BBB-On-Chip Modeling Service

The blood-brain barrier (BBB) presents a formidable challenge in the development of therapeutics for central nervous system (CNS) disorders. Its highly selective nature restricts the passage of most neurotherapeutics from the bloodstream into the brain. Overcoming this hurdle is paramount for effective treatment strategies. Creative Biolabs offers cutting-edge BBB-on-chip modeling services, providing researchers with advanced, physiologically relevant in vitro systems to accelerate CNS drug discovery and development.

The Challenge: Bridging the Gap in Preclinical CNS Research

Traditional preclinical models for BBB research, such as static Transwell cultures and animal models, have inherent limitations:

• Static In Vitro Models (e.g., Transwell): Often lack the dynamic microenvironment of the human BBB, including crucial mechanical forces like fluid shear stress. This can result in unstable barrier properties, lower expression of key transporters, and limited predictive capacity for drug permeability and efficacy.
• Animal Models: While valuable, animal models exhibit species-specific differences in BBB tightness, transporter expression, and metabolic activity, making direct extrapolation of results to humans unreliable. Furthermore, animal studies are often expensive, time-consuming, and raise ethical concerns. These models also make it difficult to conduct mechanistic studies at the molecular and cellular levels in real-time.

The Solution: Next-Generation BBB-on-Chip Technology

Microfluidic organ-on-a-chip technology has emerged as a powerful alternative, enabling the creation of dynamic, human-relevant BBB models. These BBB-on-chip systems recapitulate key structural and functional aspects of the native human BBB, offering significant advantages for preclinical research.

Creative Biolabs' BBB-on-Chip Modeling Service: Features and Capabilities

At Creative Biolabs, we leverage state-of-the-art microfluidic platforms to construct robust and predictive human BBB models. Our service is built upon technology that integrates sophisticated chip design with advanced cell culture techniques.

Fig.1 Human Blood-Brain Barrier reconstituted on a microfluidic Organ Chip, showing distinct vascular and parenchymal channels with co-cultured iPS-BMVECs, astrocytes, and pericytes.¹

Key Platform Features:

• Physiological Microenvironment: Our chips feature multi-layered architectures, often comprising vascular and perivascular compartments separated by a porous membrane, allowing for direct cell-cell interactions and the establishment of relevant gradients.
• Human Cell-Based Models: We utilize a variety of human cell sources, including primary human brain microvascular endothelial cells (HBMECs), astrocytes, pericytes, and induced pluripotent stem cell (iPSC)-derived cells, to construct biomimetic barriers.
• Dynamic Culture with Perfusion: Models are cultured under continuous, gravity-driven or precisely controlled perfusion, mimicking physiological shear stress. This is crucial for promoting endothelial cell differentiation, barrier tightness, and functional transporter expression.
• Extracellular Matrix (ECM) Integration: Vessels are often grown against or within physiologically relevant ECM gels (e.g., collagen-I, Matrigel) to mimic the in vivo basement membrane structure better.
• Real-Time Barrier Integrity Monitoring: We incorporate non-invasive transendothelial electrical resistance (TEER) measurements to assess barrier function in real-time quantitatively.
• Quantitative Permeability Assessment: Apparent permeability of fluorescent tracers and test compounds is measured to evaluate barrier tightness and drug transport kinetics. Our systems demonstrate size-dependent molecular transport with apparent permeability values comparable to in vivo measurements.
• High-Throughput Capabilities: Many of our platforms are designed for parallel culture of multiple chips, enabling higher throughput for screening and complex study designs.

Advantages of Our BBB-on-Chip Models:

• Enhanced Barrier Function: Dynamic culture on-chip significantly improves barrier properties, including higher TEER values and lower passive permeability compared to static Transwell models. We observe robust expression of tight junction proteins (e.g., ZO-1, Occludin, Claudin-5) and adherens junction proteins (e.g., VE-cadherin, PECAM-1).
• Functional Efflux Transporters: Our models exhibit physiologically relevant activity of ABC transporters (e.g., P-gp, BCRP, MRPs), crucial for predicting drug efflux and brain penetration. This allows for accurate assessment of transporter-mediated drug interactions.
• Reversible Barrier Modulation: We can model the transient opening of the BBB using hyperosmolar agents like mannitol, followed by barrier recovery, mimicking clinical strategies for enhanced drug delivery.
• Neuroinflammation Modeling: Our BBB-on-chips can simulate neuroinflammatory conditions through exposure to pro-inflammatory cytokines (e.g., TNFα, IL−1β). This induces measurable barrier disruption (decreased TEER, increased permeability), aberrant cell morphology, and increased expression of cell adhesion molecules (CAMs) like ICAM-1 and VCAM-1, which correlates with increased monocyte adhesion.
• Immune Cell Transmigration Studies: We facilitate the study of leukocyte (e.g., T cell, monocyte) adhesion, extravasation, and migration across the inflamed BBB in response to chemokine gradients (e.g., CXCL12). This includes testing the efficacy of therapeutic antibodies like Natalizumab in blocking T cell adhesion and migration.
• Predictive Drug Permeability and Efficacy: The permeability of model drugs on our chips shows a strong correlation with in vivo human data (B/P ratio). We also support co-culture models, for instance, interfacing the BBB with 3D tumor spheroids to simultaneously evaluate BBB penetration and anti-cancer drug efficacy.
• Nanoparticle and Biologics Transport: Our platforms are suitable for investigating the transport mechanisms of various therapeutic modalities, including nanoparticles and antibodies, across the BBB. This includes receptor-mediated transcytosis studies.
• Advanced Astrocytic Components: We can incorporate 3D astrocytic networks that exhibit more in vivo-like ramified morphology, polarized aquaporin-4 (AQP4) expression at end-feet, and reduced reactive gliosis markers (e.g., LCN2, VIM) compared to 2D cultures. These models can also be used to study astrocytic responses to inflammatory stimuli.

Applications of Our BBB-on-Chip Services:

• Screening and selection of CNS drug candidates based on BBB permeability.
• Mechanistic studies of drug transport (passive diffusion, active transport, efflux).
• Evaluation of strategies to enhance drug delivery to the brain.
• Neurotoxicity assessment.
• Modeling neurological diseases involving BBB dysfunction (e.g., multiple sclerosis, stroke, Alzheimer's disease).
• Investigating the role of neuroinflammation in BBB integrity and immune cell trafficking.
• Testing the efficacy of anti-inflammatory and barrier-restoring therapies.
• Understanding nanoparticle and antibody transport mechanisms for targeted CNS delivery.

Our Workflow

Contact us today to discuss your project needs and discover how our BBB-on-chip models can empower your research.

Reference

1. Park, Tae-Eun et al. "Hypoxia-enhanced Blood-Brain Barrier Chip recapitulates human barrier function and shuttling of drugs and antibodies." Nature communications vol. 10,1 2621. 13 Jun. 2019, doi:10.1038/s41467-019-10588-0. Distributed under Open Access License CC BY 4.0. The original image was modified.