Bioelectronics enable precise control of organoids for better understanding of neuro diseases, neuron circuits

Cortical organoids, which are miniature three-dimensional models of brain tissue grown from stem cells, offer scientists a sophisticated and accurate model to better understand how neurons control brain functioning — but researchers are still developing methods to perform precise experiments on these delicate models.

The Rolandi group in collaboration with the Braingeneers have developed a new plug-and-play bioelectronics system that enables researchers to precisely control neuronal activity in cortical organoids, which will help unlock new discoveries on how brains form neural circuits and the underpinnings of neurodevelopmental and degenerative diseases. Beyond just the study of organoids, their system can be adapted for use in a wide range of biological experiments. 

The research team, with Professor of Electrical and Computer Engineering Marco Rolandi, Associate Professor of Electrical and Computer Engineering Mircea Teodorescu, and UCSC Genomics Institute Research Scientist Mohammed Mostajo-Radji as co-senior authors, describe their novel system in a new paper in the journal Cell Reports Methods. Former UCSC postdoc Yunjeong Park and current UCSC Ph.D. student Sebastian Hernandez led the research as co-first authors. 

“This work with brain organoids is an important proof-of-concept, because organoids are becoming the standard for looking at how organs are affected by external stimuli,” Rolandi said.

While organoid models are increasingly popular for the study of brain development, function, and evolution, the methods that currently exist for manipulating the organoids are still fairly unsophisticated, relying on optical methods or rough application of chemicals that do not allow the researchers to precisely control the timing of the manipulations. 

However, the novel methods outlined in this paper enable researchers to use the bioelectronic delivery of ions and neurotransmitters to the models to achieve precise, time-controlled experiments. The system is also easily integrated into existing experiments, as it is simply placed on top of a cell culture plate.

“This paper brings the ability to manipulate highly-relevant models with high temporal precision,” Mostajo-Radi said.

Modulating neuronal activity can help scientists better understand the wide range of human diseases that are known to be associated with hyperactivity in certain areas of the brain – such as Parkinson's disease or epilepsy. Controlling and modulating neuronal activity in brain organoids can help researchers learn more about these conditions and develop better methods of managing and treating them. 

For example, researchers could closely mimic the interaction between drugs and cells that occur in actual treatment by using the highly precise system to see how dose-level amounts of various drugs interact with the cells in an organoid at a defined time. Using tiny amounts of a drug makes the experiments “reversible” in that the organoid can return to its original state, which is especially important when researchers are quickly testing how various drugs interact with organoids grown from the stem cells of a patient.

“Brain cells communicate through both electrical impulses and chemical signals, so using neurons' own "chemical language" could enhance treatment outcomes for specific diseases,” Hernandez said.”This can be achieved by utilizing ion pumps as therapeutic devices.”

Modulating neuronal activity can also help researchers better understand how neural circuits work — the process by which neuron signals propagate and spread throughout the brain. By slowing down, speeding up, or interrupting a signal using the precise manipulation of ions, the researchers can investigate how signals are transmitted. 

“It's like having a dimmer switch for the brain's circuitry, where we can dial up the activity or calm it down,” Park said. “This tool opens up new possibilities for exploring how our brains work and develop, potentially revolutionizing our approach to neurological research and treatment."

The bioelectronic system includes an integrated ion pump that can be placed directly on top of a cell culture plate. This modular system makes it easy for scientists to integrate the system into their experiments. In the past, it has been complicated to integrate these types of bioelectronic devices with cell cultures because a researcher would have to grow their cells directly on the device, adding further complexity to the already difficult task of growing organoids. 

“Instead here, rather than having the biology adapt to the bioelectronics, we’ve adapted the bioelectronics to the biology,” Rolandi said. 

While the researchers focused on the application of their system for organoids in this paper, Rolandi emphasized that the highly modular system can be used in a wide range of biology experiments that would benefit from the precise delivery of ions to a cell plate. 

“The importance of the platform is that it goes beyond organoids,” Rolandi said. “Any type of biological system — whether it's an organoid, a cell culture, or a bacteria culture — chances are it's going to be in a well plate, and our system is plug-and-play, you just put it on top.”