Northwestern University and Shirley Ryan Ability Lab Scientists have developed a new technique that allows them to eavesdrop on the hidden electrical conversations that take place inside tiny lab-grown tissues resembling human brains.
These millimeter-sized structures, known as human neural organoids and also referred to as “mini-brains,” are powerful models of brain development and disease. But until now, scientists have only been able to record and stimulate the activity of a small portion of neurons. In other words, they lacked the coordinated rhythms, information processing, and overall network dynamics that generate the complex patterns of activity that define brain function.
For the first time, new technology overcomes its stubborn limitations. A soft three-dimensional (3D) electronic framework encases the organoid like a breathable high-tech mesh. Rather than sampling selected areas, hundreds of miniature electrodes provide near-perfect conformal coverage. This dense three-dimensional interface allows scientists to map and manipulate neural activity throughout nearly the entire organoid.
By moving from local studies to mapping true entire networks, this study brings organoid research closer to capturing how the real human brain develops, functions, and even malfunctions.
of research has been published Diary of February 18th natural biomedical engineering.
“Human stem cell-derived organoids have become a major focus of biomedical research because they enable patient-specific studies of how tissues respond to drugs and new treatments,” said the Northwestern bioelectronics pioneer. John A. Rogersled device development. “Laboratories in academia and industry have been developing these tissue constructs for years, and the National Institutes of Health (NIH) has begun funding to accelerate research in this direction. A critical missing element is hardware technology that can interrogate, stimulate, and manipulate these tiny analogs of human organs.”
“This progress is really about building the right tools for new kinds of biological models,” he said. Colin FranzThe person who led the development of organoids. “Human neural organoids are living 3D tissues containing active neural circuits that communicate via electrical signals. However, the state-of-the-art equipment we use to study them was originally designed for flat layers of cells and does not connect well with spherical and three-dimensional organoids. By creating shape-matched soft electronics that fit the Luganoid’s geometry, we can now record and stimulate from hundreds of locations on its surface at once. This allows us to study neural activity at the level of whole networks rather than isolated signals. ”
Rogers is the Louis Simpson and Kimberly Querrey Professor of Materials Science and Engineering, Biomedical Engineering, and Neurosurgery at Northwestern University and holds appointments in Northwestern Engineering and Engineering. Northwestern University Feinberg School of Medicine. he also Query Simpson Bioelectronics Institute Query Simpson Research Institute, Institute for Translational Engineering for Advanced Health Systems. An expert in regenerative neuroscience, Franz is a physician-scientist in the Shirley Ryan Ability Lab and an associate professor and attending physician in physical medicine and rehabilitation, medicine (pulmonary and critical care), and neurology at Feinberg. Rogers and Franz co-led the study with Yihui Zhang of Tsinghua University in China and John Finan of the University of Illinois at Chicago.
From fragments to full networks
Over the past decade, scientists have moved from flat dishes of neurons to self-assembling 3D mini-brains grown from human stem cells. These organoids can develop interconnected neural circuits and generate synchronized electrical rhythms reminiscent of early brain development.
“3D human-derived tissue models, such as organoids, are beginning to change the way we study diseases and develop treatments,” Franz said. “They also have the potential to reduce reliance on animal models.”
But even though these organoids form complex neural networks, researchers can only hear snippets of their electrical conversations. Because they are flat and rigid, existing recording techniques cannot adapt to the brain’s natural curves and wrinkles. By sampling activity from just a handful of sites on an organoid, researchers risk missing coordinated activity that appears throughout the structure.
“Integrated circuits in consumer electronics are completely planar and sit on wafer-based substrates,” Rogers said. “That traditional layout represents a very significant geometric mismatch compared to the spherical shape of these organoids.”
Bioelectronics “pop-up book”
To overcome this limitation, the Northwestern University team designed a soft, porous scaffold that begins as a flat, rubbery lattice and then transforms into a precisely engineered 3D shape. Controlled mechanical buckling facilitates deformation. This is the same mechanism that transforms flat paper into a 3D structure in a “pop-up” book. This framework gently hugs the organoid to its curvature. The mesh-like holes allow oxygen and nutrients to flow into the organoids, and carbon dioxide and waste products to flow out.
“To maintain tissue viability, the device structure must support these metabolic processes,” Rogers says. “Basically, the organoids need to breathe. The hardware must not significantly constrain or suffocate the organoids.”
One version of the device covered 91 percent of the organoid surface and incorporated 240 individually addressable microelectrodes. Organoids are often just 1 millimeter in diameter, so engineers had to maximize the size of the electrodes. They developed extremely miniaturized electrodes that are just 10 microns in diameter, or about the same size as an individual cell.
When the team tested systems with only eight or 32 electrodes, limited localized signals were captured. The research team used a complete 240-channel array to record synchronous oscillatory waves throughout the organoid. Because researchers know the exact location of each electrode, they can create a 3D map of the organoid’s electrical activity.
Formation and research of living nervous systems
In the experiment, the researchers observed how a signal ignited in one area and rippled throughout the network. The technique captured clear signs of coordinated communication within the organoid’s neurons by revealing seconds-long delays between distant regions.
The platform not only maps neural activity in detail, but also turns out to be sensitive to drug effects. The research team tested several compounds and observed clear and predictable changes in how the organoid networks fired. For example, exposure to 4-aminopyridine, a drug used to improve gait in multiple sclerosis patients, increased nerve signaling. But exposure to botulinum toxin, which blocks communication between nerve cells and is used to treat muscle spasms, destroyed coordinated activity. These results demonstrate that bioelectronic interfaces can detect meaningful drug responses in living human neural tissue models, demonstrating their potential as powerful tools for testing therapeutics.
But the system doesn’t just listen, it also talks. It can send tiny electrical pulses to trigger a reaction in a specific area. Combining this system with imaging and optogenetics allows scientists to observe and influence neural activity.
Scientists also discovered that the device could determine how the organoids grow. By changing the design of the microlattice, the team designed non-spherical shapes such as hexagons and cubes. Within these frameworks, organoids grew into matching shapes.
“With this ability, you can imagine assembling different types of organoids to create miniature versions of the human body,” Rogers says. “Using cubic-shaped organoids, you can stack them like Lego blocks.”
With this ability, you can imagine assembling different types of organoids to create miniature versions of the human body. Cube-shaped organoids can be stacked like Lego blocks.
what’s next
With further research, organoids could play a powerful role in future medicine. Because organoids are grown from human stem cells (even a patient’s own cells), they offer a way to model diseases and test treatments in living 3D neural networks. Researchers can also use them to study how brain disorders develop, assess drug responses, and assess whether experimental regeneration strategies can restore lost coordinated brain activity.
Using tools that map activity almost throughout organoids, scientists can assess whether potential regenerative treatments truly reshape functional circuits. This is an important step in developing effective treatments for brain disorders.
“As organoids become an increasingly high priority for NIH efforts and industry drug development efforts, technologies like this will be essential to turning these sophisticated tissue models into practical platforms for understanding disease, testing treatments, and advancing clinical neuroscience,” Franz said.
The study, “A shape-conforming porous framework for complete coverage of neural organoids and high-resolution electrophysiology,” was supported by the Query Simpson Institute for Bioelectronics, the National Institutes of Health, the National Science Foundation, the Bell Kernel Regenerative Neurorehabilitation Fund, the New Cornerstone Science Foundation, and a Haythornthwaite Foundation Research Startup Grant.