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Introduction
Neurological and psychiatric disorders such as Alzheimer’s, Parkinson’s, autism, and schizophrenia are increasing globally, creating a growing need for better understanding and treatment. However, studying the human brain remains extremely challenging due to its complexity and limited access to human brain tissue. Brain organoids, 3D tissues developed from human stem cells, serve as a promising model system for studying the brain. They can model aspects of early brain development and allow researchers to study human-specific processes in the lab. Still, current organoids still suffer from multiple limitations. My research aims to make brain organoids more useful as a model, that can help accelerate progress in neuroscience. Here I focus on two main strategies: improving the biological accuracy and complexity of organoids through tissue engineering, and developing new tools to better study and manipulate these tissues. Together, these approaches create advanced models that help us better understand brain development, disease, and potential therapies.
Tissue Engineering
Connect Organoids to Construct Brain-like Circuits
The human brain is made up of numerous specialized regions that are intricately interconnected, forming a highly complex network of networks. This sophisticated architecture is what enables the broad spectrum of cognitive, sensory, and motor functions that we carry out in our daily lives. Brain organoids have shown great potential in replicating many aspects of early brain development. However, they are still limited in size and complexity, typically modeling only simple, local neural circuits. To better emulate the brain’s structural and functional complexity—particularly the long-range connections between different regions—organoids can be connected using microfluidic devices. Individual organoids are placed into separate chambers within a microfluidic device, where they begin to extend axons. These devices can be designed to guide the growth of axons from one organoid toward another. As axons reach the neighboring organoid, they establish reciprocal connections, forming an axon bundle that functionally connects them. This method brings organoid systems closer to mimicking the actual architecture and connectivity of the human brain, opening new avenues for studying inter-regional communication, network dynamics, and neurological disorders.
Cell Patterning through Aggregation and Bioprinting
Understanding and treating neuropsychiatric and developmental disorders remains a major challenge due to the complexity of the human brain. Human brain organoids offer a promising alternative, but their utility is restricted by slow maturation, the absence of key cell types such as endothelial cells, and insufficient control over cell positioning and tissue architecture. These limitations were addressed by introducing genetically engineered stem cells into organoids and directing them to become mature neurons and endothelial cells via transcription factor overexpression. To further enhance structural accuracy and enable precise control over introduced cell types three spatial patterning techniques are employed: (1) sequential cell plating to create layered, core-shell spheroids; (2) 3D bioprinting of compacted cell-based bioinks; and (3) multichannel nozzle extrusion of patterned bioinks. Spatial control is crucial not only for accurately replicating brain structure and function but also for achieving scalable and reproducible tissue production. 3D printing cells supports the biomanufacturing of large-scale, complex human tissues and has significant implications for basic neuroscience, disease modeling, drug screening, and regenerative medicine.
Tool Development
Enhance Electrical Recordings from Organoids
As 3D neural tissues like brain organoids become widely used to model human brain function, there is a growing need for reliable methods to record their electrical activity. High-density microelectrode arrays (HD-MEAs) offer high-resolution data, but their flat surfaces make it difficult to achieve good contact with curved, 3D tissues—limiting the number of neurons that can be recorded. To address this, a simple method was developed using perfluorodecalin (PFD), a biocompatible fluorinated liquid. When applied over the tissue on the HD-MEA, the weight of PFD gently compresses the organoid to improve electrode contact, while also acting as an electrical insulator to amplify neural signal. This significantly enhances signal quality, enabling more robust detection of neural activity. The method is compatible with acute recordings and optical techniques such as optogenetics. It is easy to implement, preserves tissue viability, and provides a practical solution for more accurate functional studies of brain-like tissues in vitro.
Laser Dissection of Nerve Organoids
Studying the molecular mechanism of axons is important for understanding how the nervous system develops and functions, but isolating pure axons from human tissues is challenging. Traditional methods like manual dissection are slow, labor-intensive, and yield limited material. Faster and easier techniques are needed, especially for in vitro models like motor nerve organoids. Here a quick and low-cost method was developed to isolate axons from motor nerve organoids. These organoids were made by growing motor neuron spheroids inside a microfluidic device that guides axon growth into bundles. To collect the axons, a laser-based cutting technique was used. By illuminating a blue laser onto a black mark on the device, heat can be generated that cleanly cuts the axons without harming nearby tissue. This method allows for fast, clean axon isolation and produces high-quality samples suitable for RNA and protein analysis. It offers a practical alternative to manual dissection for studying axon biology in human neural models.
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