Brain Injury

Overview

Mild traumatic brain injury (TBI) affects millions of people each year, from car accident victims to soldiers exposed to IED blast waves. These injuries result in a wide range of symptoms, including concussion, hemorrhage, edema, diffuse axonal injury and vasospasm. The mechanisms of mechanotransduction in TBI are currently poorly understood. We are employing a series of in vitro assays, e.g. high speed stretchers, magnetic tweezers, traction force microscopy and a blast wave bioreactor, to mimic intracranial stresses in TBI and measure their cell-level effects. We aim to elucidate the molecular mechanisms of the injury, in order to develop effective therapeutic solutions.

Neuronal Injury:

Primary Investigators: Matthew Hemphill, Borna Dabiri, Josue Goss

In order to study the mechanisms of mechanotransduction following TBI, we developed a high speed stretcher model which mimics the sudden mechanical stimulus associated with injury. We aim to understand how cells respond to a rapid onset of stress or strain and how this response may initiate the pathological cascade which ultimately leads to TBI. We are currently subjecting populations of neurons cultured on flexible silicon elastomer substrates to a rapid onset stimulus delivered by the high speed stretcher. We identify injured neurons in vitro by distinct morphological alterations which are similar to those associated with diffuse axonal injury (DAI) observed following TBI in vivo. We have recently found that certain cell adhesion structures through which forces are delivered to the neuron may influence the onset of injury.

A   B Stretcher_Example_Neurons.jpg
Figure: In vitro model of TBI in a population of neurons

A:   Movie of high speed stretcher
B:   Example of neurons subjected to stretch (red arrows indicate morphology changes consistent with DAI in vivo

In order to further elucidate the cellular mechanisms underlying neuronal injury, we employ a technique called Magnetic Tweezers to deliver a local mechanical stimulus to specific regions of the neuron. This technique consists of using an electromagnet to pull on small magnetic beads which are bound to the neuron. By coating the beads with various compounds, we can control the cellular structures through which forces are delivered to the neuron. We have recently found that when we deliver forces through beads coated with fibronectin (FN), an extracellular matrix protein which has binding sites for specific integrin receptors, the extent of injury is much greater than when beads are coated with a substance that does not specifically bind integrins. These results are consistent with the high speed stretcher experiments and suggest that integrin mediated mechanical injury may be a possible explanation of neuronal injury following TBI.

A   Magnetic_Tweezer_Setup.jpg B
Figure: In vitro model of TBI in a single neuron

A:   Magnetic tweezer experimental setup
B:   Movie of neuron subjected to bead pull (red dot indicates location of bound bead)

Vascular Injury:

Primary Investigators: Patrick Alford, Ph.D; Sam Felton

Vasospasm of the cerebrovasculature can occur following TBI, especially blast-induced TBI, and is a potentially lethal dysfunction. It is characterized by a chronic vascular hypercontraction followed by cell proliferation, matrix remodeling, and arterial occlusion. While the role of chronically elevated luminal pressures is well established in arterial thickening, the response to rapid, acute pressure increases is not. Therefore, we developed a technique to study this response using the high speed stretcher and vascular smooth muscle MTFs (see the Tissue Engineering section for more on MTFs). We found that when an engineered arterial lamellae was subjected to a single rapid stretch, a strain dependent cellular response was initiated which affected the overall tissue function. We measured changes in vascular contractility and linked these with alterations in expression of contractile phenotypic markers, suggesting that a single mechanical injury may facilitate vascular smooth muscle phenotypic switching which could potentially account for the onset of cerebral vasospasm following TBI.

A   Vascular_MTF_Schematic.jpg B
Figure: In vitro model of TBI in the vasculature

A: Engineered arterial lamellae are subjected to a single high speed stretch
B: Time lapse movie of induced vascular construct contraction
Grp_photo_Jan 2014_305W_230H

What's New

Congratulations to John Ferrier for winning the 2017 LG UltraWide Festival October 18th, 2017

The DBG would like to congratulate one of our lab managers, John Ferrier, on winning the 2017 LG UltraWide Festival which was hosted by Linus Tech Tips and Austin Evans!

DBG Nanofibers Merge with Art by Carla Ciuffo August 23rd, 2017

The Disease Biophysics Group would like to congratulate and thank Tennessee based artist Carla Ciuffo in her efforts to integrate our nanofibers into her art exhibit “Cosmic Garden” at Tinney Contemporary, opening this Saturday.

“Tundra,” 2017, polished acrylic with floating museum back frame, 48×48 on display at Tinney Contemporary. (Photo: Photo courtesy of the gallery)

Thank you to our Summer Students! August 16th, 2017

Thank you to all the undergraduate students who spent time working in the lab over the summer. We wish you all the best this school year!

 

Jenny Wang, United States Military Academy at West Point
Daniel Gray, United States Military Academy at West Point
Nikita Pereverzin, United States Military Academy at West Point
Kathryn Dula, United States Military Academy at West Point
Daniel Drennan, Nicholls State University
Michael Ferris, James Madison University
Karla Rivera, Barry University
John Doyle, University of Massachusetts at Lowell
Madeleine Dahl, Salem State University
Nikita Budnik, McGill University
Karaghen Hudson, Harvard University
Sayo Eweje, Harvard University
Michael Peters, Harvard University
Gabriela Berner, Harvard University

Welcome Dr. Ardoña! August 15th, 2017

The DBG would like to extend a warm welcome to our newest postdoctoral fellow, Dr. Herdeline Ardoña. Herdeline recently completed her Ph.D. in Chemistry at Johns Hopkins University,  where she was a part of Prof. Tovar’s lab.  Welcome, Herdeline!

Welcome Dr. Liu! June 23rd, 2017

The DBG would like to extend a warm welcome to our newest postdoctoral fellow, Dr. Qihan Liu. Qihan completed his Ph.D. in Prof. Zhigang Suo’s lab here at Harvard University, where he focused on the mechanics and physics of soft materials.  Welcome, Qihan!