Researchers at Korea Advanced Institute of Science and Technology (KAIST) have 3D printed brain-like tissue with a multilayered structure, alongside an integrated system to monitor neural activity in real time.
Led by Professors Je-Kyun Park and Yoonkey Nam from the Department of Bio and Brain Engineering, the team addressed a key challenge in neuroscience: building brain-like structures with materials soft enough to support neuron growth, yet stable enough to retain complex shapes.
Most existing systems rely on high-viscosity bioinks to maintain form during printing, but these often restrict the development of neural networks. Softer, low-viscosity hydrogels better mimic brain tissue mechanics and promote cell activity, but they are notoriously difficult to pattern with precision. Published in the journal Biosensors and Bioelectronics, the research provides a new way to study how structure and function interact in brain tissue.
“This research is a joint development achievement of an integrated platform that can simultaneously reproduce the complex multilayered structure and function of brain tissue,” said Professor Park.
Platform integrating brain-structure-mimicking neural network model construction and functional measurement technology. Image via KAIST.
Stable neural activity in printed tissue
To resolve this, the researchers combined three engineering solutions into a single integrated platform. They first applied capillary pinning, a technique that uses a stainless steel micromesh to keep the dilute hydrogel in place during printing. This allowed them to achieve a resolution of 500 µm or less, approximately six times more precise than conventional methods.
Next, they used a cylindrical alignment tool to ensure that each layer of the printed structure was stacked accurately. This maintained the integrity of the multilayer network and ensured proper alignment with embedded microelectrode arrays. Finally, a dual-mode analysis system was added to monitor neural activity from multiple perspectives, capturing electrical signals from below while recording calcium imaging from above.
Using these techniques, the team created a three-layer structure with a fibrin hydrogel that closely mimics the elasticity of brain tissue. Neurons were seeded in the top and bottom layers, while the middle remained open to allow neural projections to grow through and form synaptic connections.
When stimulated, neurons in both layers responded simultaneously. The introduction of a synaptic blocker reduced the response, confirming that the observed activity was due to active signal transmission across layers.
In addition to structural fidelity and functional analysis, the platform showed a significant improvement in stability. Whereas most systems degrade after about 14 days, the KAIST platform maintained a stable connection with the microelectrode chip for over 27 days. This extended duration enables the study of long-term changes in neural connectivity and behavior.
Manufacturing on Demand
The results offer a practical tool for investigating brain function in vitro and open new possibilities for modeling neurological disorders, testing the effects of neurotoxic substances, and evaluating potential therapeutic compounds.
Integration process of stacked bioprinting technology and microelectrode chip. Image via KAIST.
Novel 3D printing approach for brain research
In recent years, 3D printing has played a growing role in advancing our understanding of brain function and creating in vitro models for studying brain development, disease mechanisms, and drug response.
Last year, University of Wisconsin-Madison (UW Madison) researchers developed a bioprinting method to create functional human brain tissue with active neural networks. Unlike conventional scaffold-based techniques that often hinder cell distribution and interlayer connectivity, their approach printed tissue horizontally using a softer bio-ink and added thrombin as a crosslinking agent to maintain structure.
The resulting tissue enabled neurons to grow, communicate through neurotransmitters, and form connections across layers. The team successfully printed cortical and striatal regions, which interacted in a biologically relevant manner, offering a model for brain development, disease research, and drug testing.
In 2020, Oxford University and The Chinese University of Hong Kong researchers developed a 3D bioprinting technique that used lipid-bilayer-supported droplet networks to precisely pre-pattern human cortical cells into soft ECM-based matrigel. By spatially arranging neural stem cells and astrocytes, the method triggered key developmental processes including neuronal migration, axon outgrowth, and astrogenesis.
Adjustments to droplet size, printing pulse, and viscosity allowed control over tissue architecture without artificial scaffolds. High-density cultures remained viable over time, leading to mature neuron and astrocyte formation. The approach enabled studies of self-organization, cell segregation, and region-specific brain development in soft printed tissues.
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Author: Ada Shaikhnag
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