Researchers led by University of Illinois Urbana-Champaign chemical and biomolecular engineering professor Hyunjoon Kong and chemistry professor Hee Sun Han, and performed by Ryan Miller, currently a post-doctoral fellow at Georgia Tech, have unveiled a breakthrough technology that could transform the way scientists build and study lab-grown brain tissue models. The innovation, called Cellular RedOx Spreading Shield (CROSS), delivers long-lasting antioxidant protection to stem cells, enabling the reliable production of high-quality extracellular vesicles (EVs) that strengthen neuron-glia networks. Jonghwi Lee, in the chemical engineering department at Chung-Ang University in South Korea, and Young Jun Kim at the Korean Institute of Science and Technology–Europe, collaborated on the project.
Why It Matters:
Stem cell-derived neuron-glia tissue models are advanced alternatives to traditional research methods, like ex vivo brain slices or animal testing, offering scalable systems to study brain development and disease, as well as to further biocomputing processes. Yet, current models often suffer from weak neural connections and immature cell networks. EVs, tiny particles produced by adipose-derived stem cells that carry biological molecules to communicate with other cells can help overcome these limitations, but producing them consistently at scale has been challenging, in large part due to oxidative stress and the propagation of aging cells within bioreactors. Conventional antioxidants can help, but they degrade quickly, limiting their effectiveness in biomanufacturing processes.
CROSS uses a highly efficient and scalable droplet microfluidic-based method for producing antioxidant crystal-loaded microgels which, when administered as a single dose, maintains antioxidant activity for up to seven days in stem cell cultures. Using N-acetylcysteine (NAC) as a model antioxidant, researchers demonstrated that CROSS preserves stem cell health, stabilizes EV production and prevents the spread of oxidative damage. The resulting EVs, enriched with neurogenic microRNA cargo, promoted structural and functional connectivity among neurons in the in vitro-assembled neural-glia tissue model.
Key Findings:
- Efficient creation of liquid microdroplets containing NAC crystals with shear flow and converting them into microgels creates CROSS with a diffusion barrier that prolongs antioxidant release, maintaining efficacy for over a week.
- CROSS suppressed the spread of cell aging in a bioreactor, such that CROSS-treated stem cells produced EVs similar to those from healthy cells never exposed to oxidative stress.
- When applied to neuron-glia tissue systems, these EVs promoted electrophysiologically functional in vitro neural tissue assembly, an important tool for studying neural development, homeostasis, diseases and biocomputing.
- Potential applications include neural tissue regeneration and biohybrid technologies.
- CROSS offers an alternative to animal testing and provides a practical solution for large-scale therapeutic EV production.
The Bottom Line:
"Our new microfluidic process provides a simple and versatile method for creating improved drug delivery carriers that can be tailored for various biological products. The small CROSS materials developed in this study could also help make the production of cell-based therapies more efficient, support the building of lab-grown tissues, and ultimately contribute to new treatment options for a range of diseases." – Hyunjoon Kong
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