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Organoids and Organs-on-Chip for Medical Research

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pathology, Diagnostics, and Therapeutics".

Deadline for manuscript submissions: closed (20 February 2026) | Viewed by 22458

Special Issue Editor

Special Issue Information

Dear Colleagues,

Organoids and Organs-on-chip (OoC) represent innovative and challenging ex vivo models, developed as essential tools for basic biology and disease research. Organoids are derived from self-organizing mammalian stem cells, comprising clusters of 3D cells cultured with near-native microanatomy. However, organoids lack some critical elements of the in vivo microenvironment that limit their physiological relevance, such as the presence of vasculature. On the other hand, the OoC allows for precise control over cellular composition, multiple cellular interactions, and the dynamical mechanical forces which cells experience in vivo. When placed within a dynamic environment, OoC is a versatile platform for assessing drug efficacy and toxicity in clinical trials before being administered to patients, thereby contributing to personalized and precision medicine.

These technologies, despite certain simplifications, can be used together, simulating the complexity of tissues and yielding miniaturized organs that replicate complex human biology in vitro. These models are appealing for their flexibility, modularity, and 3D capabilities, allowing researchers to study molecular pathways, identify new biomarkers or therapeutic targets, and explore broad clinical potential. New technologies based in artificial intelligence are being applied for complex analysis and modeling.

Consequently, this Special Issue aims to provide molecular insights into understanding and addressing the disparities in disease susceptibility, progression, and treatment response. Through a comprehensive exploration of these topics, we aim to foster advances in the comprehension of disease pathologies, personalized medicine, therapeutics, and healthcare strategies. We welcome a diverse range of submissions, including both reviews and original research papers. However, pure clinical studies are not suitable for this Issue, although clinical submissions featuring molecular experiments are welcomed. We encourage authors to present protocols, practical insights, novel methodologies, and evidence-based recommendations that can guide biological research and clinical practice. In addition, we expect contributions on new tools based in artificial intelligence for complex modelling. Together, let us propel the field of healthcare towards a personalized medicine.

Dr. Miguel Hueso
Guest Editor

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Keywords

  • organoids
  • organs-on-chip
  • tissue engineering
  • disease modeling
  • biomarkers
  • molecular pathways
  • nanotechnology
  • preclinical models
  • artificial organs
  • artificial intelligence
  • personalized medicine

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Published Papers (5 papers)

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Research

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13 pages, 3552 KB  
Article
Humanized L184Q Mutated Surfactant Protein C Gene Alters Alveolar Type 2 Epithelial Cell Fate
by Krishan G. Jain, Yang Liu, Runzhen Zhao, Preeti J. Muire, Jiwang Zhang, Qun Sophia Zang and Hong-Long Ji
Int. J. Mol. Sci. 2024, 25(16), 8723; https://doi.org/10.3390/ijms25168723 - 9 Aug 2024
Cited by 3 | Viewed by 4677
Abstract
Alveolar type 2 epithelial (AT2) cells synthesize surfactant protein C (SPC) and repair an injured alveolar epithelium. A mutated surfactant protein C gene (SftpcL184Q, Gene ID: 6440) in newborns has been associated with respiratory distress syndrome and pulmonary fibrosis. However, [...] Read more.
Alveolar type 2 epithelial (AT2) cells synthesize surfactant protein C (SPC) and repair an injured alveolar epithelium. A mutated surfactant protein C gene (SftpcL184Q, Gene ID: 6440) in newborns has been associated with respiratory distress syndrome and pulmonary fibrosis. However, the underlying mechanisms causing Sftpc gene mutations to regulate AT2 lineage remain unclear. We utilized three-dimensional (3D) feeder-free AT2 organoids in vitro to simulate the alveolar epithelium and compared AT2 lineage characteristics between WT (C57BL/6) and SftpcL184Q mutant mice using colony formation assays, immunofluorescence, flow cytometry, qRT-PCR, and Western blot assays. The AT2 numbers were reduced significantly in SftpcL184Q mice. Organoid numbers and colony-forming efficiency were significantly attenuated in the 3D cultures of primary SftpcL184Q AT2 cells compared to those of WT mice. Podoplanin (PDPN, Alveolar type 1 cell (AT1) marker) expression and transient cell count was significantly increased in SftpcL184Q organoids compared to in the WT mice. The expression levels of CD74, heat shock protein 90 (HSP90), and ribosomal protein S3A1 (RPS3A1) were not significantly different between WT and SftpcL184Q AT2 cells. This study demonstrated that humanized SftpcL184Q mutation regulates AT2 lineage intrinsically. This regulation is independent of CD74, HSP90, and RPS3A1 pathways. Full article
(This article belongs to the Special Issue Organoids and Organs-on-Chip for Medical Research)
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14 pages, 5178 KB  
Article
Development of Non-Invasive miRNA Markers for Assessing the Quality of Human Induced Pluripotent Stem Cell-Derived Retinal Organoids
by Hyo Song Park, Ji-Hong Bang, Wook Hyun Jung, Jin Young Yang, Hee Jeong Shin, Ji-Hye Son, Jung Woo Han, Si Hyung Lee, Kyung Hwun Chung, Kyunggon Kim, Hun Soo Chang and Tae Kwann Park
Int. J. Mol. Sci. 2024, 25(15), 8011; https://doi.org/10.3390/ijms25158011 - 23 Jul 2024
Cited by 5 | Viewed by 2630
Abstract
Human retinal organoids (ROs) have emerged as valuable tools for studying retinal development, modeling human retinal diseases, and screening drugs. However, their application is limited primarily due to time-intensive generation, high costs, and low reproducibility. Quality assessment of RO differentiation is crucial for [...] Read more.
Human retinal organoids (ROs) have emerged as valuable tools for studying retinal development, modeling human retinal diseases, and screening drugs. However, their application is limited primarily due to time-intensive generation, high costs, and low reproducibility. Quality assessment of RO differentiation is crucial for their application in research. However, traditional methods such as morphological evaluation and immunohistochemical analysis have limitations due to their lack of precision and invasiveness, respectively. This study aims to identify non-invasive biomarkers for RO differentiation quality using exosomal microRNAs (miRNAs), which are known to reflect cell-specific functions and development in the retina. We differentiated ROs from human induced pluripotent stem cells (hiPSCs) and classified them into ‘superior’ and ‘inferior’ groups based on morphological and immunohistochemical criteria. Exosomes from the conditioned media were isolated and analyzed for miRNA content. Our findings revealed distinct miRNA profiles between superior and inferior ROs, with superior ROs exhibiting higher miRNA diversity and specifically up- or down-regulated miRNAs. Gene ontology and pathway enrichment analyses indicated that the target genes of these miRNAs are involved in neuron proliferation and differentiation. The study suggests the potential of exosomal hsa-miR-654-3p and hsa-miR-451a as non-invasive biomarkers for real-time monitoring of RO quality, facilitating the development of standardized, efficient, and cost-effective culture methods. Full article
(This article belongs to the Special Issue Organoids and Organs-on-Chip for Medical Research)
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Review

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21 pages, 2353 KB  
Review
Mechano-Organ-on-Chip for Cancer Research
by Luyang Wang, James Chung Wai Cheung, Xia Zhao, Bee Luan Khoo and Siu Hong Dexter Wong
Int. J. Mol. Sci. 2026, 27(3), 1330; https://doi.org/10.3390/ijms27031330 - 29 Jan 2026
Cited by 1 | Viewed by 1354
Abstract
Mechano-Organ-on-Chip (Mechano-OoC) platforms are emerging as powerful microphysiological systems that place mechanical cues at the center of tumor modeling, providing a scalable and human-relevant approach to recapitulate the biophysical complexity of the tumor microenvironment. Mechanical factors such as matrix stiffness, viscoelasticity, solid stress, [...] Read more.
Mechano-Organ-on-Chip (Mechano-OoC) platforms are emerging as powerful microphysiological systems that place mechanical cues at the center of tumor modeling, providing a scalable and human-relevant approach to recapitulate the biophysical complexity of the tumor microenvironment. Mechanical factors such as matrix stiffness, viscoelasticity, solid stress, interstitial flow, confinement, and shear critically regulate cancer progression, metastasis, immune interactions, and treatment response, yet remain poorly captured by conventional in vitro models and are often studied separately in tumor-on-chip and mechanobiology research. In this review, we summarize recent advances in mechano-OoC technologies for cancer research, highlighting strategies that integrate engineered mechanical cues with microfluidics, tunable extracellular matrices, vascular and stromal interfaces, and dynamic loading to model tumor invasion, vascular transport, immune trafficking, and drug delivery. We also discuss emerging approaches for real-time, multimodal readouts, including sensor-integrated platforms and artificial intelligence-assisted data analysis, and outline key challenges that limit translation, such as device complexity, limited throughput, insufficient standardization, and inadequate validation against in vivo and clinical data. By organizing progress across platform engineering, sensing and readout, data standardization, and AI-driven analytics, this review provides a unified framework for advancing mechanobiology-aware tumor models and guiding the development of predictive preclinical platforms for precision cancer therapy. Full article
(This article belongs to the Special Issue Organoids and Organs-on-Chip for Medical Research)
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26 pages, 1522 KB  
Review
Organ-on-a-Chip: A Roadmap for Translational Research in Human and Veterinary Medicine
by Surina Surina, Aleksandra Chmielewska, Barbara Pratscher, Patricia Freund, Alexandro Rodríguez-Rojas and Iwan Anton Burgener
Int. J. Mol. Sci. 2025, 26(21), 10753; https://doi.org/10.3390/ijms262110753 - 5 Nov 2025
Cited by 7 | Viewed by 4625
Abstract
In this review we offer a guide to organ-on-chip (OoC) technologies, covering the full experimental pipeline, from organoid derivation and culture, through microfluidic device fabrication and design strategies, to perfusion systems and data acquisition with AI-assisted analysis. At each stage, we highlight both [...] Read more.
In this review we offer a guide to organ-on-chip (OoC) technologies, covering the full experimental pipeline, from organoid derivation and culture, through microfluidic device fabrication and design strategies, to perfusion systems and data acquisition with AI-assisted analysis. At each stage, we highlight both the advantages and limitations, providing a balanced perspective that aids experimental planning and decision-making. By integrating insights from stem cell biology, bioengineering, and computational analytics, this review presents a compilation of the state of the art of OoC research. It emphasizes practical considerations for experimental design, reproducibility, and functional readouts while also exploring applications in human and veterinary medicine. Furthermore, key technical challenges, standardization issues, and regulatory considerations are discussed, offering readers a clear roadmap for advancing both foundational studies and translational applications of OoC systems. Full article
(This article belongs to the Special Issue Organoids and Organs-on-Chip for Medical Research)
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Other

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13 pages, 1040 KB  
Perspective
Organoids-on-Chips Technology: Unveiling New Perspectives in Rare-Disease Research
by Xiangyang Li, Hui Wang, Xiaoyan You and Guoping Zhao
Int. J. Mol. Sci. 2025, 26(9), 4367; https://doi.org/10.3390/ijms26094367 - 4 May 2025
Cited by 7 | Viewed by 8100
Abstract
The scarcity of robust models and therapeutic options for rare diseases continues to hamper their preclinical investigation. Traditional animal models and two-dimensional cell cultures are limited in their ability to replicate human heredity-associated traits and complex pathological features. Organoids-on-a-chip approaches open up new [...] Read more.
The scarcity of robust models and therapeutic options for rare diseases continues to hamper their preclinical investigation. Traditional animal models and two-dimensional cell cultures are limited in their ability to replicate human heredity-associated traits and complex pathological features. Organoids-on-a-chip approaches open up new frontiers in rare-disease research via the integration of organ chips and organoid technology. This integrative strategy offers immense opportunities for the mimicry of disease-related traits, the clarification of the mechanisms underlying disease, and the prediction of treatment responses in a highly human-related manner. This forward-looking perspective suggests organoids on chips are transformative tools for parsing rare-disease pathogenesis, accelerating therapeutic discovery, and bridging the gap between basic research and precision medicine. Full article
(This article belongs to the Special Issue Organoids and Organs-on-Chip for Medical Research)
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