CN109789249B - 多功能疝气贴片 - Google Patents
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Abstract
本发明涉及具有抗粘连、抗菌和止血特性的外科植入物，以用于疝气修复。这些植入物包括：a)双层腹膜内网，其具有一定的厚度和孔隙率，通过PP网与涂覆于PP层上的可生物降解的聚酯基聚合物和多糖的共混体系的组合制备，通过静电纺丝技术将所述共混体系作为纳米纤维涂覆于PP层上，以及，b)双层和/或三层腹膜外复合网，其由可生物降解的聚酯基聚合物和/或多糖的共混体系通过不同的涂覆方法形成于PP/聚酯编织材料上制备。
Description
技术领域
本发明公开了一种具有抗粘连、抗菌和止血特性的复合网，所述复合网在腹膜内和腹膜外疝气手术后使用，以加速组织再生和避免术后并发症。使用静电纺丝和编织方法设计网状复合材料。
背景技术
作为物理屏障并防止组织粘连的膜被称为“抗粘连膜”。在腹膜内和盆腔手术后经常观察到组织粘连。创伤、感染、疼痛和功能障碍是患者在此类手术后愈合过程中的其他主要问题[Linsky et al.,1991,Matsuzaki et al.,2014]。特别是在疝气手术后，许多的这些并发症是常见的并且需要额外的医学治疗或甚至第二次手术来移除网状植入物[Lim etal.,2008,Collage et al.,2010]。因此，在手术期间使用抗粘连膜以避免或减少危险的并发症[Oesser et al.,2013,Obayan et al.,2013]。可生物降解的材料通常是优选的，因为它们在没有医学干预的情况下从体内移除[Oesser et al.,2013]。可单独使用或组合使用多糖、蛋白质、氧化再生纤维素、羧甲基纤维素钠、硫酸葡聚糖、透明质酸、硫酸软骨素、聚乙醇酸和聚乳酸[Lee et al.,2006]。但是，在临床应用中来自非生物降解材料的膜也是常见的。这些避免粘连的材料可以以许多不同的形式设计[Stopek et al.,2013],例如，溶液、凝胶或膜[Kim et al.,2015]。由于材料的实际固定，固体形式的抗粘连膜优于凝胶、发泡或液体剂型[Lee et al.,2006]。
现代疝气手术的基础始于1958年Usher(Polyamide贴片)使用合成贴片(聚酰胺贴片)。之后，使用编织聚酯贴片、聚丙烯网、可膨胀聚四氟乙烯(PTFE)贴片，这些产品已被置于腹壁疝气修复的历史过程中[Usher et al.,1963]。从1900年代到今天，已经引入各种贴片材料。1962年，随着单丝聚丙烯贴片的使用，30-50％的切口疝气复发率开始逐渐下降。
由于既可减少手术后患者的不适感，又可减少疝气复发的可能性，在疝气治疗中，用贴片修复是最广泛使用的方法[Rodgers et al.,2000,Arroya et al.,2001]。
合成材料最早可以在1959年安全使用[Klosterhalfen et al.,2005]，到现在已经发布开发了不同的材料。对于哪种材料是理想的贴片，研究人员和临床医生之间没有的共识。在感染不可避免的情况下从身体的相关区域去除PTFE网。初次修复后，观察到切口疝气复发率为50％。用网进行切口疝气修补是已得到所有外科医生的认可的标准治疗[Leberet al.,1998]。
广泛用于治疗疝气的复合网是最常用的治疗方法。当使用现有复合网遇到的困难时，几乎所有户外手术中面临的主要问题是发生感染、出血、生物材料和组织不相容。在这一领域，由聚合物和生物材料市场开发的不同结构和特征定义了“复合贴片”，其在组织-生物材料相容性方面给出了满意的结果，但是，尚未开发出具有所需特性的理想网。复合网用于腹膜内和腹膜外手术。用于腹膜内手术的复合网通常是双层的，其源自例如PP等不可生物降解的层和另一包含内脏粘连风险最小化的层。由于内脏粘连发生在术后的第1-2周，另一侧可包含可生物降解的聚合物以及永久性聚合物。用于腹膜外手术的复合网通常具有均匀的复合结构，以表明腹壁上整个材料的相同特性。
静电纺丝法是获得高表面/体积比的合适方法[Lee et al.,2006]。在该方法中，通过改变电压、溶液浓度、流速、针尖和收集器之间的距离，可以实际获得具有所需厚度和孔径的纳米纤维。另外，孔隙率是组织生长和再生的重要参数，因此，这种方法是有利的。
US专利号5,002,551中，将氧化再生纤维素织物用于预防手术后的腹膜内粘连，然后，为了确定其影响，在兔子的体内研究2周后处死兔子，据报道粘连降低。EU专利号0 262890 A2中，设计含有肝素的氧化再生纤维素用作防粘连膜。该膜在手术活动区域和邻近组织之间提供了物理屏障性质，也表明它没有毒性并且具有抗粘连作用。
US专利号5,364,622中，含有组织型纤溶酶原激活物(tPA)的羟乙基纤维素水凝胶用于避免在手术后可能发生的器官粘连，并且它具有抗粘连作用。
US专利号6,630,167B2描述了含有非交联透明质酸、交联透明质酸和两者的水溶液混合物泡沫溶液的泡沫。从这些溶液中获得抗粘连膜。
US专利号6,150,581中描述了一种方法，其中通过喷射法在狗腹壁上的缺损区域涂覆藻酸盐溶液，然后涂覆藻酸盐的表面区域再涂覆壳聚糖溶液以去除施用区域的粘连。
US专利号5,795,584中，由合成的可生物降解的共聚物产生的膜通过用PTFE涂覆的板的压印设置于聚丙烯(PP)网上，并因此作为多层屏障获得。在该研究中使用的聚合物是乙交酯/三亚甲基碳酸酯、乙交酯/丙交酯、乙交酯/丙交酯/三亚甲基碳酸酯共聚物。
US专利号2001/0008930A1和US专利号5,614,587研究中，作为具有生物相容性、无毒和可生物降解特征的蛋白质的胶原用作术后防粘连材料。
专利号WO2007/029913A1中，通过静电纺丝法设计了具有含有纳米尺寸纤维和防粘连性的亲水和疏水层的多层膜。疏水层由肽、氨基酸、多糖、聚原酸酯、聚碳酸酯、聚酰胺酯、聚α-氰基丙烯酸酯和聚磷腈中的至少一种组成。
US专利号2002/0173213A1公开了可生物降解和/或可吸收的材料，其通过静电纺丝法从聚合物中作为纤维中获得以减少术后粘连。该研究使用乙交酯、丙交酯、二噁烷、己内酯、三亚甲基碳酸酯，并且包含乙二醇和赖氨酸作为可生物吸收单体，并且这些单体也可以用于形成均聚物或共聚物。
中国专利号102908677A描述了一种疝气贴片，其获得自静电纺丝法，在聚乳酸-乙醇酸共聚物(PLGA)层上含有聚己内酯(PCL)，以减少施用区域的粘连性。
技术问题
用作粘连屏障的水凝胶和固体膜已引入市场超过30年。另一方面，标准网和具有抗粘连性的材料的组合是一个更新的领域。可生物降解或不可生物降解的网可以是单层或多层，用于避免粘连。然而，这些材料没有抗菌和/或止血特性以避免术后并发症。
技术方案
为了解决上述问题，本研究旨在通过新开发的具有抗粘连、抗菌和止血性能的多功能生物材料来避免例如感染、粘连形成和出血等术后并发症。
有益效果
除抗菌、止血和抗粘连性外，开发的产物还可应用于工业领域。因此，具有这些性质的所得产物对本发明具有重要意义。
最佳模式
本发明的最佳模式是设计的复合层，其是在PP网上的含有10重量％和30重量％壳聚糖的PLGA共混体系。但是，本发明不应受到这些实施例的限制。
工业实用性
本发明的抗粘连屏障特征具有工业实用性。具有无毒、抗菌、止血和组织再生特性的多层网可以解决术后并发症的问题，从而在应用于手术区域时给出最佳的便利结果。
发明内容
本发明开发了两种可用于腹膜内和腹膜外疝气手术的复合网。两种网都加速组织再生并具有抗粘连、抗菌、止血特性。产品描述如下：
·对于腹膜内应用；将涂覆的聚合物共混体系通过静电纺丝法施用于具有特定孔间距的PP网状编织材料上以获得双层膜，所述共混体系用聚酯基聚合物和壳聚糖制备。聚酯基聚合物可以是聚乙醇酸、聚乳酸、聚乙醇酸-乳酸共聚物、聚三亚甲基碳酸酯、聚乙醇酸-三亚甲基碳酸酯共聚物(polyglycolic-co-trimethylene carbonate)、聚乳酸-三亚甲基碳酸酯共聚物、聚己内酯、聚乙醇酸-己内酯共聚物、聚乳酸-己内酯共聚物、聚三亚甲基碳酸酯-己内酯共聚物(politrimetilencarbonate-co-caprolactone)。
·对于腹膜外应用；通过编织单丝或复丝聚酯、聚丙烯基纱线并用壳聚糖涂覆以获得复合材料网。
附图说明
图1.由单丝纱线获得的PP网的显微镜图像
图2.通过编织复丝聚酯、聚丙烯基纱线获得的复合材料网的显微镜图像
图3.单丝PP网的横截面SEM图像
图4.通过静电纺丝法用多糖涂覆的单丝PP网的横截面SEM图像
图5.通过静电纺丝法用多糖涂覆的PP网的表面SEM图像
图6.通过静电纺丝法用PLGA/壳聚糖50％涂覆的PP网的表面SEM图像
图7.通过静电纺丝法用聚酯/多糖共混体系涂覆的PP网的植入图
图8.含有PP网状植入物的体内研究照片
图9.用PLGA/壳聚糖30％涂覆的PP网的体内研究照片
具体实施方式
在本发明中，开发用于腹膜内和腹膜外应用的生物相容性、抗菌、止血和抗粘连网。制备步骤和所得产品的细节如下所示。
方法步骤：
步骤1.溶液和共混体系的制备
·在HFIP/乙酸(8:2v/v)溶剂混合物中制备6重量％的壳聚糖和PLGA溶液，并在环境条件下用磁力搅拌器搅拌所得共混溶液12小时。在制备的共混体系中，聚酯与多糖的重量比为50:50。进行过滤以除去未溶解的壳聚糖颗粒。
·在HFIP/乙酸(8:2v/v)溶剂混合物中制备8重量％的壳聚糖和PGA溶液，并在环境条件下用磁力搅拌器搅拌所得共混溶液12小时。在制备的共混体系中，聚酯与多糖的重量比为50:50。进行过滤以除去未溶解的壳聚糖颗粒。
·在TFA溶剂中制备3重量％的壳聚糖溶液。在环境条件下用磁力搅拌器进行溶解过程12小时。
·在HFIP溶剂中制备15重量％的PLGA溶液。在环境条件下用磁力搅拌器进行溶解过程12小时。
·在HFIP溶剂中制备5重量％的PGA溶液。在环境条件下用磁力搅拌器进行溶解过程12小时。
·在HFIP溶剂中制备4重量％的壳聚糖和PLGA溶液，并在环境条件下用磁力搅拌器搅拌12小时。在制备的共混体系中多糖的比例为总物质的约30％。进行过滤以除去溶解的壳聚糖颗粒。
·在HFIP溶剂中制备6重量％的壳聚糖和PLGA溶液，在环境条件下用磁力搅拌器搅拌12小时。在制备的共混体系中多糖的比例为总物质的约10％。进行过滤以除去溶解的壳聚糖颗粒。
步骤2.静电纺丝共混体系的应用
将溶液和共混体系放入注射器中，并将其置于静电纺丝装置的泵中。然后将PP网涂覆于铝圆筒上；应用优化的电压参数值、针尖与收集器之间的距离和流速。随着铝圆筒的旋转，在PP网上均匀地收集纤维结构。收集所需量的产物后，将双层网在40℃真空烘箱中完全干燥1天。
步骤3.编织复合网的制备和涂覆方法
使用通过编织方法的单丝PP和复丝PGA纱线设计用于腹膜外应用的复合网。
·使用“浸涂”方法将壳聚糖溶液涂覆于设计的网。在2％乙酸溶液中制备2％浓度的壳聚糖。进行过滤以从所得溶液中除去未溶解的壳聚糖颗粒。将制备的溶液置于培养皿中，并将网浸入溶液中。在涂覆两面后，将网在真空烘箱中干燥。将干燥的网在1M NaOH溶液中中和，然后在真空烘箱中再次干燥。
在以上实施例中详述本发明，但本发明不限于本文所述的实施例。
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Claims (13)
1.具有生物相容性、抗菌性、止血性和抗粘连性的复合网，所述复合物包含不可降解的网；所述网通过可生物降解的聚酯基聚合物/壳聚糖混合物于六氟异丙醇(HFIP)溶剂中的共混体系，并通过静电纺丝法作为纳米纤维涂覆于聚丙烯层上制备。
2.根据权利要求1所述的网，其中使用的聚酯是聚乙醇酸、聚乳酸、聚乙醇酸-乳酸共聚物、聚三亚甲基碳酸酯、聚乙醇酸-三亚甲基碳酸酯共聚物、聚乳酸-三亚甲基碳酸酯共聚物、聚己内酯、聚乙醇酸-己内酯共聚物、聚乳酸-己内酯共聚物、聚三亚甲基碳酸酯-己内酯共聚物。
3.根据权利要求1所述的网，其中所述聚酯的分子量(Mn)为10000-1000000Da。
4.根据权利要求1所述的网，其中制备的共混体系中聚酯/壳聚糖混合物与HFIP的重量比为1-90％。
5.根据权利要求1所述的网，其中制备的共混体系中壳聚糖与聚酯的重量比为0.1-99.1％。
6.根据权利要求1所述的网，其中所用的聚酯优选为聚乙醇酸-乳酸共聚物(PLGA)。
7.根据权利要求1所述的网，其中制备的共混体系中壳聚糖/聚酯混合物的溶液量为4重量％。
8.根据权利要求7所述的网，其中对于制备的具有HFIP的共混体系，壳聚糖/聚酯混合物中的壳聚糖的重量比为30％。
9.根据权利要求1所述的网，其中制备的共混体系中的壳聚糖/聚酯混合物的溶液量为6重量％。
10.根据权利要求9所述的网，其中对于制备的具有HFIP的共混体系，壳聚糖/聚酯混合物中的壳聚糖的重量比为10％。
11.根据权利要求1所述的网，其中聚丙烯/聚酯编织材料的聚酯丝的数目是1-100。
12.根据权利要求1所述的网，其中聚酯/壳聚糖层的孔隙率为10-80％，且聚酯/壳聚糖层的孔径为10nm-10微米。
13.根据权利要求1所述的网，其中通过静电纺丝制备的聚酯/壳聚糖的纳米纤维的直径为10-1000nm。
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| CN110354306B (zh) * | 2019-08-12 | 2021-10-01 | 天津百和至远医疗技术有限公司 | 纤维支架及其制备方法 |
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2016
- 2016-06-15 EP EP16736622.8A patent/EP3471791B1/en active Active
- 2016-06-15 US US16/310,454 patent/US20190321154A1/en not_active Abandoned
- 2016-06-15 WO PCT/IB2016/053534 patent/WO2017216609A1/en unknown
- 2016-06-15 CN CN201680088093.5A patent/CN109789249B/zh not_active Expired - Fee Related
- 2016-06-15 JP JP2018565853A patent/JP2019517892A/ja active Pending
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| Publication number | Priority date | Publication date | Assignee | Title |
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| WO2008075398A2 (en) * | 2006-12-20 | 2008-06-26 | Di.Pro S.A.S. Di Buemi Enrico & C. | Surgical prosthesis including a woven mesh for surgical use and a method of manufacturing thereof |
Also Published As
| Publication number | Publication date |
|---|---|
| JP2019517892A (ja) | 2019-06-27 |
| EP3471791B1 (en) | 2020-08-05 |
| WO2017216609A1 (en) | 2017-12-21 |
| CN109789249A (zh) | 2019-05-21 |
| EP3471791A1 (en) | 2019-04-24 |
| US20190321154A1 (en) | 2019-10-24 |
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