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A microphysiological spheroid system for modeling glioblastoma structure and therapy response.
Glioblastoma (GBM) is a lethal, highly aggressive primary brain tumor. Even with maximal surgical resection, chemo, and radiotherapy, the median survival is less than 15 months with universal recurrence. Recalcitrance of GBM arises from its cellular, genetic, epigenetic, and microenvironment heterogeneity that evolves spontaneously over time and as a result of treatment. The primary objective of this study was to create and characterize a tunable, heterocellular 3D spheroid platform that mirrors the cell-cell interactions of the GBM niche and to utilize this model to investigate mechanisms of resistance to standard therapy. We established three spheroid models of increasing complexity: tumor-only (G1), tumor-microglia (G2), and a full niche model including astrocytes (G3). These spheroids exhibited realistic growth dynamics, viability, and morphometric properties. Spheroids were treated with chemotherapeutic drugs: Doxorubicin and Carboplatin. Interestingly, while drug treatment induced cell death in the simpler G1 and G2 models, the inclusion of SVG astrocytes in Group 3 resulted in a marked reduction in efficacy of Doxorubicin. The significant shift from high drug sensitivity in G1 to survival in G3 provides direct evidence of environment-mediated drug resistance, where the glial niche confers a protective metabolic and structural shield to the tumor cells. Our findings may validate the heterocellular spheroid as a high-fidelity model for some aspects of the GBM microenvironment. The transition from high sensitivity in monocultures to resistance in multi-lineage model (G3) underscores the protective role of glia within the tumor microenvironment. This platform provides a robust tool for high-throughput screening of sensitizing agents designed to disrupt these protective interactions to overcome chemoresistance in brain tumors as well as enabling dissection of heterocellular interactions, molecular signaling, and therapeutic responses in a physiologically accurate 3D context.
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Integrating ex vivo platforms with AI to guide glioblastoma treatment.
PURPOSE: Ex vivo platforms can rapidly and cost-effectively screen patient-derived tumor cells or tissue. Artificial intelligence (AI) algorithms can search and identify patterns in large datasets and provide predictions. This review focuses on integrating microphysiological platforms with AI to inform physician and patient decision-making. METHODS AND RESULTS: Combining efficacy, safety, and pharmacology results from drug screens with the output of extensive AI searches can yield insights to guide physician and patient decision-making and potentially improve a patient's prognosis. We detail ex vivo platforms at different stages of development that represent the diversity of approaches: a microphysiological system and a high-throughput screen that assesses drug cytotoxicity in both bulk and drug-tolerant tumor cells. We review AI approaches that can enhance the utility of microphysiological platforms. CONCLUSION: Integrating emerging microphysiological platforms with AI is expected to significantly impact physician and patient choice of treatment.
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Long-term exposure to excessive norepinephrine in the brain induces tau aggregation, neuronal death, and cognitive deficits in early tau transgenic mice.
Alzheimer's disease (AD) is marked by the presence of intraneuronal neurofibrillary tangles (NFTs), which are primarily composed of hyperphosphorylated tau protein. The locus coeruleus (LC), the brain's main source of norepinephrine (NE), is one of the earliest regions to develop NFTs and experience neurodegeneration in AD. While LC-derived NE plays beneficial roles in cognition, emotion, locomotion, and the sleep-wake cycle, its impact on tau pathology is unclear. To explore this relationship, we administered intraperitoneal injections of either N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine (DSP4), a selective neurotoxin for noradrenergic neurons, or reboxetine (RBX), a norepinephrine reuptake inhibitor, to decrease or increase NE levels, respectively, in early tau transgenic mice expressing mutant human P301L tau (ADLPTau) for two months. Only the RBX-treated mice exhibited cognitive deficits, as evidenced by their performance in the Y-maze, novel object recognition, and contextual fear conditioning tests. Immunohistochemical analysis revealed increased hyperphosphorylated tau aggregates in the LC and hippocampus of the RBX-treated mice. Furthermore, neuronal apoptosis was observed in the hippocampal CA1 region of these mice. Western blotting showed that RBX injections led to the overactivation of tau kinases PKA and GSK3β, resulting in hyperphosphorylated tau, neuronal loss, and cognitive impairments. Consistent with these findings, human brain organoids exposed to higher NE concentrations also displayed elevated hyperphosphorylated tau and increased activity of the same tau kinases. These findings suggest that excessive NE exposure accelerates tau pathology by overactivating the tau kinases. Thus, modulating NE levels in the brain via the LC-NE system could be a potential therapeutic strategy for tau-related AD.
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Biosensor-Enhanced Organ-on-a-Chip Models for Investigating Glioblastoma Tumor Microenvironment Dynamics.
Glioblastoma, an aggressive primary brain tumor, poses a significant challenge owing to its dynamic and intricate tumor microenvironment. This review investigates the innovative integration of biosensor-enhanced organ-on-a-chip (OOC) models as a novel strategy for an in-depth exploration of glioblastoma tumor microenvironment dynamics. In recent years, the transformative approach of incorporating biosensors into OOC platforms has enabled real-time monitoring and analysis of cellular behaviors within a controlled microenvironment. Conventional in vitro and in vivo models exhibit inherent limitations in accurately replicating the complex nature of glioblastoma progression. This review addresses the existing research gap by pioneering the integration of biosensor-enhanced OOC models, providing a comprehensive platform for investigating glioblastoma tumor microenvironment dynamics. The applications of this combined approach in studying glioblastoma dynamics are critically scrutinized, emphasizing its potential to bridge the gap between simplistic models and the intricate in vivo conditions. Furthermore, the article discusses the implications of biosensor-enhanced OOC models in elucidating the dynamic features of the tumor microenvironment, encompassing cell migration, proliferation, and interactions. By furnishing real-time insights, these models significantly contribute to unraveling the complex biology of glioblastoma, thereby influencing the development of more accurate diagnostic and therapeutic strategies.
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Decoding cellular dynamics and microenvironmental responses in organ-on-chip systems through real-time sensing.
Organ-on-Chip (OoC) systems hold extraordinary promise for predictive drug development and disease modeling. Yet, their translational impact is constrained by several challenges, one of which is the inability to monitor cellular microenvironments and tissue behavior in real time, without destructive sampling. In the absence of real-time sensing capabilities, OoC characterization often relies on intermittent or endpoint measurements, where inputs and endpoints are known, but transient cellular mechanisms driving biological responses remain elusive. This ambiguity limits mechanistic insights and complicates model validation essential for pre-clinical decision-making. Integrating sensing capabilities into OoCs resolves this gap by enabling continuous, non-invasive monitoring of multi-parametric cellular and microenvironmental dynamics. This review presents an overview of the current state of real-time OoC sensing, examining how electrochemical, optical, affinity-based, and mechanical sensing modalities capture real-time data related to barrier integrity, metabolic shifts, ion dynamics, biomarker secretion, and contractile force. It discusses data from representative organ systems (brain, gut, liver, kidney, etc.), commercially available platforms, and disease-modeling applications, highlighting enhanced predictive potential relative to the conventional pre-clinical models. Innovations in multi-modal sensors and AI/ML-based data analysis are advancing OoCs toward high-throughput drug safety and efficacy assessments. However, persistent challenges such as sensor miniaturization, lack of standardized calibration protocols, batch-to-batch reproducibility, signal interference in complex media, economic barriers, and lack of binding international regulatory guidelines impede scalable translation. Addressing these gaps through co-ordinated standardization, regulatory harmonization, and infrastructure development is essential to unlock OoCs as routine pre-clinical tools capable of reducing animal use, accelerating therapeutic translation, and improving patient outcomes.
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Challenges and Future Perspectives in Modeling Neurodegenerative Diseases Using Organ-on-a-Chip Technology.
Neurodegenerative diseases (NDDs) affect more than 50 million people worldwide, posing a significant global health challenge as well as a high socioeconomic burden. With aging constituting one of the main risk factors for some NDDs such as Alzheimer's disease (AD) and Parkinson's disease (PD), this societal toll is expected to rise considering the predicted increase in the aging population as well as the limited progress in the development of effective therapeutics. To address the high failure rates in clinical trials, legislative changes permitting the use of alternatives to traditional pre-clinical in vivo models are implemented. In this regard, microphysiological systems (MPS) such as organ-on-a-chip (OoC) platforms constitute a promising tool, due to their ability to mimic complex and human-specific tissue niches in vitro. This review summarizes the current progress in modeling NDDs using OoC technology and discusses five critical aspects still insufficiently addressed in OoC models to date. Taking these aspects into consideration in the future MPS will advance the modeling of NDDs in vitro and increase their translational value in the clinical setting.
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[Revolutionizing physiology: advances in organ-on-a-chip technology].
To address the low predictability (92% clinical failure rate) and high costs associated with species differences in traditional animal testing, this research advocates for New Approach Methodologies (NAMs) in alignment with the US FDA Modernization Act 2.0. The central achievement presented is the development of a "human Heart-on-a-chip." This microfluidic device co-cultures human iPS-derived cardiomyocytes, fibroblasts, and vascular endothelial cells to mimic living 3D tissue structures and fluid environments. The system demonstrated superior physiological reproducibility compared to conventional methods in evaluating drug responses (e.g., nifedipine) and detecting fatal side effects like QT prolongation. In addition to the heart, applications are advancing across diverse organ and disease models, including the construction of ischemia-reperfusion injury models using kidney chips and pulmonary fibrosis models using lung chips, the evaluation of barrier functions via blood-brain barrier (BBB) chips, and the analysis of interactions between cancer cells and immune cells using cancer chips. It is concluded that these technologies enable high-precision in vitro reproduction of human physiology and pathology, thereby improving the efficiency of drug screening, reducing economic losses, and accelerating the paradigm shift toward the 3Rs (Replacement, Reduction, and Refinement) in animal experimentation.
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Membrane-Integrated Organ-on-a-Chip Systems.
Membranes play a key role in many organ-on-a-chip (OOC) platforms due to nutrient and mass transport, barrier formation, and mechanical signaling. However, despite their key role in OOC devices, the relationship between membrane design parameters and device performance is limited in the literature. Here, this review gives a critical overview of not only the types of membranes for OOC devices (natural, synthetic, hybrid, and emerging functional membranes) but also defines the key engineering design requirements for the selection and integration of membranes with microfluidic OOC platforms. Additionally, it presents types of organ-specific OOC devices (lung, kidney, liver, blood-brain barrier, and intestine models), highlighting existing challenges and limitations in the fabrication of such platforms. The paper also presents future directions toward smart, multifunctional membranes.
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Modeling respiratory viral infections and investigating immune responses: new advances in human organ chip models.
Respiratory viral infections pose persistent global health threats, yet traditionalin vitroand animal models inadequately recapitulate human tissue microenvironments. Organ-on-a-chip technology integrates microfluidic engineering with cell biology to recreate three-dimensional architectures, mechanical forces, and multicellular interactions of the human respiratory system. This review systematically summarizes recent advances in organ-on-a-chip platforms for modeling respiratory viral infections and host immune responses. We highlight their unique capabilities in simulating alveolar-capillary barriers, lymphoid follicle formation, and multi-organ axes including lung-brain and gut-lung communication. Furthermore, we discuss applications in antiviral drug screening, vaccine evaluation, and personalized medicine, while addressing current challenges and future directions toward standardized, multi-organ integrated, and intelligently monitored systems.
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Integrated microfluidic three-organ chip for real-time toxicity analysis of fluorotelomer alcohols in the gut-vascular-nerve axis.
Perfluoroalkyl substances (PFASs), persistent environmental contaminants linked to neurodevelopmental toxicity, cannot be adequately modeled by traditional in vitro systems due to their inability to recapitulate multi-organ interactions. To address this limitation, we developed and engineered a tri-organ gut-vascular-nerve axis chip that reconstructs the bidirectional gut-brain communication through an integrated endothelial barrier. Unlike dispersed 2D cultures on D-polylysine plates, our 3D platform supports cross-linked neurite outgrowth, self-assembled microvascular tubules, and a tightly sealed intestinal epithelia, coupled with integrated solid-phase extraction-mass spectrometry for real-time tracking of PFAS dynamics. We demonstrate that intestinal epithelial cells metabolize fluorotelomer alcohols into bioactive fluorotelomer carboxylic acids, which may transit vascular channels to neural compartments, inducing neuronal dysfunction and driving axis-wide alterations in metabolic activity, oxidative stress responses, and inflammatory signaling. This physiologically relevant model provides novel mechanistic insights into PFAS neurotoxicity and establishes a robust organ-on-chip paradigm for environmental toxicology.