Organ Model: Central Nervous System

Synopsis

Watch this on-demand webinar for a closer look at the Emulate Brain-Chip R1, a first-in-class, isogenic Organ-Chip model designed to advance human-relevant research of the blood–brain barrier (BBB) and neurovascular unit (NVU). Presented by Emulate scientists Erin Greguske, PhD, and Randy Daughters, PhD, this webinar walks viewers through the development, characterization, and applications of this comprehensive five-cell iPSC model. Attendees will learn how the Brain-Chip R1 recreates key NVU interactions, maintains a tight and stable BBB-like barrier, and enables more predictive studies in neuroinflammation, BBB transport, and CNS drug discovery. 

Key Learning Points 

• Overview of the Brain-Chip R1 and how five isogenic iPSC-derived cell types recreate essential features of the human NVU.
• Characterization of barrier function, transporter expression, and glial resting-state behavior across the experimental window.
• How the Chip-R1™ Rigid Chip minimizes drug absorption, improving compound recovery and quantitative BBB permeability measurements.
• Applications in BBB transport, neuroinflammation modeling, and CNS drug development, including examples of functional assays and readouts.

Overview

Learn how our Brain-Chip R1 can be applied to emulate the complex functions and physiology of the human neurovascular unit.

In this technical note, we review how the Brain-Chip R1 provides a reproducible, resting-state NVU model suitable for studies of BBB transport, permeability, and neuroinflammatory mechanisms.

Key highlights:

• Incorporates five iPSC-derived cell types, including proprietary BMECs that exhibit a physiologically relevant brain microvascular endothelial–like phenotype
• Maintains resting-state glia and a tight, stable barrier throughout a four-day experimental window
• Features a streamlined, 12-day direct-to-chip workflow with no pre-plating or expansion steps, enabling robust and reproducible performance
• Built on the Chip-R1™ Rigid Chip, which minimizes drug absorption to support reliable BBB transport studies
  

The Brain-Chip R1 is an isogenic, human-relevant Organ-Chip model designed to recapitulate the cellular diversity and functional interactions of the neurovascular unit (NVU). This model integrates five human iPSC-derived cell types—neurons, astrocytes, microglia, pericytes, and Emulate’s proprietary brain microvascular endothelial cells (BMECs)—within the dynamic, perfused microenvironment of the Chip-R1™ Rigid Chip.

Organ Model: Brain

Applications: Neuroscience

Highlights

This work covers several key components of establishing a functional brain-on-a-chip model to create a controlled environment that simulates the brain’s extracellular matrix and vasculature. These include incorporating various cell types, such as astrocytes, endothelial cells, pericytes, and immune cells, as well as the use of human-induced pluripotent stem cells (iPSCs) to derive these cell types, procedures to establish a functional multicultural system to study cell–cell interactions within the neurovascular unit, and methods to evaluate the model’s functionality through imaging techniques and biochemical assays.

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Organ Model: Spinal cord (ALS)

Application: Neurodegeneration

Highlights

In this study, researchers used Organ-Chips—specifically spinal cord chips (SC-chips)—to model young-onset, sporadic ALS by combining patient-derived iPSC motor neurons with brain endothelial-like cells. The microfluidic flow in the SC-chips enhanced motor neuron maturation and health, enabling the emergence of distinct neuronal subpopulations. Analyses revealed ALS-specific disruptions in glutamatergic and synaptic signaling, supporting the model’s relevance for studying disease mechanisms and its potential for future drug screening.

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Organ Model: Brain (Blood-Brain Barrier)

Application: ADME, Cancer

Highlights

• The authors created a human BBB-Chip by culturing iPSC-derived brain microvascular endothelial cells opposite neural cells under microfluidic flow, thereby modeling the key structural and functional features of the human blood–brain barrier.
• They validated the chip’s barrier integrity using fluorescent dextran leakage assays, and confirmed the expression of tight junction markers (such as claudin-5 and occludin) in the endothelial layer.
• By flowing their engineered nanobioparticles (NBPs) through the endothelial channel and collecting effluent from the neuronal side, they demonstrated receptor-mediated transcytosis across the BBB compartment in a way that closely mimics human physiology.
• Through targeted blocking experiments and siRNA knockdown of HER3, they showed that NBP passage across the in vitro BBB depends on HER3 interactions and caveolae-associated pathways, offering mechanistic insights that can guide future brain-targeted drug delivery strategies.

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Organ Model: Brain (BBB)

Application: ADME, Inflammation

How Organ-Chips Were Used: The limited translatability of preclinical experimental findings to patients remains an obstacle for successful treatment of brain diseases. Relevant models to elucidate mechanisms behind brain pathogenesis, including cell-specific contributions and cell-cell interactions, and support successful targeting and prediction of drug responses in humans are urgently needed, given the species differences in brain and blood-brain barrier (BBB) functions. Human microphysiological systems (MPS), such as Organ-Chips, are emerging as a promising approach to address these challenges. Here, the authors examined and advanced a Brain-Chip that recapitulates aspects of the human cortical parenchyma and the BBB in one model. 

Methods: The authors utilized human primary astrocytes and pericytes, human induced pluripotent stem cell (hiPSC)-derived cortical neurons, and hiPSC-derived brain microvascular endothelial-like cells and included for the first time on-chip hiPSC-derived microglia. 

Results: Using Tumor necrosis factor alpha (TNFα) to emulate neuroinflammation, the authors demonstrate that this model recapitulates in vivo-relevant responses. Importantly, they show microglia-derived responses, highlighting the Brain-Chip’s sensitivity to capture cell-specific contributions in human disease-associated pathology. They then tested BBB crossing of human transferrin receptor antibodies and conjugated adeno-associated viruses. They demonstrate successful in vitro/in vivo correlation in identifying crossing differences, underscoring the model’s capacity as a screening platform for BBB crossing therapeutic strategies and ability to predict in vivo responses. 

Conclusions: These findings highlight the potential of the Brain-Chip as a reliable and time-efficient model to support therapeutic development and provide mechanistic insights into brain diseases, adding to the growing evidence supporting the value of MPS in translational research and drug discovery.

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Organ Model: Brain (Blood Brain Barrier)

Application: Neuroscience, ADME

Abstract: The blood-brain-barrier (BBB) is made up of blood vessels whose permeability enables the passage of some compounds. A predictive model of BBB permeability is important in the early stages of drug development. The predicted BBB permeabilities of drugs have been confirmed using a variety of in vitro methods to reduce the quantities of drug candidates needed in preclinical and clinical trials. Most prior studies have relied on animal or cell-culture models, which do not fully recapitulate the human BBB. The development of microfluidic models of human-derived BBB cells could address this issue. We analyzed a model for predicting BBB permeability using the Emulate BBB-on-a-chip machine. Ten compounds were evaluated, and their permeabilities were estimated. Our study demonstrated that the permeability trends of ten compounds in our microfluidic-based system resembled those observed in previous animal and cell-based experiments. Furthermore, we established a general correlation between the partition coefficient (𝐾𝑝) and the apparent permeability (𝑃𝑎𝑝𝑝). In conclusion, we introduced a new paradigm for predicting BBB permeability using microfluidic-based systems.

Organ Model: Brain

Application: Neuroscience

Abstract: While cells in the human body function in an environment where the blood supply constantly delivers nutrients and removes waste, cells in conventional tissue culture well platforms are grown with a static pool of media above them and often lack maturity, limiting their utility to study cell biology in health and disease. In contrast, organ-chip microfluidic systems allow the growth of cells under constant flow, more akin to the in vivo situation. Here, we differentiated human induced pluripotent stem cells into dopamine neurons and assessed cellular properties in conventional multi-well cultures and organ-chips. We show that organ-chip cultures, compared to multi-well cultures, provide an overall greater proportion and homogeneity of dopaminergic neurons as well as increased levels of maturation markers. These organ-chips are an ideal platform to study mature dopamine neurons to better understand their biology in health and ultimately in neurological disorders.

INTRODUCTION

• Delivery of genomic medicine to the central nervous system (CNS) is a major hurdle for clinical applications of gene therapy; the blood–brain barrier (BBB) limits the brain distribution of virtually all intravenously administered macromolecules.
• Several adeno-associated virus (AAV) serotypes, most notably AAV9, distribute to the brain after intravenous (IV) administration but require high doses to achieve limited expression.
• AAV capsid engineering has produced novel variants that are superior to their parental serotypes and have progressed into the clinic for several indications. However, translation of clinical programs from preclinical models to humans remains a challenge for the entire gene therapy field, including capsid engineering efforts.
  • Two factors for a stringent selection campaign have emerged: library designs that incorporate functional cellular transduction pressure, and selection of appropriate in vitro and/or in vivo models.
• In this study, we employed SIFTER™ (Selecting In vivo For Transduction and Expression of RNA) to engineer capsids with improved CNS transduction following IV administration in Cynomolgus macaque (non-human primates [NHPs]). This was followed by implementation of an all human cell model of the BBB that recapitulates many key BBB properties to address discordant capsid performance observed in vitro vs in vivo and between species.