Table 2.

Summary of existing human organoids-on-chips models used for biomedicine.

Types of organoids-on-chips	Organoid sources	Co-cultured cells	ECM	Chip design	Application
Brain	• hESCs 145	• N.A.	• Collagen and Laminin	• A two-dimensional compartment consists of a top membrane coupled to a media reservoir and a bottom coverslip	• Modeling the physics of the folding brain
	• hiPSCs 61, 72, 87, 114, 122, 132, 134, 146, 147, 148	• Cerebral organoids, endothelial cells and pericytes 61	• Tissue-derived brain extracellular matrix and Matrigel 146 • Matrigel, Collagenase IV and Gelatin 148 • CaA 134, 147 • Matrigel 61, 72, 87, 114, 132	• A perfusable chip contained parallel channels 72, 87 • Microwell/micropillar array chip 114, 122, 132, 134, 147 • A resin chip with wells, coverslips and channels 61, 148 • A perfusable chip system consists of three layers with five chambers without free-pump 146	• Modeling brain development in vitro • Revealing the risk of developing neurodevelopmental disorders due to environmental factors (e.g., nicotine, ethanol, cadmium and prenatal valproic acid) during pregnancy • In situ high-resolution time-lapse imaging and cell tracking of brain organoids on-chip
Lung	• Lung cancer tissue 136	• N.A.	• Matrigel 136, 149	• A microwell array chip 136, 149	• Assessing drug sensitivity responses
	• Tumor-free tissue 103	• N.A.	• Collagen I	• A sandwiched chip with PET membrane	• Organoid-based expansion of patient-derived primary alveolar type 2 cells for the establishment of preclinical models of the alveolus
Intestine	• Duodenum 57	• Macrophages, intestinal myofibroblasts, HUVECs and C. parvum oocysts	• Collagen I and Matrigel	• 3D hydrogel-containing microfluidic device	• Modelling tube-shaped mini-intestine and long-term parasite infection
	• Colon 124, 150	• N.A.	• Matrigel	• A microfluidic chip contains a semi-opened microwell array connected by the medium channel and the surrounded pressure channel 124 • A nested array chip consisted of 96 units 150	• Culturing human colon tumor organoids and evaluating nanoparticles under peristalsis • Drug testing in colorectal cancer therapy
	• Colon 137	• Human umbilical vein endothelial cells and primary human lung fibroblasts	• Matrigel, Fibrinogen, Laminin and Collagen IV	• Customizable 384-well IFlowPlate	• Establish vascularized human colon organoid model to explore the cross-talk between the vasculature and the organoids in tissue inflammation
	• Colon 55, 116, 151, 152, 153 • Duodenum 154 • Normal organoid, ulcerative colitis organoid, Crohn's disease organoid, and colorectal cancer organoid 155	• Dendritic cells, T cells, mononuclear phagocytes 116 • HIMECs 151, 153 • HMVEC 152 • Human fecal microbiome 155	• Collagen I and Matrigel 55, 152, 154, 155 • Matrigel, Collagen I and Hydrogel 116 • Collagen IV, Fibronectin and Matrigel 153 • Collagen IV, Matrigel and Fibronectin 151	• A sandwiched PDMS chip with membrane 151, 152, 153, 154, 155 • A GOFlowChip contains two-layer PMMA body, central culture well, silicone gasket and glass coverslip bottom 116	• Investigating the impact of biomechanical and biochemical cues (e.g., morphogen gradient, flow, peristalsis, interleukin 22, Milk Oligosaccharides, niacinamide and tryptophan) on human intestinal morphogenesis and gut barrier function • Molding microbiome or mononuclear phagocyte interactions with the gut epithelium
Retina	• hiPSCs 156	• Retinal pigment epithelium	• HA and Matrigel	• A microfluidic chip contains a reservoir and organoid layer, porous membrane layer, and media channel layer	• Analysis of AAV retinal gene therapy vectors Modeling retinopathy induced by anti-malarial and antibiotic drugs
Spine	• hESCs 127	• N.A.	• Laminin	• A resin chip consists of a 3D-printed organoid holder and a PC membrane	• Modeling nociceptive circuitry for pain therapeutics discovery
Breast	• Endothelialized pancreatic cancer patient 157	• Normal human lung fibroblasts, endothelial cells and immune cells	• Fibrinogen and Matrigel	• A multiplexed platform contains AngioTube scaffolds and a 96-well base plate	• Investigating progression and drug sensitivity in cell lines and patient-derived organoids
Kidney	• hiPSCs 77, 158	• Adult human endothelia and fibroblasts 77	• Fibrinogen and Gelatin 77 • Matrigel 158	• A perfusable millifluidic chip using a 3D printer	• Exploring the effect of biochemical and biomechanical factors on vascularization and maturation
Liver	• hiPSCs 34, 117, 121	• N.A.	• NaA, Fibrinogen and Cs 117	• A perfusable micropillar chip 34, 121 • All-aqueous droplet microfluidic device 117	• In situ generating 3D organoids and modeling nonalcoholic fatty liver disease
Pancreas/islet	• hiPSCs 35, 113, 133, 159 • Pancreatic ductal adenocarcinoma cancer patients 160	• N.A.	• NaA and Cs 113 • CaA 133 • Alg/PEI 159 • Matrigel 160	• An all-aqueous microfluidic system 113, 133, 159 • A multilayer microfluidic chip with porous membrane 35 • A reversibly clamped two-layer chamber chip consists of a 200-well array and an overlying layer of fluidic channels 160	• Enabling stem cell organoid engineering to recapitulate organ-specific features in terms structure and function Dynamic and combinatorial drug screening of tumor organoids in an automated way
Liver-islet axis	• hiPSCs 10	• N.A.	• N.A.	• A microfluidic device consists of two culture compartments connected by parallel network	• Recapitulating human liver-islet axis for drug therapy of type 2 diabetes
Liver-heart axis	• hiPSCs 90, 161	• N.A.	• GelMA, Fibrin and Fibronogen 161	• A chip consists of a top layer, through-hole PDMS layer, PC membrane and bottom layer 90 • Multisensor-integrated microfluidic chip 161	• Assessment of drug responses such as drug metabolism and toxicity
Liver-stomach- intestine axis	• Primary hepatocytes, small intestine and corpus stomach 162	• Induced hepatic cells, HUVECs and primary fibroblasts	• Decellularized liver extracellular Matrix	• A microplate array based microffuidic device	• Highthroughput drug screening
Liver-heart-lung-testis-brain axis	• Primary cells, hiPSCs and adult testicular tissues 163	• Hepatocytes stellate cells, Kupffer cells, liver endothelial cells, cardiomyocytes, cardiac fibroblast, cardiac endothelium cells, alveolar epithelial A549 cells, lung fibroblasts, bronchial epithelial cells, HUVEC, spermatogonial stem cells, leydig cells, sertoli cells, peritubular cells, brain microvascular endothelial cells (HBMEC), brain vascular pericytes (HBVP), astrocytes, microglial, oligodendrocytes, and neural cells	• Collagen I, human testis ECM, Poly-L-Lysine, Matrigel, HA and Gelatin	• A composite chip consists of PMMA, glass and an adhesive film	• Exploring complex drug and toxin interactions between multi-tissue types in vitro
Liver-heart-lung-intestine-testis-brain axis	• Human primary cells or hiPSCs, fresh rabbit colons, adult testicular tissues and normal adult human testicular tissue 164	• Human primary cardiac fibroblasts, lung microvasculature endothelial cells, airway stromal mesenchymal cells, bronchial epithelial cells, HUVECs, rabbit colonic smooth muscle cells, Caco-2 cells, primary spermatogonia, Leydig, sertoli and peritubular myiod cells, brain microvasculature endothelial cells, brain vascular pericytes, astrocytes, microglia, oligodendrocytes, and neurons	• Lung-specific ECM, Collagen I human testis ECM, HA, Gelatin and Fibrin	• A PDMS-free device by layering PMMA and adhesive films with chambers, channels, and ports formed by laser cutting	• Predicting drug efficacy and liver and cardiac toxicity during human Phase I, II and III clinical trials

Human induced pluripotent stem cells (hiPSCs), Human embryonic stem cells (hESCs), Human umbilical vein endothelial cell (HUVEC), Human intestinal microvascular endothelial cells (HIMECs), Human capillary microvascular endothelial cells (HMVEC), Polydimethylsiloxane (PDMS), Poly(methyl methacrylate) (PMMA), HyaluronicAcid (HA), Gelatin methacryloyl (GelMA), Sodium alginate (NaA), Ca-alginate (CaA), Poly(ethylene imine) (PEI), Chitosan (Cs), polycarbonate (PC), polylactic acid (PLA) ,Polyvinyl alcohol (PVA), Dextran sodium sulfate (DSS), Melted poly (ethylene glycol) dimethyl ether (PEGDM), N.A. indicates that the specified feature has not been measured or reported.