Traumatoids: Modeling traumatic brain injury with organoids

Traumatic brain injury (TBI) affects millions of people worldwide each year, often leading to long-term neurodegeneration and significantly increasing the risk of dementia in patients. To understand TBI, current research methods heavily rely on animal testing, which not only causes animal suffering but may also fail to accurately represent human brain processes due to key differences between human and animal physiology. This project aims to advance our knowledge of TBI by creating a human-based research model. Using advanced stem cell technology, we will develop three-dimensional "traumatoids". These are lab-grown human brain models that mimic the effects of traumatic brain injuries. This approach will provide a humane and highly relevant alternative to animal models, paving the way for better insights into TBI and more effective treatments. Central to our research questions is exploring the role of the extracellular matrix (ECM), the structural network surrounding cells, in TBI progression. During a TBI, the ECM may become disrupted, and its mechanical integrity changed, affecting cell functions and worsening the injury over time. However, these dynamics remain poorly understood. By studying the ECM in traumatoids, this project will not only validate the fidelity of our model system to recapitulate traumatic events but also help uncover key biological mechanisms behind TBI progression. To achieve this, we will engineer and build a specialized platform that can precisely deliver mechanical injuries to specific areas of the traumatoids. We will observe the dynamics of these local injuries using advanced microscopy techniques before delving into the trauma-responding genes inside individual cells using state-of- the-art sequencing technologies. We will then combine mechanical readings of injury sites with injury dynamics and molecular profiling in a comprehensive "mechano-biological map" of trauma responses. Finally, these findings will be validated using human brain tissue from TBI patients to ensure relevance to real-world conditions. The development of traumatoids not only advances our understanding of brain injuries but also aligns with the 3R principles with a commitment to reducing animal testing. Ultimately, this work holds the potential to transform how we study and treat traumatic brain injuries, benefiting millions of patients worldwide.