Advances in human organoids-on-chips in biomedical research

Abstract

Organoids-on-chips is opening up new frontier of research in biomedical field by combining organoids and organs-on-chips technology. The integrative technology offers great opportunities to maximize the potentials of organoids with higher fidelity, thus building advanced organ model systems in a physiologically relevant manner. In this review, we highlight the key features of organoids-on-chips and how this integrative technology could be used to build organoids in higher fidelity under controlled cellular microenvironment. We then introduce the recent progress of organoids-on-chips and their applications in biomedical research. We also discuss the opportunities and challenges of the nascent field of organoids-on-chips that lie ahead to accelerate their utility in disease research, drug testing, and regenerative medicine.

Keywords

organoid / organs-on-chips / organoids-on-chips / stem cell / biomedical research

References

[1] Bartfeld S, Clevers H. Stem cell-derived organoids and their application for medical research and patient treatment. J Mol Med 2017;95:729–38.

[2] Rossi G, Manfrin A, Lutolf MP. Progress and potential in organoid research. Nat Rev Genet 2018;19:671–87.

[3] Takahashi T. Organoids for drug discovery and personalized medicine. Annu Rev Pharmacol Toxicol 2019;59:447–62.

[4] Yin X, Mead BE, Safaee H, et al. Engineering stem cell organoids. Cell Stem Cell 2016;18:25–38.

[5] Clevers H. Modeling development and disease with organoids. Cell 2016;165:1586–97.

[6] Cruz NM, Song XW, Czerniecki SM, et al. Organoid cystogenesis reveals a critical role of microenvironment in human polycystic kidney disease. Nat Mater 2017;16:1112–9.

[7] Drost J, Clevers H. Translational applications of adult stem cell-derived organoids. Development 2017;144:968–75.

[8] Fatehullah A, Tan SH, Barker N. Organoids as an in vitro model of human development and disease. Nat Cell Biol 2016;18:246–54.

[9] Heo I, Dutta D, Schaefer DA, et al. Modelling cryptosporidium infection in human small intestinal and lung organoids. Nat Microbiol 2018;3:814–23.

[10] Huch M, Knoblich JA, Lutolf MP, et al. The hope and the hype of organoid research. Development 2017;144:938–41.

[11] Nie J, Gao Q, Wang Y, et al. Vessel-on-a-chip with hydrogel-based microfluidics. Small 2018;14:e1802368.

[12] Bhatia SN, Ingber DE. Microfluidic organs-on-chips. Nat Biotechnol 2014;32:760–72.

[13] Huh D, Torisawa YS, Hamilton GA, et al. Microengineered physiological biomimicry: organs-on-chips. Lab Chip 2012;12:2156–64.

[14] Bhise NS, Manoharan V, Massa S, et al. A liver-on-a-chip platform with bioprinted hepatic spheroids. Biofabrication 2016;8:014101.

[15] Li Z, Jiang L, Zhu Y, et al. Assessment of hepatic metabolism-dependent nephrotoxicity on an organs-on-a-chip microdevice. Toxicol In Vitro 2018;46:1–8.

[16] Wang L, Tao T, Su W, et al. A disease model of diabetic nephropathy in a glomerulus-on-a-chip microdevice. Lab Chip 2017;17:1749–60.

[17] Guo Y, Li Z, Su W, et al. A biomimetic human gut-on-a-chip for modeling drug metabolism in intestine. Artif Organs 2018;42:1196–205.

[18] Takebe T, Zhang B, Radisic M. Synergistic engineering: organoids meet organs-on-a-chip. Cell Stem Cell 2017;21:297–300.

[19] Zhu Y, Wang L, Yu H, et al. In situ generation of human brain organoids on a micropillar array. Lab Chip 2017;17:2941–50.

[20] Wang Y, Wang L, Zhu Y, et al. Human brain organoid-on-a-chip to model prenatal nicotine exposure. Lab Chip 2018;18:851–60.

[21] Sunghee EP, Andrei G, Dongeun H. Organoids-on-a-chip. Science 2019;364:960–5.

[22] Lancaster MA, Knoblich JA. Organogenesis in a dish: modeling development and disease using organoid technologies. Science 2014;345:1247125.

[23] Sato T, Vries RG, Snippert HJ, et al. Single Lgr5 stem cells build crypt-villus structures in vitro without a mesenchymal niche. Nature 2009;459:262–5.

[24] Lancaster MA, Renner M, Martin CA, et al. Cerebral organoids model human brain development and microcephaly. Nature 2013;501:373–9.

[25] Qian X, Nguyen HN, Song MM, et al. Brain-region-specific organoids using mini-bioreactors for modeling ZIKV exposure. Cell 2016;165:1238–54.

[26] Assawachananont J, Mandai M, Okamoto S, et al. Transplantation of embryonic and induced pluripotent stem cell-derived 3D retinal sheets into retinal degenerative mice. Stem Cell Rep 2014;2:662–74.

[27] Chen YW, Huang SX, de Carvalho A, et al. A three-dimensional model of human lung development and disease from pluripotent stem cells. Nat Cell Biol 2017;19:542–9.

[28] Takebe T, Sekine K, Enomura M, et al. Vascularized and functional human liver from an iPSC-derived organ bud transplant. Nature 2013;499:481–4.

[29] Narayanan S, Surette FA, Hahn YS. The immune landscape in nonalcoholic steatohepatitis. Immune Netw 2016;16:147–58.

[30] Huch M, Gehart H, van Boxtel R, et al. Long-term culture of genome-stable bipotent stem cells from adult human liver. Cell 2015;160:299–312.

[31] Morizane R, Bonventre JV. Generation of nephron progenitor cells and kidney organoids from human pluripotent stem cells. Nat Protoc 2017;12:195–207.

[32] Broutier L, Andersson-Rolf A, Hindley CJ, et al. Culture and establishment of self-renewing human and mouse adult liver and pancreas 3D organoids and their genetic manipulation. Nat Protoc 2016;11:1724–43.

[33] Sato T, Stange DE, Ferrante M, et al. Long-term expansion of epithelial organoids from human colon, adenoma, adenocarcinoma, and Barrett’s epithelium. Gastroenterology 2011;141:1762–72.

[34] McCracken KW, Cata EM, Crawford CM, et al. Modelling human development and disease in pluripotent stem-cell-derived gastric organoids. Nature 2014;516:400–4.

[35] Chen YW, Huang SX, de Carvalho ALRT, et al. A three-dimensional model of human lung development and disease from pluripotent stem cells. Nat Cell Biol 2017;19:542–9.

[36] Eiraku M, Takata N, Ishibashi H, et al. Self-organizing optic-cup morphogenesis in three-dimensional culture. Nature 2011;472:51–6.

[37] Eiraku M, Watanabe K, Matsuo-Takasaki M, et al. Self-organized formation of polarized cortical tissues from ESCs and its active manipulation by extrinsic signals. Cell Stem Cell 2008;3:519–32.

[38] Giandomenico SL, Mierau SB, Gibbons GM, et al. Cerebral organoids at the air-liquid interface generate diverse nerve tracts with functional output. Nat Neurosci 2019;22:669–79.

[39] Wang X, Yamamoto Y, Wilson LH, et al. Cloning and variation of ground state intestinal stem cells. Nature 2015;522:173–8.

[40] Shevde NK, Mael AA. Techniques in embryoid body formation from human pluripotent stem cells. Methods Mol Biol 2013;946:535–46.

[41] Kasendra M, Tovaglieri A, Sontheimer-Phelps A, et al. Development of a primary human small intestine-on-a-chip using biopsy-derived organoids. Sci Rep 2018;8:2871.

[42] Workman MJ, Gleeson JP, Troisi EJ, et al. Enhanced utilization of induced pluripotent stem cell-derived human intestinal organoids using microengineered chips. Cell Mol Gastroenterol Hepatol 2018;5:669–677.e2.

[43] Tao TT, Wang YQ, Chen WW, et al. Engineering human islet organoids from iPSCs using an organ-on-chip platform. Lab Chip 2019;19:948–58.

[44] Wang YQ, Wang H, Deng PW, et al. In situ differentiation and generation of functional liver organoids from human iPSCs in a 3D perfusable chip system. Lab Chip 2018;18:3606–16.

[45] Wang YQ, Wang L, Guo YQ, et al. Engineering stem cell-derived 3D brain organoids in a perfusable organ-on-a-chip system. RSC Adv 2018;8:1677–85.

[46] Kretzschmar K, Clevers H. Organoids: modeling development and the stem cell niche in a dish. Dev Cell 2016;38:590–600.

[47] Somaweera H, Ibraguimov A, Pappas D. A review of chemical gradient systems for cell analysis. Anal Chim Acta 2016;907:7–17.

[48] Kim S, Kim HJ, Jeon NL. Biological applications of microfluidic gradient devices. Integr Biol (Camb) 2010;2:584–603.

[49] Demers CJ, Soundararajan P, Chennampally P, et al. Development-on-chip: in vitro neural tube patterning with a microfluidic device. Development 2016;143:1884–92.

[50] Rifes P, Isaksson M, Rathore GS, et al. Modeling neural tube development by differentiation of human embryonic stem cells in a micro-fluidic WNT gradient. Nat Biotechnol 2020;38:1265–73.

[51] Lee KK, McCauley HA, Broda TR, et al. Human stomach-on-a-chip with luminal flow and peristaltic-like motility. Lab Chip 2018;18:3079–85.

[52] Sun X, Nunes SS. Biowire platform for maturation of human pluripotent stem cell-derived cardiomyocytes. Methods 2016;101:21–6.

[53] Zhao Y, Rafatian N, Feric NT, et al. A platform for generation of chamber-specific cardiac tissues and disease modeling. Cell 2019;176:913–927.e18.

[54] Wang Y, Kim R, Gunasekara DB, et al. Formation of human colonic crypt array by application of chemical gradients across a shaped epithelial monolayer. Cell Mol Gastroenterol Hepatol 2018;5:113–30.

[55] Creff J, Courson R, Mangeat T, et al. Fabrication of 3D scaffolds reproducing intestinal epithelium topography by high-resolution 3D stereolithography. Biomaterials 2019;221:119404.

[56] Yin F, Zhu Y, Wang Y, et al. Engineering brain organoids to probe impaired neurogenesis induced by cadmium. ACS Biomater Sci Eng 2018;4:1908–15.

[57] Karzbrun E, Kshirsagar A, Cohen SR, et al. Human brain organoids on a chip reveal the physics of folding. Nat Phys 2018;14:515–22.

[58] Nikolaev M, Mitrofanova O, Broguiere N, et al. Homeostatic mini-intestines through scaffold-guided organoid morphogenesis. Nature 2020;585:574–8.

[59] Daniel E, Azizoglu DB, Ryan AR, et al. Spatiotemporal heterogeneity and patterning of developing renal blood vessels. Angiogenesis 2018;21:617–34.

[60] Semenza GL. Vasculogenesis, angiogenesis, and arteriogenesis: mechanisms of blood vessel formation and remodeling. J Cell Biochem 2007;102:840–7.

[61] Zhou J, Li YS, Chien S. Shear stress-initiated signaling and its regulation of endothelial function. Arterioscler Thromb Vasc Biol 2014;34:2191–8.

[62] Chistiakov DA, Orekhov AN, Bobryshev YV. Effects of shear stress on endothelial cells: go with the flow. Acta Physiol (Oxf) 2017;219:382–408.

[63] Homan KA, Gupta N, Kroll KT, et al. Flow-enhanced vascularization and maturation of kidney organoids in vitro. Nat Methods 2019;16:255–62.

[64] Rajasekar S, Lin DSY, Abdul L, et al. IFlowPlate-A CUSTOMIZED 384-well plate for the culture of perfusable vascularized colon organoids. Adv Mater 2020;32:e2002974.

[65] Zhang S, Wan Z, Kamm RD. Vascularized organoids on a chip: strategies for engineering organoids with functional vasculature. Lab Chip 2021;21:473–88.

[66] Lai BFL, Huyer LD, Lu RXZ, et al. InVADE: integrated vasculature for assessing dynamic events. Adv Funct Mater 2017;27:1703524.

[67] Zhang B, Montgomery M, Chamberlain MD, et al. Biodegradable scaffold with built-in vasculature for organ-on-a-chip engineering and direct surgical anastomosis. Nat Mater 2016;15:669–78.

[68] Skardal A, Murphy SV, Devarasetty M, et al. Multi-tissue interactions in an integrated three-tissue organ-on-a-chip platform. Sci Rep 2017;7:8837.

[69] Trapecar M, Wogram E, Svoboda D, et al. Human physiomimetic model integrating microphysiological systems of the gut, liver, and brain for studies of neurodegenerative diseases. Sci Adv 2021;7:eabd1707.

[70] Ronaldson-Bouchard K, Teles D, Yeager K, et al. A multi-organ chip with matured tissue niches linked by vascular flow. Nat Biomed Eng 2022;6:351–71.

[71] Kim HJ, Li H, Collins JJ, et al. Contributions of microbiome and mechanical deformation to intestinal bacterial overgrowth and inflammation in a human gut-on-a-chip. Proc Natl Acad Sci USA 2016;113:E7–15.

[72] Trujillo-de Santiago G, Lobo-Zegers MJ, Montes-Fonseca SL, et al. Gut-microbiota-on-a-chip: an enabling field for physiological research. Microphysiol Syst 2018;2:7.

[73] Barata D, van Blitterswijk C, Habibovic P. High-throughput screening approaches and combinatorial development of biomaterials using microfluidics. Acta Biomater 2016;34:1–20.

[74] Kim JA, Hong S, Rhee WJ. Microfluidic three-dimensional cell culture of stem cells for high-throughput analysis. World J Stem Cells 2019;11:803–16.

[75] Zhang YS, Aleman J, Shin SR, et al. Multisensor-integrated organs-on-chips platform for automated and continual in situ monitoring of organoid behaviors. Proc Natl Acad Sci U S A 2017;114:E2293–302.

[76] Schuster B, Junkin M, Kashaf SS, et al. Automated microfluidic platform for dynamic and combinatorial drug screening of tumor organoids. Nat Commun 2020;11:5271.

[77] Zhu Y, Wang L, Yin F, et al. A hollow fiber system for simple generation of human brain organoids. Integr Biol (Camb) 2017;9:774–81.

[78] Zhu Y, Wang L, Yin F, et al. Probing impaired neurogenesis in human brain organoids exposed to alcohol. Integr Biol (Camb) 2017;9:968–78.

[79] Schepers A, Li C, Chhabra A, et al. Engineering a perfusable 3D human liver platform from iPS cells. Lab Chip 2016;16:2644–53.

[80] Wang Y, Wang H, Deng P, et al. Modeling Human Nonalcoholic Fatty Liver Disease (NAFLD) with an organoids-on-a-chip system. ACS Biomater Sci Eng 2020;6:5734–43.

[81] Sidar B, Jenkins BR, Huang S, et al. Long-term flow through human intestinal organoids with the gut organoid flow chip (GOFlowChip). Lab Chip 2019;19:3552–62.

[82] Patel SN, Ishahak M, Chaimov D, et al. Organoid microphysiological system preserves pancreatic islet function within 3D matrix. Sci Adv 2021;7:eaba5515.

[83] Achberger K, Cipriano M, Duchs MJ, et al. Human stem cell-based retina on chip as new translational model for validation of AAV retinal gene therapy vectors. Stem Cell Rep 2021;16:2242–56.

[84] Achberger K, Probst C, Haderspeck J, et al. Merging organoid and organ-on-a-chip technology to generate complex multi-layer tissue models in a human retina-on-a-chip platform. Elife 2019;8:e46188.

[85] Xue YT, Seiler MJ, Tang WLC, et al. Retinal organoids on-a-chip: a micro-millifluidic bioreactor for long-term organoid maintenance. Lab Chip 2021;21:3361–77.

[86] Schutgens F, Rookmaaker MB, Margaritis T, et al. Tubuloids derived from human adult kidney and urine for personalized disease modeling. Nat Biotechnol 2019;37:303–13.

[87] Tao TT, Deng PW, Wang YQ, et al. Microengineered multi-organoid system from hiPSCs to recapitulate human liver-islet axis in normal and Type 2 diabetes. Adv Sci 2022;9:e2103495.

[88] Pasca SP. The rise of three-dimensional human brain cultures. Nature 2018;553:437–45.

[89] Kelava I, Lancaster MA. Stem cell models of human brain development. Cell Stem Cell 2016;18:736–48.

[90] Feinberg DA, Mark AS. Human brain motion and cerebrospinal fluid circulation demonstrated with MR velocity imaging. Radiology 1987;163:793–9.

[91] Cui KL, Wang YQ, Zhu YJ, et al. Neurodevelopmental impairment induced by prenatal valproic acid exposure shown with the human cortical organoid-on-a-chip model. Microsyst Nanoeng 2020;6:49.

[92] Rahmani S, Breyner NM, Su HM, et al. Intestinal organoids: a new paradigm for engineering intestinal epithelium in vitro. Biomaterials 2019;194:195–214.

[93] Tao T, Wang Y, Chen W, et al. Engineering human islet organoids from iPSCs using an organ-on-chip platform. Lab Chip 2019;19:948–58.

[94] Yin F, Zhang X, Wang L, et al. HiPSC-derived multi-organoids-on-chip system for safety assessment of antidepressant drugs. Lab Chip 2021;21:571–81.

[95] Gjorevski N, Sachs N, Manfrin A, et al. Designer matrices for intestinal stem cell and organoid culture. Nature 2016;539:560–4.

[96] Liu H, Wang Y, Cui K, et al. Advances in hydrogels in organoids and organs-on-a-chip. Adv Mater 2019;31:e1902042.

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