Organ-on-Chip Approaches for Intestinal 3D In Vitro Modeling
2021; Elsevier BV; Volume: 13; Issue: 2 Linguagem: Inglês
10.1016/j.jcmgh.2021.08.015
ISSN2352-345X
AutoresJoana Marantes Pimenta, Ricardo Ribeiro, Raquel Almeida, Pedro F. Costa, Marta Alves da Silva, Bruno Pereira,
Tópico(s)Innovative Microfluidic and Catalytic Techniques Innovation
ResumoThe intestinal epithelium has one of the highest turnover rates in the human body, which is supported by intestinal stem cells. Culture models of intestinal physiology have been evolving to incorporate different tissue and microenvironmental elements. However, these models also display gaps that limit their similarity with native conditions. Microfluidics technology arose from the application of microfabrication techniques to fluid manipulation. Recently, microfluidic approaches have been coupled with cell culture, creating self-contained and modular in vitro models with easily controllable features named organs-on-chip. Intestine-on-chip models have enabled the recreation of the proliferative and differentiated compartments of the intestinal epithelium, the long-term maintenance of commensals, and the intraluminal perfusion of organoids. In addition, studies based on human primary intestinal cells have shown that these systems have a closer transcriptomic profile and functionality to the intestine in vivo, when compared with other in vitro models. The design flexibility inherent to microfluidic technology allows the simultaneous combination of components such as shear stress, peristalsis-like strain, 3-dimensional structure, oxygen gradient, and co-cultures with other important cell types involved in gut physiology. The versatility and complexity of the intestine-on-chip grants it the potential for applications in disease modeling, host-microbiota studies, stem cell biology, and, ultimately, the translation to the pharmaceutical industry and the clinic as a reliable high-throughput platform for drug testing and personalized medicine, respectively. This review focuses on the physiological importance of several components that have been incorporated into intestine-on-chip models and highlights interesting features developed in other types of in vitro models that might contribute to the refinement of these systems. The intestinal epithelium has one of the highest turnover rates in the human body, which is supported by intestinal stem cells. Culture models of intestinal physiology have been evolving to incorporate different tissue and microenvironmental elements. However, these models also display gaps that limit their similarity with native conditions. Microfluidics technology arose from the application of microfabrication techniques to fluid manipulation. Recently, microfluidic approaches have been coupled with cell culture, creating self-contained and modular in vitro models with easily controllable features named organs-on-chip. Intestine-on-chip models have enabled the recreation of the proliferative and differentiated compartments of the intestinal epithelium, the long-term maintenance of commensals, and the intraluminal perfusion of organoids. In addition, studies based on human primary intestinal cells have shown that these systems have a closer transcriptomic profile and functionality to the intestine in vivo, when compared with other in vitro models. The design flexibility inherent to microfluidic technology allows the simultaneous combination of components such as shear stress, peristalsis-like strain, 3-dimensional structure, oxygen gradient, and co-cultures with other important cell types involved in gut physiology. The versatility and complexity of the intestine-on-chip grants it the potential for applications in disease modeling, host-microbiota studies, stem cell biology, and, ultimately, the translation to the pharmaceutical industry and the clinic as a reliable high-throughput platform for drug testing and personalized medicine, respectively. This review focuses on the physiological importance of several components that have been incorporated into intestine-on-chip models and highlights interesting features developed in other types of in vitro models that might contribute to the refinement of these systems. SummaryThis review focuses on the different biological parameters that advanced 3-dimensional intestinal in vitro models, particularly intestine-on-chip systems, should incorporate to better mimic the full complexity of the intestinal tissue and microenvironment. This review focuses on the different biological parameters that advanced 3-dimensional intestinal in vitro models, particularly intestine-on-chip systems, should incorporate to better mimic the full complexity of the intestinal tissue and microenvironment. The intestine is a critical organ in the digestive system, mainly because of its role in nutrient absorption. Intestinal microarchitecture (including plicae circulares, villi, and microvilli) is designed specifically to increase surface area and therefore enhance the efficiency of the absorptive processes.1Mescher AL. Junqueira's basic histology: text and atlas. 14th ed. McGraw-Hill, Columbus, OH, US2015Google Scholar However, the intestinal luminal microenvironment is quite hostile, with constant exposure to low levels of pH, microorganisms, and xenobiotics. Therefore, the intestinal epithelium has one of the highest turnover rates in the human body,2Li H.J. Ray S.K. Singh N.K. Johnston B. Leiter A.B. Basic helix-loop-helix transcription factors and enteroendocrine cell differentiation.Diabetes Obes Metab. 2011; 13: 5-12Crossref PubMed Scopus (69) Google Scholar also exhibiting a fast and reliable mechanism of regeneration upon mucosal injury. This is ensured by a population of resident intestinal stem cells (ISCs) located within submucosal invaginations called crypts of Lieberkühn. At the bottom of the crypts, ISCs are shielded from the aggressive luminal environment and protected from pathogenic agents by surrounding Paneth cells that secrete antimicrobial peptides. Over the past years, different ISC markers have been described, with the leucine-rich repeat-containing G-protein–coupled receptor 5 (LGR5) being the most well known. LGR5+ cells are an intestinal multipotent stem cell population, showing self-renewing activity and the potential for originating absorptive, goblet, Paneth, enteroendocrine, microfold, and tuft cells.3Barker N. Van Es J.H. Kuipers J. Kujala P. Van Den Born M. Cozijnsen M. Haegebarth A. Korving J. Begthel H. Peters P.J. Clevers H. Identification of stem cells in small intestine and colon by marker gene Lgr5.Nature. 2007; 449: 1003-1007Crossref PubMed Scopus (3771) Google Scholar,4Gehart H. Clevers H. Tales from the crypt: new insights into intestinal stem cells.Nat Rev Gastroenterol Hepatol. 2019; 16: 19-34Crossref PubMed Scopus (291) Google Scholar LGR5+ cells are found primarily at the bottom of the crypt, interspersed with Paneth cells. Each ISC divides every 24 hours and can give rise to transit-amplifying cells and/or other ISCs. Although the latter remain undifferentiated at the bottom of the crypt, the former move upward on the epithelial layer in direction of the villus top, while becoming differentiated.5Marshman E. Booth C. Potten C.S. The intestinal epithelial stem cell.Bioessays. 2002; 24: 91-98Crossref PubMed Scopus (470) Google Scholar The ISC niche gathers several signaling molecules and growth factors necessary to maintain the stem cell population and ensure continuous proliferation and regeneration of the epithelium.4Gehart H. Clevers H. Tales from the crypt: new insights into intestinal stem cells.Nat Rev Gastroenterol Hepatol. 2019; 16: 19-34Crossref PubMed Scopus (291) Google Scholar In fact, signaling pathways such as Wnt, Notch, and bone morphogenetic protein (BMP) form opposing morphogenic gradients along the crypt/villus axis that are responsible for creating compartmentalized proliferative (crypt) and differentiated (villus) zones. Paneth and subepithelial mesenchymal cells are among the main contributors to the maintenance of the ISC niche. The understanding of the intestinal function and homeostatic process is fundamental for modeling disease conditions and the development of novel therapeutic approaches. In this context, several in vitro and in vivo models are being used in the laboratory to mimic intestinal features as closely as possible. Recently, gut organoids have emerged as a promising platform for biomedical research and applications.6Sato T. Vries R.G. Snippert H.J. Van De Wetering M. Barker N. Stange D.E. Van Es J.H. Abo A. Kujala P. Peters P.J. Clevers H. Single Lgr5 stem cells build crypt-villus structures in vitro without a mesenchymal niche.Nature. 2009; 459: 262-265Crossref PubMed Scopus (3834) Google Scholar Although organoids usually are referred to as mini-organs, their simplistic structure does not fully mimic a complex organ. Therefore, biofabrication techniques have been used to develop devices that can surpass organoid limitations. In this regard, microfluidic devices recently emerged as interesting platforms for in vitro models of human organs. The perfusion created in microfluidic devices mimics the function of blood circulation in tissues, allowing communication between different tissues and biochemical environments through microchannels or porous membranes.7Aziz A.U.R. Geng C. Fu M. Yu X. Qin K. Liu B. The role of microfluidics for organ on chip simulations.Bioengineering. 2017; 4: 39Crossref Scopus (40) Google Scholar The features and structure of microfluidic devices are completely tunable so that a variety of components of a system can be included for a better representation of complex physiological environments. Taking this range of possibilities into account, microfluidic devices permit a reductionist representation of an organ's functions, creating organ-on-chip systems. Organs-on-chip are designed considering the characteristics of the organ's functional units; therefore, they include the different cell types of the organ, recapitulate the structural organization, as well as the organ-specific physical and biochemical microenvironment. As a result, organ-on-chip platforms provide a more precise control of cell culture.8Park S.E. Georgescu A. Huh D. Organoids-on-a-chip.Science. 2019; 364: 960-965Crossref PubMed Scopus (261) Google Scholar Since the first intestine-on-chip was developed in 2008 by Kimura et al,9Kimura H. Yamamoto T. Sakai H. Sakai Y. Fujii T. An integrated microfluidic system for long-term perfusion culture and on-line monitoring of intestinal tissue models.Lab Chip. 2008; 8: 741Crossref PubMed Scopus (217) Google Scholar a number of intestines-on-chip have been reported in the literature (Table 1). These models, designed to mimic intestinal structure and physiology, have been providing valuable insights regarding host-microbiota interaction,10Kim H.J. Huh D. Hamilton G. Ingber D.E. Human gut-on-a-chip inhabited by microbial flora that experiences intestinal peristalsis-like motions and flow.Lab Chip. 2012; 12: 2165Crossref PubMed Scopus (968) Google Scholar, 11Jalili-Firoozinezhad S. Gazzaniga F.S. Calamari E.L. Camacho D.M. Fadel C.W. Bein A. Swenor B. Nestor B. Cronce M.J. Tovaglieri A. Levy O. Gregory K.E. Breault D.T. Cabral J.M.S. Kasper D.L. Novak R. Ingber D.E. A complex human gut microbiome cultured in an anaerobic intestine-on-a-chip.Nat Biomed Eng. 2019; 3: 520-531Crossref PubMed Scopus (276) Google Scholar, 12Shah P. Fritz J.V. Glaab E. Desai M.S. Greenhalgh K. Frachet A. Niegowska M. Estes M. Jäger C. Seguin-Devaux C. Zenhausern F. Wilmes P. A microfluidics-based in vitro model of the gastrointestinal human–microbe interface.Nat Commun. 2016; 7: 11535Crossref PubMed Scopus (293) Google Scholar intestinal inflammatory diseases,13Kim H.J. Li H. Collins J.J. Ingber D.E. Contributions of microbiome and mechanical deformation to intestinal bacterial overgrowth and inflammation in a human gut-on-a-chip.Proc Natl Acad Sci U S A. 2016; 113: E7-E15Crossref PubMed Scopus (495) Google Scholar, 14Shin W. Kim H.J. Intestinal barrier dysfunction orchestrates the onset of inflammatory host–microbiome cross-talk in a human gut inflammation-on-a-chip.Proc Natl Acad Sci U S A. 2018; 115: E10539-E10547Crossref PubMed Scopus (121) Google Scholar, 15Maurer M. Gresnigt M.S. Last A. Wollny T. Berlinghof F. Pospich R. Cseresnyes Z. Medyukhina A. Graf K. Gröger M. Raasch M. Siwczak F. Nietzsche S. Jacobsen I.D. Figge M.T. Hube B. Huber O. Mosig A.S. A three-dimensional immunocompetent intestine-on-chip model as in vitro platform for functional and microbial interaction studies.Biomaterials. 2019; 220119396Crossref PubMed Scopus (51) Google Scholar and are becoming relevant platforms for pharmacologic assays16Kasendra M. Luc R. Yin J. Manatakis D.V. Kulkarni G. Lucchesi C. Sliz J. Apostolou A. Sunuwar L. Obrigewitch J. Jang K. Hamilton G.A. Donowitz M. Karalis K. Duodenum Intestine-Chip for preclinical drug assessment in a human relevant model.eLife. 2020; 9e50135Crossref PubMed Scopus (78) Google Scholar, 17Shim K.Y. Lee D. Han J. Nguyen N.T. Park S. Sung J.H. Microfluidic gut-on-a-chip with three-dimensional villi structure.Biomed Microdevices. 2017; 19: 37Crossref PubMed Scopus (105) Google Scholar, 18Pocock K. Delon L. Bala V. Rao S. Priest C. Prestidge C. Thierry B. Intestine-on-a-chip microfluidic model for efficient in vitro screening of oral chemotherapeutic uptake.ACS Biomater Sci Eng. 2017; 3: 951-959Crossref PubMed Scopus (52) Google Scholar and organoid cultures.19Sidar B. Jenkins B.R. Huang S. Spence J.R. Walk S.T. Wilking J.N. Long-term flow through human intestinal organoids with the gut organoid flow chip (GOFlowChip).Lab Chip. 2019; 19: 3552-3562Crossref PubMed Google Scholar,20Nikolaev M. Mitrofanova O. Broguiere N. Geraldo S. Dutta D. Tabata Y. Elci B. Brandenberg N. Kolotuev I. Gjorevski N. Clevers H. Lutolf M.P. Homeostatic mini-intestines through scaffold-guided organoid morphogenesis.Nature. 2020; 585: 574-578Crossref PubMed Scopus (168) Google Scholar The main advantage of intestine-on-chip models is the incorporation of dynamic fluid flow, which can be applied to simulate blood circulation, basally supplying epithelial cells with nutrients and growth factors as well as intraluminal flow, mimicking the circulation of nutrients, drugs, and pathogens inside the intestine.Table 1Main Features and Components of Intestine-on-Chip Models Reported in the LiteratureReferenceIntestinal cellsCo-culturePeristalsis simulationOxygen gradientDevice materialMembrane material and ECMFabrication techniqueMajor observationsMain parameter testedKimura et al, 20089Kimura H. Yamamoto T. Sakai H. Sakai Y. Fujii T. An integrated microfluidic system for long-term perfusion culture and on-line monitoring of intestinal tissue models.Lab Chip. 2008; 8: 741Crossref PubMed Scopus (217) Google ScholarCaco-2NoNoNoPDMSPolyester, type I collagenPhotolithographyAllowed long-term culture (up to 30 days), induced polarized transport activityMicrofluidics and mechanical stimulationKim et al, 201210Kim H.J. Huh D. Hamilton G. Ingber D.E. Human gut-on-a-chip inhabited by microbial flora that experiences intestinal peristalsis-like motions and flow.Lab Chip. 2012; 12: 2165Crossref PubMed Scopus (968) Google ScholarCaco-2L rhamnosusCyclic strainNoPDMSPDMS, type I collagen and Matrigel mixSoft lithographyFluid flow accelerated intestinal epithelial differentiation and organization into villi-like structures, mechanical stimulation enhanced specific differentiation features, sustained long-term co-culture with commensal bacteriaKim and Ingber, 201321Kim H.J. Ingber D.E. Gut-on-a-Chip microenvironment induces human intestinal cells to undergo villus differentiation.Integr Biol (Camb). 2013; 5: 1130Crossref PubMed Scopus (416) Google ScholarCaco-2NoCyclic strainNoPDMSPDMS, type I collagen and Matrigel mixSoft lithographyObserved increased proliferative activity at the base of villi-like structures and differentiation into the 4 major intestinal epithelial cell typesPocock et al, 201718Pocock K. Delon L. Bala V. Rao S. Priest C. Prestidge C. Thierry B. Intestine-on-a-chip microfluidic model for efficient in vitro screening of oral chemotherapeutic uptake.ACS Biomater Sci Eng. 2017; 3: 951-959Crossref PubMed Scopus (52) Google ScholarCaco-2NoNoNoPDMSPolycarbonate, MatrigelSoft lithographyDefined a permeability coefficient across the intestinal barrier for lipophilic drugsTriestch et al, 201722Trietsch S.J. Naumovska E. Kurek D. Setyawati M.C. Vormann M.K. Wilschut K.J. Lanz H.L. Nicolas A. Ng C.P. Joore J. Kustermann S. Roth A. Hankemeier T. Moisan A. Vulto P. Membrane-free culture and real-time barrier integrity assessment of perfused intestinal epithelium tubes.Nat Commun. 2017; 8: 262Crossref PubMed Scopus (136) Google ScholarCaco-2NoNoNoGlass, polystyrene, and proprietary polymersMembrane-free (PhaseGuide; MIMETAS,Leiden, the Netherlands), type I collagenNot describedEstablished a high-throughput platform with pumpless flow, showed its suitability for epithelial barrier integrity studies, first commercially available modelGuo et al, 201823Guo Y. Li Z. Su W. Wang L. Zhu Y. Qin J. A biomimetic human Gut-on-a-Chip for modeling drug metabolism in intestine.Artif Organs. 2018; 42: 1196-1205Crossref PubMed Scopus (29) Google ScholarCaco-2NoNoNoPDMSNitrocellulose, type I collagenSoft lithographyEngineered a 4-parallel cell culture chamber device, evaluated drug metabolism (exposure to verapamil and ifosfamide)Workman et al, 201824Workman M.J. Gleeson J.P. Troisi E.J. Estrada H.Q. Kerns S.J. Hinojosa C.D. Hamilton G.A. Targan S.R. Svendsen C.N. Barrett R.J. Enhanced utilization of induced pluripotent stem cell–derived human intestinal organoids using microengineered chips.Cell Mol Gastroenterol Hepatol. 2018; 5: 669-677.e2Abstract Full Text Full Text PDF PubMed Scopus (123) Google ScholariPSC-derived human intestinal organoids and Caco-2NoNoNoPDMSPDMS, MatrigelSoft lithographyShowed the feasibility of intestinal organoid–derived culture on a microengineered chip, continuous luminal flow led to the development of villus-like projections, the culture system was biologically responsive to inflammatory cytokinesSidar et al, 201919Sidar B. Jenkins B.R. Huang S. Spence J.R. Walk S.T. Wilking J.N. Long-term flow through human intestinal organoids with the gut organoid flow chip (GOFlowChip).Lab Chip. 2019; 19: 3552-3562Crossref PubMed Google ScholariPSC-derived human intestinal organoidsNoNoNoPolymethyl methacrylateMembrane-free (central well), MatrigelLaser cuttingEstablished luminal and extraluminal flow in single intestinal organoids, cell viability was unaffected by long-term porting and luminal flowKasendra et al, 201825Kasendra M. Tovaglieri A. Sontheimer-Phelps A. Jalili-Firoozinezhad S. Bein A. Chalkiadaki A. Scholl W. Zhang C. Rickner H. Richmond C.A. Li H. Breault D.T. Ingber D.E. Development of a primary human Small Intestine-on-a-Chip using biopsy-derived organoids.Sci Rep. 2018; 8: 2871Crossref PubMed Scopus (322) Google ScholarHuman duodenal organoids (pediatric donors)HIMECsCyclic strainNoPDMSPDMS, type I collagen and Matrigel mixSoft lithographyTranscriptome of the intestinal tissue-on-chip more closely resembled that of the duodenum in vivo than the initial organoid culture from which it was derived, co-culture with endothelial cells accelerated the formation of the epithelial monolayerKasendra et al, 202016Kasendra M. Luc R. Yin J. Manatakis D.V. Kulkarni G. Lucchesi C. Sliz J. Apostolou A. Sunuwar L. Obrigewitch J. Jang K. Hamilton G.A. Donowitz M. Karalis K. Duodenum Intestine-Chip for preclinical drug assessment in a human relevant model.eLife. 2020; 9e50135Crossref PubMed Scopus (78) Google ScholarHuman duodenal organoids (adult donors)HIMECsCyclic strainNoPDMSPDMS, type IV collagen and Matrigel mix (epithelial side), type IV collagen and fibronectin mix (vascular side)Soft lithographyShowed culture system suitability for studying intestinal metabolism and drug transportYin et al, 202026Yin J. Sunuwar L. Kasendra M. Yu H. Tse C. Talbot C. Boronina T.N. Cole R.N. Karalis K. Donowitz M. Fluid shear stress enhances differentiation of jejunal human enteroids in Intestine-Chip.Am J Physiol Gastrointest Liver Physiol. 2020; 320: G258-G271Crossref PubMed Scopus (7) Google ScholarHuman jejunal organoids (adult donors)HUVECsCyclic strainNoPDMSPDMS, type IV collagenSoft lithographyShear stress generated by luminal and basolateral flow produced a model of continuous intestinal differentiation, no villi-like structures observed with stem cell expansion media on the luminal sideShin et al, 201927Shin W. Hinojosa C.D. Ingber D.E. Kim H.J. Human intestinal morphogenesis controlled by transepithelial morphogen gradient and flow-dependent physical cues in a microengineered Gut-on-a-Chip.iScience. 2019; 15: 391-406Abstract Full Text Full Text PDF PubMed Scopus (65) Google ScholarHuman colon organoids (adult donors) and Caco-2NoNoNoPDMSPDMS, type I collagen and Matrigel mixSoft lithographyObserved that fluid flow was more determinant than mechanical deformation for induction of 3D morphogenesis, removal of basolaterally secreted Wnt antagonists, such as DKK1, rapidly triggered villi-like intestinal morphogenesis mediated by FZD9Sontheimer-Phelps et al, 202028Sontheimer-Phelps A. Chou D.B. Tovaglieri A. Ferrante T.C. Duckworth T. Fadel C. Frismantas V. Sutherland A.D. Jalili-Firoozinezhad S. Kasendra M. Stas E. Weaver J.C. Richmond C.A. Levy O. Prantil-Baun R. Breault D.T. Ingber D.E. Human Colon-on-a-Chip enables continuous in vitro analysis of colon mucus layer accumulation and physiology.Cell Mol Gastroenterol Hepatol. 2020; 9: 507-526Abstract Full Text Full Text PDF PubMed Scopus (80) Google ScholarHuman colon organoids (pediatric and adult donors)NoNoNoPDMSPDMS, type I collagen and Matrigel mixSoft lithographyReplicated the colonic mucus bilayer, spontaneous differentiation of mucus-producing MUC2+ goblet cells observed at similar levels to those present in the human colon in vivoRichardson et al, 202029Richardson A. Schwerdtfeger L.A. Eaton D. McLean I. Henry C.S. Tobet S.A. A microfluidic organotypic device for culture of mammalian intestines ex vivo.Analytical Methods. 2020; 12: 297-303Crossref Google ScholarMouse colon tissue explantIntestinal submucosal and muscular layers, microbiotaNoYesCyclin olefin polymer and polyurethaneMembrane-free, no ECMInjection moldingDual-flow microfluidics allowed for the culture of full-thickness explants over 3 days, recapitulated the in vivo oxygen gradient across the epithelial layerShim et al, 201717Shim K.Y. Lee D. Han J. Nguyen N.T. Park S. Sung J.H. Microfluidic gut-on-a-chip with three-dimensional villi structure.Biomed Microdevices. 2017; 19: 37Crossref PubMed Scopus (105) Google ScholarCaco-2NoNoNoPDMS, PET, and glassCollagen 3D scaffoldSoft lithography and micromoldingCombined a 3D collagen scaffold mimicking human intestinal villi with fluidics, the culture system enhanced metabolic activityArchitectural cuesCostello et al, 201730Costello C.M. Phillipsen M.B. Hartmanis L.M. Kwasnica M.A. Chen V. Hackam D. Chang M.W. Bentley W.E. March J.C. Microscale bioreactors for in situ characterization of GI epithelial cell physiology.Sci Rep. 2017; 7: 12515Crossref PubMed Scopus (37) Google ScholarCaco-2NoNoNoVeroClear-RGD810 (Stratasys, Minneapolis, MN)Polyethylene-vinyl-acetate 3D scaffold3D printing and micromoldingBioreactor culture with a villi polymeric scaffold led to cell differentiation and apoptosis gradients, observed physiological levels of glucose absorptionNikolaev et al, 202020Nikolaev M. Mitrofanova O. Broguiere N. Geraldo S. Dutta D. Tabata Y. Elci B. Brandenberg N. Kolotuev I. Gjorevski N. Clevers H. Lutolf M.P. Homeostatic mini-intestines through scaffold-guided organoid morphogenesis.Nature. 2020; 585: 574-578Crossref PubMed Scopus (168) Google ScholarMouse proximal small intestine organoidsCryptosporidium parvumNoNoPDMSType I collagen and Matrigel mix–coated 3D scaffoldSoft lithography and laser ablationEstablished a long-lived and tube-shaped intestinal epithelial culture system by using crypt-like microcavities under flow, induced topography-guided self-organization of a functional epithelium with crypt- and villus-like domains similar to that observed in vivo, the culture system showed self-regeneration capacity and response to bacterial infectionShah et al, 201612Shah P. Fritz J.V. Glaab E. Desai M.S. Greenhalgh K. Frachet A. Niegowska M. Estes M. Jäger C. Seguin-Devaux C. Zenhausern F. Wilmes P. A microfluidics-based in vitro model of the gastrointestinal human–microbe interface.Nat Commun. 2016; 7: 11535Crossref PubMed Scopus (293) Google ScholarCaco-2L rhamnosus GG and Bacteroides caccaeNoYesPolycarbonatePolycarbonate, type I collagen (epithelial chamber) and porcine gastric mucin (microbial chamber)Computer-controlled milling, laser cutting, and boltingEngineered a modular architecture consisting of 3 microchambers to facilitate human and microbial cell interface, allowed measuring individual transcriptional responses in different infectious contexts and real-time monitoring of oxygen concentrationsMicrobiota co-cultureKim et al, 201613Kim H.J. Li H. Collins J.J. Ingber D.E. Contributions of microbiome and mechanical deformation to intestinal bacterial overgrowth and inflammation in a human gut-on-a-chip.Proc Natl Acad Sci U S A. 2016; 113: E7-E15Crossref PubMed Scopus (495) Google ScholarCaco-2Human gut microbiota, E coli, human PBMCs, human microvascular endothelial cells, and human lymphatic microvascular endothelial cellsCyclic strainNoPDMSPDMS, type I collagen and Matrigel mixSoft lithographyEstablished a stable long-term co-culture system of commensal and pathogenic microbes with intestinal epithelial cells, lack of mechanical stimulation induced bacterial overgrowth, similar to what is observed in IBD patients, emulated intestinal infection and inflammatory responsesShin and Kim, 201814Shin W. Kim H.J. Intestinal barrier dysfunction orchestrates the onset of inflammatory host–microbiome cross-talk in a human gut inflammation-on-a-chip.Proc Natl Acad Sci U S A. 2018; 115: E10539-E10547Crossref PubMed Scopus (121) Google ScholarCaco-2Human gut microbiota, E coli, PBMCsCyclic strainNoPDMSPDMS, type I collagen and Matrigel mixSoft lithographyRe-created a dextran sodium sulfate–induced epithelial inflammatory response, described intestinal barrier dysfunction as a critical trigger of inflammation onset in the gutGrassart et al, 201931Grassart A. Malardé V. Gobba S. Sartori-Rupp A. Kerns J. Karalis K. Marteyn B. Sansonetti P. Sauvonnet N. Bioengineered human Organ-on-Chip reveals intestinal microenvironment and mechanical forces impacting Shigella infection.Cell Host Microbe. 2019; 26: 435-444.e4Abstract Full Text Full Text PDF PubMed Scopus (61) Google ScholarCaco-2S flexneriCyclic strainNoPDMSPDMS, type I collagen and Matrigel mixSoft lithographyEnabled the replication of Shigella infection hallmarks, Shigella invaded directly via the luminal side of the epithelium composed solely of enterocytes, 3D crypt-like structures provided a safe harbor for bacteria against luminal washoutTovaglieri et al, 201932Tovaglieri A. Sontheimer-Phelps A. Geirnaert A. Prantil-Baun R. Camacho D.M. Chou D.B. Jalili-Firoozinezhad S. De Wouters T. Kasendra M. Super M. Cartwright M.J. Richmond C.A. Breault D.T. Lacroix C. Ingber D.E. Species-specific enhancement of enterohemorrhagic E. coli pathogenesis mediated by microbiome metabolites.Microbiome. 2019; 7: 43Crossref PubMed Scopus (55) Google ScholarHuman colon organoids (pediatric and adult donors)HIMECs, EHECNoNoPDMSPDMS, type I collagen and Matrigel mixSoft lithographyObserved that infectious activity of EHEC is promoted by human gut microbiome metabolites, when compared with those derived from mouse, recapitulated the proinflammatory and anti-inflammatory cytokine profiles induced by EHEC infectionSunuwar et al, 202033Sunuwar L. Yin J. Kasendra M. Karalis K. Kaper J. Fleckenstein J. Donowitz M. Mechanical stimuli affect Escherichia coli heat-stable enterotoxin-cyclic GMP signaling in a human enteroid intestine-chip model.Infect Immun. 2020; 88 (e00866–19)Crossref PubMed Scopus (18) Google ScholarHuman jejunal organoids (adult donors)NoCyclic strainNoPDMSPDMS, type IV collagenSoft lithographyFlow and mechanical strain increased extracellular cyclic guanosine monophosphate secretion in response to EHEC-produced heat-stable enterotoxin AShin et al, 201934Shin W. Wu A. Massidda M.W. Foster C. Thomas N. Lee D.W. Koh H. Ju Y. Kim J. Kim H.J. A robust longitudinal co-culture of obligate anaerobic gut microbiome with human intestinal epithelium in an anoxic-oxic interface-on-a-chip.Front Bioeng Biotechnol. 2019; 7: 13Crossref PubMed Scopus (62) Google ScholarCaco-2Bifidobacterium adolescentis and Eubacterium halliiCyclic strainYesPDMSPDMS, type I collagen and Matrigel mixSoft lithographySimulated a steady-state vertical oxygen gradient, the transepithelial anoxic–oxic interface allowed co-culture with obligate anaerobesOxygen gradientJalili-Firoozinezhad et al, 201911Jalili-Firoozinezhad S. Gazzaniga F.S. Calamari E.L. Camacho D.M. Fadel C.W. Bein A. Swenor B. Nestor B. Cronce M.J. Tovaglieri A. Levy O. Gregory K.E. Breault D.T. Cabral J.M.S. Kasper D.L. Novak R. Ingber D.E. A complex human gut microbiome cultured in an anaerobic intestine-on-a-chip.Nat Biomed Eng. 2019; 3: 520-531Crossref PubMed Scopus (276) Google ScholarCaco-2 and human ileal organoids (pediatric donors)Bacteroides fragilis, human gut microbiota, HIMECsCyclic strainYesPDMSPDMS, type I collagen and Matrigel mixSoft lithographyEstablished an oxygen gradient compatible with co-culture of a complex community of anaerobic commensal microorganismsBeaurivage et al, 201935Beaurivage C. Naumovska E. Chang Y.X. Elstak E.D. Nicolas A. Wouters H. van Moolenbroek G. Lanz H.L. Trietsch S.J. Joore J. Vulto P. Janssen R.A.J. Erdmann K.S. Stallen J. Kurek D. Development of a gut-on-a-chip model for high throughput disease modeling and drug discovery.Int J Mol Sci. 2019; 20: 5661Crossref Scopus (63) Google ScholarCaco-2NoNoNoGlass, polystyrene, and proprietary polyme
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