CN114377211A - 基于壳聚糖人工肩袖补片及其制备方法 - Google Patents
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- CN114377211A CN114377211A CN202210062329.5A CN202210062329A CN114377211A CN 114377211 A CN114377211 A CN 114377211A CN 202210062329 A CN202210062329 A CN 202210062329A CN 114377211 A CN114377211 A CN 114377211A
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Abstract
一种基于壳聚糖人工肩袖补片，包括肩袖补片本体，PET补片基底层，含阿司匹林和塞来昔布之一种或几种壳聚糖为负载抗炎药物层，含VEGF和TGFβ之一种或几种壳聚糖为负载促愈合药物层，实现早期抑制炎症反应，在修复期促进成血管达到促进移植物整合的作用。
Description
技术领域
本发明属于组织修复领域，尤其涉及到一种基于壳聚糖人工肩袖补片，用于肩袖的修复，抑制炎症的发生和发展，利于进一步发挥促愈合作用，以及制取补片的方法。
背景技术
肩袖撕裂可引起关节疼痛、功能减弱、僵硬和活动范围限制，并使社会承担巨大的经济负担。巨大肩袖撕裂是指撕裂口＞5cm或者累及≥2根肌腱的肩袖损伤，目前治疗以手术修复为主。部分患者术后肩关节功能得到了极大的改善，但再撕裂率较高，可达15％～94％。再撕裂的原因与撕裂大小、血液供应、脂肪浸润、年龄、吸烟和肌肉萎缩等因素相关。有研究表明撕裂大小与再撕裂相关性较大，因为张力是导致肩袖修补手术失败的一项重要原因，因此巨大肩袖撕裂的手术方式仍然是一大难题，需要设计更好的方法来避免再撕裂的发生。应用肩袖补片替代缺损的肌腱，进行无张力或微张力修复被认为能够促进愈合，降低再撕裂的发生。
目前临床常常采取手术将移植材料替代和修补受损的软组织。当前常用的移植材料包括自体、异体和人工移植物三大类。其中自体或者异体移植组织由于具有良好的生物活性，因此，它们占据主要市场份额。临床主要利用自体或者移植组织主要进行两类手术。1、修复增强，当软组织例如韧带或者肌腱受损撕裂时，通过手术将自体或者异体组织例如阔筋膜等对受损的软组织进行缝合，利用自体或者异体组织的天然生物活性，诱导自身组织再生，实现恢复受损组织的原来功能。2、替代手术，当软组织例如韧带或者肌腱断裂无法进行缝合修补的时候，通过取自体异体的肌腱进行重建手术。但是不论是修复增强还是替代手术，因为受损的韧带或肌腱组织是维持身体运动的主要的力学结果，因此对于移植物的生物力学和生物活性都有着很高的要求，而且存在供区病损、异体反应、愈合时间长以及宿主携带疾病等风险，导致符合客观临床需求的自体或者异体移植组织不多。应用肩袖补片替代缺损的肌腱，进行无张力或微张力修复被认为能够促进愈合，降低再撕裂的发生。虽然人工肩袖补片具有生物力学方面的优势，但其存在异物反应或局部炎症等问题。因此改进人工补片性能，降低异物反应或炎症反应，促进人工补片的生物整合是人工补片研发的关键科学问题。
发明内容
本发明的一个目的是提供一种基于壳聚糖的促愈合人工肩袖补片，促进组织修复。
本发明的另一个目的是提供一种制取基于壳聚糖的促愈合人工肩袖补片的方法，随着壳聚糖的降解缓慢释放药物，以及生长因子等，实现早期抑制炎症反应，在修复期促进成血管达到促进移植物整合的作用。
本发明的技术方案如下：
一种肩袖补片，包括肩袖补片本体，所述肩袖补片本体包括：
补片基底层，为PET(聚对苯二甲酸乙二醇酯)层；
负载抗炎药物层，由壳聚糖制成，含阿司匹林和塞来昔布之一种或几种；
负载促愈合药物层，由壳聚糖制成，含VEGF和TGF-β之一种或几种；
负载抗炎药物层设置于负载促愈合药物层上，负载促愈合药物层覆于补片基底层上。
优选的是，还包括设置在所述肩袖补片本体四周的缝合区，其上具有若干缝合孔以与待修复部位缝合。
本发明的肩袖补片，其制备方法包括以下步骤：
将含TGF-β的壳聚糖静电纺膜和含阿司匹林或塞来昔布的壳聚糖水凝胶覆盖在所述PET补片基底层上，得到人工肩袖补片成品。
优选的是，所述基于壳聚糖人工肩袖补片的制备方法中，所述PET补片预处理包括：
将PET补片(或剪成预定长度)浸泡在75wt％乙醇溶液中，并超声处理30分钟，超声结束后用去离子水冲洗PET补片表面，以除去PET补片表面杂质；将清洁后的PET补片在真空干燥箱中室温干燥至恒重。
优选的是，所述壳聚糖微球载体采用以下步骤制成：
称取2g壳聚糖溶解于100ml 0.2mol/L的醋酸溶液中，同时，取液体石蜡于容器中作为油相，加入表面活性剂Span 80、Tween80(5:2.质量比)作为复配型乳化剂，搅拌均匀后，升温至40℃,600～650r/min转速搅拌条件下，将壳聚糖醋酸溶液缓慢加入到复配型乳化剂中，乳化形成油包水乳液，然后将饱和的戊二醛-甲苯溶液分两次逐滴加入乳液，交联固化后，将产物经离心分离，并用无水乙醇洗涤1次、石油醚反复洗涤3次，最后在丙酮中分散后于室温干燥得到壳聚糖微球。
优选的是，所述基于壳聚糖人工肩袖补片的制备方法中，所述负载TGF-β或VEGF的壳聚糖电纺纤维膜采用以下步骤制成：
将0.90g壳聚糖、0.10g聚丙烯酸钠溶于质量分数为10％的乙酸溶液中加入0.5mLTGF-β溶液，搅拌24小时后得到含有TGF-β的壳聚糖静电纺溶液。设定环境温度为25℃、湿度为60％，连接静电纺丝装置。将电纺溶液放入带直径0.7mm针头的2ml注射器中，调整溶液的流速为3.0m/h、电压为15kV、接收距离为15cm，收集纺丝制成载TGF-β的壳聚糖电纺纤维膜。制成的电纺纤维膜置于真空容器内干燥过夜待用。
优选的是，所述基于壳聚糖人工肩袖补片的制备方法中，所述的抗炎药物层，采用负载塞来昔布/阿司匹林的壳聚糖水凝胶，以下步骤制成：
将壳聚糖加入1v/v％的乙酸溶液(壳聚糖微球与乙酸的体积比为1∶50)，密封后搅拌1h，制备壳聚糖溶液。将聚乙烯醇水溶液与壳聚糖溶液以6∶4的质量比混合，按15∶1的质量比在混合溶液中加入质量分数为10％的Tween80混匀，之后干燥1h以去除气泡。然后导入容器内，密封后置于－20℃冷冻箱中20h；取出后室温下融化8h，此过程重复7次。在容器内加入1wt％NaOH溶液浸泡12h，加入0.9％氯化钠溶液调整pH至中性，制得未载药的壳聚糖水凝胶，将6mg/ml塞来昔布溶液及3.1mg/ml阿司匹林抽滤溶液加入壳聚糖水凝胶中，振荡混匀即得。
本发明具有以下有益效果：
最外层壳聚糖负载抗炎药物，释放周期约为3-5天，内层为负载促愈合的壳聚糖电纺纤维膜，缓释周期约为1-2周。
通过将PET补片基底层结合壳聚糖能够缓减补片植入后引起的异物反应。
壳聚糖的活性吸附中心是表面自由氨基，许多无机酸、有机酸和酸性化合物，甚至两性化合物，都能被壳聚糖吸附结合。人体内存在的葡萄糖胺。而乙酰葡萄糖胺是体内透明质酸的基本组成单位。因此壳聚糖对人体细胞有很好的亲和性，不会产生排斥反应。
壳聚糖分子中具有活性的-NH2侧基，可以通过化学方法被酸化成盐、导入羟基，得到具有水溶性、醇溶性、表面活性等各种功能的壳聚糖衍生物材料。活性的-NH2.，侧基还可以先与过渡金属离子形成配合物，然后交联制备具有模板剂记忆力和选择吸附性能的壳聚糖衍生物材料，这类材料具有良好的血液相容性、生物相容性、生物官能性，在医学领域对细胞组织不产生毒性。
可以利用壳聚糖分子上的OH和-NH2：发生化学反应制备具有抑菌活性的N，O-羟甲基化壳聚糖，其中相对分子质量对抑菌活性有显著影响，如随相对分子质量的降低抑菌活性显著增强，相对分子质量低于5000时，材料对金黄色葡萄球菌抑制杀灭作用明显。
用壳聚糖作为药物载体可以稳定药物中的成分，促进药物吸收，延缓或控制药物的溶解速度，帮助药物达到靶器官，并且抗酸、抗溃疡，防止药物对胃的刺激。
壳聚糖可用于制备微球，制成的微球黏附性好。壳聚糖微球表面富有多糖链，能被特异性细胞或组织所识别，可靶向投递药物至病灶部位贮存、释放；壳聚糖微球表面可接功能基团，以吸附或包裹的方式灵活负载不同药物。壳聚糖载药微球药物释放与壳聚糖分子量有关，一般药物的释放速率随壳聚糖的分子量增大而减小，且壳聚糖浓度越高，药物从壳聚糖中扩散进入生物介质的速率越低。
壳聚糖载药微球最重要的应用就是临床给药。在肌腱韧带手术治疗过程中，为如果直接给予药物，药物的快速弥散将无法使损伤局部达到理想的给药浓度，因而往往需要超剂量注射，这可能导致不必要的药物副作用。类似地，如果将药物直接吸附或接枝到支架材料上，通常需要高浓度的药物以达到持续释放的效果，与此同时还需要注意药物突释的风险，而使用壳聚糖包裹缓释药物能有效减少给药次数，控制药物的释放速率，延长药物的作用时间，在一段时间内维持有效的药物浓度，降低药物的毒副作用，让病人更容易配合治疗。
本发明的其它优点、目标和特征将部分通过下面的说明体现，部分还将通过对本发明的研究和实践而为本领域的技术人员所理解。
附图说明
图1为本发明提供的人工肩袖补片的一个实施例的结构示意图；
图2为免疫组织化学IL-1β表达结果图；
图3为PET壳聚糖涂层载抗炎症和促愈合药物组的组织染色图。
具体实施方式
下面结合附图对本发明做进一步的详细说明，以令本领域技术人员参照说明书文字能够据以实施。
应当理解，本文所使用的诸如“具有”、“包含”以及“包括”术语并不配出一个或多个其它元件或其组合的存在或添加。
本实施例提供的肩袖补片，以PET为基底层补片层，补片基底层由PET直接压制或者复丝编织而成。
肩袖补片的厚度为2mm，具有三种尺寸：4×6×2、4×4×2，3×4×2，四周有缝合区及缝合孔。经线较纬线密，上下有一定拉伸距离，但左右相对固定；上下各有一根带子，术中可塞组织，不需缝合，以贴合为主。
在一个实施例中，还包括设置在肩袖补片本体四周的缝合区，其上具有若干缝合孔以与待修复部位缝合。
在一个实施例中，肩袖补片本体上还覆盖有壳聚糖电纺纤维膜和水凝胶，用于装载抑制炎症的分子和促愈合的分子。
实施例1补片的制备
将含TGF-β的壳聚糖静电纺膜和含阿司匹林或塞来昔布的壳聚糖水凝胶覆盖在所述PET补片基底层上，得到人工肩袖补片成品。
将PET补片剪成预定长度后浸泡在75wt％乙醇溶液中，并超声处理30分钟，超声结束后用去离子水冲洗PET补片表面，以除去PET补片表面杂质；将清洁后的PET补片在真空干燥箱中室温干燥至恒重。
载TGF-β的壳聚糖电纺纤维膜由壳聚糖微球与TGF-β制成电纺液后，再由静电纺制成。壳聚糖微球载体采用以下步骤制成：
称取2g壳聚糖溶解于100ml 0.2mol/L的醋酸溶液中。同时，取一定量的液体石蜡于烧杯中作为油相，按质量比5:2加入表面活性剂Span 80和Tween80作为复配型乳化剂，搅拌均匀后，升温至40℃，转速600～650r/min搅拌条件下，将醋酸溶液缓慢逐滴加入到复配型乳化剂中，乳化形成稳定的油包水乳液，然后将饱和的戊二醛-甲苯溶液分两次逐滴加入乳液，交联固化后，将产物经离心分离，并用无水乙醇洗涤1次、石油醚反复洗涤3次，最后再丙酮中分散后于室温干燥得到壳聚糖微球。
采用以下步骤制成：
取1μg TGF-β，800r/min离5min，加入20μL柠檬酸(10mmol/L)调节pH值为3.0室温放置10min后加入5mL含适量牛血清白蛋白的PBS，制成浓度为200μg/L的TGF-β溶液。
将0.90g壳聚糖微球、0.10g聚丙烯酸钠溶于质量分数为10％的乙酸溶液中并加入TGF-β溶液0.5ml，搅拌24小时后得到含TGF-β的壳聚糖溶液，作为静电纺溶液。设定环境温度为25℃、湿度为60％，连接静电纺丝装置。将电纺溶液放入带直径0.7mm针头的2ml注射器中，调整溶液的流速为3.0m/h、电压为15kV、接收距离为15cm，收集纺丝制成载TGF-β的壳聚糖电纺纤维膜。制成的电纺纤维膜置于真空容器内干燥过夜待用。
负载抗炎药物层，采用壳聚糖水凝胶，负载阿司匹林和/或塞来昔布采用以下步骤制成：
在超纯水中加入5g的聚乙烯醇并加热至60℃，20min后可见明显溶胀的聚乙烯醇，置于磁力搅拌器上90℃搅拌3h，配制聚乙烯醇水溶液。在洁净的烧杯中加入1g的壳聚糖，在通风厨中加入1v/v％的乙酸溶液(壳聚糖与乙酸的体积比为1∶50)，密封后于磁力搅拌器上搅拌1h，制备壳聚糖溶液。将聚乙烯醇水溶液与壳聚糖溶液以6∶4的质量比混合，按15∶1的质量比在混合溶液中加入表面活性剂聚山梨酯80磁力搅拌30min，之后置于真空干燥箱中1h以去除气泡。然后导入无菌24孔板内，每孔约2mL混合液，密封后置于－20℃冷冻箱中20h；取出后室温下融化8h，此过程重复7次。在24孔板内加入少许1％NaOH溶液浸泡12h，加入0.9％氯化钠溶液调整pH至中性，最后置于超纯水中保存。扫描电镜下观察壳聚糖复合水凝胶的微观结构。将6mg/ml塞来昔布溶液及3.1mg/ml阿司匹林抽滤溶液缓慢加入壳聚糖复合水凝胶中，振荡混匀。
图1是本发明制得补片一实施例的示意图，包括PET补片基底层1，以及第一壳聚糖负载抗炎药物层4、第二壳聚糖负载生物因子层2、第三壳聚糖负载生物因子层3和和第四壳聚糖负载抗炎药物层5。抗炎药物为阿司匹林和塞来昔布之一种或几种。
实施例2性能测试
动物实验分组：a.PET组；b.PET壳聚糖涂层载抗炎症和促愈合药物组。
补片的编织：补片两端进行缝线编织，使其用于缝合肩袖残端和肱骨头端固定。补片编织后的大小为长10mm宽4mm，厚2mm，适用于兔冈下肌肌腱缝合模型。将缝合好的补片进行生物力学测试，满足兔冈下肌撕裂最大需求约130N。
①2.5-3.5kg新西兰大白兔，麻醉好后肩关节备皮，冈下肌腱上方作约4cm平行切口，逐层钝性分离，暴露冈下肌腱。紧贴肱骨止点将冈下肌切除，作约6mm缺损。
②将补片与冈下肌残端进行4mm重叠缝合，在肱骨头止点处作2个1mm骨道，穿入另一端补片缝线，将补片固定于肱骨头止点处。逐层缝合，切口消毒，注射青霉素，术毕。
③术后笼养，不限制活动。术后1、6、12周进行局部抗炎监测(免疫组化)，组织学观察(HE、Masson)，冈下肌脂肪浸润，生物力学测试。
一周后a组和b组免疫组织化学IL-1β表达结果参见图2所示。1周后b组免疫组化炎性反应低；6周时b组血管显著更多，6周、12周b组的组织学HE染色结果显示补片周围胶原纤维更为有序，厚度更厚(图3)。12周时最大拉力：PET壳聚糖涂层载抗炎症和促愈合药物组为：130.76±28.55N，PET组为：77.22±7.98N。
尽管本发明的实施方案已公开如上，但其并不仅仅限于说明书和实施方式中所列运用，它完全可以被适用于各种适合本发明的领域，对于熟悉本领域的人员而言，可容易地实现另外的修改，因此在不背离权利要求及等同范围所限定的一般概念下，本发明并不限于特定的细节。
Claims (8)
1.一种基于壳聚糖人工肩袖补片，包括肩袖补片本体，其特征在于，由上至下包括：
第一壳聚糖负载抗炎药物层；
第二壳聚糖负载生物因子层；
补片基底层，为PET补片基底层；
第三壳聚糖负载生物因子层；和
第四壳聚糖负载抗炎药物层；
抗炎药物为阿司匹林和塞来昔布之一种或几种；
生物因子为含VEGF和TGF-β之一种或几种。
2.如权利要求1所述的基于壳聚糖人工肩袖补片，其特征在于，还包括设置在所述肩袖补片本体四周的缝合区，其上具有若干缝合孔以与待修复部位缝合。
3.如权利要求1所述的基于壳聚糖人工肩袖补片的制备方法，其特征在于，采用壳聚糖微球与抗炎药物制成电纺液后，再制成静电纺纤维膜。
4.如权利要求3所述的基于壳聚糖人工肩袖补片的制备方法，其特征在于，所述的壳聚糖微球的制备方法如下：
称取2g壳聚糖溶解于100ml 0.2mol/L的醋酸溶液中，同时，取液体石蜡于容器中作为油相，按5:2质量比加入表面活性剂Span 80和Tween80作为复配型乳化剂，搅拌均匀后，升温至40℃，转速600～650r/min搅拌，将壳聚糖醋酸溶液缓慢加入到复配型乳化剂中，乳化形成油包水乳液，然后将饱和的戊二醛-甲苯溶液分两次逐滴加入乳液，交联固化后，将产物经离心分离，并用无水乙醇洗涤1次、石油醚反复洗涤3次，最后在丙酮中分散后于室温干燥得到壳聚糖微球。
5.如权利要求3所述的基于壳聚糖人工肩袖补片的制备方法，其特征在于，包括以下步骤：
将分别含有生物因子的壳聚糖电纺纤维膜，以及抗炎药物的壳聚糖水凝胶，并依次覆盖在所述PET补片基底层上，得到人工肩袖补片成品。
6.如权利要求5所述的基于壳聚糖人工肩袖补片的制备方法，其特征在于，所述的PET补片基底层经如下方法预处理：
将PET补片基底层浸泡在75wt％乙醇溶液中，并超声处理，超声结束后用去离子水冲洗PET补片基底层表面，以除去PET补片基底层表面杂质。
7.如权利要求3所述的基于壳聚糖人工肩袖补片的制备方法，其特征在于，将0.90g壳聚糖、0.10g聚丙烯酸钠溶于24g乙酸/三氟乙酸混合溶剂中，并加入0.5mL TGF-β溶液搅拌24小时后得到含有TGF-β的壳聚糖静电纺溶液，连接静电纺丝装置，调整溶液的流速、电压和接收距离，收集纺丝制成载TGF-β的壳聚糖电纺纤维膜。
8.如权利要求3所述的基于壳聚糖人工肩袖补片的制备方法，其特征在于，按壳聚糖微球与乙酸的体积比1∶50将壳聚糖加入1v/v％的乙酸溶液，密封后搅拌，制备壳聚糖溶液，将聚乙烯醇水溶液与壳聚糖溶液以6∶4的质量比混合，按15∶1的质量比在混合溶液中加入聚山梨酯80混匀，之后干燥1小时以去除气泡；
然后导入容器内，密封后置于－20℃冷冻箱中20小时，取出后室温下融化8小时，此过程重复7次；
在容器内加入1wt％NaOH溶液浸泡12小时，加入0.9％氯化钠溶液调整pH至中性，制得未载药的壳聚糖水凝胶，将6mg/ml塞来昔布溶液及3.1mg/ml阿司匹林抽滤溶液加入壳聚糖水凝胶中，振荡混匀即得。
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