Organ-on-a-chip Research Articles (Page 1)

Metabolic dysfunction-associated steatotic liver disease (MASLD) and its progressive form metabolic dysfunction-associated steatohepatitis (MASH) are prevalent chronic liver diseases that are closely linked to metabolic syndrome, type 2 diabetes, and cardiovascular complications. Despite their rising incidence and growing socioeconomic burden, effective therapies remain limited. Traditional preclinical models often fail to replicate the complexity of human MASLD, particularly in capturing the interplay between patient-specific predisposition, metabolic dysfunction, immune activation and progressive fibrosis. In this review, a comprehensive overview of emerging human-based in vitro and ex vivo platforms is provided for use in MASLD research, including conventional 2D cultures, organoids, 3D spheroids, precision-cut liver slices, microphysiological systems, and bioprinted constructs. Their utility is evaluated for modeling different stages of MASLD and MASH and their alignment with key disease hallmarks is discussed. Furthermore, the different models are assessed for their capability to model pathophysiologically relevant nutritional exposure, to emulate genetic risk factors, to reflect the complex hepatic cell repertoire and to conduct high-throughput drug screenings. Recent successful applications of MASLD and MASH models are highlighted in drug discovery and development. Together, these insights aim to guide the refinement of human MASLD models to narrow the translational gap in MASH drug development.

Aging is a complex, multifaceted process affecting all organ systems, with vascular aging playing a central role in organismal health decline. Beyond its role in circulation, the vascular system acts as a dynamic interface between tissues, influencing countless physiological functions such as tissue regeneration and repair, immune responses, and metabolic balance. Importantly, age-related vascular impairment-characterized by a peculiar set of endothelial aging hallmarks-exacerbates age-related diseases (ARDs) such as cardiovascular disorders, neurodegeneration, chronic kidney disease, sarcopenia, and osteoporosis. This review combines basic concepts of angioscience and aging biology with translational interventions to devise clinical strategies promoting a functional rejuvenation of old and compromised blood vessels, fostering the prevention, delay or treatment of ARDs. Starting from the description of the cellular and molecular mechanisms driving vascular aging, a cutting-edge perspective on the organ-specific vascular impairment and its impact on tissue function is offered. Given the central role of the vasculature in aging, how targeting vascular aging through pharmacological, genetic, and lifestyle interventions holds promise for mitigating its systemic consequences and improving healthspan is discussed. Finally, how the combination of animal models (e.g., parabiosis) and novel microphysiological systems, coupled with multi-omics and artificial intelligence-driven analyses, is advancing the field toward the identification of strategies that promote vascular resilience and extend healthspan, addressing one of the most pressing biomedical challenges of a worldwide aging population is highlighted.

Commentary on FDA's shift from animal testing and implications for drug attrition - The time to act is now.

Challenges and solutions in measuring commonly used biomarkers for drug-induced liver injury in a liver-on-a-chip platform.

Innovative engineering approaches to model host-microbiome interactions in vitro.

Metastasis, the leading cause of cancer-related mortality, is a complex process involving tumor cell detachment from the primary site, survival and dissemination through the circulation, and colonization of distant organs. At each stage, tumor cells face adaptive pressures from successive biological and biomechanical challenges in the local microenvironment, which collectively shape their progression. Traditional in vitro models often fail to replicate these dynamics, while animal models are limited by species differences and restricted real-time monitoring. Microphysiological systems (MPS) have emerged as powerful tools to address these limitations, delivering physiologically relevant cues and precise experimental control to recapitulate step-specific metastatic contexts. This review outlines recent advances in MPS designs for modeling critical hallmarks of metastasis, beginning with matrix interactions, stromal cells, and mechanical forces from the tumor microenvironment that drive epithelial-mesenchymal transition and invasion. The discussion then transitions to MPS that reproduce vascular physiology during intravasation, circulation, and extravasation, and concludes with organ-specific environments for studying colonization and organotropic behavior in the final stages of metastasis. Additionally, common MPS configurations, categorized into horizontal and vertical compartmental arrangements, and strategies for integrating vascularization are explored. Together, these advances highlight the potential of MPS in elucidating metastatic mechanisms and advancing targeted therapies.

Microbubble (MB) technology is uniquely suited for integration into microphysiological systems (MPS) for high throughput three-dimensional (3D) tissue culture, drug screening and toxicity testing. MBs are spherical compartments with nanoliter volumes produced in an array format. Here, we present a novel hybrid MB-fluidic MPS that combines 3D tissue culture with controlled fluid flow to improve nutrient delivery, waste removal, and physiological relevance. Computational fluid dynamics (CFD) simulations were used to model velocity and solute diffusion profiles as a function of MB aspect ratio (AR), with validation by fluorescent polystyrene microsphere optical tracking. Simulations reveal pronounced velocity decoupling and shear dampening effects with intra-MB flow velocities over 200-fold lower than the main channel-allowing high channel flow rates for efficient exchange while preserving low-shear microenvironments, optimal for tissue culture. Additionally, tissues spatially compartmentalized in individual MBs are not dislodged under high flow conditions. This allowance for high channel flow rates, decoupled from the MB microenvironment, enables the use of millifluidic devices which are less difficult to manufacture and control than microfluidic devices. Simulations also showed that MBs with AR values between 2 and 3 offered a balance between nutrient transport and retention of cell-secreted factors. In contrast, rectilinear wells exhibited flow splitting and lactate accumulation at AR > 2, highlighting a key advantage of the spherical MB geometry. We fabricated a millifluidic MB device using fused deposition modeling (FDM) 3D printing and a novel molding strategy to create optically clear, leak-free flow channels. Murine salivary gland tissues cultured under flow in this device showed preserved acinar cell marker gene expression and reduced ductal markers, supporting the hypothesis that dynamic flow enhances tissue fidelity. This MB-fluidic platform enables scalable, high-content 3D culture systems suitable for organoid, tumor spheroid, and tissue mimetic applications in drug discovery and toxicology.

Purpose: Conventional 2-dimensional cultures and animal models have limited ability to reproduce the structural complexity, dynamic mechanical cues, and sustained functionality of native skeletal muscle tissue. To overcome these limitations, skeletal muscle-on-a-chip platforms have been developed as advanced in vitro systems for studying muscle physiology, pathology, and regeneration.Current Concepts: These microengineered systems incorporate essential features of skeletal muscle, including 3-dimensional architecture, cellular alignment, contractile function, and responsiveness to biochemical and mechanical stimuli. Recent advances, such as vascularization, multi-organ integration, and spaceflight-compatible designs, have expanded their applications in disease modeling and drug screening.Discussion and Conclusion: This review examines key engineering strategies, biological performance metrics, and representative applications of skeletal muscle-on-a-chip systems. It also addresses technical challenges, including long-term functionality, measurement standardization, and clinical translation, and considers future prospects for their integration into preclinical testing and regenerative medicine.

Purpose: This review outlines recent advances in skin-on-a-chip (SoC) and skin-integrated multi-organ-on-a-chip (MOC) technologies, emphasizing their potential to enhance dermatological research and drug testing by mimicking human physiology.Current Concepts: SoCs integrate skin models into microfluidic systems with dynamic perfusion, thereby enabling more physiologically relevant skin responses. MOC platforms link skin models with organ models such as the liver or gut, allowing the study of systemic interactions, including drug metabolism, immune responses, and inflammation.Discussion and Conclusion: These microphysiological systems reproduce human physiology more closely than traditional models. Although technical challenges remain, ongoing development may significantly improve drug screening, disease modeling, and personalized dermatological applications.

Purpose: The development of patient-derived microphysiological systems (P-MPS) marks a pivotal advancement in precision medicine. This review aims to assess the clinical relevance, technological evolution, and translational utility of P-MPS by examining how these systems integrate patient-specific biological materials into physiologically meaningful platforms for disease modeling and therapeutic decision-making.Current Concepts: P-MPS utilize primary cells, organoids, or induced pluripotent stem cells derived from individual patients, incorporating them into dynamic in vitro systems that recapitulate native tissue architecture and function. These platforms advance beyond conventional preclinical models by enabling more accurate simulation of patient-specific disease mechanisms, drug responses, and cellular interactions. Recent engineering innovations—including microfluidic integration, perfusion control, and scalable chip designs—have enhanced the physiological fidelity, throughput, and reproducibility of P-MPS. Simultaneously, advancements in AI-based imaging analytics and immune cell integration have further broadened their clinical applicability across a range of organ systems and disease states.Discussion and Conclusion: As healthcare continues to shift toward precision and functional medicine, P-MPS serve as a practical bridge between bench research and clinical application. These systems facilitate patient stratification, therapeutic screening, and personalized treatment development, while reducing dependence on animal models and enhancing translational predictability. Nevertheless, widespread adoption will require ongoing efforts in platform standardization, workflow integration, and regulatory validation. With continued progress in bioengineering and data analytics, P-MPS are poised to transform clinical research and empower clinicians with actionable, patient-specific insights.

Precision Nanomedicine: A Necessary Convergence of Nanodrug Development, Organotypic Models and Microphysiological Systems

Abstract Advanced biomanufacturing technologies are rapidly transforming the development of microphysiological systems (MPS), which serve as sophisticated in vitro platforms to model human organ structure and function with high fidelity. This review highlights cutting-edge biofabrication strategies, including 3D bioprinting technologies (such as inkjet, extrusion-based, digital light processing, stereolithography, and laser direct writing), microfluidics, modular tissue engineering, and electrohydrodynamic manufacturing that enable precise fabrication of complex, multicellular, and physiologically relevant tissue models. The integration of microfluidic systems enhances MPS by supporting dynamic perfusion, mechanical stimulation, and real-time monitoring, while modular approaches such as cell spheroid, organoid, and cell sheet assembly facilitate scalable and reproducible tissue engineering. Electrohydrodynamic techniques like electrospinning and melt electrowriting are emphasized for their ability to fabricate nanostructured scaffolds that closely mimic native extracellular matrix properties. This review also examines the selection and application of biomaterials, ranging from natural and synthetic polymers to hybrid composites and stimuli responsive hydrogels, that underpin the structural and functional integrity of MPS. Finally, the broad applications of advanced biomanufactured MPS in drug screening, toxicology, disease modeling, and regenerative medicine are discussed, emphasizing their potential to reduce reliance on animal models and accelerate biomedical discoveries toward clinical translation. The convergence of real-time sensing, smart materials, and modular design principles is identified as a key driver for the next generation of physiologically relevant and patient specific in vitro models.

Sex-specific cell culture methods and microphysiological systems can enhance our understanding of how biological sex influences health and disease. Here, we investigated the effects of estradiol and dihydrotestosterone on primary human lung and ocular fibroblasts as well as in human umbilical vein and retinal microvascular endothelial cells from both female and male donors. Treatment of female cells with estradiol and male cells with dihydrotestosterone in 2D culture significantly enhanced proliferation, mitochondrial membrane potential, and upregulated genes associated with bioenergetics and stress responses. Conversely, treatment of female cells with dihydrotestosterone and of male cells with estradiol decreased bioenergetic potential and inhibited cell proliferation. A microphysiological model of bulk tissue vasculogenesis revealed that estradiol enhances vasculogenesis in female tissues and inhibits vasculogenesis in male tissues. Collectively, these findings demonstrate that the sex hormone composition of culture medium significantly influences bioassay readouts in a sex-specific manner.

Microphysiological systems (MPSs) have emerged as alternatives to animal testing in drug development, following the FDA Modernization Act 2.0. Double-layer channel-type MPS chips with porous membranes are widely used for modeling various organs, including the intestines, blood–brain barrier, renal tubules, and lungs. However, these chips faced challenges owing to optical interference caused by light scattering from the porous membrane, which hinders cell observation. Trans-epithelial electrical resistance (TEER) measurement offers a non-invasive method for assessing barrier integrity in these chips. However, existing electrode-integrated MPS chips for TEER measurement have non-uniform current densities, leading to compromised measurement accuracy. Additionally, chips made from polydimethylsiloxane have been associated with drug absorption issues. This study developed an electrode-integrated MPS chip for TEER measurement with a uniform current distribution and minimal drug absorption. Through a finite element method simulation, electrode patterns were optimized and incorporated into a polyethylene terephthalate (PET)-based chip. The device was fabricated by laminating PET films, porous membranes, and patterned gold electrodes. The chip’s performance was evaluated using a perfused Caco-2 intestinal model. TEER levels increased and peaked on day 5 when cells formed a monolayer, and then they decreased with the development of villi-like structures. Concurrently, capacitance increased, indicating microvilli formation. Exposure to staurosporine resulted in a dose-dependent reduction in TEER, which was validated by immunostaining, indicating a disruption of the tight junction. This study presents a TEER measurement MPS platform with a uniform current density and reduced drug absorption, thereby enhancing TEER measurement reliability. This system effectively monitors barrier integrity and drug responses, demonstrating its potential for non-animal drug-testing applications.

Microphysiological systems (MPS) contain multiple cell types in three dimensions and often incorporate fluidic shear forces. There is interest in MPS for disease and efficacy modeling, safety and disposition studies. Animal cell-based MPS are needed to provide confidence in the translation of data from human cell-based MPS. We developed rat and dog quad-culture liver MPS incorporating primary hepatocytes, sinusoidal endothelial, Kupffer, and stellate cells. Using cryopreserved primary cells, we established a protocol for co-culturing cells under physiological flow conditions. Cells were evaluated for viability, morphology, and function (e.g. albumin production, cytochrome P450, and flavin-containing monooxygenase [FMO] activity). Optimized culture conditions maintained high-quality rat and dog liver chips for up to 7 days. Model performance was evaluated with ABT-288, a histamine-3 receptor antagonist that caused elevated serum transaminases in dogs but not rats. This finding was partially attributed to the high levels of FMO-mediated N-oxide metabolites produced in the dog. Key findings in our study were (i) dog chips showed much higher FMO-mediated N-oxidation compared with rat, and (2) dog chips exhibited modestly higher sensitivity to ABT-288 toxicity endpoints (albumin, alanine transaminase, and lactate dehydrogenase) compared with rat. Species differences in N-oxidation were not observed in rat and dog liver microsomes or 2D hepatocyte monocultures, suggesting that properties of the quad-culture MPS were necessary to model higher FMO activity observed in dogs in vivo. The data suggest that this preclinical species liver chip model provides novel understanding of in vitro to in vivo translation of ABT-288 dog liver toxicity.

Microphysiological systems as a pillar of the Human Exposome Project.

Microphysiological Systems as an Emerging In Vitro Approach for the Evaluation of Drug ADME and Toxicity

Hyperoxaluria is a pathological condition characterized by increased levels of oxalate in the urine, which may result in the deposition of oxalate stones, first in the kidneys, with the risk of incurring chronic kidney disease, and, in the most severe forms, systemically. Endogenous and exogenous sources, linked to the hepatic metabolism of glyoxylate, the direct precursor of oxalate, and dietary intake, respectively, contribute to oxalate presence in the human circulation, ultimately removed by excretion in the urine. Disruption of oxalate homeostasis may result in hyperoxaluria, either as a primary disease (PH) in the case of genetic defects in the enzymes responsible for the hepatic metabolism of glyoxylate, or secondary to other conditions (SH), involving excessive oxalate intake or intestinal malabsorption, the latter condition also known as enteric hyperoxaluria (EH). While therapeutic strategies targeting key glyoxylate metabolic pathways have advanced the clinical management of PH, EH has lagged behind, partly because of the heterogeneity of the conditions at its basis, but also because of the lack of suitable disease models. The recent development of microphysiological systems, or organ-on-a-chip, able to reproduce the physiological functions of human organs and tissues with increasing complexity and accuracy, would represent a step forward in the mechanistic dissection of EH pathogenesis. In this perspective, we discuss the strategies for EH modeling in a microphysiological system, in light of the recent literature and our work, and evaluate how this implementation might be instrumental for the development of novel therapeutic strategies.

Advancements in Microfluidic Organ-on-a-chip for Oral Medicine.

Drug-drug interactions (DDIs) pose significant challenges in pharmacotherapy, affecting drug efficacy and safety. Traditional in vitro and in vivo models often fail to accurately predict clinically relevant DDIs, necessitating the development of advanced testing platforms. This review explores cutting-edge in vitro and in vivo systems, including chimeric mice with humanized livers, clustered regularly interspaced short palindromic repeats-CRISPR-associated animal models, liver microphysiological systems, and 3-dimensional spheroids and organoids that enhance the assessment of DDIs. These models enable the precise evaluation of drug metabolism, enzyme induction/inhibition, and transporter-mediated interactions under physiologically relevant conditions. In addition, we discuss the latest advancements in predictive modeling techniques for DDIs, focusing on physiologically based pharmacokinetic models and machine learning approaches. Physiologically based pharmacokinetic models integrate drug-specific and system-specific parameters to simulate DDIs dynamically, bridging the gap between preclinical and clinical findings. Machine learning-based predictive tools use vast datasets to identify complex interaction patterns, improving DDI risk assessment in early drug development. By integrating these novel experimental and computational approaches, researchers can achieve more accurate, quantitative DDI predictions, facilitating safer drug design and regulatory decision-making. The review highlights these emerging methodologies, emphasizing the need for continued refinement to enhance their predictive power and translational relevance. Future research should focus on optimizing hybrid strategies that combine mechanistic and data-driven models to achieve robust, clinically meaningful DDI assessments. SIGNIFICANCE STATEMENT: This review showcases advanced experimental and computational tools to improve drug-drug interaction prediction. These innovations enhance drug-drug interaction accuracy, support safer drug development, aid regulatory and clinical decisions, reduce adverse reactions, and optimize patient care.