Search Results (46)

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 review proposes mechanical crosstalk between stromal tension and vascular shear/flow as a unifying principle for integrating fibroblast-populated collagen lattices (FPCLs) with perfusable micro-physiological systems (MPSs). We argue that current in vitro platforms either emphasize fibroblast-driven matrix contraction (as with FPCLs) or flow-mediated vascular dynamics (as with MPSs) but rarely consider the reciprocity between these forces. By defining a mechanobiological framework that couples cellular contractility, extracellular matrix (ECM) remodeling, and shear-dependent endothelial responses, we reframe FPCL–MPS hybrids as “living devices” capable of capturing mechano-transduction across stromal and vascular compartments. This review (1) delineates the mechanobiology of FPCLs, highlighting their tension generation, matrix remodeling, and disease relevance; (2) surveys perfusable MPS design principles, focusing on shear stress, barrier function, and multicellular integration; (3) formulates a crosstalk paradigm in which stromal tension and vascular shear coregulate tissue physiology; (4) synthesizes engineering strategies for integrating FPCLs into MPSs; and (5) outlines challenges and future directions involving multiscale measurements, multi-omics, artificial intelligence, and regulatory standardization. To our knowledge, this review is among the first to explicitly frame stromal tension and vascular shear as a unified mechanobiological axis. Full article

Per- and polyfluoroalkyl substances are persistent environmental contaminants increasingly implicated in neurotoxicity. Establishing causality and mechanisms relevant to Alzheimer’s disease, Parkinson’s disease, and multiple sclerosis requires human-relevant systems that capture exposure, barrier function, and brain circuitry. We review advanced cellular platforms—iPSC-derived neuronal and glial cultures, cerebral and midbrain organoids, and chip-based microphysiological systems—that model disease-relevant phenotypes (Aβ/tau pathology, dopaminergic vulnerability, myelination defects) under controlled PFAS exposures and defined genetic risk backgrounds. Modular, fluidically coupled BBB-on-chip → brain-organoid microphysiological systems have been reported, enabling chronic, low-dose PFAS perfusion under physiological shear, real-time barrier integrity readouts such as transepithelial/transendothelial electrical resistance (TEER), quantification of PFAS partitioning and translocation, and downstream neuronal–glial responses assessed by electrophysiology and multi-omics. Across platforms, convergent PFAS-responsive processes emerge—mitochondrial dysfunction and oxidative stress, lipid/ceramide dysregulation, neuroinflammatory signaling, and synaptic/network impairments—providing a mechanistic scaffold for biomarker discovery and gene–environment interrogation with isogenic lines. We outline principles for exposure design (environmentally relevant ranges, longitudinal paradigms), multimodal endpoints (omics, electrophysiology, imaging), and cross-lab standardization to improve comparability. Together, these models advance the quantitative evaluation of PFAS neurotoxicity and support translation into risk assessment and therapeutic strategies. Full article

Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal malignancies. An unmet need exists for reliable biomarkers and in vitro models capable of predicting patient drug response to advance personalized medicine. Traditional models fail to represent the tumor’s complexity and the role of the stromal environment in chemoresistance. Patient-derived organoids (PDOs) overcome these limitations, enabling multi-omics profiling and reliable drug testing for functional precision medicine. This review provides a comprehensive overview of PDAC PDO research, emphasizing the following major areas: (i) the genetic and phenotypic fidelity of PDOs, (ii) their predictive value for drug response and chemoresistance, (iii) the integration of the extracellular matrix and tumor microenvironment (TME) components, and (iv) emerging technologies. Studies confirm that PDOs faithfully represent the primary tumor’s specific genetic features and retain intratumoral heterogeneity. PDO-based platforms have demonstrated a strong correlation between in vitro drug sensitivity and in vivo efficacy in xenograft models, validating their utility for identifying drug candidates, repurposing existing drugs, and determining effective combinations. Efforts are ongoing to integrate crucial TME components, like cancer-associated fibroblasts, using innovative co-culture platforms such as fused PDOs and InterOMaX, to better model desmoplasia and chemoresistance mechanisms. Furthermore, PDO technology is converging with microphysiological systems and artificial intelligence tools to facilitate high-throughput drug screening and dynamic, real-time monitoring of therapeutic effects. The integration of PDOs into biobanks and advanced screening platforms holds the potential to accelerate drug discovery and improve therapeutic outcomes for PDAC patients, if challenges related to protocol standardization and regulatory acceptance are addressed. Full article

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. Full article

The female reproductive system represents a highly complex regulatory network governing critical physiological functions, encompassing reproductive capacity and endocrine regulation that maintains female physiological homeostasis. The in vitro simulation system provides a novel tool for biomedical research and can be used as physiological and pathological models to study the female reproductive system. Recent advances in this technology have evolved from 2D and 3D printing to organ-on-a-chip (OOC) and microfluidic systems, which has emerged as a transformative platform for modeling the female reproductive system. These microphysiological systems integrate microfluidics, 3D cell culture, and biomimetic scaffolds to replicate key functional aspects of reproductive organs and tissues. They have enabled precise simulation of hormonal regulation, embryo-endometrium interactions, and disease mechanisms such as endometriosis and gynecologic cancers. This review highlights the current state of female reproductive OOCs, including ovary-, uterus-, and fallopian tube-on-a-chip system, their applications in assisted reproduction and disease modeling, and the technological hurdles to their widespread application. Though significant barriers remain in scaling OOCs for high-throughput drug screening, standardizing protocols for clinical applications, and validating their predictive value against human patient outcomes, OOCs have emerged as a transformative platform to model complex pathologies, offering unprecedented insights into disease mechanisms and personalized therapeutic interventions. Future directions, including multi-organ integration for systemic reproductive modeling, incorporation of microbiome interactions, and clinical translation for mechanisms of drug action, will facilitate unprecedented insights into reproductive physiology and pathology. Full article

Microphysiological systems (MPSs), such as organ-on-a-chip platforms, are promising alternatives to animal testing for drug development and physiological research. The BioStellar™ Plate is a commercial MPS platform featuring an open-top culture chamber design with on-chip stirrer pumps that circulate culture medium through six independent, dual microchannel-connected chamber multiorgan units. Although this design enables a circular flow, the open-top culture chamber format prevents the application of fluidic shear stress, a force that cells experience in vivo, which affects their behavior and function. To address this, we developed two fluidic shear stress attachments for the BioStellar™ Plate. These attachment channel fluids provide controlled mechanical stimulation to cultured cells. The flow dynamics were simulated using COMSOL Multiphysics to estimate shear stress levels. The attachments were fabricated and validated through fluorescent bead tracking and biological assays. The FSSA-D is designed for flat-bottom standard cell cultures, while the FSSA-I is designed for epithelial monolayers, enabling the application of fluidic shear stress across the basal membrane. Experiments with intestinal epithelial cells (Caco-2) demonstrated that both attachments enhanced cell barrier function under a fluidic environment, as indicated by higher transepithelial electrical resistance (TEER). These findings demonstrate that the attachments are practical tools for mechanobiology research with MPS platforms. Full article

Background/Objectives: The inner blood–retinal barrier (iBRB) is a specialized neurovascular interface essential for retinal homeostasis and visual function and is compromised in several vision-threating conditions. Therefore, the ability to model iBRB function and dysfunction in a controlled, reproducible and scalable manner is crucial for pharmaceutical research. However, the complex anatomy and physiology of the iBRB raise challenges for cell-based in vitro modeling. Methods/Results: This review follows the evolution of iBRB models—from simple monolayers of retinal endothelial cells (ECs) to sophisticated multicellular microphysiological systems (MPs). Advanced diverse microfluidic platforms aim to replicate key structural, biochemical and functional aspects of the iBRB, each incorporating distinct strategies regarding cell sourcing, device design, flow dynamics and functional readouts. Conclusions: Despite their limitations, these models are highly valuable for drug screening and mechanistic studies aimed at preserving or restoring barrier integrity while also helping to bridge the translational gap in ophthalmic drug discovery. Full article

Organ-on-a-chip (OoC) devices simulate human organs within a microenvironment, potentially surpassing traditional preclinical methods and paving the way for innovative treatments. A thorough understanding of the current state of OoC design enables the development of more precise and relevant models that replicate not only the structure of organs but also their intricate cellular interactions and responses to external stimuli. This knowledge facilitates the optimization of biomimetic materials and allows for the real-time simulation of physiological microenvironments. By keeping abreast of new microfabrication techniques, we can explore opportunities to create customized and highly functional OoCs. Objective: To provide a comprehensive overview of microphysiological platform designs. Methods: This systematic review was registered in PROSPERO under the number CRD42022352569. We adhered to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. The eligibility criteria included studies utilizing human tissue, either primary or secondary lineage cells. Results: A total of 9.790 papers were retrieved from the Scopus, Embase, IEEE and Web of Science databases. After removing duplicates and applying a 10-year publication filter, 3.150 articles were screened by title and abstract. Full-text analyses were then performed. Eighteen studies met the eligibility criteria and were included in this systematic review. In this review, we examine the principles of OoC design, focusing on structure, dimensions, cell culturing options and manufacturing techniques. We also examine recent advances and future prospects in the field. Conclusions: Microphysiological devices in health research can facilitate drug discovery and improve our understanding of human physiology. They contribute to more ethical research by reducing the number of animals used in experiments. Full article

Organoids and microphysiological systems (MPSs) have emerged as physiologically relevant platforms that recapitulate key structural and functional features of human organs, tissues, and microenvironments. As one of the essential components that define the success of these systems, hydrogels play the central role of providing a three-dimensional, biomimetic scaffold that supports cell viability, spatial organization, and dynamic signaling. Natural polymer-based hydrogels, derived from materials such as collagen, gelatin, hyaluronic acid, and alginate, offer favorable properties including biocompatibility, degradability, and an extracellular matrix-like architecture. This review presents recent advances in the design and application of such hydrogels, focusing on crosslinking strategies (physical, chemical, and hybrid), the viscoelastic characteristics, and stimuli-responsive behaviors. The influence of these materials on cellular processes, such as stemness maintenance, differentiation, and morphogenesis, is critically examined. Furthermore, the applications of organoid culture and dynamic MPS platforms are discussed, highlighting their roles in morphogen delivery, barrier formation, and vascularization. Current challenges and future perspectives toward achieving standardized, scalable, and translational hydrogel systems are also addressed. Full article

Accurate in vitro models of intestinal permeability are essential for predicting oral drug absorption. Standard models like Caco-2 cells have well-known limitations, including lack of segment-specific physiology, but are widely used. Emerging models such as organoid-derived monolayers and microphysiological systems (MPS) offer enhanced physiological relevance but require comparative validation. We performed a head-to-head evaluation of Caco-2 cells, human jejunal (J2) and duodenal (D109) enteroid-derived cells, and EpiIntestinal^TM tissues cultured on either static Transwell and flow-based MPS platforms. We assessed tissue morphology, barrier function (TEER, dextran leakage), and permeability of three model small molecules (caffeine, propranolol, and indomethacin), integrating the data into a physiologically based gut absorption model (PECAT) to predict human oral bioavailability. J2 and D109 cells demonstrated more physiologically relevant morphology and higher TEER than Caco-2 cells, while the EpiIntestinal^TM model exhibited thicker and more uneven tissue structures with lower TEER and higher passive permeability. MPS cultures offered modest improvements in epithelial architecture but introduced greater variability, especially with enteroid-derived cells. Predictions of human fraction absorbed (F_abs) were most accurate when using static Caco-2 data with segment-specific corrections based on enteroid-derived values, highlighting the utility of combining traditional and advanced in vitro gut models to optimize predictive performance for F_abs. While MPS and enteroid-based systems provide physiological advantages, standard static models remain robust and predictive when used with in silico modeling. Our findings support the need for further refinement of enteroid-MPS integration and advocate for standardized benchmarking across gut model systems to improve translational relevance in drug development and regulatory reviews. Full article

New approach methodologies (NAMs), including microphysiological systems (MPSs), can recapitulate structural and functional complexities of organs. Vanoxerine was reported to induce cardiac adverse events, including torsade de points (TdP), in a Phase III clinical trial. Despite earlier nonclinical animal models and Phase I–II clinical trials, events of QT prolongation or proarrhythmia were not observed. Here, we utilized cardiac NAMs to evaluate the functional consequences of vanoxerine treatment on human cardiac excitation–contraction coupling. The cardiac MPS used in this study was a microfabricated fluidic culture platform with human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) capable of evaluating voltage, intracellular calcium handling, and contractility. Likewise, the hiPSC-CM comprehensive in vitro proarrhythmia assay (CiPA) was employed based on multielectrode array (MEA). Vanoxerine treatment delayed repolarization in a concentration-dependent manner and induced proarrhythmic events in both NAM platforms. The complex cardiac MPS displayed a frequency-dependent vanoxerine response such that EADs were eliminated at a faster pacing rate (1.5 Hz). Moreover, exposure analysis revealed a 99% vanoxerine loss in the cardiac MPS. TdP risk analysis demonstrated high to intermediate TdP risk at clinically relevant concentrations of vanoxerine and frequency-independent EAD events in the hiPSC-CM CiPA model. These findings demonstrate that nonclinical cardiac NAMs can recapitulate clinical outcomes, including detection of vanoxerine-induced delayed repolarization and proarrhythmic effects. Moreover, this work provides a foundation to evaluate the safety and efficacy of novel compounds to reduce the dependence on animal studies. Full article

Background/Objectives: VitroScreenORA^® (by VitroScreen srl) Dermo Papilla spheroids, based on two micro-physiological systems (non-vascularized DP and vascularized VASC-DP), were used to study the molecular mechanisms behind hair cycle regression. Methods: Dermal papilla cells (HFDPC) were cultured to develop both models. Hair cycle regression was induced by exposing DP spheroids to TGF-β1 for 72 h and/or FGF-18 for an additional 24 h. Catagen phase entrance was evaluated by modulating specific genes (FGF7, CCND1, and WNT5B). The VASC-DP model was obtained by sequentially co-culturing HFDPC and primary dermal microvascular endothelial cells (HMDEC), mimicking the surrounding capillary loop. The vascular system’s impact was assessed at 5 and 10 days using IF on CD31 (micro-vessels) and Fibronectin (FN). Nanostring nCounter^® technology was applied to investigate the transcriptional signature based on the WNT pathway. Extended culture time up to 11 days simulated natural hair cycle regression, monitored by versican and FN expression (IF). Minoxidil, Doxorubicin, and Retinol-based products were used to modify physiological aging over time. Results: Data shows that the vascular system improves tissue physiology by modulating the associated genes. Extended culture time confirms progressive DP structure degeneration that is partially recoverable with Retinol-based treatments. Conclusions: Both models provide a reliable platform to investigate the hair cycle, paving the way for new testing systems for personalized therapies. Full article

The liver is a vital organ responsible for a broad range of metabolic functions, including glucose and lipid metabolism, detoxification, and protein synthesis. Its structural complexity, characterized by hexagonal hepatic lobules composed of diverse parenchymal and non-parenchymal cell types, supports its broad spectrum of physiological activities. Traditional in vitro liver models have contributed significantly to our understanding of hepatic biology and the development of therapies for liver-related diseases. However, static culture systems fail to replicate the dynamic in vivo microenvironment, particularly the continuous blood flow and shear stress that are critical for maintaining hepatocyte function and metabolic zonation. Recent advances in microphysiological systems (MPS) incorporating dynamic fluid flow have addressed these limitations by providing more physiologically relevant platforms for modeling liver function. These systems offer improved fidelity for applications in drug screening, toxicity testing, and disease modeling. Furthermore, the integration of liver MPS with other organ models in multi-organ-on-chip platforms has enabled the investigation of inter-organ crosstalk, enhancing the translational potential of in vitro systems. This review summarizes recent progress in the development of dynamic liver MPS, highlights their biomedical applications, and discusses future directions for creating more comprehensive and predictive in vitro models. Full article

Traditional pre-clinical drug evaluation methods, including animal experiments and static cell cultures using human-derived cells, face critical limitations such as interspecies differences, ethical concerns, and poor physiological relevance. More recently, microphysiological systems (MPSs) that use microfluidic devices to mimic in vivo conditions have emerged as promising platforms. By enabling perfusion cell culture and incorporating human-derived cells, MPSs can evaluate drug efficacy and toxicity in a more human-relevant manner. However, standard MPS protocols rely on discrete medium changes, causing abrupt changes in drug concentrations that do not reflect the continuous pharmacokinetics seen in vivo. To overcome this limitation, we developed a Dialysis Membrane-integrated Microfluidic Device (DMiMD) which maintains continuous drug concentrations through selective medium change via a dialysis membrane. The membrane’s molecular weight cut-off (MWCO) enables the retention of high-molecular-weight drugs while facilitating the passage of essential low-molecular-weight nutrients such as glucose. We validated the membrane’s molecular selectivity and confirmed effective nutrient supply using cells. Additionally, anticancer drug efficacy was evaluated under continuously changing drug concentrations, demonstrating that the DMiMD successfully mimics in vivo drug exposure dynamics. These results indicate that the DMiMD offers a robust in vitro platform for accurate assessment of drug efficacy and toxicity, bridging the gap between conventional static assays and the physiological complexities of the human body. Full article