Table 1.

The comparisons of different model systems for biomedicine.

Models	Benefits	Limitations
2D cell cultures	• Low equipment dependency and easy to operate for researchers • Minoring basic structure and function, such as tissue barriers/interfaces • Convenient to study mechanisms of drugs or exogenous substances • Easy to conduct high-flux research and large-scale drug screening	• Big differences in genetic and epigenetics information compared to human native tissues. • Fail to recreate the complexity of inter-organ interactions and drug pharmacokinetics • Cannot reflect dynamic physiological conditions and pharmacokinetics of organs in vivo • Difficult for long-term culture to maintain tissue functions
Animal models	• Systematically studying the body's response to exogenous substances (e.g., drugs, viruses, vaccines) and pathogenesis • Nonhuman primates are more representative of humans • Some biomedical signals contribute to human studies	• Operation is time-consuming, cumbersome and high-cost • Difficult for in situ imaging and on-line monitoring • Difficult to reproduce human biological responses and accurately predict drug safety • No gold standard for extrapolation results from animal models to humans • Limited throughput
OOCs	• In vivo-like microenvironment elements (e.g., multicellular component, shear stress, mechanical tension, extracellular matrix, fluid) • Representing the human-relevant physiological and pathological features at the organ level • Minoring tissue barriers/interfaces • Studying cell-cell/matrix/virus/drug interaction • Real-time imaging and on-line monitoring • Highly integrating multi-techniques (e.g., biosensors, hydrogels, 3D bioprinting) into organ chips	• Low throughput • Limited cell types can be assembled in a certain space • The hydrophobic PDMS absorbs hydrophobic small molecules, possibly affecting the accuracy and precision of drug detection • No gold standard for commercialization • Low flux for drug screening
HOs	• Simulating key features of human native organs or tissues with high fidelity and complex cellular components • Can differentiate into various organoids following given protocols • Long-term preservation of cell phenotype and genotype in vitro • Large-scale omics analysis and drug screening • Greatly contribute to drug discovery and guiding the medications • Available for studies from virus tropism to abundant cell types	• Poorly controlled biochemical and physical environmental signals (e.g., shear stress, mechanical tension, gradient, fluid) • Lack of complicated cellular microenvironment • Relying on ill-defined matrices from animals (e.g. Matrigel) • Low success rate of generating patient-derived organoids • Heterogeneity of tumor organoids derived from patients • Outcomes aren't stable due to individual difference
OrgOCs	• Integrating complex microenvironment components (e.g., oxygen gradient, biofactors) with more physiological correlation • High maturation and fidelity of the organoids in structure and function • Real-time monitoring and in situ observation • Alternatives of animal models for drug testing and disease modeling • Cost-effective and time-saving • Systemic responses and long-term toxicity prediction • Expediently realize organoid-organoid communication and organoid-matrix interaction • Accurate prediction of drug response during preclinical stages and phase 1/2 clinical trials • Narrowing the gap between in vitro and in vivo states	• Difficult to successfully construct multi-organoids under the same culture condition • Difficult to long-term coculture of different organoids in an equivalent condition to simulate long-term chronic diseases • Creating maps and standardized evaluation systems in specific disease states is still a problem • Artificial intelligence and computer simulation are needed to identify different forms and phenotypes of organoids in physiological and pathological states • Defined hydrogels are still lacking to replace traditional materials • The hydrophobic PDMS absorbs hydrophobic small molecules, possibly affecting the accuracy and precision of drug detection