Advances in gut–brain organ chips

Abstract

The brain and gut are sensory organs responsible for sensing, transmitting, integrating, and responding to signals from the internal and external environment. In-depth analysis of brain–gut axis interactions is important for human health and disease prevention. Current research on the brain–gut axis primarily relies on animal models. However, animal models make it difficult to study disease mechanisms due to inherent species differences, and the reproducibility of experiments is poor because of individual animal variations, which leads to a significant limitation of real-time sensory responses. Organ-on-a-chip platforms provide an innovative approach for disease treatment and personalized research by replicating brain and gut ecosystems in vitro. This enables a precise understanding of their biological functions and physiological responses. In this article, we examine the history and most current developments in brain, gut, and gut–brain chips. The importance of these systems for understanding pathophysiology and developing new drugs is emphasized throughout the review. This article also addresses future directions and present issues with the advancement and application of gut–brain-on-a-chip technologies.

References

[1] KaplanL, ChowBW, GuC. Neuronal regulation of the blood-brain barrier and neurovascular coupling. Nat Rev Neurosci. 2020; 21(8):416-432.

[2] SweeneyMD, ZhaoZ, MontagneA, Nelson AR, ZlokovicBV. Blood-brain barrier: from physiology to disease and back. Physiol Rev. 2019; 99(1):21-78.

[3] W.H. Organization. ATLAS country resources for neurological disorders. 2017 https://www.who.int/publications/i/item/atlas-country-resources-for-neurological-disorders

[4] AgirmanG, YuKB, HsiaoEY. Signaling inflammation across the gut-brain axis. Science. 2021; 374(6571):1087-1092.

[5] Goralczyk-BinkowskaA, Szmajda-Krygier D, KozlowskaE. The microbiota-gut-brain axis in psychiatric disorders. Int J Mol Sci. 2022; 23(19):11245.

[6] MayerEA, NanceK, ChenS. The gut-brain axis. Annu Rev Med. 2022; 73:439-453.

[7] SocalaK, Doboszewska U, SzopaA, et al. The role of microbiota-gut-brain axis in neuropsychiatric and neurological disorders. Pharmacol Res. 2021; 172:105840.

[8] BoucauJ, MarinoC, ReganJ, et al. Duration of shedding of culturable virus in SARS-CoV-2 omicron (BA.1) infection. N Engl J Med. 2022; 387(3):275-277.

[9] ChangL, WeiY, HashimotoK. Brain–gut–microbiota axis in depression: a historical overview and future directions. Brain Res Bull. 2022; 182:44-56.

[10] Claudino Dos SantosJC, Lima MPP, BritoGAC, VianaGSB. Role of enteric glia and microbiota-gut-brain axis in parkinson disease pathogenesis. Ageing Res Rev. 2023; 84:101812.

[11] DengY, ZhouM, WangJ, et al. Involvement of the microbiota-gut-brain axis in chronic restraint stress: disturbances of the kynurenine metabolic pathway in both the gut and brain. Gut Microbes. 2021; 13(1):1-16.

[12] GongW, GuoP, LiY, et al. Role of the gut-brain axis in the shared genetic etiology between gastrointestinal tract diseases and psychiatric disorders: a genome-wide pleiotropic analysis. JAMA Psychiatry. 2023; 80(4):360-370.

[13] FairbrassKM, LovattJ, BarberioB, Yuan Y, GracieDJ, FordAC. Bidirectional brain–gut axis effects influence mood and prognosis in IBD: a systematic review and meta-analysis. Gut. 2022; 71(9):1773-1780.

[14] ParkerA, Fonseca S, CardingSR. Gut microbes and metabolites as modulators of blood-brain barrier integrity and brain health. Gut Microbes. 2020; 11(2):135-157.

[15] AgirmanG, HsiaoEY. SnapShot: the microbiota-gut-brain axis. Cell. 2021; 184(9):2524-2524 e1.

[16] ChenC, LiaoJ, XiaY, et al. Gut microbiota regulate Alzheimer’s disease pathologies and cognitive disorders via PUFA-associated neuroinflammation. Gut. 2022; 71(11):2233-2252.

[17] DoroszkiewiczJ, Groblewska M, MroczkoB. The role of gut microbiota and gut-brain interplay in selected diseases of the central nervous system. Int J Mol Sci. 2021; 22(18):10028.

[18] van NormanGA. Limitations of animal studies for predicting toxicity in clinical trials: is it time to rethink our current approach? JACC Basic Transl Sci. 2019; 4(7):845-854.

[19] CorroC, Novellasdemunt L, LiVSW. A brief history of organoids. Am J Physiol Cell Physiol. 2020; 319(1):C151-C165.

[20] CowanCS, RennerM, De GennaroM, et al. Cell types of the human retina and its organoids at single-cell resolution. Cell. 2020; 182(6):1623-1640 e34.

[21] LeSavageBL, SuharRA, BroguiereN, Lutolf MP, HeilshornSC. Next-generation cancer organoids. Nat Mater. 2022; 21(2):143-159.

[22] Pleguezuelos-ManzanoC, Puschhof J, van den BrinkS, GeurtsV, BeumerJ, CleversH. Establishment and culture of human intestinal organoids derived from adult stem cells. Curr Protoc Immunol. 2020; 130(1):e106.

[23] RevahO, GoreF, KelleyKW, et al. Maturation and circuit integration of transplanted human cortical organoids. Nature. 2022; 610(7931):319-326.

[24] BroutierL, Andersson-Rolf A, HindleyCJ, et al. Culture and establishment of self-renewing human and mouse adult liver and pancreas 3D organoids and their genetic manipulation. Nat Protoc. 2016; 11(9):1724-1743.

[25] DrostJ, Karthaus WR, GaoD, et al. Organoid culture systems for prostate epithelial and cancer tissue. Nat Protoc. 2016; 11(2):347-358.

[26] GleaveAM, CiX, LinD, WangY. A synopsis of prostate organoid methodologies, applications, and limitations. Prostate. 2020; 80(6):518-526.

[27] Grapin-BottonA, KimYH. Pancreas organoid models of development and regeneration. Development. 2022; 149(20):dev201004.

[28] LancasterMA, RennerM, MartinCA, et al. Cerebral organoids model human brain development and microcephaly. Nature. 2013; 501(7467):373-379.

[29] LawlorKT, Vanslambrouck JM, HigginsJW, et al. Cellular extrusion bioprinting improves kidney organoid reproducibility and conformation. Nat Mater. 2021; 20(2):260-271.

[30] MansourAA, Goncalves JT, BloydCW, et al. An in vivo model of functional and vascularized human brain organoids. Nat Biotechnol. 2018; 36(5):432-441.

[31] TranT, SongCJ, NguyenT, et al. A scalable organoid model of human autosomal dominant polycystic kidney disease for disease mechanism and drug discovery. Cell Stem Cell. 2022; 29(7):1083-1101 e7.

[32] TrujilloCA, MuotriAR. Brain organoids and the study of neurodevelopment. Trends Mol Med. 2018; 24(12):982-990.

[33] TrushO, Takasato M. Kidney organoid research: current status and applications. Curr Opin Genet Dev. 2022; 75:101944.

[34] WuH, Uchimura K, DonnellyEL, KiritaY, MorrisSA, HumphreysBD. Comparative analysis and refinement of human PSC-derived kidney organoid differentiation with single-cell transcriptomics. Cell Stem Cell. 2018; 23(6):869-881 e8.

[35] MotallebnejadP, ThomasA, SwisherSL, Azarin SM. An isogenic hiPSC-derived BBB-on-a-chip. Biomicrofluidics. 2019; 13(6):064119.

[36] DelongLM, RossAE. Open multi-organ communication device for easy interrogation of tissue slices. Lab Chip. 2023; 23(13):3034-3049.

[37] KoenigL, RammeAP, FaustD, et al. A human stem cell-derived brain-liver chip for assessing blood-brain-barrier permeation of pharmaceutical drugs. Cells. 2022; 11(20):3295.

[38] LiZ, LiD, GuoY, WangY, SuW. Evaluation of hepatic drug-metabolism for glioblastoma using liver-brain chip. Biotechnol Lett. 2021; 43(2):383-392.

[39] XuY, ShenB, PanX, et al. Palmatine ameliorated lipopolysaccharide-induced sepsis-associated encephalopathy mice by regulating the microbiota-gut-brain axis. Phytomedicine. 2024; 124:155307.

[40] MayerEA, Tillisch K, GuptaA. Gut/brain axis and the microbiota. J Clin Invest. 2015; 125(3):926-938.

[41] WangQ, YangQ, LiuX. The microbiota-gut-brain axis and neurodevelopmental disorders. Protein Cell. 2023; 14(10):762-775.

[42] YuanH, Silberstein SD. Vagus nerve and Vagus nerve stimulation, a comprehensive review: part II. Headache. 2016; 56(2):259-266.

[43] YuanH, Silberstein SD. Vagus nerve and vagus nerve stimulation, a comprehensive review: part III. Headache. 2016; 56(3):479-490.

[44] YuanH, Silberstein SD. Vagus nerve and Vagus nerve stimulation, a comprehensive review: part I. Headache. 2016; 56(1):71-78.

[45] AmirifarL, Shamloo A, NasiriR, et al. Brain-on-a-chip: recent advances in design and techniques for microfluidic models of the brain in health and disease. Biomaterials. 2022; 285:121531.

[46] KeuteM, Gharabaghi A. Brain plasticity and vagus nerve stimulation. Auton Neurosci. 2021; 236:102876.

[47] DinanTG, CryanJF. Regulation of the stress response by the gut microbiota: implications for psychoneuroendocrinology. Psychoneuroendocrinology. 2012; 37(9):1369-1378.

[48] BercikP, Collins SM, VerduEF. Microbes and the gut-brain axis. Neurogastroenterol Motil. 2012; 24(5):405-413.

[49] FosterJA, McVey Neufeld KA. Gut-brain axis: how the microbiome influences anxiety and depression. Trends Neurosci. 2013; 36(5):305-312.

[50] FrankiensztajnLM, Elliott E, KorenO. The microbiota and the hypothalamus-pituitary-adrenocortical (HPA) axis, implications for anxiety and stress disorders. Curr Opin Neurobiol. 2020; 62:76-82.

[51] VodickaM, ErgangP, HrncirT, et al. Microbiota affects the expression of genes involved in HPA axis regulation and local metabolism of glucocorticoids in chronic psychosocial stress. Brain Behav Immun. 2018; 73:615-624.

[52] ZhouJN, FangH. Transcriptional regulation of corticotropin-releasing hormone gene in stress response. IBRO Rep. 2018; 5:137-146.

[53] D’AmelioP, SassiF. Gut microbiota, immune system, and bone. Calcif Tissue Int. 2018; 102(4):415-425.

[54] SittipoP, Lobionda S, LeeYK, MaynardCL. Intestinal microbiota and the immune system in metabolic diseases. J Microbiol. 2018; 56(3):154-162.

[55] CryanJF, O’Riordan KJ, CowanCSM, et al. The microbiota-gut-brain axis. Physiol Rev. 2019; 99(4):1877-2013.

[56] DicksonD. Doctored report revives debate on 1957 mishap. Science. 1988; 239(4840):556-557.

[57] RojasOL, Probstel AK, PorfilioEA, et al. Recirculating intestinal IgA-producing cells regulate neuroinflammation via IL-10. Cell. 2019; 176(3):610-624 e18.

[58] FitzpatrickZ, FrazerG, FerroA, et al. Gut-educated IgA plasma cells defend the meningeal venous sinuses. Nature. 2020; 587(7834):472-476.

[59] BlutheRM, Michaud B, KelleyKW, DantzerR. Vagotomy blocks behavioural effects of interleukin-1 injected via the intraperitoneal route but not via other systemic routes. Neuroreport. 1996; 7(15–17):2823-2827.

[60] YamMF, LohYC, TanCS, Khadijah AdamS, Abdul Manan N, BasirR. General pathways of pain sensation and the major neurotransmitters involved in pain regulation. Int J Mol Sci. 2018; 19(8):2164.

[61] LaiNY, MusserMA, Pinho-RibeiroFA, et al. Gut-innervating nociceptor neurons regulate Peyer’s patch microfold cells and SFB levels to mediate salmonella host defense. Cell. 2020; 180(1):33-49 e22.

[62] BonazB, BazinT, PellissierS. The vagus nerve at the interface of the microbiota-gut-brain axis. Front Neurosci. 2018; 12:49.

[63] MargolisKG, CryanJF, MayerEA. The microbiota-gut-brain axis: from motility to mood. Gastroenterology. 2021; 160(5):1486-1501.

[64] FungTC, OlsonCA, HsiaoEY. Interactions between the microbiota, immune and nervous systems in health and disease. Nat Neurosci. 2017; 20(2):145-155.

[65] BravoJA, Forsythe P, ChewMV, et al. Ingestion of lactobacillus strain regulates emotional behavior and central GABA receptor expression in a mouse via the vagus nerve. Proc Natl Acad Sci U S A. 2011; 108(38):16050-16055.

[66] SgrittaM, Dooling SW, BuffingtonSA, et al. Mechanisms underlying microbial-mediated changes in social behavior in mouse models of autism Spectrum disorder. Neuron. 2019; 101(2):246-259 e6.

[67] Aron-WisnewskyJ, Warmbrunn MV, NieuwdorpM, ClementK. Metabolism and metabolic disorders and the microbiome: the intestinal microbiota associated with obesity, Lipid Metabolism, and Metabolic Health-Pathophysiology and Therapeutic Strategies. Gastroenterology. 2021; 160(2):573-599.

[68] Abdel-HaqR, Schlachetzki JCM, GlassCK, MazmanianSK. Microbiome-microglia connections via the gut-brain axis. J Exp Med. 2019; 216(1):41-59.

[69] BarcikW, PuginB, WestermannP, et al. Histamine-secreting microbes are increased in the gut of adult asthma patients. J Allergy Clin Immunol. 2016; 138(5):1491-1494 e7.

[70] PauloseJK, Cassone VM. The melatonin-sensitive circadian clock of the enteric bacterium Enterobacter aerogenes. Gut Microbes. 2016; 7(5):424-427.

[71] DurantiS, RuizL, LugliGA, et al. Bifidobacterium adolescentis as a key member of the human gut microbiota in the production of GABA. Sci Rep. 2020; 10(1):14112.

[72] LiuX, HuangL, ShiY, et al. Ganoderma lingzhi culture enhance growth performance via improvement of antioxidant activity and gut probiotic proliferation in Sanhuang broilers. Front Vet Sci. 2023; 10:1143649.

[73] DalileB, Van Oudenhove L, VervlietB, VerbekeK. The role of short-chain fatty acids in microbiota-gut-brain communication. Nat Rev Gastroenterol Hepatol. 2019; 16(8):461-478.

[74] CummingsJH, PomareEW, BranchWJ, Naylor CP, MacfarlaneGT. Short chain fatty acids in human large intestine, portal, hepatic and venous blood. Gut. 1987; 28(10):1221-1227.

[75] MorrowJD, OppMR. Diurnal variation of lipopolysaccharide-induced alterations in sleep and body temperature of interleukin-6-deficient mice. Brain Behav Immun. 2005; 19(1):40-51.

[76] WuBG, Sulaiman I, WangJ, et al. Severe obstructive sleep apnea is associated with alterations in the nasal microbiome and an increase in inflammation. Am J Respir Crit Care Med. 2019; 199(1):99-109.

[77] GaoT, WangZ, DongY, Cao J, ChenY. Butyrate ameliorates insufficient sleep-induced intestinal mucosal damage in humans and mice. Microbiol Spectr. 2023; 11(1):e0200022.

[78] SampsonTR, Mazmanian SK. Control of brain development, function, and behavior by the microbiome. Cell Host Microbe. 2015; 17(5):565-576.

[79] GrabruckerS, Marizzoni M, SilajdzicE, et al. Microbiota from Alzheimer’s patients induce deficits in cognition and hippocampal neurogenesis. Brain. 2023; 146(12):4916-4934.

[80] QuL, LiY, LiuF, et al. Microbiota-gut-brain Axis dysregulation in Alzheimer’s disease: multi-pathway effects and therapeutic potential. Aging Dis. 2024; 15(3):1108-1131.

[81] JandhyalaSM, Talukdar R, SubramanyamC, VuyyuruH, Sasikala M, Nageshwar ReddyD. Role of the normal gut microbiota. World J Gastroenterol. 2015; 21(29):8787-8803.

[82] WiertsemaSP, van Bergenhenegouwen J, GarssenJ, KnippelsLMJ. The interplay between the gut microbiome and the immune system in the context of infectious diseases throughout life and the role of nutrition in optimizing treatment strategies. Nutrients. 2021; 13(3):886.

[83] WuHJ, WuE. The role of gut microbiota in immune homeostasis and autoimmunity. Gut Microbes. 2012; 3(1):4-14.

[84] LiuJ, LuR, ZhengX, et al. Establishment of a gut-on-a-chip device with controllable oxygen gradients to study the contribution of Bifidobacterium bifidum to inflammatory bowel disease. Biomater Sci. 2023; 11(7):2504-2517.

[85] MilaniN, Parrott N, Ortiz FranyutiD, et al. Application of a gut-liver-on-a-chip device and mechanistic modelling to the quantitative in vitro pharmacokinetic study of mycophenolate mofetil. Lab Chip. 2022; 22(15):2853-2868.

[86] MittalE, CuppG, KangYA. Simulating the effect of gut microbiome on cancer cell growth using a microfluidic device. Sensors (Basel). 2023; 23(3):1265.

[87] ShinW, KimHJ. 3D in vitro morphogenesis of human intestinal epithelium in a gut-on-a-chip or a hybrid chip with a cell culture insert. Nat Protoc. 2022; 17(3):910-939.

[88] De GregorioV, Sgambato C, UrciuoloF, VecchioneR, NettiPA, ImparatoG. Immunoresponsive microbiota-gut-on-chip reproduces barrier dysfunction, stromal reshaping and probiotics translocation under inflammation. Biomaterials. 2022; 286:121573.

[89] ZhangS, XuG, WuJ, et al. Microphysiological constructs and systems: biofabrication tactics, biomimetic evaluation approaches, and biomedical applications. Small Methods. 2024; 8(1):e2300685.

[90] PediaditakisI, Kodella KR, ManatakisDV, et al. Modeling alpha-synuclein pathology in a human brain-chip to assess blood-brain barrier disruption. Nat Commun. 2021; 12(1):5907.

[91] LyuZ, ParkJ, KimKM, et al. A neurovascular-unit-on-a-chip for the evaluation of the restorative potential of stem cell therapies for ischaemic stroke. Nat Biomed Eng. 2021; 5(8):847-863.

[92] ChoAN, JinY, AnY, et al. Microfluidic device with brain extracellular matrix promotes structural and functional maturation of human brain organoids. Nat Commun. 2021; 12(1):4730.

[93] MahumaneGD, KumarP, du ToitLC, Choonara YE, PillayV. 3D scaffolds for brain tissue regeneration: architectural challenges. Biomater Sci. 2018; 6(11):2812-2837.

[94] RaoZ, LinT, QiuS, et al. Decellularized nerve matrix hydrogel scaffolds with longitudinally oriented and size-tunable microchannels for peripheral nerve regeneration. Mater Sci Eng C Mater Biol Appl. 2021; 120:111791.

[95] XuJ, WuZ, ZhangM, et al. The role of the gastrointestinal system in neuroinvasion by SARS-CoV-2. Front Neurosci. 2021; 15:694446.

[96] CadenaM, NingL, KingA, et al. 3D bioprinting of neural tissues. Adv Healthc Mater. 2021; 10(15):e2001600.

[97] LiuX, HaoM, ChenZ, et al. 3D bioprinted neural tissue constructs for spinal cord injury repair. Biomaterials. 2021; 272:120771.

[98] ParkerKE, LeeJ, KimJR, et al. Customizable, wireless and implantable neural probe design and fabrication via 3D printing. Nat Protoc. 2023; 18(1):3-21.

[99] SullivanMA, LaneS, VolkerlingA, Engel M, WerryEL, KassiouM. Three-dimensional bioprinting of stem cell-derived central nervous system cells enables astrocyte growth, vasculogenesis, and enhances neural differentiation/function. Biotechnol Bioeng. 2023; 120(10):3079-3091.

[100] TangM, RichJN, ChenS. Biomaterials and 3D bioprinting strategies to model glioblastoma and the blood-brain barrier. Adv Mater. 2021; 33(5):e2004776.

[101] MaoS, FonderC, RubbyMF, Phillips GJ, SakaguchiDS, QueL. An integrated microfluidic chip for studying the effects of neurotransmitters on neurospheroids. Lab Chip. 2023; 23(6):1649-1663.

[102] TunesiM, IzzoL, RaimondiI, Albani D, GiordanoC. A miniaturized hydrogel-based in vitro model for dynamic culturing of human cells overexpressing beta-amyloid precursor protein. J Tissue Eng. 2020; 11:2041731420945633.

[103] ChenYP, DingZY, YuYS, et al. Recent advances in investigating odor-taste interactions: psychophysics, neuroscience, and microfluidic techniques. Trends Food Sci Tech. 2023; 138:500-510.

[104] KimMH, KimD, SungJH. A gut-brain Axis-on-a-Chip for studying transport across epithelial and endothelial barriers. J Ind Eng Chem. 2021; 101:126-134.

[105] RaimondiMT, AlbaniD, GiordanoC. An organ-on-A-Chip engineered platform to study the microbiota-gut-brain Axis in neurodegeneration. Trends Mol Med. 2019; 25(9):737-740.

[106] LohJS, MakWQ, TanLKS, et al. Microbiota-gut-brain axis and its therapeutic applications in neurodegenerative diseases. Signal Transduct Target Ther. 2024; 9(1):37.

[107] KimMH, van Noort D, SungJH, ParkS. Organ-on-a-Chip for studying gut-brain interaction mediated by extracellular vesicles in the gut microenvironment. Int J Mol Sci. 2021; 22(24):13513.

[108] KimNY, LeeHY, ChoiYY, et al. Effect of gut microbiota-derived metabolites and extracellular vesicles on neurodegenerative disease in a gut-brain axis chip. Nano Converg. 2024; 11(1):7.

[109] ChapinAA, Rajasekaran PR, QuanDN, et al. Electrochemical measurement of serotonin by Au-CNT electrodes fabricated on microporous cell culture membranes. Microsyst Nanoeng. 2020; 6:90.

[110] TrapecarM, WogramE, SvobodaD, et al. Human physiomimetic model integrating microphysiological systems of the gut, liver, and brain for studies of neurodegenerative diseases. Sci Adv. 2021; 7(5):eabd1707.

[111] Picollet-D’hahanN, ZuchowskaA, Lemeunier I, Le GacS. Multiorgan-on-a-chip: A systemic approach to model and decipher inter-organ communication. Trends Biotechnol. 2021; 39(8):788-810.

[112] ParkD, LeeJ, ChungJJ, Jung Y, KimSH. Integrating organs-on-chips: multiplexing, scaling, vascularization, and innervation. Trends Biotechnol. 2020; 38(1):99-112.

[113] WagnerKT, NashTR, LiuB, Vunjak-Novakovic G, RadisicM. Extracellular vesicles in cardiac regeneration: potential applications for tissues-on-a-Chip. Trends Biotechnol. 2021; 39(8):755-773.

[114] BeaurivageC, Naumovska E, ChangYX, et al. Development of a gut-on-A-chip model for high throughput disease modeling and drug discovery. Int J Mol Sci. 2019; 20(22):5661.

[115] GrassartA, Malarde V, GobaaS, et al. Bioengineered human organ-on-Chip reveals intestinal microenvironment and mechanical forces impacting shigella infection. Cell Host Microbe. 2019; 26(3):435-444 e4.

[116] Jalili-FiroozinezhadS, Gazzaniga FS, CalamariEL, et al. A complex human gut microbiome cultured in an anaerobic intestine-on-a-chip. Nat Biomed Eng. 2019; 3(7):520-531.

[117] NikolaevM, Mitrofanova O, BroguiereN, et al. Homeostatic mini-intestines through scaffold-guided organoid morphogenesis. Nature. 2020; 585(7826):574-578.

[118] GuoY, LuoR, WangY, et al. SARS-CoV-2 induced intestinal responses with a biomimetic human gut-on-chip. Sci Bull (Beijing). 2021; 66(8):783-793.

[119] LanikWE, LukeCJ, NolanLS, et al. Microfluidic device facilitates in vitro modeling of human neonatal necrotizing enterocolitis-on-a-chip. JCI Insight. 2023; 8(8):e146496.

[120] KimJ, LeeKT, LeeJS, et al. Fungal brain infection modelled in a human-neurovascular-unit-on-a-chip with a functional blood-brain barrier. Nat Biomed Eng. 2021; 5(8):830-846.

[121] JangM, ChoiN, KimHN. Hyperglycemic Neurovasculature-on-A-Chip to study the effect of SIRT1-targeted therapy for the type 3 diabetes "Alzheimer’s disease". Adv Sci (Weinh). 2022; 9(34):e2201882.

[122] ChoiJH, ChoiHK, LeeKB. In situ detection of neuroinflammation using multicellular 3D neurovascular-unit-on-a-Chip. Adv Funct Mater. 2023; 33(46):2304382.

[123] SeoS, JangM, KimH, et al. Neuro-glia-vascular-on-a-chip system to assess aggravated neurodegeneration via brain endothelial cells upon exposure to diesel exhaust particles. Adv Funct Mater. 2023; 33(12):2370074.

[124] ShanerS, LuH, LenzM, Garg S, VlachosA, AsplundM. Brain stimulation-on-a-chip: a neuromodulation platform for brain slices. Lab Chip. 2023; 23(23):4967-4985.

[125] WesterhofTM, YangBA, MerillNM, et al. Blood-brain barrier remodeling in an organ-on-a-chip device shows Dkk1 to be a regulator of early metastasis. Adv Nanobiomed Res. 2023; 3(4):2200036.

[126] ZhuY, ZhangX, SunL, WangY, ZhaoY. Engineering human brain Assembloids by microfluidics. Adv Mater. 2023; 35(14):e2210083.

RIGHTS & PERMISSIONS

2024 The Author(s). Cell Proliferation published by Beijing Institute for Stem Cell and Regenerative Medicine and John Wiley & Sons Ltd.