Brain-on-a-Chip Model Constructed from Cryopreserved Human Brain Microvasculature Facilitates Brain Disease Research and Drug Testing
Release time:
2026-01-26
Within the human brain lies an extraordinarily complex and intricate network of blood vessels. It is responsible not only for delivering oxygen and nutrients but also, through a natural defense barrier called the blood-brain barrier (BBB), strictly regulates the exchange of substances between blood and brain tissue. This structure plays an irreplaceable role in maintaining normal brain function and defending against harmful substances. However, due to the complex structure and unique functions of human cerebral vasculature, scientists have long struggled to replicate its physiological properties in vitro, significantly hindering progress in brain disease research and drug development.
Recently, a research team from Vanderbilt University in the United States achieved a key breakthrough in this field. They successfully developed a human cerebral vascular chip model based on microfluidic technology. Using an enzyme-free isolation method, they extracted microvessels from cryopreserved post-mortem human brain tissue and cultured them within a biomimetic gelatin-based hydrogel. This model can highly replicate the anatomical structure and physiological function of human cerebral blood vessels, including a complete and selectively permeable blood-brain barrier. The research findings have been published in the authoritative international journal Advanced Healthcare Materials.
Original article link: https://doi.org/10.1002/adhm.202504167
Challenge: Why is Human Cerebral Vasculature So Difficult to Model?
Blood vessels in the human brain exhibit diverse morphologies, ranging from large arteries to dense capillary networks. They also need to establish functional interactions with brain cells to form the blood-brain barrier—a defensive line composed of special tight junctions that only allows specific molecules to pass, protecting the brain from toxins and pathogens. Previous attempts to reconstruct such structures in vitro often struggled to balance structural authenticity with functional integrity, particularly achieving limited success in simulating the selective permeability of the BBB.
Breakthrough: "Reviving" Blood Vessels on a Chip
To address these challenges, the research team adopted an innovative strategy: gently extracting native microvessel fragments from cryopreserved post-mortem human brain tissue using an enzyme-free isolation method and embedding them into a biomimetic gelatin-based hydrogel to create a three-dimensional microenvironment. Subsequently, the researchers placed these vascularized hydrogels into a specially designed microfluidic chip. A custom perfusion system provided a dynamic fluidic environment simulating human arterial pulsations, thereby enabling long-term survival, growth, and functional expression of the vessels.
A major highlight of this method is its "native" quality. The enzyme-free processing avoids damaging the vascular structure, allowing the extracted microvessels to retain their original cellular composition (including arteries and capillaries) and spatial organization. This means the "vascular map" on the chip nearly replicates the real structure found in the human brain.
"Living" Validation on a Chip: Dual Simulation of Structure and Function
Through a series of experiments, the research team confirmed that this chip model not only presents a complex three-dimensional vascular network but also exhibits highly realistic physiological functions:
At the structural level, immunofluorescence staining revealed that the vessels within the chip formed distinct concentric arterial structures, a capillary mesh distribution, and surrounding astrocyte end-feet, highly consistent with observations in real human brain tissue.
At the functional level, by simulating a classic blood-brain barrier test—observing whether fluorescent molecules (Texas Red-labeled dextran) of a certain molecular weight could penetrate the vessels—the results showed that capillaries on the chip effectively prevented dye leakage. Their permeability was comparable to real levels in the human body, indicating the model possesses a highly selective barrier function.
Furthermore, the accompanying pulsatile perfusion system can simulate human arterial blood pressure waveforms, providing near-physiological mechanical stimulation to the vessels. This helps maintain their physiological activity and responsiveness, supporting long-term observation and intervention experiments on the model for several weeks.
Significance and Prospects: Opening New Avenues for Brain Science and Neurological Disease Research
This research advances the intersection of bioengineering and neuroscience. The constructed "human cerebral vascular chip" represents the first comprehensive simulation of the human cerebral vascular system from structure to function. It provides an unprecedented in vitro platform for exploring cerebral blood flow regulation, BBB mechanisms, and brain diseases closely related to vasculature, such as neuroinflammation, Alzheimer's disease, and stroke.
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