Chinese Journal of Tissue Engineering Research ›› 2017, Vol. 21 ›› Issue (2): 303-308.doi: 10.3969/j.issn.2095-4344.2017.02.025
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Received:
2016-10-31
Online:
2017-01-18
Published:
2017-02-27
Contact:
Fei Jian, M.D., Associate chief physician, Department of General Surgery, Ruijin Hospital, Shanghai Jiao Tong University, Shanghai 200025, China
About author:
Zhao Zhi-feng, School of Clinical Medicine, Ruijin Hospital, Shanghai Jiao Tong University, Shanghai 200025, China
Supported by:
the “Star Plan” Excellent Project of Shanghai Medical Union in 2014
CLC Number:
Zhao Zhi-feng, Yang Zhi-xun, Li Feng, Musha Hamushan, Shi Yi-fan, Fei Jian, Zhang Jun, Cui Wen-guo.
2.1 载药电纺支架的临床应用 在药物控释体系中可搭载药物的种类广泛,常用的有抗生素[2]、化疗药[3]、蛋白质及DNA等[4-5]。材料选择较少受制于组织和药物兼容性的困扰,针对不同理化性质的药物均有妥善的封装技术,如涂层式、包埋式及胶囊式(同轴混纺)。常用的亲脂性药物有布洛芬[4]、头孢唑啉[5]、紫杉醇及伊曲康唑等[6-7],亲水性药物有头孢西丁及盐酸四环素等[8-10]。由于选材的灵活性及材料参数的易控性,电纺纤维得以应用于组织工程的不同环境,如骨骼、消化道、皮肤等,所发挥的功能也灵活多变,如伤口愈合、辅助化疗、组织生长等。 2.1.1 组织工程 组织工程的应用以蛋白质与核酸等生物大分子的携载与释放为主。纤维封装蛋白以生长因子局部作用为主,同时加入不同的辅助成分加以保护或调控,以促进组织生长恢复。Chew等[4]以牛血清白蛋白作为载体搭载人神经生长因子后,与聚己内酯和聚己内酯-乙基乙烯磷酸盐复合共聚物聚合制成纺丝,随后在纺丝材料中置入对人神经生长因子具有可逆神经显形反应的PC12细胞,细胞增殖反应证实了纺丝中的蛋白介质可长期保持生物活性。在另一项研究中,通过同轴共纺技术将牛血清白蛋白封装于聚己内酯纤维,再通过加入不同浓度聚乙二醇调节牛血清白蛋白的释放速度[11]。结果提示,加入的聚乙二醇含量与牛血清白蛋白释放速度呈正相关。作为多聚物载体的聚己内酯/聚己内酯-乙基乙烯磷酸盐,在搭载胶质细胞源性神经营养因子用于促进边缘神经细胞再生的研究也取得了进展,并且胶质细胞源性神经营养因子的释放长达2个月[12]。Casper 等[13]通过将低分子肝素纺入聚环氧乙烷及聚乳酸-羟基乙酸等,利用其与生长因子间的高亲合力结合并进入体内发挥生物活性,包括成纤维细胞生长因子、血管内皮生长因子等。除传统蛋白外,近年来蚕丝蛋白以其良好的机械性能和理化性质在组织工程中受到广泛关注。在一项实验中,研究人员使用蚕丝蛋白、骨形态形成蛋白2及羟磷灰石钠米颗粒的水溶液合成多聚纤维,用于培养人间充质干细胞[14]。结果提示成骨作用明显且抗拉伸强度佳,在骨组织工程中具有潜在应用价值。 携载核酸的电纺纤维用于细胞内转录的应用也取得了一定成果。Luu等[15]将质粒DNA封装入聚乳酸-聚乙二醇载体合成共聚物,其后80%的质粒基因(β-半乳糖苷酶基因)在20 d的时间内得到了表达。在成骨细胞MC3T3-E1系中的转录实验显示,纤维内DNA活性明显优于裸DNA活性,但仍较商用转染试剂低,提示仍存在一定改进空间。为了提高DNA分子在电纺过程中的稳定性,研究人员探索出一种将溶剂诱导的压缩DNA与聚乳酸-聚乙二醇-聚乳酸三嵌段共聚物合并的方法,结果提示转录效率明显提升[16]。载核酸纤维目前的主要应用方向是将编码特定蛋白的质粒导入细胞,使之长期表达,并在局部组织发挥组织工程作用。新加坡国立大学的一项研究使用编码重组人骨形态发生蛋白2的质粒与几丁质纳米颗粒混合后,分散在聚乳酸-羟基乙酸共聚物/羟磷灰石基质中,作用于人骨髓间充质干细胞,在裸鼠骨骼愈合中表现出明显促进作用[17]。因为生长因子半衰期较短,传统纤维的单次搭载量很难满足长期需要,因此利用编码蛋白的质粒反转录导入细胞,诱导长期表达为此类研究提供了全新的思路。 2.1.2 肿瘤化疗 化疗支架的主流应用方式是在肿瘤切除后植入药物洗脱涂层。然而随着电纺支架的快速发展,传统支架的主流地位受到了一定的挑战。Xu等[18]在聚乙二醇-聚乳酸二联支架中封装卡莫司汀,作用于鼠恶性胶质瘤细胞,取得明显的生长抑制效果,显示了电纺支架在化疗中的价值。另一项搭载紫杉醇的聚乳酸-羟基乙酸共聚物膜在C6神经胶质瘤治疗中的研究,进一步扩展了纤维的应用范围[19]。该实验通过加入有机盐三过氧化三丙酮,以增加溶液的传导率,使载药率达到90%。结果提示可控药物释放为一级释放,周期达到了61 d之久,并释放了80%左右的总载药量。离体细胞毒实验中高达70%的C6神经元胶质细胞在72 h后被杀灭。针对药物溶解性的多样性,一项研究通过将水溶性药物盐酸阿霉素以乳化剂的形式电纺在脂溶性聚乙二醇-聚乳酸的形式探索了可能的解决方案,结果显示此类共纺式载药支架具有均一的药物分布及稳定药物释放曲线,较好解决了药物与材料的相容性问题[20]。在载药基础上,人们还对药物-支架协同应用进行了探索。一项研究对聚乳酸-羟基乙酸共聚物纳米纤维膜促进柔红霉素的抗肿瘤效果进行评估,结果提示聚乳酸-羟基乙酸共聚物-柔红霉素纤维相对于柔红霉素对A431品系具有更强的细胞毒作用[21]。在体实验还观察到该纤维具有一定的血管生成抑制作用,提示了载药支架新的应用前景。 2.1.3 创面愈合 电纺支架材料在创面愈合领域具有得天独厚的优势。高孔隙率的支架对于组织的定植、生长、迁移与物质交换提供了绝佳环境的同时,还可通过微孔结构及覆膜阻隔外界有害物质的侵袭;可塑性及多样性的优势则有利于其适应不同组织微环境;利用支架携载生物制剂如抗生素、促血管生成因子等也为其扩展多种功能提供了可能。在一项表皮损伤修复实验中,研究人员将重组人表皮生长因子通过聚乙二醇-氨基酸化学键整合到聚己内酯及聚已内酯-聚乙二醇嵌段聚合的电纺纤维中,随后在纤维表面生长的表皮细胞出现表皮细胞特异基因的显著表达[22]。在糖尿病鼠背部伤口恢复模型实验中,纺丝纤维组伤口修复显著优于控制组。 14 d时的免疫组织化学染色实验也提示在新修复伤口部位检测到了显著的表皮生长因子受体的表达。 目前腹部手术最为常见的术后并发症之一就是腹腔粘连。有文献报道指出,特定细菌感染与术后腹腔粘连存在强相关关系,并且是可能的诱发因素之一[2]。电纺纤维膜因具有纳米级别孔径及高比表面积,作为隔菌屏障及在体释药系统在防治术后腹膜粘连及腹腔感染中具有潜在价值。Bölgen等[2]使用聚已内酯电纺纤维膜,搭载抗生素Biteral在小鼠模型中对抗肠道厌氧菌,以测试其预防腹腔粘连的效果。由于术后感染最多发于数小时内,因此实验采用了突释设计,近80%的药物在3 h内释放,18 h后完全释放。在小鼠模型实验中,载药支架组的腹膜生长范围及粘连度明显降低,同时腹膜恢复明显加快。同时作者还注意到电纺纤维降解速度明显逊于腹膜组织恢复速度,提示今后的实验可以向调整分子大小加快降解速度的方向发展。 2.2 电纺支架的新进展 2.2.1 新材料的使用 科研人员也在不断扩展着新材料的使用。一项伊朗的研究使用聚乳酸-羟基乙酸共聚物与黄芪胶混合电纺,测试了其搭载盐酸四环素应用于牙周组织的再生[23]。材料使用了混合纤维及芯-壳结构纤维两种构型。结果提示两种构型中黄芪胶部分均表现出稳定的盐酸四环素释放速率且周期高达75 d。实验使用的黄芪胶属于自然高分子,由水溶性和非水溶性部分混合而成,相对聚乳酸-羟基乙酸共聚物具有更好的载药力、水分吸附作用及药物兼容性,并且有文献表明有促进细胞增殖的作用[24]。此实验证实,聚乳酸-羟基乙酸共聚物-黄芪胶芯壳结构纤维具有稳定持久的释药速率,良好的生物相容性、抗菌性及机械性能,在牙周组织疾病药物控释领域具有广泛前景。 近年来,介孔硅纳米颗粒以其巨大的比表面积及多孔率逐渐引起人们关注[25]。最早的介孔材料M41S家族材料在1990年被发现,其后便飞速发展[26]。与普通多孔硅纳米颗粒相比,介孔硅纳米颗粒孔径在2-50 nm,且具有诸多优势[27],其优点为:表面积及孔径相对较大,利于载药[28];介孔结构以及可调节的孔径使载/释药过程可控易操作[29];表面易修饰,可用于控制靶向药物释放[30];在细胞毒作用[31]、生物可降解[32]、体内分布及排泄中表现出较好的安全性[33];与磁性材料、荧光材料结合可支持生物显像[34]。但传统的介孔硅纳米颗粒经常出现尺寸分布不稳定及介孔结构缺陷的问题。对此,She等[35]提出了使用丙烯酸树脂辅助合成中空介孔二氧化硅纳米颗粒(HMSNs)的新策略。该策略以丙烯酸树脂颗粒为核心,加入硅纳米颗粒,在树脂核心上均匀分布并完成自组装,形成稳定的颗粒,完成后的材料具有670 m2/g的高表面积,120 nm直径及2.5 nm均一孔径,稳定的品控为其封装药物及临床应用打下了坚实基础。其后作者使用5-氟尿嘧啶测试达到了194.5 mg(5-氟尿嘧啶)/g(中空介孔二氧化硅纳米颗粒)的高载药率并实现了稳定释药。与表皮生长因子共轭后,还可在SW480直肠癌细胞中高效特异地完成细胞内化作用。这均提示了搭载表皮生长因子的中空介孔二氧化硅纳米颗粒材料通过表皮生长因子-EGFR相互作用在胞内给药治疗结直肠癌方面的潜在应用价值。 新材料的使用也引入了新的研究治疗思路。Yan 等[36]研究了植入金纳米棒AuNRs的聚乙烯醇/壳聚糖电纺纤维的给药/显像双重作用。在载药实验中,作者在卵巢肿瘤细胞SKOV3中使用载有阿霉素的金纳米棒聚乙烯醇/壳聚糖载药电纺纤维培养,提示金纳米棒纤维表现出更强的细胞毒作用。在细胞染色共焦显像中,染色后的药物主要分布于细胞核中,提示材料释药功能的高特异性和有效性。得益于金纳米棒的光学性质,使作为细胞成像介质发挥作用,为其在评估疗效及预后等方面提供了全新思路。 2.2.2 条件控制释放 功能化电纺纤维搭载化疗药想要提高治疗效率,减少不良反应,就需要针对靶点的生理需要进行速率控制。就pH诱导的药物释放而言,常用的pH敏感材料包括藻酸纤维、壳聚糖、聚(甲基丙烯酸接枝聚(乙二醇))[37]、聚(甲基丙烯酸-N-乙烯基吡咯烷酮)等[38]。其中丙烯酸树脂最初由Shen等[39]在2011年发现并电纺成功,目前被广泛应用于口服剂型如胶囊包衣中,也用于制备胃肠道微球或纳米药物控释颗粒[40]。一项搭载5-氟尿嘧啶的丙烯酸树脂在pH调控下的药物释放实验结果表明,通过控制核芯部分两级释放,可使材料在胃中保持稳定,而在肠道中大量释放,从而在结直肠癌治疗中发挥最大功效[41]。Jassal等[42]则通过表面修饰达到pH控制释放的效果。实验使用聚己内酯通过水解作用在表面引入功能基团-COOH。pH敏感基团-COOH和盐酸阿霉素的铵基,通过静电作用稳定结合在聚已内酯纤维表面。实验结果提示该材料具有高而稳定的载/释药率。肿瘤与正常组织区别之一即在于其酸碱度因为高代谢率而相对偏低,因此这一研究成果对于肿瘤的局部治疗具有重要意义。 除pH诱导释放外,也有对pH/磁双重调控载药模型进行了探索的案例[43]。该案例介绍了一种由K-卡拉胶及羧甲基壳聚糖纤维制成的多聚物,并将磁性材料Fe3O4纳米颗粒以原位合成的方式整合到其中。结果提示交变磁场强度与材料释药量呈正相关。这一结果也与Likhitkar、Bajpai[44]以淀粉基磁性颗粒的顺铂释放实验类似。药物释放增加的原理是交变磁场强度加剧了磁性颗粒的固有运动,引起电纺链的机械形变、松弛,促进药物加强释放[45]。利用这一规律,通过制作与支架配套的控制开关,使之实现远程控制释药。这一功能必将极大地增强载药支架的功能性与可操作性。 2.2.3 活体细胞携载纤维 电喷活体细胞植入电纺材料用于治疗领域的研究仍相对处于早期。有实验表明,对处于原肠胚的多细胞斑马鱼胚胎组织使用生物电喷技术处理后,细胞正常分裂、分化过程并未受到影响[46]。被电喷处理过的细胞也仍然保持了生物活性,说明短时高电压对细胞的蛋白质及DNA等关键结果的影响相对局限,将来改用交流电压尚可进一步减少对活体细胞的损害。在此成果基础上,通过加入诱导分化的生长因子诱导组织修复或重建,将进一步扩展电纺纤维的应用价值。"
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