CN113577014A - 医疗器械、水凝胶及其制备方法与应用 - Google Patents
医疗器械、水凝胶及其制备方法与应用 Download PDFInfo
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- CN113577014A CN113577014A CN202110405989.4A CN202110405989A CN113577014A CN 113577014 A CN113577014 A CN 113577014A CN 202110405989 A CN202110405989 A CN 202110405989A CN 113577014 A CN113577014 A CN 113577014A
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Abstract
本发明公开了一种医疗器械、水凝胶及其制备方法与应用，该水凝胶由抗菌肽与缓冲液经反应聚合而成，所述抗菌肽为以下氨基酸序列表示的多肽或其多肽衍生物：Pro‑Phe‑Lys‑Leu‑Ser‑Leu‑His‑Leu‑NH2。本发明的水凝胶可自愈、可注射、在体内和体外均能被降解，完全降解所需时间适中，能在充分达到药效后进行降解；对细菌和真菌的生长和增值具有显著的抑制作用，具有抗菌、抗炎活性及良好的止血性能；且具有细胞毒性小，基本不表现溶血活性，具有良好的生物相容性等优点；本发明的水凝胶防粘连活性良好，不粘连伤口，能在37℃快速交联，具良好的预防术后粘连的效果，在临床应用方面具有明显优势。
Description
技术领域
本发明涉及一种水凝胶，尤其涉及一种多肽水凝胶的及其制备方法与应用，及该水凝胶适用的医疗器械。
背景技术
粘连是由于手术、身体损伤或炎症后自然愈合过程而形成的瘢痕组织纤维带，通常由手术过程中发生的创伤、细菌感染、异物残留等造成。无论手术程序和手术位置如何，几乎所有的手术后都会出现粘连，其中腹腔、盆腔术后粘连发生率为60％左右，开腹手术术后粘连率可高达90％以上。术后粘连容易导致肠梗阻、女性不孕、腹痛等症状，其中15-30％的患者需要第二次手术来解除粘连(即粘连溶解)。粘连的存在会严重增加患者手术风险和治疗时间而增加患者痛苦和经济负担，因此亟需发展有效的术后粘连屏障。然而，尽管临床上对粘附屏障(尤其腹部和心胸外科手术的)有着巨大的需求，但粘附屏障在实际应用中的应用率却很低，在腹部手术中的应用率不到10％。
目前临床上用于预防粘连的材料主要是由多糖和/或合成聚合物(可吸收和不可吸收的种类)制成固体聚合物膜或水凝胶两类，其发挥作用的方式都是作为瘢痕组织和周围器官之间的物理屏障。当前最普遍使用的商业化的防粘连产品主要用于腹部手术，是由透明质酸和羧甲基纤维素以薄膜(如Seprafilm、赛诺菲/Genzyme)或机织物(如Interceed、Ethicon)形式构成的固体可吸收膜(Biomaterials 28(2007)975–983)。实际上，这些产品很难完全覆盖靶组织，形成有效的物理屏障。通常这些物理隔膜由于在手术后降解过快，或者由于组织的自然移动而脱落而不能有效阻止粘连的形成。此外，由于薄膜和织物还存在不能完全覆盖具有不规则表面或严重折叠的组织(例如，分别为心脏和小肠的大血管)的问题，而使得任何未覆盖的中间空间仍有形成粘连的风险。
为了克服固体防粘膜应用中产生的问题，也有很多研究致力于由壳聚糖、透明质酸和/或羧甲基纤维素组成的可喷雾聚合物溶液的研发。虽然可喷雾聚合物溶液易于应用，但由于其在受伤或发炎组织部位停留时间短，因此在防止粘连方面仅起到了轻微的效果。此外，近年来发展的通过原位聚合方式形成的水凝胶虽被证明可以增加其在体内停留时间，然而这些系统中交联的不可逆性通常使得它们变得很脆弱或者无法适应体内组织的动态运动，再加之它们其它潜在的副作用而使得它们的使用受到限制。
一般地，制备水凝胶材料主要有两大类，一类是合成高分子，一类是天然生物材料如多糖和蛋白质、多肽等。其中多肽是由氨基酸以肽键连接在一起而形成的化合物，在体内易被蛋白酶水解为氨基酸，对机体不会产生不良影响。因此，由多肽交联形成的水凝胶具有良好的生物相容性，是一种有前景的生物材料(Adv.Mater.2017,1604062)。
综上所述，尽管已经存在许多用于术后防粘连的材料，但是术后粘连预防仍然存在挑战，遏制预防术后注定是一项长期而艰巨的任务。基于天然生物多肽分子研发新型防粘连材料是预防术后粘连及其并发症的一个重要方向。
发明内容
本发明的目的在于提供一种医疗器械、水凝胶及其制备方法与应用，该水凝胶具有良好的抗菌、止血以及防粘连等功效。本发明的发明人经过大量的实验研究，证明该抗菌肽制成水凝胶后具有对创面无粘连、能自愈、可注射、温度敏感、具有抗菌和止血性能等优点，同时具有可以负载药物或生长因子的空间微结构，可负载各类药物或生长因子，实现敷料的功能化治疗、实现创面治疗中抗菌、抗炎、为创面提供湿性环境等功能。此外，还能将本发明的水凝胶搭配各类医疗器械使用，实现更加方便、高效的治疗作用。
为达上述目的，本发明提供一种水凝胶，该水凝胶由抗菌肽与缓冲液经反应聚合而成，该抗菌肽具有以下氨基酸序列：Pro-Phe-Lys-Leu-Ser-Leu-His-Leu-NH2(953.17Da)。
上述氨基酸序列的衍生物或修饰物同样适用于本发明。
本发明的水凝胶为微米多孔结构。
本发明的微米多孔结构的孔径为0.05um-200um。
本发明的缓冲液可以为碳酸盐溶液、亚硫酸盐溶液、DMEM细胞培养液以及磷酸盐缓冲液，优选磷酸盐缓冲液；其中磷酸盐缓冲液为将Na2HPO4、KH2PO4、KCl以及NaCl按比例溶解于去离子水中制得，抗菌肽与磷酸盐缓冲液的组分及配比以摩尔比计为抗菌肽：Na2HPO4：KH2PO4：KCl：NaCl＝(1-40)：(1-10)：(1-5)：(1-5)：(50-200)，优选抗菌肽：Na2HPO4：KH2PO4：KCl：NaCl＝(1-40)：10：2：2.7：137。
作为优选地，本发明的磷酸盐缓冲液的组分还包括二磷酸腺苷(ADP)，以摩尔比计二磷酸腺苷与Na2HPO4的比例为(1-10)：(1-100)，优选二磷酸腺苷与Na2HPO4的摩尔比为1：10。
本发明的反应可以为物理反应或化学反应，优选离子交联聚合反应，反应温度为0-60℃，反应时间为1-120min。
本发明还提供一种水凝胶的制备方法，该水凝胶的制备方法包括以下步骤：
步骤S1：将抗菌肽溶于二甲基亚砜，得到抗菌肽的溶解液，备用；
步骤S2：将抗菌肽的溶解液加入至缓冲液中，在超声或搅拌条件下进行离子交联聚合反应，得到水凝胶。
本发明的水凝胶中的溶剂主要为水，次要为二甲基亚砜(DMSO)，其中二甲基亚砜的体积含量小于5％。
本发明的制备方法，优选地还包括以下步骤：
步骤S3：缓冲液中还可加入药物和/或生长因子，得到负载药物或生长因子的水凝胶。
本发明的药物优选为抗菌药物或消炎药物，生长因子优选为促伤口愈合生长因子。
本发明还提供一种水凝胶在防粘连药物中的应用，该防粘连药物包含负载有药物或生长因子的水凝胶和至少一种药学上可接受的药用载体和/或辅料。
本发明的防粘连药物为片剂、胶囊、糖衣片剂、粒剂、滴剂、喷雾剂、冲洗剂、漱口剂、用于皮肤表面的油膏和药贴、以及用于注射的无菌溶液中的至少一种剂型。本发明的药物为抗菌药物或消炎药物，生长因子为促伤口愈合生长因子。
本发明的水凝胶可以直接对创面进行冲洗、喷涂、湿敷或覆盖，制作成方便使用的喷雾剂，直接喷敷于创面形成保护膜，能瞬间止血、保持创面湿润，创造利于上皮细胞的生长和愈合的低氧环境，加速伤口愈合；同时水凝胶中的抗菌肽，起到快速广谱持久的杀菌作用，伤口愈合后抗菌肽分解为氨基酸代谢，避免粘连和残留。
此外，本发明的水凝胶还可依据病症或创面的位置，选择合适的使用方法及制作成相应的适用剂型；例如，创伤、挫伤、擦伤、术后伤口、烧烫伤、溃疡清创后，可将本发明的水凝胶喷涂换出、或湿敷并包扎；痔疮、肛脓肿、肛瘘、肛裂、造口、造瘘、会阴侧切、包皮环切术后可将本发明的水凝胶喷涂或湿敷包扎；放疗前后，可将本发明的水凝胶对局部皮肤进行喷涂或湿敷；糖尿病足、脉管炎、老年性褥疮慢性不愈合伤口，清创后可将本发明的水凝胶喷涂患处；口腔异味、口腔术后护理可将本发明的水凝胶制作成漱口剂直接含于口腔漱口后排出；癣、疱疹、粉刺等，可将本发明的水凝胶喷涂或湿敷于创面；因刺激皮肤出现不适、痛痒、干燥、脱皮等现象，可将本发明的水凝胶直接喷涂或湿敷，以此改善皮肤健康。
本发明的水凝胶还可负载各类药物或生长因子，从而实现功能化治疗。
本发明再提供一种医疗器械，该医疗器械具有上述水凝胶。
本发明的水凝胶可涂覆于医疗器械的至少一个表面上形成材料。
本发明的医疗器械的形式为由医用敷料、纤维、网片、粉末、微球、薄片、海绵、泡沫、缝合锚定器械、导管、支架、外科手术平头钉、板和螺丝、药物递送器械、防粘屏障和组织粘合剂组成的群组中的任一者。
本发明的纤维为织物；薄片为膜或夹片；缝合锚定器械为缝合线或U形钉。
本案的发明人首次发现抗菌肽Pro-Phe-Lys-Leu-Ser-Leu-His-Leu-NH2能形成水凝胶的现象；并以抗菌肽与磷酸盐缓冲液为原料，经离子交联聚合反应得到水凝胶，开发了抗菌肽形成水凝胶的制备方法。本发明将抗菌肽应用于水凝胶的制备过程中，拓宽了抗菌肽的应用途径，同时还丰富了水凝胶的种类。
同时，本发明以抗菌肽为组分的水凝胶不粘连伤口，具有抗菌活性和止血性能、可自愈、温度敏感、可注射、对细胞无粘附特性以及无副作用等优点，同时水凝胶具有微米多孔结构，可用于药物包载与缓释，如可以负载消炎药物或者表皮生长因子、血管生长因子等，加速伤口愈合，减少瘢痕组织纤维的形成。
此外，本发明的水凝胶的制备方法工艺步骤少，操作方便，对人员操作要求低，原料种类简单，大大节约了生产成本。本发明的医疗器械具有该水凝胶，从而实现更加方便、高效的治疗作用，能广泛应用于临床中。
附图说明
图1为抗菌肽J-1的溶解液及本发明的水凝胶的图片；
其中，A为抗菌肽J-1的溶解液的图片；B为实施例1的水凝胶的图片；C为实施例2的水凝胶的图片。
图2为实施例2的水凝胶的扫描电镜显微结构图；
其中，A为抗菌肽J-1溶解于去离子水，并在室温干燥后的电镜图片；B为抗菌肽J-1水凝胶在室温干燥后的电镜图片；C为抗菌肽J-1水凝胶在冷冻干燥后的电镜图片。
图3为本发明的水凝胶和对照组对E.coli、S.aureus及C.albicans增殖的抑制作用柱状图。
图4为本发明的E.coli、S.aureus及C.albicans在培养板上的生长情况图。
图5为本发明的水凝胶的体外降解性能图；其中，A列为本发明的水凝胶在体外不同PH环境中完全降解所需时间柱状图；B列为本发明的水凝胶在体外降解过程中，质量随时间变化曲线图。
图6为本发明的水凝胶在小鼠体内降解情况图；
其中，A为皮下注射水凝胶后的小鼠；B-E分别为水凝胶在注射1、3、5、10天后的B超超声图。
图7为各实验组对小鼠成纤维细胞NIH3T3的增殖情况柱状图。
图8为各实验组对人红细胞的溶血作用情况图。
图9为本发明中大鼠术后腹壁-盲肠粘连模型构建过程示意图。
图10为本发明中水凝胶在大鼠腹壁-盲肠粘连模型中防粘连作用。
图11为本发明中水凝胶处理一周后粘连部位术组织学检查图。
图12为本发明中各实验组的肝脏出血模型的止血情况图；
其中，0s、60s和120s代表水凝胶的作用时间。
图13为本发明中各实验组作用120s后小鼠肝脏的总出血量柱状图。
图14为本发明中各实验组小鼠出血时间柱状图。
图15为本发明的一实施例的水凝胶的制备方法步骤流程图。
具体实施方式
下面将结合实施例对本发明的实施方案进行详细描述，但是本领域技术人员将会理解，下列实施例仅用于说明本发明，而不应视为限定本发明的范围。本发明中实施例所用的抗菌肽Pro-Phe-Lys-Leu-Ser-Leu-His-Leu-NH2购自“国肽生物”，并将其命名为“抗菌肽J-1”，经HPLC分析，其纯度在95％以上。实施例中未注明具体条件者，按照常规条件或制造商建议的条件进行。所用试剂或仪器未注明生产厂商者，均为可以通过市购获得的常规产品。
一、水凝胶的制备
本发明的水凝胶具有抗菌、止血以及防粘连的作用，能作为医用防粘水凝胶敷料使用。该水凝胶含有抗菌肽Pro-Phe-Lys-Leu-Ser-Leu-His-Leu-NH2或其衍生物，该水凝胶为微米多孔结构，该微米多孔结构的孔径为0.05um-200um。
本发明的水凝胶是由抗菌肽J-1与缓冲液经离子交联聚合而成，抗菌肽J-1的氨基酸序列为Pro-Phe-Lys-Leu-Ser-Leu-His-Leu-NH2(953.17Da)。本发明并不特别限制抗菌肽J-1，抗菌肽J-1的修饰物或抗菌肽J-1的衍生物同样也适用于本发明。
如图15所示，为本发明的一实施例的水凝胶的制备方法步骤流程图，本发明的水凝胶的制备方法具体包括以下步骤：
步骤S1：将抗菌肽J-1溶于二甲基亚砜，得到浓度为100mM的抗菌肽J-1的溶解液，备用；将Na2HPO4、KH2PO4、KCl以及NaCl按比例溶解于去离子水中，得到磷酸盐缓冲液，备用；
步骤S2：将抗菌肽J-1的溶解液加入至磷酸盐缓冲液中，抗菌肽J-1的终浓度为1.5-40mM，在超声或搅拌条件下进行离子交联聚合反应，得到负载药物和/或生长因子的水凝胶；
作为优选地，还包括步骤S3：在步骤S2制备水凝胶的过程中，提前在磷酸盐缓冲液中加入药物或生长因子，得到负载药物或生长因子的水凝胶。
本发明于步骤S2中，离子交联聚合反应的反应温度为0-60℃，反应时间为1-120min。
本发明于步骤S3中，药物为抗菌药物或消炎药物，生长因子为促伤口愈合的生长因子。
作为优选地，本发明的磷酸盐缓冲液中还包括二磷酸腺苷(ADP)组分，以摩尔比计ADP与Na2HPO4的比例为(1-10)：(1-100)。本发明的水凝胶的溶剂组成中，主要成分为水，其次为二甲基亚砜(DMSO)，DMSO的体积比例小于5％。
本发明的抗菌肽J-1的溶解液如图1中A所示。本发明的水凝胶能应用在防粘连药物中，将药物或生长因子负载于水凝胶，即得到防粘连水凝胶药物，将水凝胶负载于纱布或其他可实施的载体上，得到防粘连水凝胶敷料。
为能更清楚地理解本发明水凝胶的制备方法，特举以下较佳实施例进行说明。
实施例1
本实施例中水凝胶的制备方法如下：将二甲基亚砜溶解的抗菌肽J-1母液(100mM)，加入到由Na2HPO4：10mM；KH2PO4：2mM；KCl：2.7mM；NaCl：137mM配成的磷酸盐缓冲液中(PH值调为6.0-8.0)，按照体积比3：97混合，在室温聚合120分钟，即可得到水凝胶。
本实施例制备的水凝胶经测试可自愈、可注射，室温干燥后显纤维状，冻干后具有微米多孔结构，该水凝胶的态样如图1中B所示。
实施例2
本实施例中水凝胶的制备方法如下：将二甲基亚砜溶解的抗菌肽J-1母液(100mM)，加入到由Na2HPO4：10mM；KH2PO4：2mM；KCl：2.7mM；NaCl：137mM配成的磷酸盐缓冲液中(PH值调为6.0-8.0)，按照体积比3：47混合，在室温聚合120分钟，即可得到水凝胶。
本实施例制备的水凝胶经测试可自愈、可注射，室温干燥后显纤维状，冻干后具有微米多孔结构，该水凝胶的态样如图1中C所示。
如图2所示，为本实施例制备的水凝胶的扫描电镜显微结构，A为抗菌肽J-1溶解于去离子水并在室温干燥后的电镜图片；B为抗菌肽J-1水凝胶在室温干燥后的电镜图片；C为抗菌肽J-1水凝胶在冷冻干燥后的电镜图片。
实施例3
本实施例中水凝胶的制备方法如下：将二甲基亚砜溶解的抗菌肽J-1母液(100mM)，加入到由Na2HPO4：10mM；KH2PO4：2mM；KCl：2.7mM；NaCl：137mM配成的磷酸盐缓冲液中(PH值调为6.0-8.0)，按照体积比1：10混合，在室温聚合30分钟，即可得到水凝胶。
本实施例制备的水凝胶经测试可自愈、可注射，室温干燥后显纤维状，冻干后具有微米多孔结构。
实施例4
本实施例中水凝胶的制备方法如下：将二甲基亚砜溶解的抗菌肽J-1母液(100mM)，加入到由Na2HPO4：10mM；KH2PO4：2mM；KCl：2.7mM；NaCl：137mM配成的磷酸盐缓冲液中(PH值调为6.0-8.0)，按照体积比1：5混合，在室温聚合5分钟，即可得到水凝胶。
本实施例制备的水凝胶经测试可自愈、可注射，室温干燥后显纤维状，冻干后具有微米多孔结构。
实施例5
本实施例中水凝胶的制备方法如下：将二甲基亚砜溶解的抗菌肽J-1母液(100mM)，加入到由Na2HPO4：10mM；KH2PO4：2mM；KCl：2.7mM；NaCl：137mM配成的磷酸盐缓冲液中(PH值调为6.0-8.0)，按照体积3：97混合，在37℃聚合10分钟，即可得到水凝胶。
本实施例制备的水凝胶经测试可自愈、可注射，室温干燥后显纤维状，冻干后具有微米多孔结构。
实施例6
本实施例中水凝胶的制备方法如下：将二甲基亚砜溶解的抗菌肽J-1母液(100mM)，加入到由Na2HPO4：10mM；KH2PO4：2mM；KCl：2.7mM；NaCl：137mM配成的磷酸盐缓冲液中(PH值调为6.0-8.0)，按照体积1：47混合，在37℃聚合5分钟，即可得到水凝胶。
本实施例制备的水凝胶经测试可自愈、可注射，室温干燥后显纤维状，冻干后具有微米多孔结构。
实施例7
本实施例中水凝胶的制备方法如下：将二甲基亚砜溶解的抗菌肽J-1母液(100mM)，加入到由Na2HPO4：10mM；KH2PO4：2mM；KCl：2.7mM；NaCl：137mM配成的磷酸盐缓冲液中(PH值调为6.0-8.0)，按照体积1：10混合，在37℃聚合2分钟，即可得到水凝胶。
本实施例制备的水凝胶经测试可自愈、可注射，室温干燥后显纤维状，冻干后具有微米多孔结构。
实施例8
本实施例中水凝胶的制备方法如下：将二甲基亚砜溶解的抗菌肽J-1母液(100mM)，加入到由Na2HPO4：10mM；KH2PO4：2mM；KCl：2.7mM；NaCl：137mM配成的磷酸盐缓冲液中(PH值调为6.0-8.0)，按照体积1：5混合，在37℃聚合1分钟，即可得到水凝胶。
本实施例制备的水凝胶经测试可自愈、可注射，室温干燥后显纤维状，冻干后具有微米多孔结构。
实施例9
本实施例中水凝胶的制备方法如下：将二甲基亚砜溶解的抗菌肽J-1母液(100mM)，加入到由Na2HPO4：9mM；KH2PO4：1.8mM；KCl：2.43mM；NaCl：123mM；ADP：1mM配成的磷酸盐缓冲液中(PH值调为6.0-8.0)，按照体积1：5合，在37℃聚合1分钟，即可得到水凝胶。
本实施例制备的水凝胶经测试可自愈、可注射，室温干燥后显纤维状，冻干后具有微米多孔结构。
二、水凝胶抗菌活性测定
以实施例2(记为水凝胶1)、实施例9(记为水凝胶2)制备方法得到的水凝胶为测试样品，抗菌实验所用菌株为革兰氏阴性菌E.coli(ATCC 25922)，革兰氏阳性菌S.aureus(ATCC 29213)，真菌C.albicans(ATCC 14053)。细菌所用培养基为Mueller-Hinton(MH)培养基，真菌所用培养基为Sabouraud dextrose(SD)培养基。测试时先取200uL抗菌肽水凝胶加入到1.5mL Eppendorf管中，然后向管中水凝胶上方小心加入400uL菌液(1*106cfu/mL)，然后置摇床中(转速为120rpm)在37℃培养。培养24h后取上清，测OD600，以各管中所取菌液的OD600为纵坐标作柱状图，以PBS溶液作为对照组。
如图3所示，为本发明的水凝胶和对照组对E.coli、S.aureus及C.albicans增殖的抑制作用柱状图。从图3中可以看出，与对照组相比，水凝胶1和水凝胶2均能显著抑制所测试细菌和真菌的增殖；在测试OD值前，各管中分别取100uL菌悬液，适当稀释后均匀涂布在准备好的培养板上，然后37℃培养过夜。如图4所示，为本发明的E.coli、S.aureus及C.albicans在培养板上的生长情况图。从图4中可以看出，对照组所取菌液在培养板上长满了菌落，而水凝胶1和水凝胶2的大肠杆菌、金黄色葡萄球菌及白色念珠菌均无菌落生长。
由此可以看出，本发明的水凝胶对细菌和真菌的生长和增值具有显著的抑制作用。
三、水凝胶体外、体内降解性测定
体外降解性测定：
以实施例2、实施例9制备方法得到的水凝胶(分别记为水凝胶1和水凝胶2)为测试样品，水凝胶的体外降解按以下操作方法进行：取200uL的水凝胶置于提前称好重量的1.5mL的EP管里，然后在水凝胶上面加入200μL PH值分别为6.4、7.4和8.4的PBS溶液，在37℃培养箱孵育24h后，吸去水凝胶上面的溶液，记录剩余水凝胶的质量；然后在EP管中再加入200μL PBS溶液，再次孵育，直至所有水凝胶全部降解。然后以各个PH环境管中的水凝胶完全分解时间为纵坐标做柱状图。
如图5所示，为本发明的水凝胶的体外降解性能图；其中，A列为水凝胶1和水凝胶2在体外不同PH环境中完全降解所需时间柱状图；B列为水凝胶1和水凝胶2在体外降解过程中，质量随时间变化曲线图。从图5中A中可以看出，在PH值为6.4的PBS缓冲液存在的情况下水凝胶1和水凝胶210天可以完全降解完，在PH值为7.4和8.4的PBS缓冲液存在的情况下水凝胶1和水凝胶2分别18天、20天降解完。以降解天数为横坐标、水凝胶质量为纵坐标作图，结果如图5中B列所示，从图中可以看出水凝胶1和水凝胶2的降解基本与时间呈线性降解。
体内降解性测定：
以实施例2、实施例9方法制备得到的水凝胶(分别记为水凝胶1和水凝胶2)为测试样品，对水凝胶的体内降解进行测定。相比于体外环境，体内环境更加复杂，涉及到多种组织液，酶及动物运动的影响。水凝胶在动物体内的降解测定是通过将水凝胶注射到小鼠皮下，其快速在注射部位恢复成胶，并通过B超超声检测水凝胶在小鼠皮下组织的残留情况。
如图6所示，为本发明的水凝胶在小鼠体内降解情况图；从左向右分别为水凝胶1和水凝胶2在注射1、3、5、10天后的B超超声图，从图中可以看出，水凝胶1和水凝胶2在动物体内可逐步降解，至第十天可基本完全降解。
由此可以看出，本发明的水凝胶可自愈、可注射、在体内和体外均能被降解，完全降解所需时间适中，能在充分达到药效后进行降解。
四、水凝胶生物相容性测定
以实施例2、实施例9制备方法得到的水凝胶(分别记为水凝胶1和水凝胶2)为测试样品。本发明水凝胶的生物相容性是通过测定其对哺乳动物细胞(所用细胞为小鼠成纤维细胞NIH3T3)毒性及其对人红细胞的溶血活性进行评价。
(1)具体地，对哺乳动物细胞的毒性通过MTT法进行测定，具体操作步骤如下：预先在96孔板中加入100uL的水凝胶，然后在水凝胶上方小心加入100uL的DMEM培养基平衡24h后吸去DMEM培养基，然后每孔接种5000个细胞(100uL)，在细胞培养箱孵育24小时，后加入MTT孵育4h，弃上清，每孔加入150uL的DMSO将甲瓒充分溶解，用酶标仪测OD570。阳性对照组采用与水凝胶1、水凝胶2具有相同抗菌肽J-1浓度的生理盐水溶液，记为溶液1和溶液2，阴性对照组采用DMEM培养基，其他实验方法一致。
如图7所示，为各实验组对小鼠成纤维细胞NIH3T3的增殖情况柱状图，。从图7的结果可以看出，小鼠成纤维细胞NIH3T3在水凝胶1和水凝胶2处理组孔中的增殖与阴性对照孔中基本相同，显示出极低的细胞毒性。
(2)测定水凝胶对人红细胞的溶血活性时，将水凝胶1、水凝胶2、溶液1(与水凝胶1具有相同抗菌肽J-1浓度的生理盐水溶液)、溶液2与水凝胶2具有相同抗菌肽J-1浓度的生理盐水溶液)，PBS(阴性对照组)及2％的Triton(阳性对照组)各取200uL分别加入到1.5mLEP管中，然后每管中加入800μL8％的人红细胞，在37℃培养箱中孵育1h后离心(1200g)，拍照观察血红素的释放程度；然后从每个管中取上清，测定OD490，定量计算溶血率。
如图8所示，为各实验组对人红细胞的溶血作用情况图。从图8的结果可以看出，本发明的水凝胶基本不表现溶血活性。
由此可以看出，本发明的水凝胶细胞毒性小，基本不表现溶血活性，具有良好的生物相容性。
五、水凝胶在大鼠腹壁-盲肠损伤粘连模型中防粘连活性测定
以实施例2、实施例9制备方法得到的水凝胶(分别记为水凝胶1和水凝胶2)为测试样品。测定水凝胶敷料术后抗粘连作用使用的大鼠为清洁级SD大鼠，所用大鼠在温度为22～24℃，相对湿度为45％～55％环境下单笼饲养，术前12小时对实验大鼠禁食。
腹壁-盲肠损伤粘连模型的建立：用(3mg/mL)戊巴比妥钠(麻醉剂量为1mL/100g)通过腹腔注射麻醉大鼠，然后将大鼠固定于加热手术台，下腹部备皮，消毒，铺巾，沿下腹部皮肤中心线做5cm切口。用止血钳夹住右侧腹壁，在腹壁内距离中心切口约1cm处首先用手术刀划出深度约0.5mm、大小约1cm×2cm的区域，之后使用眼科剪将该区域的浅层肌剥离，形成出血创面；然后在与腹壁创面相对应的盲肠表面用手术刷轻轻磨擦直到盲肠浆膜层被破坏至有明显的点状出血，至此腹壁盲肠缺损制作完成。然后用30缝合线将盲肠的肠系膜缝合固定于腹壁创面的右上角处，以保证腹壁和盲肠的创伤面相互之间能够充分接触，分组干预(分为对照组和水凝胶处理组，每组6只大鼠)，最后使用4-0缝合线对腹壁肌肉层和皮肤层分别进行连续缝合关腹，所有操作均在无菌条件下进行。
手术时对照组用生理盐水冲洗，水凝胶处理组在创面每只大鼠给予2mL水凝胶并涂抹均匀。术后7天，开腹发现对照组大鼠均形成了腹壁盲肠致密的粘连(见图9)，几乎所有大鼠粘连评分为5分；水凝胶1和水凝胶2处理组中均未发生粘连，且损伤的腹壁创面愈合良好，能看到轻微的浅色疤痕其面积明显小于初始创面，盲肠也基本恢复正常，部分可见轻微擦伤痕迹(见图10)，粘连评分为0，水凝胶组有一个发生粘连，但不是在创面粘连，而是手术切口与盲肠粘连。
术后7天对粘连组织进行分析，对照组大鼠标本HE染色结果显示腹壁和盲肠之间通过致密的粘连组织连接在一起，Masson染色结果显示在粘连区域有大量的胶原纤维存在(见图11)；在水凝胶1和水凝胶2处理组中，大鼠腹壁和盲肠的创面恢复良好，未发生粘连，创面表层已经出现层次清楚、均匀分布的新生间皮层，创面有部分炎性细胞浸润。通过Masson染色，在间皮细胞层下方可以看到不同程度的纤维化组织(见图11)。
由此可以看出，本发明的水凝胶防粘连活性良好。
六、水凝胶在小鼠肝脏出血模型中止血性能测定
以实施例2(PBS+肽水凝胶组)和实施例9(ADP+肽水凝胶组)的方法进行制备的水凝胶为测试样品。测定水凝胶止血性能所用小鼠为雄性昆明系小鼠，体重18-22g，所用小鼠在温度为22～24℃，相对温度为45％～55％环境下饲养，术前12h对实验小鼠禁食。
肝脏出血模型的建立：实验共分三组，分别为对照组、PBS+肽水凝胶组、ADP+肽水凝胶组，每组8只小鼠。用40mg/kg体重的戊巴比妥钠麻醉小鼠，然后将小鼠固定在手术台上，腹部备皮，使用碘伏对手术区域进行消毒；然后在腹部取一个直径为1.5cm左右的纵向切口，逐层分离，充分暴露肝脏右页，随后将事先称好重量的滤纸片垫在肝脏右页下方，用21G的针头将肝脏右页正中间刺穿，随后立即敷200uL水凝胶在伤口处(对照组不做任何处理)，拍照记录肝脏出血过程；记录肝脏出血时间；实验结束后取出滤纸片，称重，计算出血量。
如图12所示，为本实施例中各实验组的肝脏出血模型的止血情况图；其中，0s、60s和120s代表水凝胶的作用时间，从图12中可以看出PBS+肽水凝胶组和ADP+肽水凝胶组相较于不做任何处理的对照组止血作用明显。如图13所示，为本实施例中各实验组作用120s后小鼠肝脏的总出血量柱状图，从图13的结果可以看出，小鼠肝脏的出血量为ADP+肽水凝胶组＜PBS+肽水凝胶组＜对照组。如图14所示，为本实施例中各实验组小鼠出血时间柱状图，从图14的结果可以看出，小鼠肝脏在使用ADP+肽水凝胶25s后完全止血，在使用PBS+肽水凝胶组40s s后完全止血，在对照组不经处理的情况下则需要85s完全止血。
由此可以看出，本发明的水凝胶具有良好的止血作用。
综上所述，本发明的水凝胶可自愈、可注射、在体内和体外均能被降解，完全降解所需时间适中，能在充分达到药效后进行降解；对细菌和真菌的生长和增值具有显著的抑制作用，具有抗菌、抗炎活性及良好的止血性能；且具有细胞毒性小，基本不表现溶血活性，具有良好的生物相容性等优点；本发明的水凝胶防粘连活性良好，不粘连伤口，能在37℃快速交联，具良好的预防术后粘连的效果，在临床应用方面具有明显优势。
以上对本发明具体实施方式的描述并不限制本发明，本领域技术人员可以根据本发明作出各种改变或变形，只要不脱离本发明的精神，均应属于本发明所附权利要求的范围。
Claims (17)
1.一种水凝胶，其特征在于，所述水凝胶由抗菌肽与缓冲液经反应聚合而成，所述抗菌肽为以下氨基酸序列表示的多肽或其多肽衍生物：Pro-Phe-Lys-Leu-Ser-Leu-His-Leu-NH2。
2.根据权利要求1所述的水凝胶，其特征在于，所述水凝胶为微米多孔结构。
3.根据权利要求2所述的水凝胶，其特征在于，所述微米多孔结构的孔径为0.05μm-200μm。
4.根据权利要求1所述的水凝胶，其特征在于，所述缓冲液为磷酸盐缓冲液；所述抗菌肽与磷酸盐缓冲液的组分及配比以摩尔比计为抗菌肽：Na2HPO4：KH2PO4：KCl：NaCl＝(1-40)：(1-10)：(1-5)：(1-5)：(50-200)。
5.根据权利要求4所述的水凝胶，其特征在于，所述磷酸盐缓冲液的组分还包括二磷酸腺苷，以摩尔比计所述二磷酸腺苷与Na2HPO4的比例为(1-10)：(1-100)。
6.根据权利要求4所述的水凝胶，其特征在于，所述反应为离子交联聚合反应，反应温度为0-60℃，反应时间为1-120min。
7.一种根据权利要求1-6任一项所述的水凝胶的制备方法，其特征在于，所述水凝胶的制备方法包括以下步骤：
步骤S1：将抗菌肽溶于二甲基亚砜，得到抗菌肽的溶解液，备用；
步骤S2：将抗菌肽的溶解液加入至缓冲液中，在超声或搅拌条件下进行离子交联聚合反应，得到水凝胶。
8.根据权利要求7所述的水凝胶的制备方法，其特征在于，还包括以下步骤：
步骤S3：缓冲液中还加入药物和/或生长因子，得到负载药物或生长因子的水凝胶。
9.根据权利要求8所述的水凝胶的制备方法，其特征在于，所述药物为抗菌药物或消炎药物，所述生长因子为促伤口愈合生长因子。
10.根据权利要求7所述的水凝胶的制备方法，其特征在于，所述二甲基亚砜的体积含量小于5％。
11.一种根据权利要求1-6任一项所述的水凝胶在防粘连药物中的应用，其特征在于，所述防粘连药物包含负载有药物和/或生长因子的所述水凝胶和至少一种药学上可接受的药用载体和/或辅料。
12.根据权利要求11所述的应用，其特征在于，所述防粘连药物为片剂、胶囊、糖衣片剂、粒剂、滴剂、喷雾剂、冲洗剂、漱口剂、用于皮肤表面的油膏和药贴、以及用于注射的无菌溶液中的至少一种剂型。
13.根据权利要求11所述的应用，其特征在于，所述药物为抗菌药物或消炎药物，所述生长因子为促伤口愈合生长因子。
14.一种医疗器械，其特征在于，具有权利要求1-6任一项所述的水凝胶。
15.根据权利要求14所述的医疗器械，其特征在于，所述水凝胶涂覆于所述医疗器械的至少一个表面上形成材料。
16.根据权利要求14所述的医疗器械，其特征在于，所述医疗器械的形式为由医用敷料、纤维、网片、粉末、微球、薄片、海绵、泡沫、缝合锚定器械、导管、支架、外科手术平头钉、板和螺丝、药物递送器械、防粘屏障和组织粘合剂组成的群组中的任一者。
17.根据权利要求16所述的医疗器械，其特征在于，所述纤维为织物；所述薄片为膜或夹片；所述缝合锚定器械为缝合线或U形钉。
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| WO2022143217A1 (zh) * | 2020-12-30 | 2022-07-07 | 广州图微科创生物科技有限公司 | 医疗器械、水凝胶及其制备方法与应用 |
| CN115869459A (zh) * | 2021-09-27 | 2023-03-31 | 广州图微科创生物科技有限公司 | 促伤口愈合的多肽水凝胶及其制备方法与应用 |
| CN116942889A (zh) * | 2023-06-06 | 2023-10-27 | 广州图微科创生物科技有限公司 | 一种止血防粘连多肽水凝胶的制备方法 |
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Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2022143217A1 (zh) * | 2020-12-30 | 2022-07-07 | 广州图微科创生物科技有限公司 | 医疗器械、水凝胶及其制备方法与应用 |
| CN115869459A (zh) * | 2021-09-27 | 2023-03-31 | 广州图微科创生物科技有限公司 | 促伤口愈合的多肽水凝胶及其制备方法与应用 |
| CN114349870A (zh) * | 2022-03-21 | 2022-04-15 | 天津辅元生物医药科技有限公司 | 一种兼具防粘连功效的重组抗菌肽及其制备方法和应用 |
| CN114349870B (zh) * | 2022-03-21 | 2022-06-03 | 天津辅元生物医药科技有限公司 | 一种兼具防粘连功效的重组抗菌肽及其制备方法和应用 |
| CN116942889A (zh) * | 2023-06-06 | 2023-10-27 | 广州图微科创生物科技有限公司 | 一种止血防粘连多肽水凝胶的制备方法 |
| CN116942889B (zh) * | 2023-06-06 | 2024-02-02 | 广州图微科创生物科技有限公司 | 一种止血防粘连多肽水凝胶的制备方法 |
Also Published As
| Publication number | Publication date |
|---|---|
| KR20230126734A (ko) | 2023-08-30 |
| US20240058502A1 (en) | 2024-02-22 |
| WO2022143217A1 (zh) | 2022-07-07 |
| CN113577014B (zh) | 2023-03-24 |
| AU2021415951A1 (en) | 2023-07-27 |
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