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Volume 39 Issue 3
May  2021
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WANG Jirong, GONG Hai, LU Guangzhao, DENG Li. Research progress in nanomaterials in hemostasis[J]. Journal of Pharmaceutical Practice and Service, 2021, 39(3): 211-214. doi: 10.12206/j.issn.1006-0111.202012015
Citation: WANG Jirong, GONG Hai, LU Guangzhao, DENG Li. Research progress in nanomaterials in hemostasis[J]. Journal of Pharmaceutical Practice and Service, 2021, 39(3): 211-214. doi: 10.12206/j.issn.1006-0111.202012015

Research progress in nanomaterials in hemostasis

doi: 10.12206/j.issn.1006-0111.202012015
  • Received Date: 2020-12-18
  • Rev Recd Date: 2021-04-21
  • Available Online: 2021-05-25
  • Publish Date: 2021-05-25
  • Nanomaterials, with the advantages of unique microstructure, have been widely used in the fields of material manufacturing, microelectronics and computer technology, medicine and health, environment and energy. Compared with traditional hemostatic materials, nanomaterials can improve the bioavailability and stability of traditional hemostatic drugs to a certain extent, enhance the controlled and targeted release of drugs, which lay a good foundation for the development of new-style modern hemostatic nanomaterials. This paper reviews the advanced design and application progress of various nanomaterials in hemostasis, such as liposomes, nanoparticles, self-assembled nano peptides, nanofibers, etc. Finally, the challenges and prospects of hemostatic nanomaterials are briefly described.
  • [1] TIEN H C, SPENCER F, TREMBLAY L N, et al. Preventable deaths from hemorrhage at a level I Canadian trauma center[J]. J Trauma: Inj Infect Crit Care,2007,62(1):142-146. doi:  10.1097/01.ta.0000251558.38388.47
    [2] WANG X X, LIU Q, SUI J X, et al. Recent advances in hemostasis at the nanoscale[J]. Adv Health Mater,2019,8(23):e1900823. doi:  10.1002/adhm.201900823
    [3] DRULIS-KAWA Z, DOROTKIEWICZ-JACH A. Liposomes as delivery systems for antibiotics[J]. Int J Pharm,2010,387(1-2):187-198. doi:  10.1016/j.ijpharm.2009.11.033
    [4] AKBARZADEH A, REZAEI-SADABADY R, DAVARAN S, et al. Liposome: classification, preparation, and applications[J]. Nanoscale Res Lett,2013,8(1):102. doi:  10.1186/1556-276X-8-102
    [5] MICHAEL FITZPATRICK G. Novel platelet products under development for the treatment of thrombocytopenia or acute hemorrhage[J]. Transfus Apher Sci,2019,58(1):7-11. doi:  10.1016/j.transci.2018.12.010
    [6] CHAN V, SARKARI M, SUNDERLAND R, et al. Platelets loaded with liposome-encapsulated thrombin have increased coagulability[J]. J Thromb Haemost,2018,16(6):1226-1235. doi:  10.1111/jth.14006
    [7] NISHIKAWA K, HAGISAWA K, KINOSHITA M, et al. Fibrinogen γ-chain peptide-coated, ADP-encapsulated liposomes rescue thrombocytopenic rabbits from non-compressible liver hemorrhage[J]. J Thromb Haemost,2012,10(10):2137-2148. doi:  10.1111/j.1538-7836.2012.04889.x
    [8] HICKMAN D A, PAWLOWSKI C L, SHEVITZ A, et al. Intravenous synthetic platelet (SynthoPlate) nanoconstructs reduce bleeding and improve ‘golden hour’ survival in a porcine model of traumatic arterial hemorrhage[J]. Sci Rep,2018,8(1):3118. doi:  10.1038/s41598-018-21384-z
    [9] SINGH R, LILLARD J W. Nanoparticle-based targeted drug delivery[J]. Exp Mol Pathol,2009,86(3):215-223. doi:  10.1016/j.yexmp.2008.12.004
    [10] HERRERO-VANRELL R, RINCÓN A C, ALONSO M, et al. Self-assembled particles of an elastin-like polymer as vehicles for controlled drug release[J]. J Control Release,2005,102(1):113-122. doi:  10.1016/j.jconrel.2004.10.001
    [11] BARSHTEIN G, ARBELL D, YEDGAR S, et al. Hemodynamic functionality of transfused red blood cells in the microcirculation of blood recipients[J]. Front Physiol,2018,9:41. doi:  10.3389/fphys.2018.00041
    [12] BIRANJE S S, MADIWALE P V, PATANKAR K C, et al. Hemostasis and anti-necrotic activity of wound-healing dressing containing chitosan nanoparticles[J]. Int J Biol Macromol,2019,121:936-946. doi:  10.1016/j.ijbiomac.2018.10.125
    [13] MEDDAHIPELLE A, LEGRAND A, MARCELLAN A, et al. Organ repair, hemostasis, and in vivo bonding of medical devices by aqueous solutions of nanoparticles[J]. Angewandte Chemie,2014,53(25):6369-6373. doi:  10.1002/anie.201401043
    [14] KUDELA D, SMITH S A, MAY-MASNOU A, et al. Clotting activity of polyphosphate-functionalized silica nanoparticles[J]. Angew Chem Int Ed Engl,2015,54(13):4018-4022. doi:  10.1002/anie.201409639
    [15] SUNDARAM M N, AMIRTHALINGAM S, MONY U, et al. Injectable chitosan-nano bioglass composite hemostatic hydrogel for effective bleeding control[J]. Int J Biol Macromol,2019,129:936-943. doi:  10.1016/j.ijbiomac.2019.01.220
    [16] GKIKAS M, PEPONIS T, MESAR T, et al. Systemically administered hemostatic nanoparticles for identification and treatment of internal bleeding[J]. ACS Biomater Sci Eng,2019,5(5):2563-2576. doi:  10.1021/acsbiomaterials.9b00054
    [17] ELLIS-BEHNKE R G, LIANG Y X, TAY D K, et al. Nano hemostat solution: immediate hemostasis at the nanoscale[J]. Nanomedicine,2006,2(4):207-215. doi:  10.1016/j.nano.2006.08.001
    [18] CHENG T Y, WU H C, HUANG M Y, et al. Self-assembling functionalized nanopeptides for immediate hemostasis and accelerative liver tissue regeneration[J]. Nanoscale,2013,5(7):2734-2744. doi:  10.1039/c3nr33710c
    [19] MORGAN C E, DOMBROWSKI A W, RUBERT PÉREZ C M, et al. Tissue-factor targeted peptide amphiphile nanofibers as an injectable therapy to control hemorrhage[J]. ACS Nano,2016,10(1):899-909. doi:  10.1021/acsnano.5b06025
    [20] HUANG Z M, ZHANG Y Z, KOTAKI M, et al. A review on polymer nanofibers by electrospinning and their applications in nanocomposites[J]. Compos Sci Technol,2003,63(15):2223-2253. doi:  10.1016/S0266-3538(03)00178-7
    [21] YIN M, WANG Y, ZHANG Y, et al. Novel quaternarized N-halamine chitosan and polyvinyl alcohol nanofibrous membranes as hemostatic materials with excellent antibacterial properties[J]. Carbohydr Polym,2020,232:115823. doi:  10.1016/j.carbpol.2019.115823
    [22] LIU R, DAI L, SI C L, et al. Antibacterial and hemostatic hydrogel via nanocomposite from cellulose nanofibers[J]. Carbohydr Polym,2018,195:63-70. doi:  10.1016/j.carbpol.2018.04.085
    [23] DONG R H, QIN C C, QIU X, et al. In situ precision electrospinning as an effective delivery technique for cyanoacrylate medical glue with high efficiency and low toxicity[J]. Nanoscale,2015,7(46):19468-19475. doi:  10.1039/C5NR05786H
    [24] CHEN S, CARLSON M A, ZHANG Y S, et al. Fabrication of injectable and superelastic nanofiber rectangle matrices (“peanuts”) and their potential applications in hemostasis[J]. Biomaterials,2018,179:46-59. doi:  10.1016/j.biomaterials.2018.06.031
    [25] SASMAL P, DATTA P. Tranexamic acid-loaded chitosan electrospun nanofibers as drug delivery system for hemorrhage control applications[J]. J Drug Deliv Sci Technol,2019,52:559-567. doi:  10.1016/j.jddst.2019.05.018
    [26] KING D R, SCHREIBER M A. The mRDH bandage provides effective hemostasis in trauma and surgical hemorrhage[J]. J Trauma,2011,71(2 Suppl 1):S167-S170.
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Research progress in nanomaterials in hemostasis

doi: 10.12206/j.issn.1006-0111.202012015

Abstract: Nanomaterials, with the advantages of unique microstructure, have been widely used in the fields of material manufacturing, microelectronics and computer technology, medicine and health, environment and energy. Compared with traditional hemostatic materials, nanomaterials can improve the bioavailability and stability of traditional hemostatic drugs to a certain extent, enhance the controlled and targeted release of drugs, which lay a good foundation for the development of new-style modern hemostatic nanomaterials. This paper reviews the advanced design and application progress of various nanomaterials in hemostasis, such as liposomes, nanoparticles, self-assembled nano peptides, nanofibers, etc. Finally, the challenges and prospects of hemostatic nanomaterials are briefly described.

WANG Jirong, GONG Hai, LU Guangzhao, DENG Li. Research progress in nanomaterials in hemostasis[J]. Journal of Pharmaceutical Practice and Service, 2021, 39(3): 211-214. doi: 10.12206/j.issn.1006-0111.202012015
Citation: WANG Jirong, GONG Hai, LU Guangzhao, DENG Li. Research progress in nanomaterials in hemostasis[J]. Journal of Pharmaceutical Practice and Service, 2021, 39(3): 211-214. doi: 10.12206/j.issn.1006-0111.202012015
  • 创伤大出血是人类创伤死亡的第二大死因,占创伤死亡总数的15%[1]。在院前止血阶段,传统止血材料在一定程度上存在止血效果不佳、储存时间短、应用不方便等缺点,使得控制创伤大出血仍是一大亟待解决的难题。进入到院内手术阶段,简单的纱布止血仍是一种常规选择,这为开发新型止血材料提供了广阔的空间。纳米技术可以在纳米尺度上改造并利用微观结构,赋予了纳米材料改良的扩散性和溶解性、易于穿透生理屏障、比表面积大、药物的缓控和靶向释放等独特优势[2]。近年来,基于脂质体、纳米粒、自组装纳米肽等纳米止血材料的研究日益深入,为现代化新型止血材料的发展奠定了良好基础。本文旨在综述脂质体、纳米粒、自组装纳米肽、纳米纤维等多种纳米止血材料的前沿设计和应用进展,为下一步研究应用提供参考。

  • 脂质体是一种研究广泛的纳米递送系统。它通常由磷脂和胆固醇制备而成,形成磷脂分子亲水头部插入亲水介质,疏水尾部伸向疏水介质的球形结构,直径大小一般在20 nm到10 µm[3]。脂质体的性质随脂质种类、表面电荷、粒径大小和制备方法的不同而有很大差异[4]。在止血方面,脂质体可以包裹止血生物大分子,提高其稳定性和生物相容性,降低生物大分子的副作用;脂质体也可偶联止血多肽链,在增强多肽链稳定性的同时发挥其止血效果。根据脂质体发挥功能的不同,可以将其大致分为止血生物大分子内载脂质体和止血多肽链修饰脂质体[5]。Chan等将凝血酶包裹到纳米脂质体中,并通过体外监测血小板活化、血块收缩等实验来评估其凝血功能。研究结果表明,装载凝血酶的脂质体能被血小板内吞利用,使这种血小板对激动剂更加敏感[6]。Nishikawa等开发了一种纤维蛋白原γ链修饰并内载二磷酸腺苷(adenosine diphosphate,ADP)的脂质体。该脂质体平均直径为210 nm,通过糖蛋白GⅡb/Ⅲa与活化的血小板相互作用以及ADP对血小板的增强聚集来实现静脉治疗患急性血小板减少症兔肝出血模型的有效止血,并且在动物肺部、肾脏和肝脏未检测到血栓形成[7]。Hickman等评估了血管性血友病因子结合肽、胶原结合肽以及纤维蛋白原模拟肽修饰的脂质体对治疗猪股动脉出血的止血效能。实验结果表明,该脂质体处理的猪在前30 min的失血率显著低于对照组,并最终实现了完全止血。处理组动物的股动脉血块富含掺杂脂质体的血小板,而在其他器官组织样本中没有发现血栓形成[8]

  • 纳米粒指由大分子物质组成的固体胶体颗粒,其粒径大小通常为10~1000 nm[9]。天然与合成聚合物的纳米粒载药稳定性良好,且易于表面修饰,并可以通过调节聚合物的特性和表面修饰来实现药物的可控释放和靶向定位[10]。带电荷的纳米颗粒能与带相反电荷的血细胞或者纤维蛋白原产生静电作用,中和表面电荷后诱导其聚集,促进血液的凝固[11]。Biranje等采用离子凝胶法制备壳聚糖纳米颗粒,通过冷冻干燥将其组装成多孔壳聚糖敷料。该壳聚糖敷料平均孔径为4.074 nm,比表面积为61.83 m2/g,具有孔隙率高、溶胀性好、生物降解性好、生物相容性好等特点,有利于促进止血和创面愈合[12]。Meddahipelle等研究证明了二氧化硅与氧化铁纳米溶液经过纳米桥联过程可以在1 min内实现大鼠皮肤和肝脏伤口的止血和组织修复[13]。Kudela等研究制备了一种多磷酸盐功能化的二氧化硅纳米颗粒,并证明了将多磷酸盐附着于二氧化硅纳米颗粒可以产生显著增强止血的协同效应,缩短凝血时间。这种多磷酸盐功能化的二氧化硅纳米颗粒可以增强损伤部位的靶向性,最大限度地减少血栓形成并发症的风险[14]。Sundaram等合成了一种平均直径约14 nm的生物玻璃纳米颗粒,并将其掺入壳聚糖水凝胶中,制备了复合水凝胶。该水凝胶具有良好的剪切稀释性和可注入性,在体内、外凝血实验中表现出快速有效的凝血作用。这种生物玻璃纳米颗粒细胞毒性低,血液相容性好,是一种有潜力的创伤止血材料[15]。Gkikas等研究制备了纤维蛋白功能序列甘氨酰-精氨酰-甘氨酰-天门冬氨酰-丝氨酸(Gly-Arg-Gly-Asp-Ser,GRGDS)功能化的聚乳酸羟基乙酸/聚乙二醇(PLGA-PEG)纳米颗粒。研究结果表明,这种生物相容性良好的纳米颗粒静脉注射后会积累在啮齿动物受损肝脏的血凝块中,从而减少失血并显著提高存活率。PLGA-PEG-GRGDS纳米粒通过生物素、1,1'-双十八烷基-3,3,3',3'-四甲基吲哚二碳菁高氯酸盐(DiD)细胞膜荧光染料和金标记后,可以借助共聚焦显微镜、免疫组织化学和CT成像来辅助诊断内出血[16]

  • 自组装纳米肽(self-assembled nanopeptides,SAP)是指将相对简单的肽链通过非共价自组装而形成的有序纳米结构肽。它不仅能用于药物递送,而且能在体内任何潮湿的离子环境中形成一种纳米纤维屏障,并能浓缩血液有形成分来控制出血。自组装纳米肽生物相容性良好,能在生物体内分解成天然氨基酸,可以被周围组织用于修复。Ellis-Behnke等用自组装纳米短肽RADA16-I制备了一系列不同质量浓度的溶液。在脑、股动脉和肝切口的小鼠模型中,局部使用不同浓度的溶液治疗均能显著缩短止血时间。电子显微镜显示,该溶液会自组装成屏障,阻止血液流动并促进相邻细胞的移动来修复受损部位。这种自组装纳米短肽无毒、无免疫原性,并且其降解产物是氨基酸,可用于组织修复,是一种良好的止血材料[17]。Cheng等制备了纤维蛋白功能序列(GRGDS)与层黏连蛋白功能序列酪氨酰-异亮氨酰-甘氨酰-丝氨酰-精氨酸(Tyr-Ile-Gly-Ser-Arg,YIGSR)的自组装纳米肽,并研究证明了该纳米肽具有良好的生物相容性与局部止血效果,并可显著促进肝组织再生[18]。Morgan等将3种组织因子特异性结合多肽序列(EGRNCETHKDDQL,RLMTQDCLQQRSK,RTLAFVRFK序列)共价结合到两亲性肽链骨架,自组装成3种纳米肽纤维。研究发现,只有RTLAFVRFK序列所结合的纳米肽纤维才可以显著减少失血量,且增加纤维的密度可以增强止血效果。生物相容性实验表明,该纳米肽纤维不会诱导红细胞溶血,不会在肝损伤部位诱导炎症,并在血浆中30 min后仍有70%材料保持结构的完整性[19]

  • 纳米纤维通常指直径为1~100 nm,并且具有一定长度的线状纳米材料。它可以通过静电纺丝技术从各种天然与合成聚合物中提取制备而成。纳米纤维具有比表面积大、可调节的孔隙率和易表面功能化等优点,使其在抗菌止血敷料、给药系统以及组织工程等生物医学领域被广泛应用。特殊材料的电纺纳米纤维可形成纳米纤维垫,具有比表面积大和孔隙率高的优点,并能与止血药物共混应用,最终达到快速止血的效果[20]。Yin等研究开发了基于季铵化N-卤胺壳聚糖和聚乙烯醇的新型抗菌止血纳米纤维膜。该电纺膜具有均匀的纳米纤维结构,孔隙率高,与细胞外基质相似,具有优异的吸水性能和良好的力学性能。细胞相容性实验结果表明,人成纤维细胞可以在这种膜上黏附并增殖,从而证明了其良好的生物相容性。在全血凝固实验中,该膜表现出良好的凝血活性,不仅具有显著的血浆吸附性,而且能诱导血小板黏附和活化[21]。Liu等将氨基化纳米银和明胶引入羧化纤维素纳米纤维中,成功制备了一种纳米复合水凝胶。该复合水凝胶具有较强的机械性能、抗菌性能和良好的止血性能,在体内外创面愈合模型评价中显示出良好的生物相容性和创面愈合效果[22]。Dong等设计了一种以氰基丙烯酸酯为原料,用于内脏止血的气体辅助原位电纺丝装置。该装置可以提高氰基丙烯酸酯聚合物的沉积精度,避免组织黏连;辅助气流可以将聚合纤维吹到组织表面,可在几秒钟内完成肝脏止血[23]。Chen等以聚己内酯为原料,制备出一种可注射的聚己内酯花生状纳米纤维颗粒。该纳米纤维颗粒可通过套管或注射器输送到受伤部位,与血液接触后几秒内重新膨胀到原来的形状,能有效控制出血。此外,涂覆明胶层的花生状纳米纤维颗粒显示出比商用纱布和Gelfoam®更好的血液凝血效果[24]。Sasmal等以聚乙烯醇和壳聚糖为原料,通过静电纺丝技术制备了聚乙烯醇/壳聚糖复合纳米纤维膜,并将止血药氨甲环酸负载其上。这种纳米纤维膜显示出良好的血液相容性与抗生物膜形成性能,并且纤维膜中的壳聚糖成分显著增强了氨甲环酸的止血效果[25]。快速止血剂mRDH由乙酰氨基葡萄糖纳米纤维材料组成,具有血管收缩,血小板活化,红细胞聚集等止血机制。mRDH创伤绷带可有效控制严重内脏损伤和肝破裂的出血,已被FDA批准用于军事和民用环境中快速控制肢体创伤的出血[26]

  • 纳米材料因其独特的优势,在止血方面有着广泛的研究和应用价值。脂质体、纳米粒、自组装纳米肽等可以通过外部修饰和内部负载止血材料实现良好的止血效果。然而,由于纳米材料出现时间短,评价宏观物质的体系尚难以全方面衡量纳米止血材料的潜在安全性,这使得纳米材料在止血方面的应用受到了很大的限制。虽然纳米止血材料存在诸多未解难题,但不妨碍研究工作者在此领域继续研究拓展。研究人员首先需要从止血机制入手,着力探究机体内细胞分子层面的止血机制,为开发新型纳米止血材料提供机制保证。此外,材料工程是纳米止血材料的基础,开发新型天然与合成的止血化合物并深入研究其止血机制是开发新型纳米止血材料的关键一环。最后,全面系统地评价止血材料的安全性(生物相容性、细胞遗传毒性等)是运用纳米止血材料的底线。研究工作者应不断致力于开发纳米止血材料安全性评价体系,深入研究机体止血机制,增强止血材料与操作者的交互性,最终研发出一种安全、便捷、高效的新型纳米止血材料。

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