基于微流控芯片的体外血脑屏障模型构建与应用研究进展
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摘要
血脑屏障(blood-brain barrier, BBB)能控制血脑两侧的物质转运,保证中枢神经组织内环境的稳定,对神经系统疾病药物的研发有着重要的影响。建立体外高保真BBB模型对BBB功能进行研究,对药物、毒素等的屏障渗透性的评估等具有重要意义。然而, BBB结构的复杂性导致其难以在体外较好的复制, BBB芯片可以使系统微型化、减少细胞和培养基用量,同时可以诱导剪切力产生,与传统体外BBB模型相比具有一定优势。本文对BBB芯片模型的建立,模型的表征方法及其在神经炎症、脑肿瘤研究和药物评价方面的应用进行综述,为建立更可靠的体外BBB模型提供参考。
The blood-brain barrier(BBB) not only maintains the stability of the environment within the central nervous system by controlling the transport of substances on both sides of the blood and brain, but also plays an important role in the R&D of new drugs for neurological disorders. The establishment of an in vitro high-fidelity model to study BBB function is imperative for assessing barrier permeability of drugs and xenobiotics. However,the complexity of the BBB structure makes it difficult to replicate with an in vitro model. Compared to the tradi‐tional in vitro BBB model, the BBB-on-chip provides certain advantages in miniaturizing the system, reducing the amount of cells and medium required, and allowing simultaneously induction of shear stress. We review here the BBB-on-chip models from their establishment and characterization to applications in research of neuroinflamma‐tion, brain tumor and drug evaluation.
The blood-brain barrier(BBB) not only maintains the stability of the environment within the central nervous system by controlling the transport of substances on both sides of the blood and brain, but also plays an important role in the R&D of new drugs for neurological disorders. The establishment of an in vitro high-fidelity model to study BBB function is imperative for assessing barrier permeability of drugs and xenobiotics. However,the complexity of the BBB structure makes it difficult to replicate with an in vitro model. Compared to the tradi‐tional in vitro BBB model, the BBB-on-chip provides certain advantages in miniaturizing the system, reducing the amount of cells and medium required, and allowing simultaneously induction of shear stress. We review here the BBB-on-chip models from their establishment and characterization to applications in research of neuroinflamma‐tion, brain tumor and drug evaluation.
引文
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[2]Hawkins BT,Davis TP.The blood-brain barrier/neurovascular unit in health and disease[J].Pharmacol Rev,2005,57:173-185.
[3]Cardoso FL,Brites D,Brito MA.Looking at the blood-brain barrier:molecular anatomy and possible investigation approaches[J].Brain Res Rev,2010,64:328-363.
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[5]Chen LJ,Lu CT,Zhao YZ,et al.Ultrasonic microbubbles for glioma-targeted drug delivery[J].Acta Pharm Sin(药学学报),2015,50:99-103.
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[9]Fan JX,Wang S,Meng XS,et al.Study of cancer cell apoptosis induced by Schizonepeta tenuifolia with microfluidic chip technology[J].Acta Pharm Sin(药学学报),2017,52:126-131.
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[15]Sang J,Liu P,Zhao BQ.Molecular composition of blood-brain barrier:research advances[J].J Int Pharm Res(国际药学研究杂志),2011,38:201-205.
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[18]Abbott NJ,Dolman DE,Patabendige AK.Assays to predict drug permeation across the blood-brain barrier,and distribution to brain[J].Curr Drug Metab,2008,9:901-910.
[19]Booth R,Kim H.Characterization of a microfluidic in vitro model of the blood-brain barrier(μBBB)[J].Lab Chip,2012,12:1784-1792.
[20]Wolff A,Antfolk M,Brodin B,et al.In vitro blood-brain barrier models-an overview of established models and new microfluidic approaches[J].J Pharm Sci,2015,104:2727-2746.
[21]Huh D,Torisawa YS,Hamilton GA,et al.Microengineered physiological biomimicry:organs-on-chips[J].Lab Chip,2012,12:2156-2164.
[22]Cucullo L,Aumayr B,Rapp E,et al.Drug delivery and in vitro models of the blood-brain barrier[J].Curr Opin Drug Discov Devel,2005,8:89-99.
[23]Santaguida S,Janigro D,Hossain M,et al.Side by side compari‐son between dynamic versus static models of blood-brain barrier in vitro:a permeability study[J].Brain Res,2006,1109:1-13.
[24]Cucullo L,McAllister MS,Kight K,et al.A new dynamic in vitro model for the multidimensional study of astrocyte-endo‐thelial cell interactions at the blood-brain barrier[J].Brain Res,2002,951:243-254.
[25]Neuhaus W,Lauer R,Oelzant S,et al.A novel flow based hollow-fiber blood-brain barrier in vitro model with immor‐talised cell line PBMEC/C1-2[J].J Biotechnol,2006,125:127-141.
[26]Frampton JP,Shuler ML,Shain W,et al.Biomedical tech‐nologies for in vitro screening and controlled delivery of neuroactive compounds[J].Cent Nerv Syst Agents Med Chem,2008,8:203-219.
[27]Modarres HP,Janmaleki M,Novin M,et al.In vitro models and systems for evaluating the dynamics of drug delivery to the healthy and diseased brain[J].J Control Release,2018,273:108-130.
[28]Liu Q,Wu C,Cai H,et al.Cell-based biosensors and their application in biomedicine[J].Chem Rev,2014,114:6423-6461.
[29]Kim JA,Kim HN,Im SK,et al.Collagen-based brain microvas‐culature model in vitro using three-dimensional printed template[J].Biomicrofluidics,2015,9:024115.
[30]Marino A,Tricinci O,Battaglini M,et al.A 3D real-scale,biomi‐metic,and biohybrid model of the blood-brain barrier fabricated through two-photon lithography[J].Small,2018,14:1870024.
[31]Cho H,Seo JH,Wong KH,et al.Three-dimensional blood-brain barrier model for in vitro studies of neurovascular pathology[J].Sci Rep,2015,5:15222.
[32]Jeong S,Kim S,Buonocore J,et al.A three-dimensional arrayed microfluidic blood-brain barrier model with integrated electrical sensor array[J].IEEE Trans Biomed Eng,2018,65:431-439.
[33]Falanga AP,Pitingolo G,Celentano M,et al.Shuttle-mediated nanoparticle transport across an in vitro brain endothelium under flow conditions[J].Biotechnol Bioeng,2017,114:1087-1095.
[34]Prabhakarpandian B,Shen MC,Nichols JB,et al.SyM-BBB:a microfluidic blood brain barrier model[J].Lab Chip,2013,13:1093-1101.
[35]Adriani G,Ma D,Pavesi A,et al.A 3D neurovascular micro‐fluidic model consisting of neurons,astrocytes and cerebral endothelial cells as a blood-brain barrier[J].Lab Chip,2017,17:448-459.
[36]Brown JA,Codreanu SG,Shi M,et al.Metabolic consequences of inflammatory disruption of the blood-brain barrier in an organ-on-chip model of the human neurovascular unit[J].JNeuroinflammation,2016,13:306.
[37]Brown JA,Pensabene V,Markov DA,et al.Recreating bloodbrain barrier physiology and structure on chip:a novel neuro‐vascular microfluidic bioreactor[J].Biomicrofluidics,2015,9:054124.
[38]Walter FR,Valkai S,Kincses A,et al.A versatile lab-on-a-chip tool for modeling biological barriers[J].Sens Actuators BChem,2016,222:1209-1219.
[39]Campisi M,Shin Y,Osaki T,et al.3D self-organized micro‐vascular model of the human blood-brain barrier with endo‐thelial cells,pericytes and astrocytes[J].Biomaterials,2018,180:117-129.
[40]Maoz BM,Herland A,FitzGerald EA.A linked organ-on-chip model of the human neurovascular unit reveals the metabolic coupling of endothelial and neuronal cells[J].Nat Biotechnol,2018,36:865-874.
[41]Sellgren KL,Hawkins BT,Grego S.An optically transparent membrane supports shear stress studies in a three-dimensional microfluidic neurovascular unit model[J].Biomicrofluidics,2015,9:061102.
[42]Bernas MJ,Cardoso FL,Daley SK,et al.Establishment of primary cultures of human brain microvascular endothelial cells to provide an in vitro cellular model of the blood-brain barrier[J].Nat Protoc,2010,5:1265-1272.
[43]Abbott NJ,Dolman DE,Drndarski S,et al.An improved in vitro blood-brain barrier model:rat brain endothelial cells co-cultured with astrocytes[J].Methods Mol Biol,2012,814:415-430.
[44]Navone SE,Marfia G,Invernici G,et al.Isolation and expansion of human and mouse brain microvascular endothelial cells[J].Nat Protoc,2013,8:1680-1693.
[45]Merkel SF,Andrews AM,Lutton EM,et al.Trafficking of AAVvectors across a model of the blood-brain barrier;a comparative study of transcytosis and transduction using primary human brain endothelial cells[J].J Neurochem,2016,140:216-230.
[46]Partyka PP,Godsey GA,Galie JR,et al.Mechanical stress regulates transport in a compliant 3D model of the blood-brain barrier[J].Biomaterials,2017,115:30-39.
[47]Deosarkar SP,Prabhakarpandian B,Wang B,et al.A novel dynamic neonatal blood-brain barrier on a chip[J].PLoS One,2015,10:e0142725.
[48]Herland A,van der Meer AD,FitzGerald EA,et al.Distinct contributions of astrocytes and pericytes to neuroinflammation identified in a 3D human blood-brain barrier on a chip[J].PLoSOne,2016,11:e0150360.
[49]Thomsen LB,Burkhart A,Moos T.A triple culture model of the blood-brain barrier using porcine brain endothelial cells,astrocytes and pericytes[J].PLoS One,2015,10:e0134765.
[50]Sorokin L.The impact of the extracellular matrix on inflamma‐tion[J].Nat Rev Immunol,2010,10:712-723.
[51]Yousif LF,Di Russo J,Sorokin L.Laminin isoforms in endo‐thelial and perivascular basement membranes[J].Cell Adh Migr,2013,7:101-110.
[52]Zhuang QC,Ning RZ,Ma Y,et al.Recent development in micro‐fluidic chips for in vitro cell-based research[J].Chin J Anal Chem(分析化学),2016,44:522-532.
[53]Achyuta AK,Conway AJ,Crouse RB,et al.A modular approach to create a neurovascular unit-on-a-chip[J].Lab Chip,2013,13:542-553.
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