| NSF Org: |
CBET Division of Chemical, Bioengineering, Environmental, and Transport Systems |
| Recipient: |
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| Initial Amendment Date: | August 18, 2016 |
| Latest Amendment Date: | August 18, 2016 |
| Award Number: | 1631656 |
| Award Instrument: | Standard Grant |
| Program Manager: |
Stephanie George
CBET Division of Chemical, Bioengineering, Environmental, and Transport Systems ENG Directorate for Engineering |
| Start Date: | August 1, 2016 |
| End Date: | December 31, 2020 (Estimated) |
| Total Intended Award Amount: | $885,000.00 |
| Total Awarded Amount to Date: | $885,000.00 |
| Funds Obligated to Date: |
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| History of Investigator: |
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| Recipient Sponsored Research Office: |
3227 CHEADLE HALL SANTA BARBARA CA US 93106-0001 (805)893-4188 |
| Sponsor Congressional District: |
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| Primary Place of Performance: |
Mechanical Engineering Dept Santa Barbara CA US 93106-5070 |
| Primary Place of
Performance Congressional District: |
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| Unique Entity Identifier (UEI): |
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| Parent UEI: |
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| NSF Program(s): | IntgStrat Undst Neurl&Cogn Sys |
| Primary Program Source: |
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| Program Reference Code(s): |
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| Program Element Code(s): |
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| Award Agency Code: | 4900 |
| Fund Agency Code: | 4900 |
| Assistance Listing Number(s): | 47.041 |
ABSTRACT
CBET - 1631656
Turner, Kimberly
The brain is a highly plastic organ, capable of learning, remembering and adapting. However, it is also a plastic material with mechanical properties of strength, hardness, and impact resistance. A major challenge in neuroengineering is to understand the biophysical properties of the brain and how these differ between individuals. In particular, how do differences in the mechanical properties of the brain alter the experience of force and the consequences of impact? A major limitation in the systematic study of force on the brain has been the inability to reliably apply impacts or pressure to individual cells. The uHammer project aims to develop just such a highly engineered tool for the application of force to individual neural cells. These single cell studies will allow us to compare individual differences in neural responses to force, including changes in cell mechanics, structure, viability, and gene expression. This project, a collaboration between industry and multi-faceted academic team, will support the Ph.D. work of two graduate students, hold a workshop to bring together top researchers interested in this important societal problem, and train undergraduate research interns, while attempting to unlock some of the mysteries surrounding the brain today.
The focus of this work is to probe the mechanical properties of neural tissue and the subsequent effects on function. To examine the consequences of force on neurons, a device must apply precise forces to single cells over a few microseconds. No existing devices provide these force and temporal responses, and developing such a device would enable broad, new classes of cellular measurements. The development of a MEMS based device (the uHammer) that uses time gated magnetic actuation to deliver milliNewton impact forces to single cells in a high throughput fashion, will enable these measurements. The device, capitalizing on recent advances in micro and nanoscale transduction, microfluidics, and analytical techniques, will allow cells to be monitored in real-time and collected after impact for analysis. The uHammer will enable entirely new classes of experiments, in which the biological consequences of impact loading can be recorded and monitored as a function of force amplitude, direction, duration, and time after loading. The focus is to develop a significantly improved understanding of the role of impact and pressure loading on individual neurons, neural progenitors, and brain tissue. The technical goals are to Design, fabricate and test a tool (the uHammer) able to apply physiologically relevant loads to single cell, optimize the device for high-throughput manipulation of neural stem cells, and quantify the effect of impact on single cell mechanics, structure, viability, colony formation and gene expression. The uHammer team of engineers, neuroscientists, biologists and industry leaders is able to tackle these challenging questions, while also providing a unique learning environment for undergraduates and graduate students. The multidisciplinary uHammer team has the ability to design new technology with the end user in mind, enable new scientific discovery, and transform it into therapies and treatments. The proposed technology will enable experiments that are not presently possible, and the link to and commitment from industrial partner Owl Biomedical, will enable rapid commercial developments. With these partnerships and goals in hand, UCSB is poised to make game-changing breakthroughs on problems including traumatic brain injury (TBI) and Alzheimers disease
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PROJECT OUTCOMES REPORT
Disclaimer
This Project Outcomes Report for the General Public is displayed verbatim as submitted by the Principal Investigator (PI) for this award. Any opinions, findings, and conclusions or recommendations expressed in this Report are those of the PI and do not necessarily reflect the views of the National Science Foundation; NSF has not approved or endorsed its content.
Traumatic Brain Injury is a leading cause of death and disability worldwide, making it a global economic and public health issue. There are many unanswered questions regarding traumatic brain injury, including connection to neurodegenerative illnesses. There is evidence among professional athletes that there is a strong connection between traumatic brain injury (TBI) and neurodegenerative illness including Alzheimer’s disease and other dementia disorders.
The intellectual merit of this project is aimed at understanding the cellular response to mechanical injury. Prior research on cellular response to mechanical stimulation has been primarily single cell based and low-throughput and thus has been performed on small numbers of cells. Through this NSF-funded project our team developed an electromagnetically-activated MEMS (microelectromechanical) device that can apply high strain (20-60%) at a high strain rate (up to 200,000 s-1) to individual cells. The micro-Hammer device has high throughput and is able to apply strain to up to 36,000 individual cells per minute, enabling studies of changes in cell populations as a result of high strain, high strain rate impacts. Importantly, cells can be collected after impact and monitored over time, allowing the time course of injury and recovery to be quantitatively assessed. During this project, the team designed, built and characterized the performance of the micro-Hammer, verifying its function using K562 cells. Once the device was characterized, neural progenitor cells were subjected to compressive stress conditions using the micro-Hammer device, and then monitored for changes in viability, expansion and gene expression. Following the micro-Hammer impact event, cells were found to exhibit TBI secondary injury mechanisms including cell death and apoptosis, as well as mechanically-sensitive neuroinflammation signaling. The project findings demonstrate that the micro-Hammer is an effective tool for applying compressive strain to cells in a high throughput fashion, allowing for statistically significant results to be obtained. By studying cellular responses to strain at high throughput, we gain important insight into the short- and long-term effects of mechanical impacts on cell function and health.
The broader impacts of this project are multifaceted. The project team consists of mechanical engineers, bioengineers, biophysicists, and neuroscientists, led by three female PIs. This interdisciplinary team provided the expertise in engineering design, imaging, mechanical analysis, and gene expression pathway studies that were needed to design, build, and use the micro-Hammer device to characterize cellular responses to high strain, high strain rate impacts. The team not only worked together to take on difficult scientific questions, but also learned valuable cross-disciplinary collaboration and communication skills. This work led to multiple journal publications, 2 PhD dissertations (one by a female mechanical engineering student) and numerous presentations at national and international meetings and seminars. Outcomes of this work were incorporated into several graduate and undergraduate classes on bioengineering and MEMS devices. Furthering the understanding of cellular damage due to force will add to the understanding of treatment and management of traumatic brain injury, an economic and global health problem facing society.
Last Modified: 07/01/2021
Modified by: Kimberly Turner
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