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#5 - A device to simulate the impact of brain trauma for explosive blast-induced Traumatic Brain Injury (TBI) and early stage TBI diagnosis
Title: Device for Simulating Explosive Blast Trauma.
NIH Reference No.: E-068-2012
Executive Summary:
General Description
Traumatic Brain Injury (TBI) is a major health concern, as it commonly occurs in competitive sports and during military operations. Since 2001, more than 240,000 US soldiers have been diagnosed with mild TBI following exposure to an explosive blast (bTBIMild cases are especially difficult to diagnose as they occur in the absence of external injuries. ). Moreover, the exact mechanism of how blast shockwaves cause the injury on the cellular level is not clearly understood. While animal model studies generate information on overall consequences of blast exposure to brain tissues, a system where tissue could be directly observed during and immediately after exposure to shockwaves would allow for better study of the physical current/future impact of the injury. Finally, since post-traumatic stress disorder (PTSD) often occurs in soldiers exposed to battle and explosions, there is a possibility that blast induced brain injury, on the cellular level, could contribute the development of PTSD. Since shockwave propagation within the skull follows a complex pattern due to shape and structure of the cranium, there might be a relationship between the position of person’s head with relation to the source of the blast and the severity of the incurred damage.
To study the effects of the shockwaves on living tissues the researchers developed a pneumatic air gun-based device that can deliver a blast via a quick release valve directly to the 96-well culture dish positioned on top of a microscope. The shockwaves generated by the system closely resemble shockwaves previously recorded during open field blasts in both waveform and duration. Furthermore, modulating the volume of fluid in the well allows for independent control over shear forces generated by the blast shockwave, which normally accompanies the transient pressure wave. The researchers can therefore simulate an explosive blast and independently study the role of both the blast shockwave pressure change and the shear forces in causing damage to the cells and tissues.
Scientific Progress
The researchers at National Institute of Child Health and Human Development applied their blast simulation device to study the response of human brain cells in culture to an explosive shockwave. By observing the calcium signaling within the cells they discovered that pressure shockwaves alone, in the absence of shear, are not sufficient to trigger responses, even when administered at known lethal levels (14 atm). In contrast, a pressure blast of less than 5 atm, combined with shear force distribution, induced a calcium signaling wave that propagated through the cell population. However, despite the presence of calcium signaling wave, no effect on cell survival was observed in 11 experiments after 24 hrs, consistent with published MRI results of victims suffering from mild bTBI yet lacking any signs of brain necrosis of edema. Recently, the researchers have identified several critical mechanisms of brain injury propagation occurring within milliseconds-to-minutes following exposure to the blast, as well as tested some treatments on cells response using their device. They are currently attempting to expand the system to look at whole brain slices rather than just cells.
Most importantly, the researchers managed to faithfully simulate the impact of a pressure shockwave similar to explosive blast in a very controlled environment during real time microscopy imaging.
Future Direction
Strengths
Weaknesses
Patent Status
US Application No. 61/590,209 filed Jan. 24, 2012
US Application No. 13/748,410 filed Jan. 24, 2012
Relevant Publications
Ravin R et al., PLoS One. 2012;7(6):e39421.Epub 2012 Jun 29. (PMID: 22768078)
NIH Reference No.: E-068-2012
Executive Summary:
- Intention Type: Device and Diagnostic
- Patent Status: Applications filed (US Application No. 61/590,209 filed 24 Jan 2012; US Application No. 13/748,410 filed 24 Jan 2012), pending in US.
- LINKs: http://goo.gl/rLXGni, http://goo.gl/XLeQCa
- NIH Reference Number: E-068-2012
- NIH Institute or Center: National Institute of Child Health and Human Development (NICHD)
- Disease Focus: Explosive blast-induced Traumatic Brain Injury (bTBI)
- Basis of Invention: Experimental device and prognostic
- How it works: Delivers controlled pressure shockwave to cultured living cells placed on a microscope stage
- Lead Inventors: Rea Ravin (NICHD), Joshua Zimmerberg (NICHD), Sergey Bezrukov (NICHD)
- Development Stage: Functional device currently in use
- Novelty: Allows for real time observation of cellular response to explosive shockwave, for example understanding bTBI and organ damage resulting from explosion pressure waves, such as in military combat. Also, detects the impact of mild cases of bTBI
- Clinical Applications:
- Screening for pharmacological compounds that may ameliorate the effects of acute brain trauma
- Testing materials capable of protecting cells from trauma, potentially identifying new materials that could be inserted into a helmet or other protective gear
- Identification of the best treatment and diagnostic path based on injury that has occurred in the emergency room, battlefield, blunt head trauma
General Description
Traumatic Brain Injury (TBI) is a major health concern, as it commonly occurs in competitive sports and during military operations. Since 2001, more than 240,000 US soldiers have been diagnosed with mild TBI following exposure to an explosive blast (bTBIMild cases are especially difficult to diagnose as they occur in the absence of external injuries. ). Moreover, the exact mechanism of how blast shockwaves cause the injury on the cellular level is not clearly understood. While animal model studies generate information on overall consequences of blast exposure to brain tissues, a system where tissue could be directly observed during and immediately after exposure to shockwaves would allow for better study of the physical current/future impact of the injury. Finally, since post-traumatic stress disorder (PTSD) often occurs in soldiers exposed to battle and explosions, there is a possibility that blast induced brain injury, on the cellular level, could contribute the development of PTSD. Since shockwave propagation within the skull follows a complex pattern due to shape and structure of the cranium, there might be a relationship between the position of person’s head with relation to the source of the blast and the severity of the incurred damage.
To study the effects of the shockwaves on living tissues the researchers developed a pneumatic air gun-based device that can deliver a blast via a quick release valve directly to the 96-well culture dish positioned on top of a microscope. The shockwaves generated by the system closely resemble shockwaves previously recorded during open field blasts in both waveform and duration. Furthermore, modulating the volume of fluid in the well allows for independent control over shear forces generated by the blast shockwave, which normally accompanies the transient pressure wave. The researchers can therefore simulate an explosive blast and independently study the role of both the blast shockwave pressure change and the shear forces in causing damage to the cells and tissues.
Scientific Progress
The researchers at National Institute of Child Health and Human Development applied their blast simulation device to study the response of human brain cells in culture to an explosive shockwave. By observing the calcium signaling within the cells they discovered that pressure shockwaves alone, in the absence of shear, are not sufficient to trigger responses, even when administered at known lethal levels (14 atm). In contrast, a pressure blast of less than 5 atm, combined with shear force distribution, induced a calcium signaling wave that propagated through the cell population. However, despite the presence of calcium signaling wave, no effect on cell survival was observed in 11 experiments after 24 hrs, consistent with published MRI results of victims suffering from mild bTBI yet lacking any signs of brain necrosis of edema. Recently, the researchers have identified several critical mechanisms of brain injury propagation occurring within milliseconds-to-minutes following exposure to the blast, as well as tested some treatments on cells response using their device. They are currently attempting to expand the system to look at whole brain slices rather than just cells.
Most importantly, the researchers managed to faithfully simulate the impact of a pressure shockwave similar to explosive blast in a very controlled environment during real time microscopy imaging.
Future Direction
- Use the system to study pharmacological effects of the calcium signaling in response to blast
- Search for additional signaling pathways acting in response to blast of varying intensity
- Test different materials and devices that can potentially reduce the impact of blast on the brain cells
- Expand the system to allow for study of entire organs, such as mouse brain, inner ear, or spleen, especially if they can be observed in real time during the blast
- Investigate the possibility of a relationship between mild bTBI and development of PTSD
Strengths
- Laboratory controlled system with high temporal and spatial resolution for study of effects of explosive blast on living cells
- High level of control of blast power; high consistency and reproducibility
- Separation of pressure shockwave effects from subsequent shear wave effects
- Imaging and analyzing cell response in real time during the blast, so even short term changes on the order of millisecond range can be recorded
- Applicable in many different cell types, tissue sections, and organs.
Weaknesses
- Lacks biological imitation of the human brain
- Does not precisely simulate the effect of blast on brain cells inside the skull
Patent Status
US Application No. 61/590,209 filed Jan. 24, 2012
US Application No. 13/748,410 filed Jan. 24, 2012
Relevant Publications
Ravin R et al., PLoS One. 2012;7(6):e39421.Epub 2012 Jun 29. (PMID: 22768078)
FIG. 1A is a perspective view of a device for generating a blast shock wave for studying the effect of the blast shock wave on biological specimens as the blast shock wave is in progress. FIG. 1B is an enlarged perspective view of a portion of FIG. 1A, showing a quick connect mechanism between a high pressure hose and a T-connector for generating the blast shock wave through the T-outlets. (Image from patent application description US20130186173 A1)
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