Researchers have built and tested structured human brain tissue, offering new tools to study how the brain develops and responds to injury.
Brain damage, whether caused by trauma, stroke or disease, can have life-changing consequences, affecting memory, movement and communication. Yet despite decades of research, effective treatments for severe brain injury remain out of reach.
At the same time, scientists face a different but related problem. The human brain is extraordinarily complex, and there are still limited ways to study how its cells develop, connect and respond to damage.
Against this backdrop, the Oxford Martin Programme on 3D Printing for Brain Repair (2020–2025) set out to explore a bold question: can structured brain tissue be built from human cells and used to better understand how the brain works and how it might be repaired?
Building brain tissue in three dimensions
Researchers set out to recreate key features of the cerebral cortex. This layered outer region of the brain has a uniform laminar structure with some regional variation that underpins functions such as perception, cognition and voluntary movement, but its structure has been difficult to model in the laboratory.
Over five years, the team developed ways to turn human stem cells into distinct types of brain cells and organise them into layered structures using 3D printing and microfluidics. In the lab, these engineered tissues maintained their structure and showed early organisation, with cells extending processes across layers and, in some cases, migrating across the layer boundary.
Figure 1: Overview of the project. Patterned 3D printing of droplets containing deep-layer neural progenitors (DNPs) or upper-layer neural progenitors (UNPs) derived from human induced pluripotent stem cells (hiPSCs) and extracellular matrix (ECM). The printed cerebral cortical tissues were cultured in vitro for functional studies and implanted into the mouse brain for studies of brain repair.
Testing how engineered tissue behaves
The next step was to test what happens when these tissues are placed in physiological environments.
Experiments using ex vivo mouse brain tissue as host showed encouraging signs of integration. Implanted cells in the 3D printed constructs were able to move into surrounding areas, extend processes into nearby tissue and show signalling activity consistent with interaction with the host brain (https://doi.org/10.1101/2022.10.28.513987). When subsequently the team implanted bilaminar constructs that contained upper- and lower-layer human neurons into young mouse brains, the neurons developed connections to different specific targets and imaging and recording demonstrated the functional interactions between graft and host,
Further refinement came from introducing astrocytes, support cells known to play a critical role in brain development and repair. Including these cells improved survival and maturation and strengthened connections, including astrocyte coupling to blood vessels. In models of traumatic brain injury, these combined constructs were associated with reduced lesion size (https://doi.org/10.1038/s41467-023-41356-w).
A foundation for future work
Although the programme has now formally concluded, it has left behind methods and insights that will shape future work in this field.
With greater control over cell types, structure and environment, researchers are now better equipped to explore how human brain tissue forms and responds to damage. In time, these approaches could support work on conditions ranging from traumatic brain injury to neurodegenerative disease, as well as deepen understanding of how the human brain develops.
Over five years, the programme has shown how combining stem cell biology, engineering and neuroscience can open up new ways of studying one of the most complex challenges in neuroscience, and lay important groundwork for future research.