Summary: Researchers have created a brain-on-a-chip using human cells to model how the blood-brain barrier (BBB) fails during systemic inflammation and disease. These microphysiological systems reproduce key aspects of the human BBB and reveal how cytokine storms and blood proteins that leak into the brain can trigger damaging changes in brain cells.
A second complementary study demonstrates that pericytes — small support cells that surround brain microvessels — can repair structural defects in the vessel wall and help restore barrier function. Together, these advances point to new ways to screen neuroprotective drugs and to develop personalized strategies to prevent brain injury during sepsis, major surgery, chemotherapy, and other conditions that provoke intense inflammation.
Key Facts:
- Inflammation Insight: Human BBB-on-a-chip models show that severe cytokine storms can collapse the blood-brain barrier and lead to neuronal injury.
- Pericyte Protection: Pericytes build structural support across damaged basement membranes, enabling endothelial cells to re-establish a tight barrier.
- Personalized Prevention: These chips could be used to screen neuroprotective drugs and to evaluate patient-specific risk before surgery, chemotherapy, or other interventions.
Source: University of Rochester
Background: Teams led by James McGrath, William R. Kenan Jr. Professor of Biomedical Engineering and director of the Translational Center for Barrier Microphysiological Systems (TraCe-bMPS), built and applied human tissue chips to study interactions at tissue interfaces such as the blood-brain barrier. By combining engineering with human-derived cells, the work aims to replace or reduce animal experiments while improving relevance to human disease.
Two recent papers, published in Advanced Science and Materials Today Bio, used these brain-on-a-chip platforms to investigate how the BBB responds to systemic inflammation and how pericytes contribute to barrier stability. The studies clarify mechanisms that may underlie cognitive decline after severe illness and point toward therapeutic strategies to protect the brain.
When inflammation harms the brain
Systemic inflammation from major surgery, infection, or sepsis can trigger a cytokine storm — an overwhelming immune response that affects organs throughout the body, including the brain. Using a fluidic BBB-on-a-chip, the team showed that a sufficiently strong cytokine stimulus disrupts barrier integrity, allowing blood proteins such as fibrinogen to enter the brain compartment and provoke harmful responses in astrocytes and other support cells.
Lead author Kaihua Chen and colleagues found that two stressors — inflammatory cytokines plus leaked blood proteins — act together to induce astrogliosis and other damaging changes. The experiments also demonstrated that physiologic blood flow (shear stress) strengthens barrier resilience: endothelial cells conditioned by shear were less likely to break down under low-dose inflammatory challenges, though very high cytokine levels still caused failure.
McGrath emphasizes the value of integrating more brain components into the chips, including microglia and neurons, to better model how inflammation translates into neuronal injury. The ultimate goal is to use high-density arrays of patient-specific chips to screen neuroprotective candidates and to guide individualized clinical decisions for patients at risk of cytokine-driven brain injury.
A missing key to brain health
The second study focused on pericytes, mural cells that wrap around microvessels and contribute to basement membrane formation and BBB stability. Prior research has associated pericyte loss with neurodegenerative diseases and inflammation, but the precise supportive role of pericytes at structural defects was not fully understood.
By engineering micropores and defects into an ultrathin, nanoporous membrane that mimics the basement membrane, McGrath’s team observed that endothelial cells struggle to form an effective barrier across large discontinuities. When pericytes were added to the basal side, they produced a matrix of structural fibers that filled those gaps, allowing endothelial cells to re-establish tight barrier function.
The experiments showed two important effects: in monoculture, endothelial cells could transmigrate through larger pores, destabilizing the barrier; in co-culture with pericytes, transmigration was reduced and barrier integrity improved. These findings support the idea that therapeutics which preserve or replace pericyte function could prevent BBB breakdown in disease.
Michelle Trempel, lead author on the pericyte study, notes that this model enables direct study of how pericyte loss contributes to chronic neurodegeneration and offers a platform for testing interventions that enhance vascular support.
Key collaborators on the studies included Harris (Handy) Gelbard, Niccolò Terrando, and Britta Engelhardt. The research received support from the National Institutes of Health and a pre-doctoral fellowship from the International Foundation for Ethical Research awarded to Kaihua Chen.
Key Questions Answered:
A: A brain-on-a-chip is a microfluidic device that uses live human cells to recreate structures such as the blood-brain barrier, enabling precise studies of brain injury, inflammation, and drug responses under controlled, physiologically relevant conditions.
A: Severe systemic inflammation weakens the blood-brain barrier so that plasma proteins and inflammatory mediators enter the brain and trigger reactive changes in astrocytes and other cells, which can contribute to neuronal dysfunction.
A: Pericytes provide structural support to the microvasculature and help maintain basement membrane continuity. Reintroducing or protecting pericytes can restore barrier integrity and may prevent degeneration linked to barrier breakdown.
About this neurology and neurotechnology research news
Author: Luke Auburn
Source: University of Rochester
Contact: Luke Auburn – University of Rochester
Image credit: Neuroscience News
Original Research (open access):
“Pericytes repair engineered defects in the basement membrane to restore barrier integrity in an in vitro model of the blood-brain barrier” by James McGrath et al., Materials Today Bio (DOI: 10.1016/j.mtbio.2025.102361).
“Shear Conditioning Promotes Microvascular Endothelial Barrier Resilience in a Human BBB-on-a-Chip Model of Systemic Inflammation Leading to Astrogliosis” by James McGrath et al., Advanced Science (DOI: 10.1002/advs.202508271).
Abstract — Pericytes and basement membrane repair
Pericytes support brain microvascular endothelial cells (BMECs) and contribute to formation and maintenance of the blood-brain barrier. Loss of pericytes is associated with BBB weakening during systemic inflammation and in neurodegenerative diseases. Using iPSC-derived pericyte-like and BMEC-like cells cultured across an ultrathin nanoporous membrane, the researchers engineered micropore defects that disrupted basement membrane laminin and impaired barrier function. Addition of pericytes on the basal side restored laminin continuity, prevented BMEC transmigration through large pores, and stabilized barrier permeability, consistent with a structural role for pericytes in microvascular support.
Abstract — Shear conditioning and BBB resilience
The blood-brain barrier protects the central nervous system during systemic inflammation. This study used a fluidic microphysiological µSiM-BBB platform to test the effects of endothelial shear conditioning (0.5 Pa for 48 hours) on barrier function. Shear conditioning reduced baseline permeability, increased glycocalyx production, and blunted inflammatory responses such as ICAM-1 upregulation and neutrophil transmigration. The conditioned barrier resisted a low-dose inflammatory challenge but was disrupted by a higher-dose cytokine combination. When astrocytes were present as neuroinflammatory sensors, a strong cytokine stimulus combined with fibrinogen triggered astrocyte activation, illustrating how leaked blood proteins amplify neuroinflammatory damage. These results validate the fluidic µSiM-BBB as a platform for studying peripheral inflammation and brain injury and for developing therapeutics that enhance vascular resilience.