混合物溶液D;
(8)按照NaBH4:CS=3:1的摩尔比将硼氢化钠溶液滴加到步骤(7)所得的混合物溶液D中,室温搅拌至溶解,制得十二烷基取代壳聚糖(DCS)溶液;
第三步DCS与RuB2A2交联
(9)用70%-100%乙醇洗涤沉淀的DCS至少三次,冷冻干燥至恒重;
(10)将DCS粉末用1%乙酸溶解制得DCS乙酸溶液,并将步骤(5)中的RuB2A2用水溶解制得RuB2A2溶液,在黑暗条件下将RuB2A2溶液滴加到DCS乙酸溶液中,并在酸性条件下交联,即得光响应抗菌水凝胶。
第三步负载骨髓间充质干细胞(BMSC)
(11)在黑暗条件下,将BMSC附着于步骤(10)合成的水凝胶表面,等待细胞的自动附着,即得缓释BMSC的光响应抑菌性水凝胶。
步骤(1)所述溶液A中Ru(bpy)2Cl2的质量浓度为0.412mmol。
步骤(2)所述溶液B中3-吡啶甲醛的质量浓度为2.472mmol。
步骤(6)所述壳聚糖溶液中壳聚糖的质量浓度为0.124mol/L。
步骤(7)所述混合物溶液D中壳聚糖中氨基与十二醛中的醛基摩尔比为1:0.1-0.8;优选1:0.4。
步骤(8)中所述硼氢化钠溶液为还原剂,是将硼氢化钠粉末溶解于水中而得;所述硼氢化钠溶液的滴加速度为200μL/min。
步骤(10)中所述RuB2A2溶液的滴加速度为200μL/min,浓度为≤0.125mg/mL。
步骤(11)呈递间充质干细胞,这里使用的是骨髓间充质干细胞。实际情况中不限于骨髓来源,包括牙源干细胞,脂肪间充质干细胞等都起到类似效果。
所述的光响应抑菌性水凝胶在制备伤口敷料或者细胞呈递药物中的应用。
本发明与现有技术相比较,具有如下显而易见的突出实质性特点和显著优点:
在无光情况下,本发明的水凝胶将伤口封闭形成屏障,发挥天然抑菌作用,防止外来细菌入侵。同时作为一种3D的水凝胶材料可以缓慢释放BMSC,由于BMSC自身的归巢作用,靶向损伤部位进行修复,并且BMSC释放的生长因子等物质具有优良的抗炎作用和促进新生血管生成的作用,可快速修复受损部位。同时,在光照条件下,水凝胶光致脱落后的RuB2A发挥了抗菌作用,并伴随着水凝胶的降解反应。具体来说:
1、本发明的水凝胶具有良好的止血和凝血作用,可激活血小板促进伤口愈合;以十二烷基壳聚糖为基础,疏松多孔,使用钌联吡啶交联DCS构建了光响应抗菌系统。这种钌交联聚合物体系在黑暗条件下具有较大的储能模量和孔隙率,适合BMSC的呈递和释放,进而使得干细胞呈递系统具有湿润、柔软、立体培养的特点,有利于伤口处生长因子和细胞因子的释放。
2、本发明的水凝胶具有良好的生物相容性和光谱抗菌能力;在光照一段时间后,DCS-RuB2A2中的吡啶甲醛脱离,RuB2/RuB2A脱离凝胶网络,借助DCS中长十二烷基链锚定在细菌膜上,起到了局部杀菌作用。此外,结合BMSC的抗炎促修复作用,可在短时间内修复口腔黏膜创面。因此,该水凝胶能够用作伤口敷料或者细胞呈递药物。
附图说明
图1DCS-RuB2A2-BMSC水凝胶的制备过程;
图2:CS和DCS的SEM图像;A和B为CS的SEM图,C和D为DCS的SEM图像;
图3:CS和DCS的FTIR光谱图;
图4:不同取代度DCS的FTIR光谱图;
图5:DCS-RuB2A2的照片;
图6:λex=450nm,14mW/cm2条件下100μmol/LRuB2A2水溶液的紫外-可见光谱演变;
图7:RuB2A2的紫外吸收峰对应的波长随光照时间变化,左部为第一阶段,右部为第二阶段;
图8:(K)交联剂在黑暗条件下(上)和光照后(下)光降解的HPLC分析;
图9:DCS-RuB2A2水凝胶的SEM图像;
图10:DCS-RuB2A2水凝胶的FTIR光谱;
图11:DCS-RuB2A2水凝胶的C、O和Ru元素的映射图像,从左至右为Ru、C、O;
图12:小鼠断尾后失血的照片(左)及失血直方图(右);
图13:小鼠凝血时间统计直方图(左)和止血时间统计直方图(右);
图14:RuB2A2体外处理后的大肠杆菌和金黄色葡萄球菌的SEM图像;
图15:不同浓度RuB2A2条件下,大肠杆菌(左)和金黄色葡萄球菌(右)的菌落数;
图16:各实验组大肠杆菌(左)和金黄色葡萄球菌(右)的抑菌圈面积;
图17:水凝胶对293T细胞的毒性以及相容性的影响;A、B分别为CS和不同取代度DCS处理24h、48h后细胞毒性,C、D分别为不同浓度的RuB2A2处理24h、48h后细胞毒性,E、F分别为各组处理24h、48h后细胞相容性;
图18:不同浓度RuB2A2条件下PI/Hochest培养24h的293T细胞的活细胞和死细胞染色图像和统计分析,其中n≥3,*p<0.05,**p<0.01,***p<0.001,****p<0.0001;
图19:CCK-8检测BMSC共培养后的293T细胞细胞活力图;
图20:细胞划痕法检测BMSC共培养后BMSC的细胞迁移能力图;
图21:D为BMSC共培养24h后细胞迁移能力统计分析的直方图;E-I为BMSC共培养24h后293T细胞的生长因子表达水平,其中n≥3,*p<0.05,**p<0.01,***p<0.001,****p<0.0001;
图22:大鼠口腔黏膜缺损模型构建示意图;
图23:大鼠口腔黏膜缺损的实验记录照片;
图24:8h后600nm处细菌培养的OD值;
图25:各组处理第4天大鼠创面HE、Masson染色、炎症因子IL-6和TNF-α及血管生成因子的免疫组化图像,其中n≥3,*p<0.05,**p<0.01,***p<0.001,****p<0.0001。
具体实施方式
以下结合具体的实施例子对上述方案做进一步说明,但本发明并不局限于这些实施方式,任何在本实施例基本精神上的改进或代替,仍属于本发明权利要求所要求保护的范围,本发明的优选实施例详述如下:
实施例一:联吡啶钌(计作RuB2A2,B为2,2'-联吡啶,A为3-吡啶甲醛)的合成:
在氩气保护下,将200mg(0.412mmol)Ru(bpy)2Cl2溶解在10mL水中,并在80℃下回流5小时;将264mg(2.472mmol)3-吡啶甲醛在10mL乙醇中溶解的溶液缓慢滴加到上述回流反应中,并将反应回流过夜;反应后,旋出乙醇,冷却至室温,加入1M NH4PF6,用二氯甲烷萃取,取下层有机相,硫酸镁干燥,过滤,蒸干溶剂,得棕红色固体,以DCM:甲醇=6:1作为洗脱液进行硅胶色谱柱分离,去除过量的3-吡啶甲醛,收集纯橙红色溶液。蒸干溶剂,以甲醇为溶剂,通过氯离子交换柱,蒸干甲醇,最终产物为棕红色固体。
实施例二:DCS的合成:
首先将1gCS加入50mL 2%乙酸水溶液中,室温下搅拌溶解;为了使反应更均匀,我们将一定量的十二醛(十二醛与壳聚糖的摩尔比:1:0.1、1:0.2、1:0.3、1:0.4、1:0.6、1:0.8)溶解在40mL乙醇中,然后将此溶液加入壳聚糖溶液中,不断搅拌直至溶解。然后将过量的硼氢化钠(NaBH4:CS=3:1)少量多次加入上述混合物中,室温搅拌至溶解。然后,加入适量的氢氧化钠(NaOH)溶液,将混合溶液的pH值调节至7.0,室温下搅拌过夜。第二天,沉淀的DCS用70%-100%乙醇洗涤至少三次,直到pH值为中性。最后,将沉淀物干燥,得到DCS粉末。
实施例三:DCS-RuB2A2-BMSC的构建:
取DCS粉末0.1g用1%乙酸2mL溶解制得DCS乙酸溶液,并取实施例1的RuB2A2用水溶解制得0.125mg/mL的RuB2A2溶液,在黑暗条件下将RuB2A2溶液500μL以200μL/min的速度滴加到DCS乙酸溶液中,并在酸性条件下交联,即得光响应抗菌水凝胶,计DCS-RuB2A2,呈棕红色,见图5;
然后在黑暗条件下,将BMSC附着于光响应抗菌水凝胶表面,等待细胞的自动附着,即得缓释BMSC的光响应抑菌性水凝胶。
本发明研究不同取代组DCS、CS、不同浓度RuB2A2的影响,同时设置Control组(不作任何处理),RuB2A2组,DCS-RuB2A2水凝胶(计作DCS+RuB2A2或DCS-RuB2A2)以及DCS-RuB2A2-BMSC水凝胶组(计作DCS+RuB2A2+BMSC或DCS-RuB2A2-BMSC)作为实验组,进行抑菌性能、细胞毒性、细胞相容性、止血与凝血性测试等实验,具体如下:
本发明利用十二烷基取代壳聚糖,使水凝胶兼具快速止血和协同抗菌光响应性能;经SEM分析以表征水凝胶的微观结构如图2;CS呈碎片状,表面平整光滑,孔隙较少,而DCS明显具有更多的孔隙,凝胶呈絮状,这种海绵状结构极大增强了吸附效果。CS和DCS的化学结构通过FTIR表征如图3,说明烷基成功地与CS上的氨基连接,并且基团特征峰的强度随摩尔比而变化(图4);经实验研究,CS水凝胶呈淡黄色,0.1-0.4取代度的DCS水凝胶呈透明色,0.6、0.8取代度的DCS水凝胶呈乳白色,并且DCS水凝胶结构明显较为紧密,随着取代度增加,凝胶变得疏松,类似凝胶海绵状结构。
本发明合成的光释放交联剂Ru(联吡啶)2(3-吡啶甲醛)2,使水凝胶具有可见光响应性能;RuB2A2在水中取代单个吡啶,生成RuB2A(H2O)和游离配体A,该过程发生在120s内(图6),通过分析RuB2A2的峰波长随光照时间的变化,结果表明RuB2A2的峰波长在光照120s后趋于稳定,这表明只有一个Ru-吡啶键完全光解。交联剂光降解的HPLC分析进一步证明光解产物为RuB2A(H2O)和游离配体A(图7,8)。RuB2A2中配体A的醛基在酸性或碱性条件下可与DCS的氨基发生席夫碱反应,形成更好的力学性能。这种水凝胶体系不仅保留了DCS的止血特性,还具有良好的光响应效果。经SEM表征DCS-RuB2A2水凝胶的微观结构(图9)。交联RuB2A2的水凝胶的结构明显更致密,证明此时的水凝胶具有更好的力学性能,这与图5中凝胶的可塑性和粘附性能密切相关。DCS-RuB2A2的FTIR结果如图10所示。EDX分析表明,Ru元素已成功与DCS水凝胶交联(图11)。
为确定DCS-RuB2A2水凝胶的止血特性,使用小鼠尾部的止血模型(图12中左图),由图可知,不同取代度DCS和CS组治疗尾部伤口的出血量明显少于纱布组,而DCS的止血效果优于CS。不同取代度DCS和CS的失血量和止血时间见图12和13。结果表明,随着DCS醛基取代度的增加,出血量和止血时间呈先降后逐渐上升趋势,取代度为0.4时止血效果最好。0.4DCS、0.6DCS都是被血液浸润的,类似于凝胶海绵,可吸收凝胶分子孔隙中的所有血液,从而发挥快速凝血的作用。
为探索RuB2A2的抗菌能力,使用大肠杆菌和金黄色葡萄球菌研究RuB2A2的潜在抗菌活性。RuB2A2处理后细菌表面的SEM表征明显改变,似有物体附着,部分细菌内容物出现在细胞外(图14)。这意味着RuB2A2附着在细菌的细胞膜上,改变了细胞膜通透性,释放出部分内容物,从而发挥杀灭细菌的作用。在琼脂板上添加不同浓度RuB2A2,随浓度升高,RuB2A2的抑菌能力逐渐增强,对大肠杆菌的抑制作用高于金黄色葡萄球菌(图15)。结合随后的细胞毒性试验,0.125mg/mL浓度的RuB2A2显著抑制了两种代表性细菌的生长,对细胞活力影响不大。因此,用于生物相容性和抗菌性能的水凝胶中的RuB2A2设定为0.125mg/mL。
图16为各实验组大肠杆菌(左)和金黄色葡萄球菌(右)的抑菌圈面积,其中RuB2A2(light)和0.4DCS-RuB2A2(light)指光照,其他组为非光照,DCS-RuB2A2在光照条件下对大肠杆菌和金黄色葡萄球菌(图16)的抑制作用明显大于其他组,对金黄色葡萄球菌的抑制作用更强。这表明光是DCS-RuB2A2发挥抑菌作用所必需的。
水凝胶作为伤口止血和愈合敷料,DCS-RuB2A2的生物安全性至关重要。293T人胚肾细胞是贴壁依赖型呈上皮样细胞,因此被用作体外实验中模拟口腔内上皮细胞的模型,经利用CCK-8测量细胞活力,图17表明CS和DCS都具有良好的生物相容性。RuB2A2处理组在低于0.125mg/mL浓度下的细胞毒性仍在可接受范围内。对于用不同浓度RuB2A2处理的细胞,24小时后检测细胞存活率和死细胞数(图18)显示,浓度低于0.125mg/mL的RuB2A2对细胞的杀伤作用可忽略不计。综合考虑抑菌作用和细胞毒性,认为0.125mg/mL为最佳浓度,在长期存在的条件下不仅不会对正常细胞产生过度的毒性,而且具有一定的抑菌作用。图17中DCS+RuB2A2+light指光照条件DCS-RuB2A2水凝胶,由于大部分口腔环境处于黑暗条件下,DCS-RuB2A2在非光照条件下的细胞毒性低(图17)。光照后吡啶甲醛脱落形成的RuB2A具有抗菌作用。24h后DCS-RuB2A2细胞活力均为80%-90%。证明DCS-RuB2A2具有良好的光控效果,口腔环境不会影响正常上皮细胞。
本发明将BMSC负载于DCS-RuB2A2表面,提升了水凝胶对口腔粘膜缺陷的愈合速度,同时水凝胶的疏松多孔的特性为BMSC提供了3D结构,更加有利于BMSC的生长以及细胞因子等的释放。
将BMSC与293T细胞共培养,BMSC的微环境促进上皮细胞生长、增殖和迁移。此外,受到BMSC微环境刺激后,293T细胞中TGF-β,PDGF,EGF,FGF和VEGF的mRNA的表达水平均显著提高(图21),证明BMSC可在短时间内迅速调动生长因子的表达,以促进下游信号通路的调控作用,这一机制为口腔内伤口的快速愈合提供可能。
为了确定在体内具有BMSC的光响应水凝胶的口腔闭合效果,在大鼠口腔上制造口腔粘膜缺损,用大肠杆菌和金黄色葡萄球菌建立感染,然后将制备的样品应用于伤口部位(图22)。
DCS-RuB2A2-BMSC治疗组没有炎症或感染形成的迹象。观察到新的口腔黏膜生长,导致伤口面积减少。第4天,用DCS-RuB2A2-BMSC和DCS-RuB2A2治疗的创面几乎完全愈合,口腔黏膜闭合,而对照组也有明显的口腔黏膜缺损。特别是DCS-RuB2A2-BMSC治疗组的口腔黏膜在愈合后变得非常光滑。因此从大鼠口腔黏膜修复模型的结果表明,DCS-RuB2A2-BMSC可以在4天内快速修复口腔黏膜(图23)。因此,这种负载骨髓间充质干细胞的光响应性抗菌水凝胶可用于快速伤口修复,促进临床口腔黏膜缺损治疗。
上面结合附图对本发明实施例进行了说明,但本发明不限于上述实施例,还可以根据本发明的发明创造的目的做出多种变化,凡依据本发明技术方案的精神实质和原理下做的改变、修饰、替代、组合或简化,均应为等效的置换方式,只要符合本发明的发明目的,只要不背离本发明的技术原理和发明构思,都属于本发明的保护范围。
Claims (10)
1.一种缓释BMSC的光响应抑菌性水凝胶的制备方法,其特征在于,包括如下步骤:
(1)在氩气保护下,将Ru(bpy)2Cl2溶解在水中,制得溶液A,将溶液A在-80℃下回流反应5小时;
(2)将3-吡啶甲醛溶解在乙醇中,制得溶液B,然后将溶液B缓慢滴加到步骤(1)的回流反应中,并将反应回流过夜;
(3)反应结束后,旋出乙醇,冷却至室温,加入NH4PF6,用DCM萃取,取下层有机相,硫酸镁干燥,过滤,蒸干溶剂,得棕红色固体;
(4)利用DCM:甲醇=6:1作为洗脱液进行硅胶色谱柱分离,去除过量的3-吡啶甲醛,收集纯橙红色溶液;
(5)蒸干溶剂,以甲醇为溶剂,通过氯离子交换柱,蒸干甲醇,最终产物为棕红色固体RuB2A2;所述RuB2A2中B为2,2'-联吡啶,A为3-吡啶甲醛;
(6)将壳聚糖加入乙酸水溶液中,室温下搅拌溶解,制得壳聚糖溶液;
(7)将十二醛溶解在乙醇中制得溶液C,然后将溶液C加入到壳聚糖溶液中,不断搅拌直至溶解,制得混合物溶液D;
(8)将硼氢化钠溶液滴加到步骤(7)所得的混合物溶液D中,室温搅拌至溶解,制得DCS溶液;
(9)用70%-100%乙醇洗涤沉淀的DCS至少三次,冷冻干燥至恒重;
(10)将DCS粉末用1%乙酸溶解制得DCS乙酸溶液,并将步骤(5)中的RuB2A2用水溶解制得RuB2A2溶液,在黑暗条件下将RuB2A2溶液滴加到DCS乙酸溶液中,并在酸性条件下交联,即得光响应抗菌水凝胶;
(11)在黑暗条件下,将BMSC附着于步骤(10)合成的水凝胶表面,等待细胞的自动附着,即得缓释BMSC的光响应抑菌性水凝胶。
2.根据权利要求1所述一种缓释BMSC的光响应抑菌性水凝胶的制备方法,其特征在于,步骤(1)所述溶液A中Ru(bpy)2Cl2的质量浓度为0.412mmol。
3.根据权利要求1所述一种缓释BMSC的光响应抑菌性水凝胶的制备方法,其特征在于,步骤(2)所述溶液B中3-吡啶甲醛的质量浓度为2.472mmol。
4.根据权利要求1所述一种缓释BMSC的光响应抑菌性水凝胶的制备方法,其特征在于,步骤(6)所述壳聚糖溶液中壳聚糖的质量浓度为0.124mol/L。
5.根据权利要求1所述一种缓释BMSC的光响应抑菌性水凝胶的制备方法,其特征在于,步骤(7)所述混合物溶液D中壳聚糖中氨基与十二醛中的醛基摩尔比为1:0.1-0.8。
6.根据权利要求1所述一种缓释BMSC的光响应抑菌性水凝胶的制备方法,其特征在于,步骤(8)中所述硼氢化钠溶液为还原剂,是将硼氢化钠粉末溶解于水中而得;所述硼氢化钠溶液的滴加速度为200μL/min。
7.根据权利要求1所述一种缓释BMSC的光响应抑菌性水凝胶的制备方法,其特征在于,步骤(8)中所述硼氢化钠溶液用量按照NaBH4:CS=3:1的摩尔比进行控制。
8.根据权利要求1所述一种缓释BMSC的光响应抑菌性水凝胶的制备方法,其特征在于,步骤(10)中所述RuB2A2溶液的滴加速度为200μL/min。
9.一种缓释BMSC的光响应抑菌性水凝胶,其特征在于,采用权利要求1~8任一项所述的方法制备得到。
10.如权利要求9所述的一种缓释BMSC的光响应抑菌性水凝胶在制备伤口敷料或者细胞呈递药物中的应用。
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