多器官微流控芯片技术及其应用
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摘要
器官微流控芯片技术通过模拟人体器官内环境来实现接近体内的体外细胞培养.基于微流控芯片器官模型的发展,构建多器官芯片整合的微流控系统为研究器官之间物质(如药物和外源性污染物)的代谢作用提供了崭新的平台.本文从不同的多细胞共培养系统角度介绍了构建多器官微流控芯片模型以及在预测和评估药物代谢及其对人体毒性测试等领域的应用,并对多器官微流控芯片技术的发展进行总结和展望.
Microfluidic organ-on-chip is a technology that realizes in vitro cell culture by simulating human organ environment.With the development of microfluidic organ-on-chip,the construction of multi-organ-chip provides a new platform for studying the metabolic function of different organs.In this paper,the recent advances of multiorgan-chip technology in different organs or tissue are reported including the build of human physiological models,drug prediction,toxicology research and other fields.And the development of multi-organ-chip technology is proposed.
Microfluidic organ-on-chip is a technology that realizes in vitro cell culture by simulating human organ environment.With the development of microfluidic organ-on-chip,the construction of multi-organ-chip provides a new platform for studying the metabolic function of different organs.In this paper,the recent advances of multiorgan-chip technology in different organs or tissue are reported including the build of human physiological models,drug prediction,toxicology research and other fields.And the development of multi-organ-chip technology is proposed.
引文
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[34]TATOSIAN D A,SHULER M L.A novel system for evaluation of drug mixtures for potential efficacy in treating multidrug resistant cancers[J].Biotechnology&Bioengineering,2009,103(1):187-198.
[35]CHEN C S,JIANG X,WHITESIDES G M.Microengineering the enviroment of mammalian cells in culture[J].Mrs Bulletin,2005,30(3):194-201.
[36]KIM L,VAHEY M D,LEE H Y,et al.Microfluidic arrays for logarithmically perfused embryonic stem cell culture[J].Lab on A Chip,2006,6(3):394-406.
[37]TOH Y C,ZHANG C,ZHANG J,et al.A novel 3D mammalian cell perfusion-culture system in microfluidic channels[J].Lab on A Chip,2007,7(3):302-309.
[38]KIM J Y,FLURI D A,MARCHAN R,et al.3Dspherical microtissues and microfluidic technology for multi-tissue experiments and analysis[J].Journal of Biotechnology,2015,205(5):24-35.
[39]ZHANG C,ZHAO Z,ABDUL RAHIM N A,et al.Towards a human-on-chip:culturing multiple cell types on a chip with compartmentalized microenvironments[J].Lab on A Chip,2009,9(22):3185.
[40]IMURA Y,ASANO Y,SATO K,et al.A microfluidic system to evaluate intestinal absorption[J].Analytical Sciences,2009,25(12):1403-1407.
[41]LOSKILL P,MARCUS S G,MATHUR A,et al.μOrgano:A Lego?-Like Plug&Play System for Modular Multi-Organ-Chips[J].PLoS One,2015,10(10):e139587.
[42]HELM M W V D,MEER A D V D,EIJKEL J C T,et al.Microfluidic organ-on-chip technology for blood-brain barrier research[J].Tissue Barriers,2016,4(2):e1179084.
[43]SELLGREN K L,BUTALA E J,GILMOUR B P,et al.A biomimetic multicellular model of the airways using primary human cells[J].Lab on A Chip,2014,14(17):3349-3358.
[44]SUNG J H,SRINIVASAN B,ESCH M B,et al.Using PBPK guided“body-on-a-chip”systems to predict mammalian response to drug and chemical exposure[J].Experimental Biology&Medicine,2014,239(9):1225.
[45]SCHULZE F,GAO X,VIRZONIS D,et al.Air quality effects on human health and approaches for its assessment through microfluidic chips[J].Genes,2017,8(10):244.
[46]DIPASRI K,MAHESH D,YILDIZ D V,et al.Lung-on-a-chip technologies for disease modeling and drug development[J].Biomedical Engineering&Computational Biology,2016,7(Suppl 1):17-27.
[47]LEI Z,JACOB D J,KEUTSCH F N,et al.Formaldehyde(HCHO)as a hazardous air pollutant:Mapping surface air concentrations from satellite and inferring cancer risks in the united states[J].Environmental Science&Technology,2017,51(10):5650.
[48]FIEDZIUSZKO S J.Applications of MEMS in communication satellites[C]∥International Conference on Microwaves,May 22-24,2000,Wroclaw,Poland.New York:IEEE,2000(3):201-211.
[49]余国膺.美国NIH、美国防部先进技术研究局和FDA合作研发尖端技术用于预测药物安全[J].中国心脏起搏与心电生理杂志,2011(6):495.
[50]HASENBERG T,MHLEDER S,DOTZLER A,et al.Emulating human microcapillaries in a multiorgan-chip platform[J].Journal of Biotechnology,2015,216:1-10.
[51]XU Z,LI E,GUO Z,et al.Design and construction of a multi-organ microfluidic chip mimicking the in vivo microenvironment of lung cancer metastasis[J].ACS Appl Mater Interfaces,1944,8(39):25840-25847.
[52]MARX U,WALLES H,HOFFMANN S,et al.‘Human-on-a-chip’developments:A translational cutting-edge alternative to systemic safety assessment and efficiency evaluation of substances in laboratory animals and man?[J].Alternatives to Laboratory Animals,2012,40(5):235-257.
[53]孙威,陈雨晴,罗国安,等.器官芯片及其应用[J].分析化学,2016,44(4):533-541.
[54]高丽娜,丁惠,徐建栋,等.微流控芯片应用进展[J].化学通报,2010,73(10):892-899.
[55]崔硕.基于微流控芯片技术的PM2.5对支气管上皮细胞16HBE上皮间质转化影响的研究[D].大连:大连医科大学,2015.
[56]MANDY B E,ALEC S T,MATTHIEU P,et al.How multi-organ microdevices can help foster drug development[J].Advanced Drug Delivery Reviews,2014,69-70.
[57]蒋西然,章燕,秦红梅,等.微流控芯片技术在公共卫生监测中的应用[J].中国医疗设备,2016,31(8):5-8.
[58]CAI Y,HONG Z,ZHU Z,et al.Applications of microfluidic chip in drug activity research[J].Chinese Journal of Pharmaceutical Analysis,2013,33(6):2013-2018.
[59]LIU W M,LI L I,REN L,et al.Diversification of microfluidic chip for applications in cell-based bioanalysis[J].Chinese Journal of Analytical Chemistry,2012,40(1):24-31.
[60]马超,申少斐,赵磊,王进义.生命分析微流控芯片的多尺度应用:从分子水平到个体水平[J].分析测试学报,2015,34(3):246-256.
[2]SACKMANN E K,FULTON A L,BEEBE D J.The present and future role of microfluidics in biomedical research[J].Nature,2014,507(7491):181-189.
[3]HUH D,MATTHEWS B D,MAMMOTO A,et al.Reconstituting organ-level lung functions on a chip[J].Science,2010,328(5986):1662.
[4]WILMER M J,NG C P,LANZ H L,et al.Kidney-on-a-chip technology for drug-induced nephrotoxicity screening[J].Trends in Biotechnology,2016,34(2):156-170.
[5]KIMURA H,IKEDA T,NAKAYAMA H,et al.An on-chip small intestine-liver model for pharmacokinetic studies[J].Journal of Laboratory Automation,2014,20(3):265.
[6]LEE P J,HUNG P J,LEE L P.An artificial liver sinusoid with a microfluidic endothelial-like barrier for primary hepatocyte culture[J].Biotechnology&Bioengineering,2007,97(5):1340-1346.
[7]GROSBERG A,ALFORD P W,MCCAIN M L,et al.Ensembles of engineered cardiac tissues for physiological and pharmacological study:heart on a chip[J].Lab on A Chip,2011,11(24):4165-4173.
[8]RYU H,OH S,LEE H J,et al.Engineering a blood vessel network module for body-on-a-chip applications[J].Journal of Laboratory Automation,2015,20(3):296.
[9]HARASHINA T,ISO R.The treatment of leukoderma after burns by a combination of dermabrasion and“chip”skin grafting[J].British Journal of Plastic Surgery,1985,38(3):301-305.
[10]BOUSSAID F,CHAI D,BOUZERDOUM A.On-chip skin detection for color CMOS imagers[J].Ecu Publications Pre,2003.
[11]PARK J,LEE B K,JEONG G S,et al.Three-dimensional brain-on-a-chip with an interstitial level of flow and its application as an in vitro model of Alzheimer's disease[J].Lab on A Chip,2014,15(1):141-150.
[12]TORISAWA Y S,SPINA C S,MAMMOTO T,et al.Bone marrow-on-a-chip replicates hematopoietic niche physiology in vitro[J].Nature Methods,2014,11(6):663-669.
[13]MCKENZIE M D,KIM S J.Breast on-a-chip:Mimicry of the channeling system of the breast for development of theranostics[J].Integrative Biology,2011,3(4):451.
[14]BAKER M.Tissue models:A living system on a chip[J].Nature,2011,471(7340):661.
[15]GRIEP L M,WOLBERS F,WAGENAAR B D,et al.BBB ON CHIP:Microfluidic platform to mechanically and biochemically modulate blood-brain barrier function[J].Biomedical Microdevices,2013,15(1):145-150.
[16]PRABHAKARPANDIAN B,SHEN M C,NICHOLS J B,et al.SyM-BBB:A microfluidic blood brain barrier model[J].Lab on A Chip,2013,13(6):1093.
[17]STUCKI A O,STUCKI J D,HALL S R,et al.A lung-on-a-chip array with an integrated bio-inspired respiration mechanism[J].Lab on A Chip,2015,15(5):1302.
[18]SUNG J H,ESCH M B,PROT J M,et al.Microfabricated mammalian organ systems and their integration into models of whole animals and humans[J].Lab on A Chip,2013,13(7):1201-1212.
[19]VAN DE MEER A D,VAN DE BERG A.Organs-on-chips:Breaking the in vitro impasse[J].Integrative Biology,2012,4(5):461.
[20]LEIST M,HASIWA N,ROVIDA C,et al.Consensus report on the future of animal-free systemic toxicity testing[J].Altex,2014,31(3):341-356.
[21]REARDON S.‘Organs-on-chips’go mainstream[J].Nature,2015,523(7560):266.
[22]安凡.3D多元类器官药物筛选芯片的设计、构建及应用[D].大连:大连理工大学,2016.
[23]JANG K J,MEHR A P,HAMILTON G A,et al.Human kidney proximal tubule-on-a-chip for drug transport and nephrotoxicity assessment[J].Integrative Biology,2013,5(9):1119-1129.
[24]WANG Y,TOH Y C,LI Q,et al.Mechanical compaction directly modulates the dynamics of bile canaliculi formation[J].Integr Biol,2013,5(2):390-401.
[25]WANG L,LIU D,BO W,et al.Design of parallel microfluidic gradient-generating networks for studying cellular response to chemical stimuli[J].Frontiers of Chemistry in China,2008,3(4):384-390.
[26]MASCHMEYER I,LORENZ A K,SCHIMEK K,et al.A four-organ-chip for interconnected long-term co-culture of human intestine,liver,skin and kidney equivalents[J].Lab on A Chip,2015,15(12):2688.
[27]MATERNE E M,RAMME A P,TERRASSO A P,et al.A multi-organ chip co-culture of neurospheres and liver equivalents for long-term substance testing[J].Journal of Biotechnology,2015,205:36-46.
[28]JONES H M,GARDNER I B,WATSON K J.Modelling and PBPK simulation in drug discovery[J].Aaps Journal,2009,11(1):155.
[29]MORAES C,MEHTA G,LESHERPEREZ S C,et al.Organs-on-a-chip:A focus on compartmentalized microdevices[J].Annals of Biomedical Engineering,2012,40(6):1211-1227.
[30]SUNG J H,KAM C,SHULER M L.A microfluidic device for a pharmacokinetic-pharmacodynamic(PK-PD)model on a chip[J].Lab on A Chip,2010,10(4):446-455.
[31]SUNG J H,SRINIVASAN B,ESCH M B,et al.Using PBPK guided“Body-on-a-Chip”systems to predict mammalian response to drug and chemical exposure[J].Exp Biol Med,2014,239(9):1225.
[32]SUNG J H,SHULER M.(98d)A micro cell culture analog(μCCA)with 3-D hydrogel culture to assess metabolism-dependent cytotoxicity of anti-cancer drugs[Z].AIChE Annual Meeting,Philadelphia,PA,USA:AIChE.2008.
[33]SUNG J H,ESCH M B,PROT J M,et al.Microfabricated mammalian organ systems and their integration into models of whole animals and humans[J].Lab on A Chip,2013,13(7):1201-1212.
[34]TATOSIAN D A,SHULER M L.A novel system for evaluation of drug mixtures for potential efficacy in treating multidrug resistant cancers[J].Biotechnology&Bioengineering,2009,103(1):187-198.
[35]CHEN C S,JIANG X,WHITESIDES G M.Microengineering the enviroment of mammalian cells in culture[J].Mrs Bulletin,2005,30(3):194-201.
[36]KIM L,VAHEY M D,LEE H Y,et al.Microfluidic arrays for logarithmically perfused embryonic stem cell culture[J].Lab on A Chip,2006,6(3):394-406.
[37]TOH Y C,ZHANG C,ZHANG J,et al.A novel 3D mammalian cell perfusion-culture system in microfluidic channels[J].Lab on A Chip,2007,7(3):302-309.
[38]KIM J Y,FLURI D A,MARCHAN R,et al.3Dspherical microtissues and microfluidic technology for multi-tissue experiments and analysis[J].Journal of Biotechnology,2015,205(5):24-35.
[39]ZHANG C,ZHAO Z,ABDUL RAHIM N A,et al.Towards a human-on-chip:culturing multiple cell types on a chip with compartmentalized microenvironments[J].Lab on A Chip,2009,9(22):3185.
[40]IMURA Y,ASANO Y,SATO K,et al.A microfluidic system to evaluate intestinal absorption[J].Analytical Sciences,2009,25(12):1403-1407.
[41]LOSKILL P,MARCUS S G,MATHUR A,et al.μOrgano:A Lego?-Like Plug&Play System for Modular Multi-Organ-Chips[J].PLoS One,2015,10(10):e139587.
[42]HELM M W V D,MEER A D V D,EIJKEL J C T,et al.Microfluidic organ-on-chip technology for blood-brain barrier research[J].Tissue Barriers,2016,4(2):e1179084.
[43]SELLGREN K L,BUTALA E J,GILMOUR B P,et al.A biomimetic multicellular model of the airways using primary human cells[J].Lab on A Chip,2014,14(17):3349-3358.
[44]SUNG J H,SRINIVASAN B,ESCH M B,et al.Using PBPK guided“body-on-a-chip”systems to predict mammalian response to drug and chemical exposure[J].Experimental Biology&Medicine,2014,239(9):1225.
[45]SCHULZE F,GAO X,VIRZONIS D,et al.Air quality effects on human health and approaches for its assessment through microfluidic chips[J].Genes,2017,8(10):244.
[46]DIPASRI K,MAHESH D,YILDIZ D V,et al.Lung-on-a-chip technologies for disease modeling and drug development[J].Biomedical Engineering&Computational Biology,2016,7(Suppl 1):17-27.
[47]LEI Z,JACOB D J,KEUTSCH F N,et al.Formaldehyde(HCHO)as a hazardous air pollutant:Mapping surface air concentrations from satellite and inferring cancer risks in the united states[J].Environmental Science&Technology,2017,51(10):5650.
[48]FIEDZIUSZKO S J.Applications of MEMS in communication satellites[C]∥International Conference on Microwaves,May 22-24,2000,Wroclaw,Poland.New York:IEEE,2000(3):201-211.
[49]余国膺.美国NIH、美国防部先进技术研究局和FDA合作研发尖端技术用于预测药物安全[J].中国心脏起搏与心电生理杂志,2011(6):495.
[50]HASENBERG T,MHLEDER S,DOTZLER A,et al.Emulating human microcapillaries in a multiorgan-chip platform[J].Journal of Biotechnology,2015,216:1-10.
[51]XU Z,LI E,GUO Z,et al.Design and construction of a multi-organ microfluidic chip mimicking the in vivo microenvironment of lung cancer metastasis[J].ACS Appl Mater Interfaces,1944,8(39):25840-25847.
[52]MARX U,WALLES H,HOFFMANN S,et al.‘Human-on-a-chip’developments:A translational cutting-edge alternative to systemic safety assessment and efficiency evaluation of substances in laboratory animals and man?[J].Alternatives to Laboratory Animals,2012,40(5):235-257.
[53]孙威,陈雨晴,罗国安,等.器官芯片及其应用[J].分析化学,2016,44(4):533-541.
[54]高丽娜,丁惠,徐建栋,等.微流控芯片应用进展[J].化学通报,2010,73(10):892-899.
[55]崔硕.基于微流控芯片技术的PM2.5对支气管上皮细胞16HBE上皮间质转化影响的研究[D].大连:大连医科大学,2015.
[56]MANDY B E,ALEC S T,MATTHIEU P,et al.How multi-organ microdevices can help foster drug development[J].Advanced Drug Delivery Reviews,2014,69-70.
[57]蒋西然,章燕,秦红梅,等.微流控芯片技术在公共卫生监测中的应用[J].中国医疗设备,2016,31(8):5-8.
[58]CAI Y,HONG Z,ZHU Z,et al.Applications of microfluidic chip in drug activity research[J].Chinese Journal of Pharmaceutical Analysis,2013,33(6):2013-2018.
[59]LIU W M,LI L I,REN L,et al.Diversification of microfluidic chip for applications in cell-based bioanalysis[J].Chinese Journal of Analytical Chemistry,2012,40(1):24-31.
[60]马超,申少斐,赵磊,王进义.生命分析微流控芯片的多尺度应用:从分子水平到个体水平[J].分析测试学报,2015,34(3):246-256.