抗感染尿管获中国专利现况

doi:10.3969/j.issn.2095-4344.2015.25.029

摘要/Abstract

摘要：

背景：导管相关尿路感染为临床诊治难点，其致病关键在于材料表面细菌生物膜形成，通过构建具有抗感染功能尿管成为研发热点。
目的：回顾抗感染尿管获中国专利的现况。
方法：以Google专利(http://www.google.com/advanced_patent_search)为检索平台，以“返回具有以下专利名的专利：尿管”进行检索，检索截至2014-03-26。
结果与结论：初检共获得949条结果，剔除无关专利，仅纳入明确陈述抗感染或抗菌尿管专利，共计23条中国专利结果纳入分析。结果表明：①抗菌涂层药物选择：大多数专利为纳米无机金属离子抗菌剂，仅4项含有抗生素涂层。②药物涂层数：大部分为多层/复合涂层。③药物释放方式：大多专利陈述为缓释释放，但释放可控性未予以交代。④制备工艺：1项专利采用化学键或离子键结合方式，2项采取共混方式，1项采取镀复，1项采用高压静电纺丝技术，12项(52.17%)陈述采用物理浸渍方式。⑤抗菌方式：1项为超声抗菌、1项为无菌套筒、1项为亲水涂层、1项为抗感染剂与高分子材料共混制备导管，其余20项(82.61%)均为含抗菌剂药物液态涂层后干燥成膜。综上，目前尚未见抗感染尿管专利转化应用于临床，相关研究多为实验室或动物实验阶段，中文抗感染尿管相关专利研究方式较为局限，研究水平亟待加强、深入。

中国组织工程研究杂志出版内容重点：生物材料；骨生物材料; 口腔生物材料; 纳米材料; 缓释材料; 材料相容性；组织工程

关键词: 生物材料, 材料相容性, 导管相关尿路感染, 抗感染尿管, 专利, 综述

Abstract:

BACKGROUND: Catheter associated urinary tract infection is a difficult problem for clinical practice management, and its key pathogenesis is the bacterial biofilm formation on the surface of the catheter material. Therefore, developing a new anti-infective urinary catheter has become an area of interest in the current studies of anti-infective biological materials.

OBJECTIVE: To review the research literatures on anti-infective urinary catheter, and provide a direction for further study and clinical application.

METHODS: All related Chinese patent papers of anti-infective urinary catheters were retrieved by Google’s proprietary search platform (http://www.google.com/advanced_patent_search) until the deadline of March 26, 2014, with the search strategy of ‘Return the patents with the following proprietary name: urinary catheter’.

RESULTS AND CONCLUSION: According to the predefined search strategy, 949 potentially relevant patent papers were screened out for further identification, and 23 papers referred to anti-infective catheters that were obviously eligible were included. The analyses showed that: (1) The antibacterial coating agents of the majority of papers were antibacterial agents of nano-inorganic metal cations, only four papers used antibiotic coated. (2) The drug-eluting catheters were mainly composite-coated. (3) The drug release modes from coating were mainly extended-release but release mechanism was not clarified. (4) The preparation process was chemical bond or ionic bond in one paper, blending methods in one paper, repeated electroplating in one paper, electrospinning technology in one paper, and physical impregnation methods in 12 papers (52.17%). (5) The antimicrobial mode was ultrasonic-antibacterial method in two patent papers, sterile sleeve in one paper, hydrophilic coating in one paper, catheter made by blending polymer material and anti-infective agents in one paper, drug coated films made by coating with antimicrobial drug liquid and drying process in 20 papers (82.61%). In conclusion, there have been no translational and applied clinical researches about the anti-infective urinary catheter, and the relevant researches were only at the laboratory level. The research methods of Chinese patent for anti-infective urinary catheter were limited, and need to be further improved.

中国组织工程研究杂志出版内容重点：生物材料；骨生物材料; 口腔生物材料; 纳米材料; 缓释材料; 材料相容性；组织工程

Key words: 生物材料, 材料相容性, 导管相关尿路感染, 抗感染尿管, 专利, 综述

中图分类号:

R318

熊国兵，王寓，邱明星. 抗感染尿管获中国专利现况[J]. 中国组织工程研究, 2015, 19(25): 4086-4090.

Xiong Guo-bing, Wang Yu, Qiu Ming-xing. Chinese patent of anti-infective urinary catheter[J]. Chinese Journal of Tissue Engineering Research, 2015, 19(25): 4086-4090.

图/表（结果） 3

参考文献

[1] Nicolle L.Urinary catheter-associated infections.Infect Dis Clin North Am.2012; 26(1):13-27.

[2] Yang L,Liu Y,Wu H,et al.Combating biofilms. FEMS Immunol Med Microbiol.2012;65(2): 146-157.

[3] Tambyah PA,Oon J.Catheter-associated urinary tract infection. Curr Opin Infect Dis.2012;25(4):365-370.

[4] Bruellhoff K,Fiedler J,Möller M,et al.Surface coating strategies to prevent biofilm formation on implant surfaces.Int J Artif Organs.2010;33(9):646-653.

[5] 陈红蕾,孙乐民,敬卿,等.SooPAT及百度、Google专利搜索引擎比较[J].高校图书馆工作,2011,31(3):46-48.

[6] Lebeaux D, Ghigo JM. Management of biofilm-associated infections: what can we expect from recent research on biofilm lifestyles? Med Sci (Paris).2012;28(8-9):727-739.

[7] Hatt JK, Rather PN.Role of bacterial biofilms in urinary tract infections.Curr Top Microbiol Immunol.2008;322:163-192.

[8] Chenoweth CE,Gould CV,Saint S.Diagnosis, management, and prevention of catheter-associated urinary tract infections. Infect Dis Clin North Am. 2014;28(1):105-119.

[9] Pickard R,Lam T,MacLennan G,et al.Antimicrobial catheters for reduction of symptomatic urinary tract infection in adults requiring short-term catheterisation in hospital: a multicentre randomised controlled trial. Lancet.2012;380(9857): 1927-1935.

[10] Johnson JR,Kuskowski MA,Wilt TJ.Systematic review: antimicrobial urinary catheters to prevent catheter-associated urinary tract infection in hospitalized patients.Ann Intern Med. 006;144(2):116-126.

[11] Pickard R,Lam T,Maclennan G,et al.Types of urethral catheter for reducing symptomatic urinary tract infections in hospitalised adults requiring short-term catheterisation: multicentre randomised controlled trial and economic evaluation of antimicrobial- and antiseptic-impregnated urethral catheters (the CATHETER trial).Health Technol Assess.2012;16(47):1-197.

[12] Meddings J,Rogers MA,Krein SL,et al.Reducing unnecessary urinary catheter use and other strategies to prevent catheter-associated urinary tract infection: an integrative review.BMJ Qual Saf.2014;23(4):277-289.

[13] Siddiq DM,Darouiche RO.New strategies to prevent catheter- associated urinary tract infections.Nat Rev Urol.2012; 9(6): 305-314.

[14] Ramanathan R, Duane TM.Urinary tract infections in surgical patients.Surg Clin North Am.2014;94(6):1351-1368.

[15] Romanò CL,Toscano M,Romanò D,et al.Antibiofilm agents and implant-related infections in orthopaedics: where are we?J Chemother.2013;25(2):67-80.

[16] 本刊中文部.本期专题：防止细菌生物膜生成的抗菌生物材料[J].中国组织工程研究与临床康复,2011,15(47): 8755,8756, 8776.

[17] 施光峰.临床留置导管相关感染的诊治进展[J].中华实用内科杂志, 2007,27(1):68-70.

[18] Tambyah PA,Oon J.Catheter-associated urinary tract infection.Curr Opin Infect Dis. 2012;25(4):365-370.

[19] Krachler AM,Orth K.Targeting the bacteria-host interface: strategies in anti-adhesion therapy.Virulence.2013;4(4): 284-294.

[20] Otto M.Physical stress and bacterial colonization.FEMS Microbiol Rev.2014;38(6):1250-1270.

[21] Rodrigues LR.Inhibition of bacterial adhesion on medical devices. Adv Exp Med Biol.2011;715:351-367.

[22] Imazatoa S,Ebia N,Takahashia Y,et al.Antibacterial activity of bactericide-immobilized filler for resin-based restoratives. Biomaterials.2003; 24(20): 3605-3609.

[23] Regev-Shoshani G,Ko M,Miller C,et al. Slow release of nitric oxide from charged catheters and its effect on biofilm formation by Escherichia coli. Antimicrob Agents Chemother. 2010;54(1):273-279.

[24] 车小强,张松营,陈云平,等.多种抗菌剂抗菌性及混合加入复合树脂的抗菌性能[J].中国组织工程研究,2013,17(16):3002-3009.

[25] Yi H,Kazuro F,Ryotaro H,et al.Generating elastic, biodegradable polyurethane/poly( lactide-co- glycolide) fibrous sheets with controlled antibiotic release via two-stream electrospinning. Biomaterials.2008;9(4): 1200-1207.

[26] Di Luca M,Maccari G,Nifosì R.Treatment of microbial biofilms in the post antibiotic era: prophylactic and therapeutic use of antimicrobial peptides and their design by bioinformatics tools. Pathog Dis.2014;70(3):257-270.

[27] 张文辉,金小海.药物涂层支架涂层的工艺[J].国际生物医学工程杂志,2006,29(1): 42-44.

[28] Norowski PA Jr,Bumgardner JD.Biomaterial and antibiotic strategies for peri-implantitis: a review.J Biomed Mater Res B Appl Biomater.2009;88(2):530-543.

[29] Bruellhoff K,Fiedler J,Möller M,et al.Surface coating strategies to prevent biofilm formation on implant surfaces.Int J Artif Organs.2010;33(9):646-653.

[30] Dong J, Zhang S, Ma J,et al.Preparation, characterization, and in vitro cytotoxicity evaluation of a novel anti-tuberculosis reconstruction implant.PLoS One.2014;9(4): e94937.

[31] Stickler DJ.Clinical complications of urinary catheters caused by crystalline biofilms: something needs to be done.J Intern Med.2014;276(2):120-129.

[32] Feneley RC,Kunin CM,Stickler DJ.An indwelling urinary catheter for the 21st century.BJU Int.2012;109(12):1746-1749.

引言

材料方法

讨论

医用生物材料尤其尿管相关尿路感染为全球性重大卫生负担，医用生物材料体内感染的关键环节在于材料表面细菌生物膜形成，细菌生物膜是细菌耐药性产生的重要机制^[1^，^7]。传统意义下的抗医用生物材料感染技术着重于强化各类抗菌素及无机金属银离子等抗菌剂的应用，而抗生素耐药性问题与金属离子等具有疗效不确切及不良反应的局限^[8-9]。通过制备抗菌药物缓释涂层进而研发新型抗感染尿管，以防治细菌生物膜相关感染为当前抗医用生物材料感染研究的主要内容^[10-12]。

细菌定植于尿管为导管相关尿路感染的首要步骤，继而发生生物膜形成、成熟，细菌生物膜的形成为感染持续的关键^[13-14]。以细菌生物膜为靶点，关注与生物膜感染相关的医疗、护理、药物、材料等因素均是减少细菌生物膜感染的重要切入点^[15-16]。导管相关感染的最佳治疗为允许情况下拔除感染导管，但主要指短期使用、易于更换的外周导管，而需持续使用导管者则更换。拔除导管并不总是可能、易行和无风险，有时尽量挽救感染导管才是切合实际的决策，尤其是长期或永久留置的导管，而一旦病原菌在导管上形成生物膜，感染就变得很难控制^[17]。

目前预防细菌生物膜形成主要通过3种途径^[6]：抗细菌黏附与杀灭黏附于材料上的细菌及两种方法的联合应用。因此，通过发掘新型抗菌药物、改造导管抗感染性能，研发抗感染医用材料成为生物医用材料研发的主要途径之一^[18]，相关文献报道通过引入具有抑菌或杀菌功能的官能团或化合物、抗生素等，以规避耐药性同时有效杀菌。

抗感染策略方面，总结本研究发现，23项专利中仅2个专利采用抗细菌黏附、10个专利应用杀灭表面细菌技术，仅一半的专利(11个，47.83%)采取了上述两种方法联合。很明显，若采用一开始即阻断细菌黏附的方法是为上策^[19]，一旦细菌黏附后，应用抗生素等抗菌剂会产生耐药性及不良反应问题，共21个专利(91.3%)应用了抗菌药物以杀灭或抑制细菌，采用抗细菌黏附的研究思路亟待加强^[20]。
抗菌涂层药物选择及作用方式方面，大多数专利为无纳米无机金属离子抗菌剂，属于无机抗菌剂，为具有抗菌作用的金属盐类或与无机载体（如有机硅乳化液、聚合物等）结合制备而成的化合物。仅4项专利(17.39%)含有抗生素涂层，针对有机抗菌剂包括多种有机酸、酯、醇、酚类物质(如生物表面活性剂^[21])、季铵盐^[22]、一氧化氮^[23]、部分合成抗生素等及天然抗菌剂（如传统中草药^[24]、微生物源性抗生素^[25]、天然肽类等^[26]）研究匮乏。涂层数方面大部分为多层/复合涂层。大多专利陈述为缓释释放发挥抗感染作用，但释放可控性未予以交代。总体而言，药物选择局限于无机金属盐类抗菌剂，大多为复合涂层但药物释放方式阐述不清楚，应当扩展药物选择范围，并尽可能明确药物释放作用方式。

活性药物的装载是整个涂层工艺成败的关键，药物涂层管材的涂层工艺对于功能化管材的成败起着关键的作用，对于已经上市的药物涂层管材，其涂层工艺是各个公司的商业机密。一般而言，将药物涂覆于生物材料表面有物理和化学方法，其中物理方法涂层工艺主要采用浸泡和喷涂，而化学方法主要是运用电化学原理进行电镀及化学键结合等方法^[27-28]。本研究纳入专利的制备工艺，1项专利采用化学键或离子键结合方式，2项采取共混方式，1项采取镀复，1项采用高压静电纺丝技术，12项(52.17%)陈述采用物理浸渍方式，另有3项专利未能从专利权利书全文获知其确切制备工艺。合计14个专利(60.87%)采用了物理方法装载，应当加强对化学装载方法、联合物理化学方法及其他新方法如组织再生膜等新技术加载抗菌药物至导管表面的相关研究^[27]。

将抗菌药物固定于材料表面制备抗菌表层以杀灭黏附病原微生物，有多种方法制备抗菌表面，包括非共价结合、共价固定、装载抗菌剂聚合基质^[29]、聚-DL-丙交酯和纳米羟基磷灰石共混等方法已有报道^[30]。本文纳入23项专利中，1项为超声抗菌、1项为无菌套筒、1项为亲水涂层、1项为抗感染剂与高分子材料共混制备导管，其余20项(82.61%)均为含抗菌剂药物液态涂层后干燥成膜。

目前，对生物膜细菌相关感染相关研究方兴未艾，然而，许多有关生物膜细菌发生及其致病机制仍未明确，大多数细菌生物膜相关研究仍处于基础研究阶段，真正应用到临床的抗细菌生物膜的治疗新方案或新材料还比较少^[31-32]。本研究纳入专利所用涂层药物主要集中于无机金属盐类抗菌剂、制备工艺多为简单的物理浸泡烘干、大多复合层涂层导致其药物缓释机制研究不明，结合笔者临床实践，尚未见有相关抗感染尿管转化应用于临床。目前，作者群体正在进行欧美与中国抗感染尿管专利现况对比分析。总结而言，中文抗感染尿管相关专利研究方式及水平较为局限，研究水平亟待加强、深入。