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Double-Layered Microphysiological System Made of Polyethylene Terephthalate with Trans-Epithelial Electrical Resistance Measurement Function for Uniform Detection Sensitivity.
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.
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In vitro platforms for reconstructing skin-microbiome interactions.
The growing recognition of the skin microbiome in regulating the host's metabolic and immune functions has spurred the development of in vitro platforms designed to recapitulate their intricate interactions, aiding research into both skin-microbiome and microbe-microbe interactions within their distinct niches. Despite these efforts, challenges remain in dissecting skin-microbiome interactions, especially due to the absence of a standardized platform for the long-term coculture of bacterial and mammalian cells. In this review, we highlight the key components in modeling an in vitro skin ecosystem and discuss the therapeutic potential of skin commensals, including recent advances and applications for engineered live biotherapeutics targeting skin diseases, to underscore the translational value of in vitro skin-microbiome interaction studies.
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Functional substrate-enhanced bioprinting technology for next-generation organ-on-a-chip: from fabrication to functionalization.
The integration of bioprinting with advanced substrate technologies offers a transformative approach to tissue engineering, providing vital insight into the development of complex organ-on-a-chip systems. Bioprinting enables the creation of sophisticated microscale biological structures, with the receiving substrate playing a critical role beyond merely supporting the printed constructs. This review explores how substrates enhance both the fabrication precision and functionality of bioprinted tissues, thereby increasing their physiological relevance and analytical capabilities. We demonstrate the potential of substrate-enhanced bioprinting in constructing advanced in vitro models by examining its recent advances, from fabrication technologies to functional applications. This technology has the potential to bridge the gap between traditional cell culture and physiologically relevant tissue models, advancing the development of next-generation organ-on-a-chip platforms.
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The potential of personalized cancer spheroids in precision therapy.
The clinical implementation of precision oncology remains challenged by intratumoral heterogeneity, complex tumor microenvironment interactions, and the limited predictive value of conventional preclinical models. 3D cancer spheroids have emerged as physiologically relevant platforms that closely mimic in vivo tumor architecture, cellular heterogeneity, hypoxic gradients, and treatment resistance mechanisms. This review highlights the growing role of cancer spheroids in drug panel testing and their application in personalized therapeutic decision-making across diverse malignancies, including breast, colorectal, ovarian, lung, head and neck, and brain cancers. Patient-derived spheroids and multicellular co-culture models preserve critical tumor-stroma and tumor-immune interactions, enabling clinically meaningful evaluation of chemotherapeutic agents, targeted therapies, immunotherapies, radiosensitizers, and combination treatment strategies. Drug panels assessed using spheroid platforms encompass platinum-based agents, EGFR and VEGF inhibitors, PARP inhibitors, immune checkpoint inhibitors, kinase inhibitors, antibody-drug conjugates, and emerging pathway-directed therapeutics. Accumulating evidence suggests that spheroid-based drug testing has the potential to recapitulate clinically relevant tumor characteristics and treatment responses and may serve as a useful preclinical approach for evaluating drug sensitivity, exploring resistance mechanisms, and assessing biomarker-associated responses within clinically relevant timeframes. Recent advances in high-throughput screening, microfluidic technologies, organ-on-chip systems, automated imaging, and artificial intelligence-driven analytics have further improved the scalability, reproducibility, and translational utility of these models. The review also discusses the current limitations, standardization challenges, and ethical considerations associated with spheroid-based drug testing. Collectively, personalized cancer spheroids represent a promising approach linking experimental oncology with precision medicine research, with potential applications in individualized drug testing and treatment optimization.
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Understanding organotropism in cancer metastasis using microphysiological systems.
Cancer metastasis, the leading cause of cancer-related deaths, remains a complex challenge in medical science. Stephen Paget's "seed and soil theory" introduced the concept of organotropism, suggesting that metastatic success depends on specific organ microenvironments. Understanding organotropism not only offers potential for curbing metastasis but also novel treatment strategies. Microphysiological systems (MPS), especially organ-on-a-chip models, have emerged as transformative tools in this quest. These systems, blending microfluidics, biology, and engineering, grant precise control over cell interactions within organ-specific microenvironments. MPS enable real-time monitoring, morphological analysis, and protein quantification, enhancing our comprehension of cancer dynamics, including tumor migration, vascularization, and pre-metastatic niches. In this review, we explore innovative applications of MPS in investigating cancer metastasis, particularly focusing on organotropism. This interdisciplinary approach converges the field of science, engineering, and medicine, thereby illuminating a path toward groundbreaking discoveries in cancer research.
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Augmented 3D Printing for Multiscale Microphysiological Systems.
Microphysiological systems (MPS) can recapitulate physiological features of human organs; however, existing engineering techniques are limited to fabricating sophisticated and functional MPS. Although 3D printing offers the potential to enhance the complexity of MPS and simplify the fabrication process, existing 3D-printed MPS suffer from challenges in fabricating multiscale structures spanning nanometers to centimeters. Recent studies suggested that these issues can be addressed by integrating multiscale ancillary techniques into 3D printing. In this review, an overview of augmented 3D-printing techniques is provided, combined with multiscale ancillary techniques for multiscale MPS fabrication, which are termed augmented 3D-printing techniques. It starts by providing an overview of 3D-printing methods and relevant multiscale ancillary techniques. Then, recent developments are highlighted in augmented 3D-printed MPS that show features that surpass those of conventional systems. This augmented approach opens the door to MPS with more physiologically relevant structures and functions, thereby marking a significant step forward in next-generation tissue engineering.
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Mechanobiological Adaptation to Hyperosmolarity Enhances Barrier Function in Human Vascular Microphysiological System.
In infectious disease such as sepsis and COVID-19, blood vessel leakage treatment is critical to prevent fatal progression into multi-organ failure and ultimately death, but the existing effective therapeutic modalities that improve vascular barrier function are limited. Here, this study reports that osmolarity modulation can significantly improve vascular barrier function, even in an inflammatory condition. 3D human vascular microphysiological systems and automated permeability quantification processes for high-throughput analysis of vascular barrier function are utilized. Vascular barrier function is enhanced by >7-folds with 24-48 h hyperosmotic exposure (time window of emergency care; >500 mOsm L-1 ) but is disrupted after hypo-osmotic exposure (<200 mOsm L-1 ). By integrating genetic and protein level analysis, it is shown that hyperosmolarity upregulates vascular endothelial-cadherin, cortical F-actin, and cell-cell junction tension, indicating that hyperosmotic adaptation mechanically stabilizes the vascular barrier. Importantly, improved vascular barrier function following hyperosmotic exposure is maintained even after chronic exposure to proinflammatory cytokines and iso-osmotic recovery via Yes-associated protein signaling pathways. This study suggests that osmolarity modulation may be a unique therapeutic strategy to proactively prevent infectious disease progression into severe stages via vascular barrier function protection.
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Drug treatment alters performance in a neural microphysiological system of information processing.
Assessment of pharmacological intervention on in vitro neural systems often emphasizes molecular and structural changes. However, neural systems fundamentally process and act on information. For preclinical assays to predict drug efficacy, they must model these physiological functions. DishBrain, an in vitro synthetic biological intelligence (SBI) assay embodying a neural system in a simulated game-world, enables the quantification of this information-processing capacity, however the question remains whether such a system permits classical pharmacological interrogation and dose-response profiling. Hyperactive glutamatergic dysregulation is linked to neurological disorders including epilepsy, and inducible overexpression of neurogenin 2 (NGN2) in human induced pluripotent stem cells (hiPSCs) generates glutamatergic cultures with dysregulated hyperactivity. We therefore tested three anti-seizure medications (ASMs), phenytoin, perampanel, and carbamazepine, on NGN2 neurons from day 21 of differentiation in this system. The key finding was that, while all compounds altered spontaneous firing, carbamazepine 200 µM significantly improved gameplay metrics. This marks the first demonstration of altered SBI following exogenous drug treatment. Notably, only inhibitory compounds enhanced goal-directed activity, linking glutamatergic attenuation to performance. Neurocomputational analysis revealed nuanced pharmacological responses during closed-loop stimulation, highlighting insights beyond spontaneous activity metrics.
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Zombosomes are anucleated cell couriers that spread α-synuclein pathology.
Astrocytes not only play a central role in orchestrating the brain's microenvironment but also are tightly connected to neurodegenerative processes. Hence, unraveling astrocytes' intercellular pathways can give important insight into disease-spreading mechanisms. Here, we describe a distinct form of actively migrating cellular vehicles, which we have named zombosomes. Zombosomes shed from astrocytes but retain their adhesive and motile properties, even though they lack nuclei. They share protein markers with their parental astrocytes, including highly packed vimentin, and are loaded with intact organelles. Importantly, zombosomes act as disease couriers, transferring α-synuclein aggregates from one cell to another, and have the capacity to infiltrate and induce pathology in cerebral organoids. Human brain sections show scattered vimentin-rich zombosomes with no attachments to nearby astrocytes, which contain deposits of aggregated α-synuclein. Taken together, our findings represent an interaction pathway between distant cells through "live" vehicles that when misused, may cause propagation of Parkinson's disease pathology.
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Detrimental effects of advanced glycation end-products (AGEs) on a 3D skeletal muscle model in microphysiological system.
Skeletal muscle is essential for maintaining body shape and supporting physiological processes. Musculoskeletal function is influenced by various factors, including nutrition, infection, injury or trauma, and advanced glycation end-products (AGEs), which are known to contribute in tissue degeneration, particularly in aging and diabetic populations. This study utilized a skeletal muscle-on-a-chip system to develop three-dimensional in vitro musculoskeletal tissue, enabling a detailed investigation of the effects of AGEs on muscle function and structure. AGEs-induced alterations on muscle were verified by assessments of musculoskeletal contractility, myotube growth, and apoptosis markers. Furthermore, metabolic changes such as modifications in collagen and NADH lifetime changes were observed using fluorescence-lifetime imaging microscopy (FLIM) in the AGEs-treated group. Our result demonstrated a significant reduction in musculoskeletal contractility and structural disruptions in response to AGEs exposure. Overall, these findings provide a robust in vitro model for elucidating the mechanisms by which AGEs impair muscle functionality and integrity, with potential implications for therapeutic strategies aimed at preserving muscle health and enhancing the quality of life in affected populations.