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Advancements in organoid models emulating metastatic niches.
Metastases cause most cancer-related deaths, underscoring the need for therapies targeting metastatic stages, including the tumor microenvironment. Yet translating biological insights into treatments remains difficult. Preclinical metastasis research largely relies on rodent models, which have species-specific limitations and are incompatible with large-scale perturbation screens in a human context. Human organoids aim to emulate organ microenvironments in vitro and, when cocultured with cancer cells, can provide complementary models. These 'chimeroids' may enable scalable studies of cancer-microenvironment interactions and support genetic and pharmacological screens to discover new targets, offering insights into the final, often lethal step of metastasis-tissue colonization. This review summarizes advances in stem cell-derived organoid models for organs frequently affected by solid tumor metastases, including the brain, lung, liver, and bone, and evaluates their ability to recreate physiologically relevant niches for studying cancer cell adaptation and colonization.
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Human Gut-Brain Interaction Chip for Dissecting the Gut-Derived LPS and Butyrate Regulation of the Blood-Brain Barrier.
The gut-brain axis (GBA) interaction is important for human health and disease prevention. Organ chips are considered a solution for GBA research. Three-dimensional (3D) cultures and microfluidics engineered in an organ chip could improve the scientific knowledge in the GBA interactions field. In this study, a novel organ chip is developed, which achieves multicellular three-dimensional cultivation by utilizing a decellularized matrix. In addition, this paper reports the rapid prototyping process of the GBA microfluidic chip in polydimethylsiloxane (PDMS) using 3D printing interconnecting poly(ethylene/vinyl acetate) (PEVA) microchannel templates. In comparison to the static culture system of the transwell model, the intestinal epithelial barrier (IEB) and blood-brain barrier (BBB) models on our chip demonstrated superior barrier function and the efflux functionality of transporters under appropriate fluidic conditions. Additionally, it is observed that butyrate protected against BBB dysfunction induced by gut-derived lipopolysaccharide (LPS) via enhancing intestinal barrier function. These results demonstrate that this multicellular, three-dimensional cultivation integrated with a fluidic shear stress simulation chip offers a promising tool for gut-brain interaction study to predict therapy of intestinal and neurological disorders.
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A Microfluidic Framework for Neuroprotective Compound Triage Across Ischemia and Neurodegeneration.
Microfluidic systems are increasingly used in neuroprotection research, but their clearest value may be to show why candidate compounds fail before costly downstream models. This critical framework review examines CNS-relevant microfluidic studies through a within-program triage logic linking chemistry-aware prescreening, blood-brain barrier/neurovascular unit (BBB/NVU) filtering, and timed validation in neuronal ischemia/reperfusion models, and treats non-CNS organ-on-a-chip and analytical microfluidic studies as engineering analogies only. The available evidence most strongly supports BBB/NVU chips as exposure- and safety-aware filters and compartmentalized neuronal oxygen-glucose deprivation platforms as timing-sensitive validation tools; droplet microfluidics contributes mainly upstream through dense dose mapping, aggregation assays and counterscreens for assay interference. A compound-centered reading also suggests that apparent activity often fails for distinct reasons, including timing mismatch, poor solubility, surface adsorption, optical artifact, inadequate multicellular context, or loss of efficacy under transport-aware testing. Taken together, the literature supports a cautious, within-program triage logic in which microfluidics is used not as a universal disease model, but as an operational framework for exposing transport, barrier, timing and assay liabilities early in neuroprotective discovery.
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Decoding Glioblastoma Complexity Through Extracellular Vesicles, Organ-on-Chip Models, and Deep Learning.
Glioblastoma (GBM) is one of the most aggressive human cancers, with therapeutic failure driven by pronounced intratumoral heterogeneity, microenvironmental plasticity, immune suppression, blood-brain barrier (BBB)-related pharmacological constraints, and adaptive resistance mechanisms. A major limitation in GBM research is the lack of a human-relevant experimental system able to reproduce these dynamic features while generating interpretable, multimodal datasets. In this context, we propose a testable organ-on-chip (OoC)-extracellular vesicle (EV)-deep learning (DL) framework in which patient-derived GBM cells, endothelial cells, astrocytes, pericytes, stromal cells, and immune components are organized within perfused microphysiological systems. EVs are selectively and temporally harvested from defined compartments, and imaging, barrier-function, sensor, and EV-cargo data are integrated through modality-specific and multimodal DL architectures. This framework is intended not as an immediately validated clinical tool but as an experimental roadmap for linking EV-mediated communication to measurable phenotypes such as BBB disruption, invasion, immune reprogramming, and drug response. We critically discuss the technical requirements of BBB-on-chip systems, EV source attribution, immune-component integration, DL model selection, data scarcity, overfitting, batch effects, domain shift, regulatory barriers, cost, throughput, and reproducibility. By repositioning OoC-EV-DL integration as a staged translational strategy rather than a clinically established solution, this work aims to define a realistic and biologically grounded route for advancing precision oncology in GBM.
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Ultrasound-Controlled Blood-Brain Barrier (BBB) Opening in a BBB-Glioblastoma Microfluidic Chip for Drug Delivery Studies.
The blood-brain barrier (BBB) is a major obstacle to treating glioblastoma (GBM) by restricting the entry of most therapeutic molecules into the brain. Interspecies differences in BBB structure and function complicate the clinical translation of animal models, highlighting the need for human-relevant in vitro BBB platforms for assessing drug permeability in GBM therapy. Here, a protocol is described for constructing a microfluidic BBB-GBM chip model. This model establishes a tri-culture system comprising human cerebral microvascular endothelial cells (HCMECs), primary astrocytes (ACs), and U87-MG cells within a Matrigel-embedded microfluidic platform. BBB integrity is verified through continuous zonula occludens-1 (ZO-1) immunostaining and FITC-dextran permeability assay. Low-intensity ultrasound (US) (1 MHz, 1 W/cm2, 30 s) is then employed to induce transient and largely reversible BBB opening, allowing tumor-targeting nanomicelles (SFN@RB@SPMs) to efficiently traverse the barrier and accumulate in GBM cells. A key feature of this protocol is the integration of real-time BBB permeability and drug delivery measurements within a single ultrasound-responsive chip, providing a powerful platform to dissect the mechanisms of ultrasound-augmented drug delivery in GBM.
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Human Blood-Brain Tumor Barrier on a Chip to Investigate Personalized Treatment for Glioblastoma Patients.
The inherent characteristics of glioblastoma (GBM), including tumoral heterogeneity and invasive capacity, combined with the presence of the blood-brain tumor barrier (BBTB), present challenges in developing effective treatment for GBM. Especially, the margins of GBM, where GBM cells infiltrate normal brain tissue, exhibit high resistance to therapies. Despite the difficulties in controlling tumor progression within this region, the GBM margin remains a critical area to be studied. Here we report a microengineered model that mimics the BBTB within the GBM margin, incorporating a 3D network of normal astrocytes and GBM cells isolated from patients newly diagnosed with GBM. The interaction between GBM cells and stromal cells results in increased vascular permeability, reactive gliosis, alterations in astrocyte behavior and immune responses to foster tumor invasiveness and progression. We compare patient-specific tumor responses to conventional chemotherapy and immune polarization in our BBTB on a chip model with clinical outcomes, demonstrating the capability of the model to predict personalized drug responses. Our BBTB model may serve as a personalized tool to examine the interactions between tumors and normal brain tissue, ultimately facilitating the screening of personalized medicine for GBM treatment.
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Bacterial extracellular vesicles indirectly destabilize a human stem cell-derived blood-brain barrier on-chip through pro-inflammatory stimulation of immune cells.
Pathogenic bacterial extracellular vesicles (BEVs) can disrupt the blood-brain barrier (BBB), leading to neuroinflammation. Prior in vitro studies of this process were performed in simple models that may have lacked important physiological factors. We sought to determine if treatment with Escherichia coli-derived BEVs could directly compromise the integrity of a BBB lab-on-chip model or if an immune component was required. Our device featured isogenic human induced pluripotent stem cell-derived brain microvascular endothelial-like cells (BMECs) and pericytes separated by an ultrathin, porous silicon nitride membrane. BEVs and free lipopolysaccharide (LPS) were capable of causing upregulation of intercellular adhesion molecule-1 on the BMEC surfaces, which is important for immune cell recruitment. However, neither BEVs nor LPS at physiologically-relevant doses caused pronounced loss of BMEC tight junction proteins, nor did they increase barrier permeability to small dye molecules. In contrast, stimulating THP-1 macrophages with BEVs led to increased production of pro-inflammatory cytokines, and conditioned media from the stimulated macrophages disrupted BMEC tight junctions and increased barrier permeability. Our work demonstrates the importance of incorporating an immune component in studies of BEV-mediated disruption of BBB models.
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An organ-on-a-chip investigation into dose-dependent, temporal dynamic effects of radiosurgery on the blood-brain barrier and its immunological response.
PURPOSE: This work used an organ-on-a-chip (OOC) model of the blood-brain barrier (BBB) to study effects of clinical radiation on barrier permeability and cytokine concentrations. METHODS: Gravity-perfused OOC devices developed in house for modeling the BBB were prepared with human endothelial cells, astrocytes, and pericytes. The devices were then irradiated to 0, 2, or 20 Gy with a 6 MV X-ray beam from a medical linear accelerator. At 0, 6, 24, and 48 h post irradiation, barrier permeability was assessed by measuring the diffusion across the barrier of Alexa Fluor-labeled dextran perfused into the vascular chamber. At these same time points, effluent was drawn from both the vascular and brain chambers and analyzed using a 10-cytokine panel. RESULTS: A statistically significant increase in barrier permeability was observed at 24 and 48 h and appeared similar between 2 and 20 Gy. For 20 Gy but not 2 Gy, a large initial increase was observed in the concentration of Granulocyte-Macrophage Colony-Stimulating Factor in the vascular chamber at 6 h, which subsequently decreased. An increase was also observed in the concentration of Interleukin-1α in the brain chamber starting at 24 h and continuing to 48 h. The concentration of Vascular Endothelial Growth Factor was observed to increase starting at 6 h and 24 h in the vascular chamber and brain chamber, respectively, and to subsequently decrease in both chambers. CONCLUSIONS: Radiation effects on the BBB including barrier permeability and cytokine concentration can be observed in a dose- and time-dependent manner using an OOC.
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Engineered Microvascular Model of the Blood-Brain-Tumor Barrier Reveals Endothelial Remodeling in Diffuse Midline Glioma.
Diffuse midline glioma (DMG) is a highly aggressive pediatric brain tumor that is difficult to treat because the blood-brain-tumor barrier (BBTB) prevents most drugs from reaching the tumor. A major obstacle for understanding this tumor-vascular niche is the lack of a perfusable vascular model of DMG. To address this, we have established an in vitro model of the DMG-BBTB, comprised of patient-derived DMG tumor cells and primary human brain microvascular endothelial cells, astrocytes, and vascular pericytes, embedded in a fibrin matrix within a microfluidic chip. We report the development and characterization of self-assembled microvascular networks, with consistent vasculature development across a range of tumor cell densities. Perfusion studies showed no significant alterations in vascular permeability when tumor cells were present. To elucidate transcriptomic changes, we employed scRNAseq on devices containing blood-brain barrier (BBB), DMG-BBTB, or tumor necrosis factor alpha (TNFα)-stimulated control. We observed significant differential gene expression between BBB and DMG-BBTB, distinct from inflammatory signatures seen with TNFα perturbation. Our analysis indicated that DMG cells adopted a mesenchymal-like phenotype, with further in silico studies predicting significant receptor-ligand crosstalk between these cells and endothelium. In summary, we developed a high-fidelity DMG-BBTB model that recapitulates transcriptomic features of patient DMG microvasculature and features perfusable vasculature.
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Drug compound screening in single and integrated multi-organoid body-on-a-chip systems.
Current practices in drug development have led to therapeutic compounds being approved for widespread use in humans, only to be later withdrawn due to unanticipated toxicity. These occurrences are largely the result of erroneous data generated by in vivo and in vitro preclinical models that do not accurately recapitulate human physiology. Herein, a human primary cell- and stem cell-derived 3D organoid technology is employed to screen a panel of drugs that were recalled from market by the FDA. The platform is comprised of multiple tissue organoid types that remain viable for at least 28 days, in vitro. For many of these compounds, the 3D organoid system was able to demonstrate toxicity. Furthermore, organoids exposed to non-toxic compounds remained viable at clinically relevant doses. Additional experiments were performed on integrated multi-organoid systems containing liver, cardiac, lung, vascular, testis, colon, and brain. These integrated systems proved to maintain viability and expressed functional biomarkers, long-term. Examples are provided that demonstrate how multi-organoid 'body-on-a-chip' systems may be used to model the interdependent metabolism and downstream effects of drugs across multiple tissues in a single platform. Such 3D in vitro systems represent a more physiologically relevant model for drug screening and will likely reduce the cost and failure rate associated with the approval of new drugs.