CN117379598B - 一种高分子水凝胶及其制备方法和用途 - Google Patents
一种高分子水凝胶及其制备方法和用途 Download PDFInfo
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Abstract
本发明涉及高分子材料的技术领域，公开了一种高分子水凝胶及其制备方法和用途，该高分子水凝胶通过如下方式制得：步骤1、合成多肽结构KN‑17；步骤2、合成基于萘普生（Npx）的多肽衍生物Npx‑FFEY，步骤3、将Npx‑FFEY与KN‑17共组装以合成稳定的半透明高分子水凝胶Npx‑FFEY/KN‑17；该高分子水凝胶能够用于促进血管新生及牙髓‑牙本质复合体再生，本发明中通过对天蚕素B多肽序列进行改造得到兼具抗菌、促成牙本质及促血管新生的新型抗菌短肽，并与多肽衍生物Npx‑FFEY经共组装得到可注射型水凝胶，无需引入其他任何化学交联剂，制备工艺简单，具有良好的生物安全性。
Description
技术领域
本发明涉及高分子材料的技术领域，尤其是涉及一种高分子水凝胶及其制备方法和用途。
背景技术
牙外伤、牙髓炎或根尖周炎在儿童时期十分常见，年轻恒牙的根管治疗(RCT)似乎不可避免。正常情况下，牙齿萌出后3年内，根尖孔会逐渐闭合。对于年轻恒牙来说，常规的根管治疗很难达到适当的根尖封闭效果。但在根尖周组织中，一些残留的有生命的牙髓组织和根尖牙乳头细胞仍保持一定的活力。根尖诱导成形术作为诱导年轻恒牙根尖封闭的传统治疗方法，是一种公认的促进根尖闭合的非手术治疗方案。近几十年来，一些材料特别是氢氧化钙和三氧化矿物凝聚体(Mineral trioxide aggregate，MTA)，可用于年轻恒牙根尖诱导成形术。氢氧化钙已经证明了其诱导钙化根尖屏障的有效性，成功率为74-100%。然而，氢氧化钙的主要缺陷是导致根壁的厚度或长度会减少，并且需要很长一段时间(6-24个月)才能获得满意的根尖屏障效果。随后，MTA逐渐替代氢氧化钙以用来缩短治疗时间。然而，MTA与氢氧化钙具有类似的缺陷，即不能诱导牙根继续发育，并且牙齿持续存在薄而脆弱的牙本质壁。此外，新的生物陶瓷材料，如Biodentine和EndoSequence根修复材料(ERRM）已经上市用于根尖修复。虽然生物陶瓷材料可以像MTA一样缩短牙根发育周期，但牙本质壁的厚度和硬度几乎没有明显改善。
再生牙髓治疗已成为促进年轻恒牙牙根继续发育的一种替代治疗方法。根尖孔尚未发育完全的年轻恒牙被认为是合适的选择，因为开放的根尖孔可以保证牙髓-牙本质复合体再生所需的充足血液供应。再生牙髓医学的基础是利用干细胞/祖细胞、支架和生长因子进行组织再生。这种策略有助于牙本质壁的硬组织沉积，从而为牙根提供足够的强度以防止折裂。值得注意的是，新生血管的形成对于组织再生也是至关重要的，尤其是在组织缺血损伤后。由于缺乏氧气或营养供应,预先血管化的组织工程策略是不可行的，体内血管化可能在再生牙髓医学中证明是有效的。牙髓血运重建可以被认为是一种细胞归巢策略，它依赖于作为根管内支架结构的血凝块、生长因子和来自根尖牙乳头(SCAP)的干细胞的输送，因为它们的解剖位置靠近根管系统的末端。此外，来自人体多个区域的间充质干细胞(MSCs)，包括骨髓、皮肤以及血管周围组织、脂肪和牙齿组织，也可以被诱导成牙髓-牙本质复合体。
近年来，抗生素及根管封闭药物导致细菌的耐药性逐渐增强，传统的根尖诱导成形术尚未达到预期效果。抗菌肽作为一种新型的抑菌剂，具有低毒性、高特异性等优势，且相互作用时间短，降低了出现细菌抵抗的几率。天蚕素-B是目前研究较为成熟的抗菌肽分子之一，因其具有良好抗菌性的同时，对成骨细胞的粘附及生长分化均起到较好的促进作用。然而，天然抗菌肽在临床应用上存在以下问题：1）氨基酸序列长，稳定性较差；2）对哺乳动物细胞毒性偏大；3）工业合成成本高昂，因此经常需要对抗菌肽进行改装以得到相应的抗菌短肽。
水凝胶是一类极为亲水的三维网络结构凝胶，拥有交联的孔隙状结构，较高的含水量及粘弹性质为其提供了良好的生物安全性，被广泛应用于药物递送及组织工程等领域。高分子水凝胶可被置于髓腔及根管进行局部给药，以期为牙髓-牙本质复合体提供3D环境的同时控制药物的释放。
发明内容
本发明的目的在于提供一种多肽结构KN-17、高分子水凝胶及其制备方法和用途，通过以天蚕素B为结构进行修饰获得KN-17，能促进新生血管形成，以解决现有技术中的生物材料在未成熟恒牙治疗过程中具有缺陷的技术问题。
本发明提供一种高分子水凝胶的制备方法，包括如下步骤：
步骤1、合成多肽结构KN-17，所述多肽结构KN-17的氨基酸序列如SEQ ID NO:1所示；
步骤2、合成基于萘普生（Npx）的多肽衍生物Npx-FFEY，所述多肽衍生物Npx-FFEY的结构式为：
步骤3、将Npx-FFEY与KN-17共组装以合成稳定的半透明高分子水凝胶Npx-FFEY/KN-17。
进一步地，在步骤1中，所述多肽结构KN-17通过将天蚕素B（cecropin B）的多肽序列截短获得。
进一步地，在步骤2中，多肽衍生物Npx-FFEY通过以2-氯三酰氯树脂为相载体，以不同的N-Fmoc保护氨基酸为原料，采用固相肽合成法获得。
进一步地，在步骤3中，合成条件为：将KN-17、Npx-FFEY加入PBS缓冲液中，调节pH值至中性，加热至KN-17和Npx-FFEY均溶解，冷却后获得水凝胶Npx-FFEY/KN-17。
进一步地，在PBS缓冲液中，在PBS缓冲液中，所述Npx-FFEY的最低浓度为5mg/ml，所述KN-17的浓度范围为1-100μmol/L。
本发明还提供了一种高分子水凝胶，由上述任一项所述的制备方法制得
本发明进一步公开了水凝胶在促进血管新生及牙髓-牙本质复合体再生中的用途。
与现有技术相比较，本发明的有益效果在于：
（1）目前临床上针对年轻恒牙根尖诱导成形术的药物或材料包括氢氧化钙糊剂、MTA及生物陶瓷等，于根尖诱导成形术后6-24个月后，牙本质桥的厚度及硬度未能达到预期效果；本发明中通过对天蚕素B多肽序列进行改造得到兼具抗菌、促成牙本质及促血管新生的新型抗菌短肽，可有效促进牙髓-牙本质复合体再生。
（2）本发明将萘普生（Npx）经多肽固相合成法制备得到多肽衍生物Npx-FFEY，可在加热-冷却下与KN-17经共组装得到高分子水凝胶，无需引入其他任何化学交联剂，制备工艺简单，具有良好的生物安全性。
（3）本发明中可注射水凝胶的制备方法，通过化学和物理交联的结合，可在生理条件下操作即可实现凝胶化，凝胶时间短，可在30分钟之内迅速固化，易于临床操作，且水凝胶粒径分布均匀。
（4）本发明的新型自组装Npx-FFEY/KN-17水凝胶可在体内受温度及酶的调控下，保持其蛋白活性的同时，可实现KN-17长期缓释的目的。
附图说明
为了更清楚地说明本发明具体实施方式或现有技术中的技术方案，下面将对具体实施方式或现有技术描述中所需要使用的附图作简单地介绍，显而易见地，下面描述中的附图是本发明的一些实施方式，对于本领域普通技术人员来讲，在不付出创造性劳动的前提下，还可以根据这些附图获得其他的附图。
图1为本发明提供的Nap-FFEY/KN-17水凝胶的形成与特性图；
图2为本发明提供的Nap-FFEY/KN-17水凝胶对DPSCs的牙源性分化的作用图；
图3为本发明提供的负载KN-17的水凝胶对粪肠球菌的生长和生物膜的形成的作用图；
图4为本发明提供的Nap-FFEY/KN-17水凝胶对大鼠磨牙髓-牙本质复合体新生血管和再生的作用图。
具体实施方式
下面将结合附图对本发明的技术方案进行清楚、完整地描述，显然，所描述的实施例是本发明一部分实施例，而不是全部的实施例。
通常在此处附图中描述和显示出的本发明实施例的组件可以以各种不同的配置来布置和设计。因此，以下对在附图中提供的本发明的实施例的详细描述并非旨在限制要求保护的本发明的范围，而是仅仅表示本发明的选定实施例。
基于本发明中的实施例，本领域普通技术人员在没有做出创造性劳动前提下所获得的所有其他实施例，都属于本发明保护的范围。
本发明实施例提供了一种多肽结构KN-17，所述多肽结构KN-17的氨基酸序列如SEQ ID NO:1所示。该多肽结构KN-17能够促进新生血管形成。
在此基础上，本发明公开了一种基于自组装肽的阳离子高分子水凝胶，含有上述KN-17，最终制备的水凝胶能够显著促进血管新生及牙髓-牙本质复合体再生中。
上述高分子水凝胶的制备包括如下步骤：
步骤1、合成多肽结构KN-17；
步骤2、合成基于萘普生（Npx）的多肽衍生物Npx-FFEY，所述多肽衍生物Npx-FFEY的结构式为：
步骤3、将Npx-FFEY与KN-17共组装以合成稳定的半透明高分子水凝胶Npx-FFEY/KN-17。
其中，在步骤1中，所述多肽结构KN-17（KWKVFKKIEKMGRNIRN）可以通过将天蚕素B（cecropin B）的多肽序列截短获得。
而在步骤2中，多肽衍生物Npx-FFEY通过以2-氯三酰氯树脂为相载体，以不同的N-Fmoc保护氨基酸为原料，采用固相肽合成法获得。
本发明实施例中的KN-17由上海得益生物科技有限公司（上海）合成，最终肽序列经高效液相色谱（HPLC）纯化（纯度>95%），质谱（MS）确认。
在一个具体的实施例中，多肽衍生物Npx-FFEY可以通过如下方式获得：
（1）将医药中间体Fmoc-Tyr(tBu)-OH(1mmol)与2-氯三酰氯树脂(1g）、20ml二氯甲烷溶液混合，室温反应1小时，使其负载到2-氯三酰氯树脂上。随后，加入含有20%哌啶的无水DMF（N,N-二甲基甲酰胺）溶液切除氨基酸的Fmoc保护基团，二氯甲烷DCM洗涤3次，DMF洗涤3次。
（2）加入N,N-二异丙基乙胺DIEA(4mmol)，苯并三氮唑-N,N,N',N'-四甲基脲六氟磷酸盐HBTU(2mmol)、Fmoc-Glu(OtBu)-OH(2mmol)反应2小时后、加入20%哌啶的无水DMF溶液切除氨基酸的Fmoc保护基团，DMF洗涤三次。
（3）按照步骤方法（2）将Fmoc-Phe-OH、Fmoc-Phe-OH和Npx连接于多肽。
（4）滤去反应溶液，并将残余物用DMF洗涤5次，每次20mL，用二氯甲烷以同样方式洗涤5次。用95%的三氟乙酸(TrfluoroaceticAcid，TFA)(具体配方为:TFA:19mL，TIS:0.5mL，H2O:0.5mL)将多肽从2-氯三酰氯树脂上裂解下来反应时间为30分钟。最后，将溶剂旋干，加入冰乙醚100mL，沉淀物用冰乙醚洗涤两次，抽干得到粗产品。粗品经HPLC分离纯化得纯品。
核磁结果如下：1H NMR (500 MHz, dmso) δ 8.15 – 8.02 (m, 4H), 7.75 –7.66 (m, 2H), 7.62 (s, 1H), 7.33 (dd, J = 8.5, 1.8 Hz,1H), 7.27 – 7.08 (m,9H), 7.08 – 6.98 (m, 5H), 6.65 (d, 2H), 4.57 – 4.45 (m, 2H), 4.38 – 4.29 (m,2H), 3.85 (s, 3H), 3.72 (q, J = 6.9 Hz, 1H), 3.04 – 2.86 (m, 3H), 2.84 – 2.68(m, 3H), 2.23 (t, J = 8.2 Hz, 2H), 1.95 – 1.84 (m, 1H), 1.80 – 1.69 (m, 1H),1.19 (d, J = 7.0 Hz, 2H)。
获得KN-17和Npx-FFEY后，具体的合成条件为：将KN-17、Npx-FFEY加入PBS缓冲液中，调节pH值至中性，可采用NaCO3调节，加热至KN-17和Npx-FFEY均溶解，冷却后即可获得水凝胶Npx-FFEY/KN-17。
考虑到最终的成胶性能，在PBS缓冲液中，控制Npx-FFEY的最低浓度为5mg/ml，KN-17的浓度范围为1-100μmol/L。
如图1所示，本发明通过标准固相多肤合成(SPPS)法初步设计了多肽衍生物Npx-FFEY，并通过反相高效液相色谱法纯化。然后，Npx-FFEY与KN-17在室温下加热冷却30分钟后，在PBS(PH7.4)中以最低浓度0.5wt(5 mg/ml）形成稳定的半透明Npx-FFEY/KN-17水凝胶(图1A示，Nap-FFEY与KN-17形成的水凝胶示意图)。随后，对制备的高分子水凝胶的性能及表征进行了检测。流变测试（Rheologytest）是为了检测水凝胶的机械性能，结果显示，在0.1~100rad/s的动态频率扫描范围内，存储模量值(G’)始终比损耗存储量值(G’’)大一个数量级，进一步证明了水凝胶的形成（图1B示出了Nap-FFEY和Nap-EEFY/KN-17水凝胶的动态频率扫描图）。通过TEM观察所得水凝胶的微观形貌。图像显示，Npx-FFEY自组装形成的水凝胶呈“纤维状”，主要由交联的纳米纤维组成，而Npx-FFEY与KN-17共组装得到的水凝胶呈“球状”(图1C示出了Nap-FFEY和Nap-EEFY/KN-17水凝胶的TEM图像)。实验结果清楚地证实了具有纳米结构和有利于组织再生性能的高分子水凝胶的成功形成。
如图2所示，在成功构建高分子水凝胶后，本发明还从成人下颌第三磨牙牙髓组织中提取了牙髓间充质干细胞（DPSCs），在成牙本质培养基中培养DPSCs。DPSCs进行成牙本质分化并进行ALP染色检测。图2中A示出了以1μM的KN-17、1μM的Nap-FFEY/KN-17、10mg/mL的Nap-FFEY或PBS（Vehicle组）处理DPSCs，2周后进行ALP染色，图2B显示了KN-17 1μM、Nap-FFEY/KN-17 1μM、Nap-FFEY 10mg/mL或溶剂处理2周后DPSCs基因表达水平的定量分析，结果表明，KN-17和Npx-FFEY/KN-17水凝胶显著促进DPSCs的ALP活性和矿化，持续时间长达2周。此外，采用qPT-PCR方法在转录水平上探讨牙本质相关特异性基因的表达。qRT-PCR检测结果显示，与对照组（即Vehicle和Npx-FFEY组）相比，KN-17组和水凝胶组的侏儒相关转录因子2 (RUNX2)、ALP、牙本质唾液磷蛋白(DSPP)和牙本质基质蛋白1(DMP-1)的转录水平均显著上调(图2C示，KN-17 1μM，Nap-FFEY/KN-17 1μM，Nap-FFEY 10mg/mL或溶剂处理DPSCs，2周后基因表达水平的定量分析)。以上结果说明KN-17及相应的水凝胶对DPSCs成牙本质分化的积极作用。
如图3所示，粪肠球菌通常是从感染的根管中分离出来的，在牙齿环境中没有营养也能生存。由于粪肠球菌具有形成生物膜的能力，粪肠球菌的去除难度较大，因此，有效抑制粪肠球菌的生长和定植对牙髓-牙本质复合体的再生至关重要。结晶紫实验表明，与对照组相比，KN-17和负载KN-17的水凝胶明显破坏了粪肠杆菌形成的生物膜(图3A示，KN-17 10μM、Nap-FFEY/KN-1710μM、Nap-FFEY 10mg/mL或PBS（Vehicle组）处理24h后粪肠杆菌的生长情况，图3B示，KN-17 10μM，Nap-FFEY/KN-17 10μM，Nap-FFEY 10mg/mL或PBS（Vehicle组）对粪肠球菌的抑菌作用)。此外，利用扫描电镜对粪肠杆菌的表面形貌进行了检测，与对照组相比，KN-17组和水凝胶组的粪肠球菌细胞膜出现波纹和破裂(图5C示，用KN-17 10μM、Nap-FFEY/KN-17 10μM、Nap-FFEY 10mg/mL或PBS处理粪肠球菌24h，扫描电镜观察粪肠球菌生物膜形成情况)。结果表明，KN-17及Npx-FFEY/KN-17对感染根管内的优势菌粪肠球菌有较好的抑菌效果，这也为牙髓-牙本质复合体的再生提供了保障。
最后，如图4所示，本发明还通过体内实验来评价水凝胶促进血管新生及牙髓-牙本质复合体的再生的作用。结合图4中A可知，本研究中，我们拔除SD大鼠上颌第一磨牙，随即进行开髓并切除冠髓，只保留根髓，随后将KN-17，Npx-FFEY，Npx-FFEY/KN-17及PBS（vehicle组）分别置入牙冠髓腔内，水门汀封闭开髓孔。将处理后的大鼠磨牙置于BALB/C-nu小鼠背部皮下组织（subcutaneous implantation）进行为期4周的移植。28天后取出磨牙进行HE染色，Masson’s trichrome染色及CD31免疫组化。如图4中B所示，结果表明，4组磨牙中牙髓均未出现感染坏死现象。KN-17及Npx-FFEY/KN-17水凝胶组中，在牙髓横截面上检测到新生成的具有典型牙本质小管结构的基质。同时，牙髓组织中含有大量血管。与KN-17组相比，水凝胶组牙本质结构更加致密。此外，如图4中C所示，Masson三色染色显示，对照组牙髓中有少量无矿化的不规则蓝染胶原纤维。Npx-FFEY组蓝染胶原纤维几乎不可见。相反，在KN-17组和水凝胶组中，矿化的蓝色胶原纤维嵌埋在牙髓横截面上，牙本质桥钙化清晰可见。此外，CD31免疫组化也用于检测血管的新生。免疫组化染色表明，对照组几乎未见CD31表达。图4D示，大鼠磨牙组织CD31表达的免疫组化染色，并且图4E根据组织学评分(h-score)对CD31表达进行评分，与Npx-FFEY组相比，KN-17组和水凝胶组在新形成的硬组织周围的CD31强度明显增强。综上所述，Npx-FFEY/KN-17水凝胶作为一种高分子生物支架材料可有效促进血管新生及牙髓-牙本质复合体再生，这为年轻恒牙根尖诱导成形提供了全新的思路。
最后应说明的是：以上各实施例仅用以说明本发明的技术方案，而非对其限制；尽管参照前述各实施例对本发明进行了详细的说明，本领域的普通技术人员应当理解：其依然可以对前述各实施例所记载的技术方案进行修改，或者对其中部分或者全部技术特征进行等同替换；而这些修改或者替换，并不使相应技术方案的本质脱离本发明各实施例技术方案的范围。
Claims (7)
1.一种高分子水凝胶的制备方法，其特征在于，包括如下步骤：
步骤1、合成多肽结构KN-17，所述多肽结构KN-17的氨基酸序列如SEQ ID NO:1所示；
步骤2、合成基于萘普生（Npx）的多肽衍生物Npx-FFEY，所述多肽衍生物Npx-FFEY的结构式为：
步骤3、将Npx-FFEY与KN-17共组装以合成稳定的半透明高分子水凝胶Npx-FFEY/KN-17。
2.根据权利要求1所述的制备方法，其特征在于，在步骤1中，所述多肽结构KN-17通过将天蚕素B（cecropin B）的多肽序列截短获得。
3.根据权利要求1所述的制备方法，其特征在于，在步骤2中，多肽衍生物Npx-FFEY通过以2-氯三酰氯树脂为相载体，以不同的N-Fmoc保护氨基酸为原料，采用固相肽合成法获得。
4.根据权利要求1所述的制备方法，其特征在于，在步骤3中，合成条件为：将KN-17、Npx-FFEY加入PBS缓冲液中，调节pH值至中性，加热至KN-17和Npx-FFEY均溶解，冷却后获得水凝胶Npx-FFEY/KN-17。
5.根据权利要求4所述的制备方法，其特征在于，在PBS缓冲液中，所述Npx-FFEY的最低浓度为5mg/ml，所述KN-17的浓度范围为1-100μmol/L。
6.一种高分子水凝胶，其特征在于，由权利要求1-5中任一项所述的制备方法制得。
7.如权利要求6所述的高分子水凝胶在促进血管新生及牙髓-牙本质复合体再生中的用途。
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