A new bioengineered neuronal circuit board "BioConNet" allows scientists to artificially engineer human brain-like wiring at scale and can be used to engineer any possible circuit.
The fully programmable, open-source, system allows generation of large-scale circuits, while maintaining the ability to focus on single connections between neurons.
This is a key advance in engineering human-like neural circuits as it allows for a new level of wiring complexity compared to previous systems. BioConNet allows scientists increased control over wiring in the culture compared to existing methods such as organoids and commercially available systems.
By combining engineering and neurobiology with the most recent stem cell culture techniques we can now create human specific, functional large scale complex neural circuits in the lab.
Senior author, Dr Andrea Serio, Reader in Neural Tissue Engineering, Group Leader at the UK Dementia Research Institute (UK DRI) at King's and Senior Group Leader at the Crick
"We can tailor these circuits for individual experiments and to understand specific diseases. This will let us understand both the mechanisms behind cell death in neurodegenerative diseases and test new potential therapies," added Dr Serio.
Growing biological neural networks
Researchers at the Institute of Psychiatry, Psychology and Neuroscience, combined microfluidic technology, a technique whereby tiny volumes of fluid are manipulated around a cell culture dish, and 3D printed moulds to cast a bio-compatible polymer into shapes perfect for directing developing neurons to specific locations.
One key difference between BioConNet and other platforms is that this is an open system, meaning there are no channels or physical barriers from the top to confine or hold neurons in place. Using the polymer device, we guide neurons into specific locations and let them self-organise.
Pacharaporn Suklai, the first author of the study.
The polymer devices had a funnel-like shape to direct the neurons and microgrooves to anchor them in place. Once the neurons had finished developing, the moulds were removed to assess the stability of the biological structure.
It was important for the researchers to find the precise conditions that the circuits flourished in. They experimented with leaving the moulds in place for lengths of time before removal
"We worked out how to keep them as a single stable unit for a circuit, which only happens when the cells number and timing are just right. Otherwise, the neurons formed multiple separate clusters and failed to consistently connect," explained Dr Suklai.
Creating brain-like conditions
The researchers wanted to create a circuit that was similar to the human cerebral cortex, the part of the brain that accounts for over 80% of its mass. However, encouraging the engineered neural networks to have the exact characteristics of human cortical circuits, requires very specific conditions. Size and shape of the devices as well as cell number emerged as key factors for creating conditions similar to the human cortex.
The cortex is not just made of neurons: there are 10 times more support cells (called glial cells) than neurons in the human cerebral cortex. These support cells structure the tissue, providing a scaffold for the neural networks.
To support the engineered neural networks, the researchers included glial cells in the culture dishes. By including glial cells, researchers achieved structure closer to real brain tissue and prevented neurons from detaching from the dish. These glial cells also changed the electrical properties of the neural networks they supported.
A test bed for disease-related genes
The new technology, BioConNet, can also be easily genetically programmed and analysed. This means that it can be used to investigate the effects of disease-implicated genes on the neural circuits. Ultimately, it is the neural circuit that governs how brains process information. Therefore, understanding how genes impact circuit function will lead to greater understanding of brain-related diseases and could help develop therapeutic targets. Future work will focus on the circuit effects of genes related to neurodegenerative conditions such as Frontotemporal Dementia and Amyotrophic Lateral Sclerosis.
Pioneering open-source science
The blueprint for the new technology is fully available to other researchers and the public. The pipeline has been published online in PLOS biology and GitHub, meaning anyone can see how the networks were engineered and use this to make similar networks of their own.
It is important for us that the platform we develop have the maximum possible impact. That's why all the materials and design are provided as open-source, and fully reproducible.
Dr Andrea Serio
This work was partly carried out at the Francis Crick Institute where Dr Serio is a Senior Group Leader.
This research was funded by the UK Dementia Research Institute. Dr Suklai was supported by the Thai Ministry of Science.
Engineering Cortical Networks: An Open Platform for Controlled Human Circuit Formation and Synaptic Analysis In Vitro (Suklai et al.) (https://doi.org/10.1002/adhm.202500857) was published in Advanced Healthcare Materials.
