Microfluidic Organ-on-a-Chip Models of Human Intestine
2018; Elsevier BV; Volume: 5; Issue: 4 Linguagem: Inglês
10.1016/j.jcmgh.2017.12.010
ISSN2352-345X
AutoresAmir Bein, Woojung Shin, Sasan Jalili‐Firoozinezhad, Min Hee Park, Alexandra Sontheimer-Phelps, Alessio Tovaglieri, Angeliki Chalkiadaki, Hyun Jung Kim, Donald E. Ingber,
Tópico(s)Cancer Cells and Metastasis
ResumoMicrofluidic organ-on-a-chip models of human intestine have been developed and used to study intestinal physiology and pathophysiology. In this article, we review this field and describe how microfluidic Intestine Chips offer new capabilities not possible with conventional culture systems or organoid cultures, including the ability to analyze contributions of individual cellular, chemical, and physical control parameters one-at-a-time; to coculture human intestinal cells with commensal microbiome for extended times; and to create human-relevant disease models. We also discuss potential future applications of human Intestine Chips, including how they might be used for drug development and personalized medicine. Microfluidic organ-on-a-chip models of human intestine have been developed and used to study intestinal physiology and pathophysiology. In this article, we review this field and describe how microfluidic Intestine Chips offer new capabilities not possible with conventional culture systems or organoid cultures, including the ability to analyze contributions of individual cellular, chemical, and physical control parameters one-at-a-time; to coculture human intestinal cells with commensal microbiome for extended times; and to create human-relevant disease models. We also discuss potential future applications of human Intestine Chips, including how they might be used for drug development and personalized medicine. SummaryOrgans-on-chips are microfluidic cell culture systems that recapitulate the structure, function, physiology, and pathology of living human organs in vitro. In this article, we review recent development of various human intestine-on-a-chip models and their potential value for disease modeling, drug discovery, and personalized medicine. Organs-on-chips are microfluidic cell culture systems that recapitulate the structure, function, physiology, and pathology of living human organs in vitro. In this article, we review recent development of various human intestine-on-a-chip models and their potential value for disease modeling, drug discovery, and personalized medicine. The major organ function of the human intestine is to carry out digestion, absorption, secretion, and motility,1Silverthorn D.U. Ober W.C. Garrison C.W. Silverthorn A.C. Johnson B.R. Human physiology: an integrated approach. Pearson/Benjamin Cummings, San Francisco2009Google Scholar in addition to establishing a protective epithelial barrier between this digestive environment and the body. In addition, intestines regulate systemic physiology by metabolizing drugs2Benet L.Z. Wu C.-Y. Hebert M.F. Wacher V.J. Intestinal drug metabolism and antitransport processes: a potential paradigm shift in oral drug delivery.J Control Release. 1996; 39: 139-143Crossref Scopus (188) Google Scholar; communicate with other organs, such as the liver3Moore F.A. Moore E.E. Poggetti R. McAnena O.J. Peterson V.M. Abernathy C.M. Parsons P.E. Gut bacterial translocation via the portal vein: a clinical perspective with major torso trauma.J Trauma Acute Care Surg. 1991; 31: 629-638Crossref Scopus (447) Google Scholar, 4Bloemen J.G. Venema K. van de Poll M.C. Damink S.W.O. Buurman W.A. Dejong C.H. Short chain fatty acids exchange across the gut and liver in humans measured at surgery.Clin Nutr. 2009; 28: 657-661Abstract Full Text Full Text PDF PubMed Scopus (217) Google Scholar and pancreas,5Ahuja M. Schwartz D.M. Tandon M. Son A. Zeng M. Swaim W. Eckhaus M. Hoffman V. Cui Y. Xiao B. Orai1-mediated antimicrobial secretion from pancreatic acini shapes the gut microbiome and regulates gut innate immunity.Cell Metab. 2017; 25: 635-646Abstract Full Text Full Text PDF PubMed Scopus (84) Google Scholar via portal flow; and they contain an enteric nervous system that forms a part of the gut-brain axis.6Cryan J.F. Dinan T.G. Mind-altering microorganisms: the impact of the gut microbiota on brain and behaviour.Nat Rev Neurosci. 2012; 13: 701-712Crossref PubMed Scopus (2487) Google Scholar, 7Mayer E.A. Gut feelings: the emerging biology of gut–brain communication.Nat Rev Neurosci. 2011; 12: 453-466Crossref PubMed Scopus (986) Google Scholar The intestine is also the major site at which commensal microbes of the gut microbiome live and interact with gut lymphoid tissues and the host immune system, which contributes significantly to intestinal homeostasis.8Garrett W.S. Gordon J.I. Glimcher L.H. Homeostasis and inflammation in the intestine.Cell. 2010; 140: 859-870Abstract Full Text Full Text PDF PubMed Scopus (556) Google Scholar, 9Round J.L. Mazmanian S.K. The gut microbiome shapes intestinal immune responses during health and disease.Nat Rev Immunol. 2009; 9: 313-323Crossref PubMed Scopus (3250) Google Scholar For example, the gut microbiome and its metabolites (eg, short-chain fatty acids) have been recently shown to play a central role in the maintenance of intestinal health, immune modulation, and the development of both enteral and nonenteral diseases.10Wong J.M. De Souza R. Kendall C.W. Emam A. Jenkins D.J. Colonic health: fermentation and short chain fatty acids.J Clin Gastroenterol. 2006; 40: 235-243Crossref PubMed Scopus (1832) Google Scholar, 11Smith P.M. Howitt M.R. Panikov N. Michaud M. Gallini C.A. Bohlooly-y M. Glickman J.N. Garrett W.S. The microbial metabolites, short-chain fatty acids, regulate colonic Treg cell homeostasis.Science. 2013; 341: 569-573Crossref PubMed Scopus (3048) Google Scholar However, analysis of gut microbiome interactions with human intestinal cells has been limited to genetic or metagenomics analysis because it has not been possible to coculture these microbes with living epithelium for more than about 1 day using conventional culture models or even more sophisticated intestinal organoid cultures. Thus, there have been great efforts to develop experimental in vitro or ex vivo models of human intestine that permit analysis of intestinal pathophysiology both in the presence and absence of living microbiome. The most common in vitro intestine models used to study barrier function or model drug absorption involve culturing an established human intestinal epithelial cell line (eg, Caco-212Hidalgo I.J. Raub T.J. Borchardt R.T. Characterization of the human colon carcinoma cell line (Caco-2) as a model system for intestinal epithelial permeability.Gastroenterology. 1989; 96: 736-749Abstract Full Text PDF PubMed Scopus (1952) Google Scholar, 13Artursson P. Karlsson J. Correlation between oral drug absorption in humans and apparent drug permeability coefficients in human intestinal epithelial (Caco-2) cells.Biochem Biophys Res Commun. 1991; 175: 880-885Crossref PubMed Scopus (1674) Google Scholar or HT-2914Pinto M.G.V. Gómez M.R. Seifert S. Watzl B. Holzapfel W.H. Franz C.M. Lactobacilli stimulate the innate immune response and modulate the TLR expression of HT29 intestinal epithelial cells in vitro.Int J Food Microbiol. 2009; 133: 86-93Crossref PubMed Scopus (113) Google Scholar, 15Eveillard M. Fourel V. Bare M.C. Kernéis S. Coconnier M.H. Karjalainen T. Bourlioux P. Servin A.L. Identification and characterization of adhesive factors of Clostridium difficile involved in adhesion to human colonic enterocyte-like Caco-2 and mucus-secreting HT29 cells in culture.Mol Microbiol. 1993; 7: 371-381Crossref PubMed Scopus (74) Google Scholar cells) on extracellular matrix (ECM)-coated, porous membranes within Transwell insert culture devices. Although these models are most commonly used by the pharmaceutical industry, this 2-dimensional (2D) culture format fails to recapitulate physiological 3-dimensional (3D) intestinal cell and tissue morphology or re-establish other key intestinal differentiated functions (eg, mucus production, villi formation, cytochrome P-450-based drug metabolism).16Kim 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: 2165-2174Crossref PubMed Scopus (1046) Google Scholar, 17Kim H.J. Ingber D.E. Gut-on-a-Chip microenvironment induces human intestinal cells to undergo villus differentiation.Integr Biol. 2013; 5: 1130-1140Crossref Scopus (443) Google Scholar These conventional static models also cannot support the coculture of commensal microbiome with human intestinal cells, which are critical for gut physiology,16Kim 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: 2165-2174Crossref PubMed Scopus (1046) Google Scholar because the bacteria rapidly overgrow and contaminate the human cell cultures within a day. Several ex vivo models, such as the everted sac18Alam M.A. Al-Jenoobi F.I. Al-mohizea A.M. Everted gut sac model as a tool in pharmaceutical research: limitations and applications.J Pharm Pharmacol. 2012; 64: 326-336Crossref PubMed Scopus (131) Google Scholar or the Ussing chamber,19Rozehnal V. Nakai D. Hoepner U. Fischer T. Kamiyama E. Takahashi M. Yasuda S. Mueller J. Human small intestinal and colonic tissue mounted in the Ussing chamber as a tool for characterizing the intestinal absorption of drugs.European Journal of Pharmaceutical Sciences. 2012; 46: 367-373Crossref PubMed Scopus (104) Google Scholar, 20Smith P. Mirabelli C. Fondacaro J. Ryan F. Dent J. Intestinal 5-fluorouracil absorption: Use of Ussing chambers to assess transport and metabolism.Pharm Res. 1988; 5: 598-603Crossref PubMed Scopus (45) Google Scholar have been developed for drug transport assays; however, their expected lifespan (<8 hours) is not sufficient to enable many studies on normal intestinal physiology, develop intestinal disease models, or study clinically relevant host-microbiome crosstalk. Although it had been technically challenging to culture primary human intestinal epithelial cells, intestinal 3D organoid cultures derived from either intestinal crypts containing endogenous intestine cells or from induced pluripotent stem cells have revolutionized the field by maintaining stem cell niches and supporting differentiation of various differentiated intestinal epithelial cell subtypes in vitro.21Sato T. Van Es J.H. Snippert H.J. Stange D.E. Vries R.G. Van Den Born M. Barker N. Shroyer N.F. Van De Wetering M. Clevers H. Paneth cells constitute the niche for Lgr5 stem cells in intestinal crypts.Nature. 2011; 469: 415-418Crossref PubMed Scopus (1723) Google Scholar, 22Jung P. Sato T. Merlos-Suárez A. Barriga F.M. Iglesias M. Rossell D. Auer H. Gallardo M. Blasco M.A. Sancho E. Isolation and in vitro expansion of human colonic stem cells.Nat Med. 2011; 17: 1225-1227Crossref PubMed Scopus (497) Google Scholar When cultured within a 3D ECM gel in medium containing Wnt, R-spondin, noggin, and other growth factors, small intestinal organoids (enteroids) also spontaneously undergo villus-crypt morphologic organization and intestinal histogenesis.22Jung P. Sato T. Merlos-Suárez A. Barriga F.M. Iglesias M. Rossell D. Auer H. Gallardo M. Blasco M.A. Sancho E. Isolation and in vitro expansion of human colonic stem cells.Nat Med. 2011; 17: 1225-1227Crossref PubMed Scopus (497) Google Scholar Each organoid line derived from an intestinal tissue biopsy of an individual patient can be grown, frozen, and revived for multiple reuses, which can potentially be used to establish biobanks23van de Wetering M. Francies H.E. Francis J.M. Bounova G. Iorio F. Pronk A. van Houdt W. van Gorp J. Taylor-Weiner A. Kester L. Prospective derivation of a living organoid biobank of colorectal cancer patients.Cell. 2015; 161: 933-945Abstract Full Text Full Text PDF PubMed Scopus (1348) Google Scholar, 24Sato T. Clevers H. SnapShot: growing organoids from stem cells.Cell. 2015; 161: 1700-1700.e1Abstract Full Text PDF PubMed Scopus (97) Google Scholar and develop multiplexed screening platforms for validating new drug candidates and to advance personalized medicine.25Fatehullah A. Tan S.H. Barker N. Organoids as an in vitro model of human development and disease.Nat Cell Biol. 2016; 18: 246-254Crossref PubMed Scopus (837) Google Scholar However, organoids are also limited in that they lack other supporting cell and tissue types found within the living intestine, such as endothelium-lined blood vessels and immune cells, which are important for drug transport, pharmacokinetic (PK) analysis, and disease modeling. They also do not experience fluid flows and cyclic mechanical deformations similar to those experienced in a peristalsing intestine that contribute significantly to intestinal health and function. Furthermore, because each enteroid forms a closed lumen when cultured within surrounding ECM gel, it is experimentally difficult to sample or manipulate luminal components (eg, microbial cells, nutrients, drugs, or toxins). This structure also significantly limits the ability of researchers to study many critical intestinal functions (eg, absorption, drug PK, or drug metabolism), in addition to critical host-microbiome interactions.26Park G.-S. Park M.H. Shin W. Zhao C. Sheikh S. Oh S.J. Kim H.J. Emulating host-microbiome ecosystem of human gastrointestinal tract in vitro.Stem Cell Rev Rep. 2017; 13: 321-334Crossref PubMed Scopus (43) Google Scholar These challenges have recently been overcome by the development of microfluidic Organ Chip models of human intestine. Organ Chips are microfluidic cell culture devices, originally fabricated using methods adapted from computer microchip manufacturing (eg, soft lithography), which contain continuously perfused chambers inhabited by living cells arranged to simulate tissue- and organ-level physiology.27Bhatia S.N. Ingber D.E. Microfluidic organs-on-chips.Nat Biotechnol. 2014; 32: 760-772Crossref PubMed Scopus (1976) Google Scholar Over the past 5 years, Organ Chip models of intestine have been engineered with increasing complexity that also include neighboring channels lined by human microvascular endothelium, and commensal microbes, immune cells, and pathogenic bacteria, and some permit application of cyclic mechanical forces that mimic peristalsis-like deformations experienced by living intestine in vivo (Figure 1). Next are review various types of engineered in vitro models that emulate the structure, function, physiology, and pathology of the living human intestine (Table 1). Also considered are the implications of this work for development of more complex disease models, drug development, and personalized medicine in the future.Table 1Design Characteristics of Microfluidic Intestine ModelsModelTEERAbsorptionCocultureMicrobiomeDifferentiationPeristalsisDrug metabolismCrypt-villus axisOxygen modulationDisease modelingStatic TranswellYes12Hidalgo I.J. Raub T.J. Borchardt R.T. Characterization of the human colon carcinoma cell line (Caco-2) as a model system for intestinal epithelial permeability.Gastroenterology. 1989; 96: 736-749Abstract Full Text PDF PubMed Scopus (1952) Google ScholarYes12Hidalgo I.J. Raub T.J. Borchardt R.T. Characterization of the human colon carcinoma cell line (Caco-2) as a model system for intestinal epithelial permeability.Gastroenterology. 1989; 96: 736-749Abstract Full Text PDF PubMed Scopus (1952) Google Scholar, 13Artursson P. Karlsson J. Correlation between oral drug absorption in humans and apparent drug permeability coefficients in human intestinal epithelial (Caco-2) cells.Biochem Biophys Res Commun. 1991; 175: 880-885Crossref PubMed Scopus (1674) Google ScholarNoYes14Pinto M.G.V. Gómez M.R. Seifert S. Watzl B. Holzapfel W.H. Franz C.M. Lactobacilli stimulate the innate immune response and modulate the TLR expression of HT29 intestinal epithelial cells in vitro.Int J Food Microbiol. 2009; 133: 86-93Crossref PubMed Scopus (113) Google Scholar, 15Eveillard M. Fourel V. Bare M.C. Kernéis S. Coconnier M.H. Karjalainen T. Bourlioux P. Servin A.L. Identification and characterization of adhesive factors of Clostridium difficile involved in adhesion to human colonic enterocyte-like Caco-2 and mucus-secreting HT29 cells in culture.Mol Microbiol. 1993; 7: 371-381Crossref PubMed Scopus (74) Google Scholar (<24 h)NoNoNoNoNoNo OrganoidNoYes95Zietek T. Rath E. Haller D. Daniel H. Intestinal organoids for assessing nutrient transport, sensing and incretin secretion.Sci Rep. 2015; 5: 16831Crossref PubMed Scopus (97) Google ScholarNoYes96Zhang Y.G. Wu S. Xia Y. Sun J. Salmonella-infected crypt-derived intestinal organoid culture system for host–bacterial interactions.Physiol Rep. 2014; 2: e12147Crossref PubMed Scopus (150) Google Scholar (<1 h)Yes21Sato T. Van Es J.H. Snippert H.J. Stange D.E. Vries R.G. Van Den Born M. Barker N. Shroyer N.F. Van De Wetering M. Clevers H. Paneth cells constitute the niche for Lgr5 stem cells in intestinal crypts.Nature. 2011; 469: 415-418Crossref PubMed Scopus (1723) Google ScholarNoYes97Lu W. Rettenmeier E. Paszek M. Yueh M.-F. Tukey R.H. Trottier J. Barbier O. Chen S. Crypt organoid culture as an in vitro model in drug metabolism and cytotoxicity studies.Drug Metab Dispos. 2017; 45: 748-754Crossref PubMed Scopus (28) Google ScholarYes21Sato T. Van Es J.H. Snippert H.J. Stange D.E. Vries R.G. Van Den Born M. Barker N. Shroyer N.F. Van De Wetering M. Clevers H. Paneth cells constitute the niche for Lgr5 stem cells in intestinal crypts.Nature. 2011; 469: 415-418Crossref PubMed Scopus (1723) Google ScholarNoYes22Jung P. Sato T. Merlos-Suárez A. Barriga F.M. Iglesias M. Rossell D. Auer H. Gallardo M. Blasco M.A. Sancho E. Isolation and in vitro expansion of human colonic stem cells.Nat Med. 2011; 17: 1225-1227Crossref PubMed Scopus (497) Google Scholar Ex vivoYes19Rozehnal V. Nakai D. Hoepner U. Fischer T. Kamiyama E. Takahashi M. Yasuda S. Mueller J. Human small intestinal and colonic tissue mounted in the Ussing chamber as a tool for characterizing the intestinal absorption of drugs.European Journal of Pharmaceutical Sciences. 2012; 46: 367-373Crossref PubMed Scopus (104) Google Scholar, 98Madsen K. Cornish A. Soper P. McKaigney C. Jijon H. Yachimec C. Doyle J. Jewell L. De Simone C. Probiotic bacteria enhance murine and human intestinal epithelial barrier function.Gastroenterology. 2001; 121: 580-591Abstract Full Text Full Text PDF PubMed Scopus (890) Google ScholarYes19Rozehnal V. Nakai D. Hoepner U. Fischer T. Kamiyama E. Takahashi M. Yasuda S. Mueller J. Human small intestinal and colonic tissue mounted in the Ussing chamber as a tool for characterizing the intestinal absorption of drugs.European Journal of Pharmaceutical Sciences. 2012; 46: 367-373Crossref PubMed Scopus (104) Google Scholar, 20Smith P. Mirabelli C. Fondacaro J. Ryan F. Dent J. Intestinal 5-fluorouracil absorption: Use of Ussing chambers to assess transport and metabolism.Pharm Res. 1988; 5: 598-603Crossref PubMed Scopus (45) Google ScholarNoYes97Lu W. Rettenmeier E. Paszek M. Yueh M.-F. Tukey R.H. Trottier J. Barbier O. Chen S. Crypt organoid culture as an in vitro model in drug metabolism and cytotoxicity studies.Drug Metab Dispos. 2017; 45: 748-754Crossref PubMed Scopus (28) Google Scholar (<3 h)Yes19Rozehnal V. Nakai D. Hoepner U. Fischer T. Kamiyama E. Takahashi M. Yasuda S. Mueller J. Human small intestinal and colonic tissue mounted in the Ussing chamber as a tool for characterizing the intestinal absorption of drugs.European Journal of Pharmaceutical Sciences. 2012; 46: 367-373Crossref PubMed Scopus (104) Google ScholarNoYes100Sjöberg Å. Lutz M. Tannergren C. Wingolf C. Borde A. Ungell A.-L. Comprehensive study on regional human intestinal permeability and prediction of fraction absorbed of drugs using the Ussing chamber technique.Eur J Pharm Sci. 2013; 48: 166-180Crossref PubMed Scopus (151) Google ScholarYes19Rozehnal V. Nakai D. Hoepner U. Fischer T. Kamiyama E. Takahashi M. Yasuda S. Mueller J. Human small intestinal and colonic tissue mounted in the Ussing chamber as a tool for characterizing the intestinal absorption of drugs.European Journal of Pharmaceutical Sciences. 2012; 46: 367-373Crossref PubMed Scopus (104) Google ScholarYes99Worton K. Candy D. Wallis T. Clarke G. Osborne M. Haddon S. Stephen J. Studies on early association of Salmonella typhimurium with intestinal mucosa in vivo and in vitro: relationship to virulence.J Med Microbiol. 1989; 29: 283-294Crossref PubMed Scopus (31) Google ScholarYes98Madsen K. Cornish A. Soper P. McKaigney C. Jijon H. Yachimec C. Doyle J. Jewell L. De Simone C. Probiotic bacteria enhance murine and human intestinal epithelial barrier function.Gastroenterology. 2001; 121: 580-591Abstract Full Text Full Text PDF PubMed Scopus (890) Google Scholar ScaffoldNoNoNoNoYes40Wang Y. Gunasekara D.B. Reed M.I. DiSalvo M. Bultman S.J. Sims C.E. Magness S.T. Allbritton N.L. A microengineered collagen scaffold for generating a polarized crypt-villus architecture of human small intestinal epithelium.Biomaterials. 2017; 128: 44-55Crossref PubMed Scopus (191) Google ScholarNoNoYes40Wang Y. Gunasekara D.B. Reed M.I. DiSalvo M. Bultman S.J. Sims C.E. Magness S.T. Allbritton N.L. A microengineered collagen scaffold for generating a polarized crypt-villus architecture of human small intestinal epithelium.Biomaterials. 2017; 128: 44-55Crossref PubMed Scopus (191) Google ScholarNoNoMicrofluidic 2-channelYes32Maoz B.M. Herland A. Henry O.Y.F. Leineweber W. Yadid M. Doyle J. Mannix R. Kujala V. Fitzgerald E.A. Parker K.K. Organs-on-chips with combined multi-electrode array and transepithelial electrical resistance measurement capabilities.Lab Chip. 2017; 17: 2294-2302Crossref PubMed Google ScholarYes30Gao D. Liu H. Lin J.-M. Wang Y. Jiang Y. Characterization of drug permeability in Caco-2 monolayers by mass spectrometry on a membrane-based microfluidic device.Lab Chip. 2013; 13: 978-985Crossref PubMed Scopus (94) Google ScholarYes37Esch M.B. Mahler G.J. Stokol T. Shuler M.L. Body-on-a-chip simulation with gastrointestinal tract and liver tissues suggests that ingested nanoparticles have the potential to cause liver injury.Lab Chip. 2014; 14: 3081-3092Crossref PubMed Google ScholarNoNoNoYes39Shim 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 (120) Google ScholarYes39Shim 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 (120) Google ScholarNoNo Ex vivoNoYes99Worton K. Candy D. Wallis T. Clarke G. Osborne M. Haddon S. Stephen J. Studies on early association of Salmonella typhimurium with intestinal mucosa in vivo and in vitro: relationship to virulence.J Med Microbiol. 1989; 29: 283-294Crossref PubMed Scopus (31) Google ScholarNoNoYes101Dawson A. Dyer C. Macfie J. Davies J. Karsai L. Greenman J. Jacobsen M. A microfluidic chip based model for the study of full thickness human intestinal tissue using dual flow.Biomicrofluidics. 2016; 10: 064101Crossref PubMed Scopus (32) Google ScholarNoNoYes101Dawson A. Dyer C. Macfie J. Davies J. Karsai L. Greenman J. Jacobsen M. A microfluidic chip based model for the study of full thickness human intestinal tissue using dual flow.Biomicrofluidics. 2016; 10: 064101Crossref PubMed Scopus (32) Google ScholarNoYes101Dawson A. Dyer C. Macfie J. Davies J. Karsai L. Greenman J. Jacobsen M. A microfluidic chip based model for the study of full thickness human intestinal tissue using dual flow.Biomicrofluidics. 2016; 10: 064101Crossref PubMed Scopus (32) Google Scholar Multichannel (HuMiX)Yes41Shah P. Fritz J.V. Glaab E. Desai M.S. Greenhalgh K. Frachet A. Niegowska M. Estes M. Jäger C. Seguin-Devaux C. A microfluidics-based in vitro model of the gastrointestinal human–microbe interface.Nat Commun. 2016; 7: 11535Crossref PubMed Scopus (326) Google ScholarNoNoYes41Shah P. Fritz J.V. Glaab E. Desai M.S. Greenhalgh K. Frachet A. Niegowska M. Estes M. Jäger C. Seguin-Devaux C. A microfluidics-based in vitro model of the gastrointestinal human–microbe interface.Nat Commun. 2016; 7: 11535Crossref PubMed Scopus (326) Google Scholar ( 7 d)Yes17Kim H.J. Ingber D.E. Gut-on-a-Chip microenvironment induces human intestinal cells to undergo villus differentiation.Integr Biol. 2013; 5: 1130-1140Crossref Scopus (443) Google Scholar, 42Kim 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. 2016; 113: E7-E15Crossref PubMed Scopus (549) Google ScholarYes16Kim 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: 2165-2174Crossref PubMed Scopus (1046) Google Scholar, 17Kim H.J. Ingber D.E. Gut-on-a-Chip microenvironment induces human intestinal cells to undergo villus differentiation.Integr Biol. 2013; 5: 1130-1140Crossref Scopus (443) Google Scholar, 42Kim 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. 2016; 113: E7-E15Crossref PubMed Scopus (549) Google ScholarYes16Kim 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: 2165-2174Crossref PubMed Scopus (1046) Google Scholar, 17Kim H.J. Ingber D.E. Gut-on-a-Chip microenvironment induces human intestinal cells to undergo villus differentiation.Integr Biol. 2013; 5: 1130-1140Crossref Scopus (443) Google ScholarYes16Kim 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: 2165-2174Crossref PubMed Scopus (1046) Google Scholar, 17Kim H.J. Ingber D.E. Gut-on-a-Chip microenvironment induces human intestinal cells to undergo villus differentiation.Integr Biol. 2013; 5: 1130-1140Crossref Scopus (443) Google Scholar, 42Kim 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. 2016; 113: E7-E15Crossref PubMed Scopus (549) Google ScholarNoYes42Kim 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. 2016; 113: E7-E15Crossref PubMed Scopus (549) Google ScholarTEER, transepithelial electrical resistance. Open table in a new tab TEER, transepithelial electrical resistance. Microfluidic devices containing hollow microchannels less than 1 mm in width support laminar fluid flow and control of nanoliter to microliter scale fluid volumes, and thus, they are amenable to use for culture of living cells. By using a syringe or a peristaltic pump, culture medium may be perfused at desired flow rates through each microchannel, which can mimic the dynamic ranges of fluid flows and associated shear stresses on the cell surface that are observed in the human intestinal lumen,28Vickerman V. Blundo J. Chung S. Kamm R. Design, fabrication and implementation of a novel multi-parameter control microfluidic platform for three-dimensional cell culture and real-time imaging.Lab Chip. 2008; 8: 1468-1477Crossref PubMed Scopus (294) Google Scholar, 29Tanaka Y. Yamato M. Okano T. Kitamori T. Sato K. Evaluation of effects of shear stress on hepatocytes by a microchip-based system.Meas Sci Technol. 2006; 17: 3167-3170Crossref Scopus (87) Google Scholar and in the blood capillaries. This fluidic control also enables delivery of nutrients, growth factors, drug compounds, or even toxins to the intestinal epithelium grown on the microfluidic channels in a highly regulated spatiotemporal manner. Most of the Intestine Chips contain 2 hollow channels separated by a common porous, ECM-coated polyester or polycarbonate membrane, which had immortalized human intestinal epithelial cells cultured on 1 of its surfaces.30Gao D. Liu H. Lin J.-M. Wang Y. Jiang Y. Characterization of drug permeability in Caco-2 monolayers by mass spectrometry on a membrane-based microfluidic device.Lab Chip. 2013; 13: 978-985Crossref PubMed Scopus (94) Google Scholar The epithelial monolayer formed in this device c
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