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Engineering organs-on-a-chip via multi-channel microfluidics.
Conventional in vitro physiological models, relying on animal studies and 2D/3D cell cultures, are fundamentally limited by interspecies biological discrepancies, ethical constraints, or inadequate replication of human physiology. Organ-on-a-chip (OoC) technology overcomes these challenges through emulating organ-specific microphysiological systems. The transformative power of this innovation lies in multi-channel microfluidic chips. These chips facilitate the formation of 3D cellular organizations and tissue interfaces via integrated porous membranes, micropillar arrays, or perfusable vascular microchannels, simultaneously allowing for precise and dynamic modulation of chemical, biological, and physical factors. Rapid technological evolution has yielded functional models of lung alveoli, the blood-brain barrier, cardiac tissues, etc., thereby advancing drug testing and disease modeling accuracy. This review systematically examines the development of OoC technology through the lens of multi-channel microfluidics by focusing on four pivotal domains: (1) the biomimetic design overview for OoCs, (2) fabrication methods including soft lithography and 3D printing, (3) applications in pathophysiological investigations, preclinical drug evaluation, and toxicological assessment, and (4) current challenges and perspectives in structural design, materials and fabrication, biological applications, and other development directions. This review is intended to provide a reference for the technological iteration and interdisciplinary application of multi-channel microfluidic chip systems.
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SliceChip: a benchtop fluidic platform for organotypic culture and serial assessment of human and rodent pancreatic slices.
Enzymatically isolated pancreatic islets are the most commonly used ex vivo testbeds for diabetes research. Recently, precision-cut living slices of human pancreas are emerging as an exciting alternative because they maintain the complex architecture of the endocrine and exocrine tissues, and do not suffer from the mechanical and chemical stress of enzymatic isolation. We report a fluidic pancreatic SliceChip platform with dynamic environmental controls that generates a warm, oxygenated, and bubble-free fluidic pathway across singular immobilized slices with continuous deliver of fresh media and the ability to perform repeat serial perfusion assessments. A degasser ensures the system remains bubble-free while systemic pressurization with compressed oxygen ensures slice medium remains adequately oxygenated. Computational modeling of perfusion and oxygen dynamics within SliceChip guide the system's physiomimetic culture conditions. Maintenance of the physiological glucose dependent insulin secretion profile across repeat perfusion assessments of individual pancreatic slices kept under physiological oxygen levels demonstrated the culture capacity of our platform. Fluorescent images acquired every 4 hours of transgenic murine pancreatic slices were reliably stable and recoverable over a 5 day period due to the inclusion of a 3D-printed bioinert metallic anchor that maintained slice position within the SliceChip. Our slice on a chip platform has the potential to expand the useability of human pancreatic slices for diabetes pathogenesis and the development of new therapeutic approaches, while also enabling organotypic culture and assessment of other tissue slices such as brain and patient tumors.
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A microphysiological system for parallelized morphological and electrophysiological read-out of 3D neuronal cell culture.
Three-dimensional in vitro models in microfluidic systems are promising tools for studying cell biology, with complex models using multiple cell types combined with high resolution imaging. Neuronal models demand electrical readout of the activity of networks of single neurons, yet classical planar microelectrode arrays struggle to capture extracellular action potentials when neural soma are suspended distant from the microelectrodes. This study introduces sophisticated microfluidic microelectrode arrays, specifically tailored for electrophysiology of 3D neuronal cultures. Using multilayer photolithography of permanent epoxy photoresists, we developed devices having 12 independent culture modules in a convenient format. Each module has two adjacent compartments for hydrogel-based 3D cell culture, with tunnels allowing projection of neurites between compartments. Microelectrodes integrated in the tunnels record action potentials as they pass between the compartments. Mesh ceilings separate the compartments from overlying wells, allowing for simple cell seeding and later nutrient, gas and waste exchange and application of test substances. Using these devices, we have demonstrated 3D neuronal culture, including electrophysiological recording and live imaging. This microphysiological platform will enable high-throughput investigation of neuronal networks for investigation of neurological disorders, neural pharmacology and basic neuroscience. Further models could include cocultures representing multiple brain regions or innervation models of other organs.
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Engineered Biomimetic Membranes for Organ-on-a-Chip.
Organ-on-a-chip (OOC) systems are engineered nanobiosystems to mimic the physiochemical environment of a specific organ in the body. Among various components of OOC systems, biomimetic membranes have been regarded as one of the most important key components to develop controllable biomimetic bioanalysis systems. Here, we review the preparation and characterization of biomimetic membranes in comparison with the features of the extracellular matrix. After that, we review and discuss the latest applications of engineered biomimetic membranes to fabricate various organs on a chip, such as liver, kidney, intestine, lung, skin, heart, vasculature and blood vessels, brain, and multiorgans with perspectives for further biomedical applications.
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A comparative review of organ-on-a-chip technologies for micro- and nanoplastics versus other environmental toxicants.
In recent years, organ-on-a-chip (OOC) technology has emerged as a groundbreaking platform to simulate complex physiological processes. Concurrently, the global presence of micro and nano-plastics (MNPs) in the environment and their ingestion has raised concerns about their impact on human health, specifically organs such as the lungs, liver, kidneys, and blood vessels. There is an added concern about their ability to cross even the blood-brain barrier (BBB). While numerous papers have been published assessing various environmental toxicants with OOCs, those for MNPs are relatively small. To ascertain current trends in methodologies and catalog the types of toxicants explored, we have gathered and analyzed papers that used OOCs to assess various environmental toxicants' impacts on these organs. Various platforms assessing MNPs were analyzed and compared to those for other environmental toxicants. Our results show that few articles have been published that used OOCs to assess MNPs' toxicity to human organs. Specifically, certain organs, such as the heart and skin, have little representation in this collection. OOC-based evaluation methods for MNP's toxicity have many advantages over the current methods - in vitro tests with 2D human cell cultures and animal studies - including lower cost, faster results, and greater physiological relevance. This review summarizes the current OOC techniques for assessing environmental toxicants and laboratory methods for evaluating MNPs' toxicity to humans. A systematic comparison of these methods provides a deeper understanding of the current techniques and suggests the optimized use of OOCs for assessing MNPs' and other pollutants' toxicity.
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Organ Chips and Translational Research: Identifying and Examining New Ethical Issues.
Organ chips, also known as organ-on-a-chip devices, tissue chips, or microphysiological systems, have emerged over the last decade as a promising translational technology amidst growing concern about the translational crisis between laboratory research and patient bedside. Pointing to high rates of failure between nonhuman animal models and safety and efficacy in humans, organ chips and similar new approach methods have attracted substantial public and private investment. As human-cell-based alternatives to animal models, organ chips promise more predictive, efficient, and ethical platforms for pharmaceutical and toxicity testing. Engineered cultivation systems that enable cells to assemble into tissue-like structures (e.g. kidney, brain, liver), organ chips mimic tissue architecture and function and live for extended periods of time. This essay considers the translational bioethics issues raised by organ chips, including those that arise early in development such as the obfuscation of cell-origin data, representation in design, and the normalization of conflicts of interest within commercialization-oriented translational science efforts. Integrating a translational bioethics lens from the outset, rather than deferring social and ethical implications analysis to downstream points in technology development and adoption, is essential to realizing the translational promise of organ chips while avoiding the reproduction of existing inequities and ethical conundrums.
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Lubricant-Coated Organ-on-a-Chip for Enhanced Precision in Preclinical Drug Testing.
In drug discovery, human organ-on-a-chip (organ chip) technology has emerged as an essential tool for preclinical testing, offering a realistic representation of human physiology, real-time monitoring, and disease modeling. Polydimethylsiloxane (PDMS) is commonly used in organ chip fabrication owing to its biocompatibility, flexibility, transparency, and ability to replicate features down to the nanoscale. However, the porous nature of PDMS leads to unintended absorption of small molecules, critically affecting the drug response analysis. Addressing this challenge, the precision drug testing organ chip (PreD chip) is introduced, an innovative platform engineered to minimize small molecule absorption while facilitating cell culture. This chip features a PDMS microchannel wall coated with a perfluoropolyether-based lubricant, providing slipperiness and antifouling properties. It also incorporates an ECM-coated semi-porous membrane that supports robust multicellular cultures. The PreD chip demonstrates its outstanding antifouling properties and resistance to various biological fluids, small molecule drugs, and plasma proteins. In simulating the human gut barrier, the PreD chip demonstrates highly enhanced sensitivity in tests for dexamethasone toxicity and is highly effective in assessing drug transport across the human blood-brain barrier. These findings emphasize the potential of the PreD chip in advancing organ chip-based drug testing methodologies.
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Impact of Neurons on Patient-Derived Cardiomyocytes Using Organ-On-A-Chip and iPSC Biotechnologies.
In the heart, cardiac function is regulated by the autonomic nervous system (ANS) that extends through the myocardium and establishes junctions at the sinus node and ventricular levels. Thus, an increase or decrease in neuronal activity acutely affects myocardial function and chronically affects its structure through remodeling processes. The neuro-cardiac junction (NCJ), which is the major structure of this system, is poorly understood and only a few cell models allow us to study it. Here, we present an innovant neuro-cardiac organ-on-chip model to study this structure to better understand the mechanisms involved in the establishment of NCJ. To create such a system, we used microfluidic devices composed of two separate cell culture compartments interconnected by asymmetric microchannels. Rat PC12 cells were differentiated to recapitulate the characteristics of sympathetic neurons, and cultivated with cardiomyocytes derived from human induced pluripotent stem cells (hiPSC). We confirmed the presence of a specialized structure between the two cell types that allows neuromodulation and observed that the neuronal stimulation impacts the excitation-contraction coupling properties including the intracellular calcium handling. Finally, we also co-cultivated human neurons (hiPSC-NRs) with human cardiomyocytes (hiPSC-CMs), both obtained from the same hiPSC line. Hence, we have developed a neuro-cardiac compartmentalized in vitro model system that allows us to recapitulate the structural and functional properties of the neuro-cardiac junction and that can also be used to better understand the interaction between the heart and brain in humans, as well as to evaluate the impact of drugs on a reconstructed human neuro-cardiac system.
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Hydrogel membranes in organ-on-a-chip devices: A review.
Organ-on-a-chip (OoC) devices represent advanced in vitro models enabling to mimic the human tissue architecture function and physiology, providing a promising alternative to the traditional animal testing methods. These devices combine the microfluidics with soft materials, specifically hydrogel membranes (HMs) for mimicking the extracellular matrix (ECM) and biological barriers, such as the blood-brain barrier (BBB). Hydrogels are ideal biomaterials for OoC systems because of their tunable properties, biocompatibility, biodegradability, and microscale self-assembly. The integration of HMs with OoC devices provides an effective way to develop dynamic, biologically relevant environments for supporting living cells targeted at drug discovery, disease modeling, and personalized medicine. Recent advancements in fabrication technologies such as additive manufacturing (3D printing), photolithography, and bioprinting have additionally advanced development of such systems. This review aims to outline the role of HMs in OoC platforms, highlighting their material properties, self-assembly behavior, and also challenges associated with their fabrication. Additionally, we visualize and discuss the latest progress made in utilizing HMs for applications in tissue engineering, drug development, and biosensing, with a focus on their interface dynamics and structural self-organization. The future perspective on OoC technology has also been patterned in order to provide a broader image on integration of OoC and HMs with personalized medicine and advanced drug delivery systems.
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Integration of microphysiological systems with computational and digital twin modeling for pharmaceutical development: a systematic review.
BACKGROUND: The pharmaceutical industry faces a productivity crisis, with only ∼10% of candidates reaching approval and development costs exceeding $1-2 billion per drug. Traditional preclinical models, particularly animal studies, show limited predictive validity for human outcomes. Microphysiological systems (MPS), including organ-on-chip devices, integrated with digital twin computational modeling, offer a promising route to improve translational prediction, yet no systematic assessment exists. OBJECTIVES: To identify, evaluate, and synthesize the published literature on integrating MPS with digital twin computational modeling for pharmaceutical development. METHODS: Following PRISMA 2020 guidelines (PROSPERO: CRD420251274941), PubMed and Europe PMC were searched from January 2010 to December 2025. Studies were included if they integrated MPS platforms with computational models (PBPK, QSP, IVIVE, PK/PD, or machine learning). Two-stage automated screening with independent verification by two researchers was applied. Data extraction captured organ systems, model types, platforms, validation approaches, pharmacokinetic parameters, software, and economic considerations. RESULTS: Of 2,044 records, 123 studies met inclusion criteria. Publication activity grew exponentially (CAGR ∼35%), with 38.2% published in 2024-2025. Liver was the most represented organ (30.9%), followed by vasculature (19.5%), gut (18.7%), and immune components (17.1%). PBPK was the predominant computational approach (18.7%), followed by PK (12.2%), IVIVE (12.2%), and machine learning (9.8%). Commercially, Emulate led (55.8%), then Mimetas (23.3%) and CN Bio (19.2%); custom/academic platforms comprised 74.2%. Validation was robust, with 95.8% discussing clinical data comparisons and 77.5% reporting average fold error. Only liver-PBPK and liver-PK qualified as established combinations (>5 studies), with many organ-model pairings unexplored. Multi-organ systems showed accelerating adoption after 2021. Economic themes were discussed qualitatively, but formal health economic analyses were absent. CONCLUSION: MPS-digital twin integration has matured from an emerging concept into a research paradigm with demonstrated translational value. Validation practices are strong and aligned with regulatory expectations, supported by the FDA Modernization Act 2.0 and the ISTAND program's acceptance of Liver-Chip technology. Liver-focused applications are the most mature and should serve as a template for expansion. Priority gaps include kidney, lung, and brain MPS-computational integration, multi-organ systems, and rigorous health economic analyses. Continued standardization and regulatory engagement will be essential to realize this approach's potential.