3D Neural Spheroid Model

The development of 3D brain cultures has had a transformative impact on the field of predictive biology, and is the foundation for much of the research at the Hoffman-Kim Lab. Using rodent neural cells or human stem cells, researchers can create ‘mini-brains’ in a high-throughput manner. These mini-brains more accurately represent features of in vivo neuronal tissue, while allowing us to maintain control over the system’s environment. 

These features – reproducibility, control, and comparatively high fidelity – make 3D culture systems a very attractive target for drug development, toxicity screening, and in vitro disease and injury modeling. Additionally, one of the things that makes the brain so interesting is that the activity within the neurons is just as important as the morphology. Our work aims to use neuronal microtissues to model network behavior, and to see how those networks are changed in pathological states. 

Under normal conditions, neurons form networks in a predictable manner. They first create connections, and display highly synchronized activity, which then become more complex as the network develops. We are starting to look at what happens to these networks when we subject the mini-brains to pathological conditions, such as traumatic injury or ischemic stroke, or when we change the composition of those networks by changing the concentrations of certain cell types. The goal of these studies is to offer new avenues of investigation into complex neurological phenomena.

Traumatic Brain Injury

• We are working to develop an in vitro traumatic brain injury platform to study the effects of compressive forces on neuronal damage and inflammation-induced injury in 3D neural microtissues.
• The goal of this work is to identify injury thresholds at early time points post-traumatic injury (0-24 hours) at which neural microtissues experience injury from multiple injury models.
• The significance of the overall work is to define injury thresholds and predict injury severity in a temporal fashion which could be useful to study both the progression of tissue damage or therapeutic interventions.
• Additionally, these injury probabilities can also be used to inform design decisions in the development of protective head gear that more effectively mitigates traumatic brain injury.
• This work is being conducted in collaboration with Prof. Christian Franck at University of Madison Wisconsin and the Physics-based Neutralization of Threats to Human Tissues and Organs (PANTHER) Research Group

Toxicology

• There is a high demand for in vitro models of the central nervous system (CNS) to study neurological disorders, injuries, toxicity, and drug efficacy. 
• The behavior of 3D-cultured cells is a more accurate model of in vivo cellular responses, especially in the brain, when compared to 2D-cultures. 
• These models can replicate complex cell–cell interactions and physiological functions, giving them the potential to decrease drug failure, improve treatments, and predict toxicity response. 
• For example, our lab works with domoic acid, a harmful neurotoxin that targets the CNS. Exposure to domoic acid, which can be found in shellfish and other seafood, has been linked to Autism Spectrum Disorder. Our goal is to develop human neural microtissues and to aid in the investigation of human response to this toxin and others.

Ischemia

• Stroke is one of the leading causes of death and disability worldwide, the most common form of which is ischemic stroke, caused by a blockage of blood flow to a specific part of the brain. 
• Treatments for ischemic stroke include clot removal and prevention of clot reformation, but there is a lack of pharmaceuticals to prevent secondary injury from occurring and/or promote regeneration. 
• Currently we are developing an in vitro model of ischemic stroke using our rodent 3D neural microtissues. We are exploring the effects of oxygen and glucose deprivation on cell viability, morphology, and function with hopes to discover potential treatment targets for this devastating injury.