W90GQZ-61840037__SOW_KHP_TAT_Final_Redacted_20160726.pdf

STATEMENT OF WORK

FOR

DEPARTMENT OF THE ARMY

RESEARCH, DEVELOPMENT AND ENGINEERING COMMAND

INTERNATIONAL TECHNOLOGY CENTER-PACIFIC

(ITC-PAC)

Study on the Mechanism of Blast-induced Traumatic Brain Injury by Using a Laser-induced Shock Wave(s), Phase-2 (Document No. W90GQZ61840037)

1. PROGRAM SCOPE/OBJECTIVES.

This proposed research focuses on investigate methods for diagnosis and treatment of blast-induced traumatic brain injury (bTBI), particularly mild bTBI. An increasing number of patients suffering from bTBI is a serious social problem in the US and other countries. However, the mechanism and pathophysiology of bTBI is still unclear, and no reliable animal model has yet been established to investigate methods for diagnosis and treatment of bTBI. New technology using laser-induced shock waves (LISWs) to examine bTBI occurring mechanism in the rat brain is explored.

The objective of this proposed effort is the development new methodology and investigate the mechanism and pathophysiology of bTBI to confirm the validity of bTBI models. The goals are:

a) Sophisticate methods of LISW generation and measurements,

b) Study effects of second and multiple impacts and,

c) Study effects of thoracic impact on the brain,

d) Study effects of LISW waveforms on pathological outcome.

Duration of this Research and Development is one year (12 Months.)

1.1. Requirements.

This is continues effort to examine for the development of the new methodology of LISW and the verification of bTBI models.

1.2. Tasks.

1.2.1. Sophisticate methods of LISW generation and measurements Same as the first term of the project under Purchase Order (PO) No. FA5209-15-P-0175, a laser target is placed on the tissue, and the target is irradiated with a nanosecond laser pulse to induce a plasma. A LISW is generated through expansion of the plasma. As a laser source, the second harmonics of a Q-switched Nd: YAG (Neodymium Yttrium Aluminum Garnet) laser (wavelength, 532 nm; pulse width, 6 ns FWHM (Full Width at Half Maximum)) or a Q-switched Ruby laser (693 nm, 20 ns) will be used.

For the rat brain, diffuse reflectance spectroscopic measurements will be performed to monitor Cortical Spreading Depression (CSD), hemodynamic changes and mitochondrial energy dysfunction. In addition to optical fiber-based measurement, Charge Coupled Device (CCD)-based multispectral imaging will be performed to detect diffuse reflectance signals. The former (fiber-based measurement) enables deeper tissue measurement, while the latter (CCD-based imaging) can provide two-dimensional information. The Monte Carlo simulation-based multiple regression analysis for the reflectance spectra will be performed to specify the optical absorption and scattering properties of brain tissue. Those optical parameters will be useful for evaluating hemodynamic changes, mitochondrial energy dysfunction, and pathophysiological changes in rat brain quantitatively. Some part of LISW generation and measurements were established at the previous project term under Purchase Order (PO) No. FA5209-15-P-0175, and the methodology will be sophisticated for the detailed data retention.

1.2.2. Effects of second and multiple impacts: Expanded Experiment #1 This is continues effort to examine multiple impacts to the brain. Even a single impact does not cause any evident damage to the brain, a second impact or multiple impacts can often result in serious damage to the brain, which is known as second impact syndrome. The mechanism of second impact syndrome is totally unknown. In our preliminary experiment, we found that application of a second or third LISW impact to the rat brain caused considerable fluctuation in arterial oxygen saturation in the rat even when the first impact led to no changes in systemic physiological parameters. This suggests the usefulness of LISWs to investigate second impact syndrome. In this study, a second LISW impact or multiple LISW impacts will be applied to the rat brain under various conditions, and measurements of systemic parameters as well as cerebral diffuse reflectance signals will be conducted to reveal the mechanism of blast-related second impact syndrome.

1.2.3. Effects of thoracic impact on the brain: Expanded Experiment #2 This is continues effort to examine a blast impact on the lung. There is a hypothesis that a blast impact on the lung leads to mild TBI (thoracic mechanism). In our preliminary experiment, we applied LISWs to the lung in a rat (not to the brain) and performed diffuse reflectance measurements for the brain. We observed prolonged hypoxemia in the brain probably due to the damage to the lung, but CSD did not occur, indicating different cerebral responses caused by the LISW impact on the brain and that on the lung. In this study, we will reveal detailed cerebral responses caused by an LISW impact(s) on the lung. We will also examine events occurring in the brain when an LISW(s) is applied to both the brain and lung. Dynamic responses and pathological outcome will be compared between groups of rats treated with three different exposure schemes: LISW impact only on the brain, only on the lung and both on the brain and lung.

1.2.4. Effects of LISW waveforms on pathological outcome: Expanded Experiment #3 This is continues effort to examine time dependent tissue damage. An impulse, which is defined as the time-integrated positive pressure component, is one of the most important parameters to determine tissue damage caused by a pressure wave. Since impulses of LISWs are the same order as those of medically relevant actual blast waves, the use of LISWs would be valid to investigate the mechanism of bTBI. However, the peak pressures and durations of LISWs are considerably different from those of actual blast waves. Thus, we need to check how the waveforms of LISWs affect the pathological outcome of rats exposed to an LISW(s).

Fortunately, we can easily modify the waveforms of LISWs by the insertion of various materials between the laser target bottom surface and tissue surface. In this study, we will investigate the pathophysiology and histopathology of the brain be exposed to an LISW(s) with various temporal pressure characteristics.

1.3. DELIVERABLES

The Contractor shall submit two (2) deliverables associated with this contract.

1.3.1. First Deliverable – Technical Concept Report

The Contractor shall submit a Technical Concept Report to ITC-PAC within thirty (30) days from the start of the project. The report shall consist of the technical approach and overall program schedule. The Technical Report shall include, at a minimum, the following information:

Project title Investigator(s)

- Name

- Position title

- Organization name

- Address

- Telephone number

- Fax number

- Email address

Technical Approach Program Schedule

1.3.2. Second Deliverable – Final Report

The Contractor shall submit a Final Report to ITC-PAC with all the results and discoveries encountered during the project at the end of the twelve (12) month period. The Final Report shall include, at a minimum, the following information:

Project title Investigator(s)

- Name

- Position title

- Organization name

- Address

- Telephone number

- Fax number

- Email address

Summary (or Abstract) of the Project Introduction (or Background) Results & Discussion Conclusions Acknowledgements References

1.4. FINANCIAL REPORT

Together with the Final Report, the Contractor shall deliver the Financial Report of the Project to ITC-PAC. The Financial Report shall include the cost spent for the Project in the following category: Overhead, and direct Cost (Equipment, Travel, Material & Supply, Publication & Report, and Computer Service).

1.5. PAYMENTS.

1.5.1. 1st Payment.

After ITC-PAC’s acceptance of the First Deliverable mentioned above (First Deliverable), the Contractor shall submit the first invoice to ITC-PAC. The first payment will be made upon ITC- PAC’s certification of the invoice.

1.5.2. Final Payment.

After ITC-PAC’s acceptance of the Second Deliverable mentioned above, the Contractor shall submit the invoice to ITC-PAC. The Final payment will be made upon ITC-PAC’s certification of the invoice.

2. PROGAM MANAGEMENT.

Tokyo University of Agriculture and Technology shall designate a single program management point of contact. The Contractor shall develop management plans to ensure that all elements of this effort are successfully executed within the program budgets and schedules.

2.1. SAFETY REQUIREMENTS.

N/A.

2.2. TRAINING REQUIREMENTS.

N/A.

3. SCHEDULE.

Duration of this effort is for a twelve (12) month period.

3.1. Within thirty (30) days from the start of the project, a Technical Report is due to ITC-PAC.

3.2. At the completion of the twelve (12) month period, a final report is due to the ITC-PAC.

4. GOVERNMENT POCS.

ITC-PAC: Dr. Kyungho Park, Director for Micro-System Programs. TEL: +81-3-6385-3119, FAX: +81-3-3423-1832, E-mail: kyungho.park3.ln@mail.mil.

5. GOVERNMENT FURNISHED PROPERTY.

None.

6. GENERAL INFORMATION.

6.1. Contractor Employees. Personnel shall meet or exceed the following requirement:

6.1.1. The Contractor shall not hire employees of the United States Government and/or employees otherwise under contract for service to the United States Government if employing such persons would create a conflict of interest, or appearance of a conflict of interest as determined by the Contractor. The Contractor shall not employ any person who is an employee of DoD, unless such person seeks and receives approval according to DODR 5500.7, Standards of Conduct.