AD_________________ (Leave blank) Award Number: W81XWH-09-1-0004 TITLE: A Novel Hand-Held Optical Imager with Real-Time Co-registration Facilities toward Diagnostic Mammography PRINCIPAL INVESTIGATOR: Sarah Erickson CONTRACTING ORGANIZATION: Florida International University Miami, FL 33199 REPORT DATE: January 2010 TYPE OF REPORT: Annual Summary PREPARED FOR: U.S. Army Medical Research and Materiel Command Fort Detrick, Maryland 21702-5012 DISTRIBUTION STATEMENT: (Check one) (cid:1) Approved for public release; distribution unlimited (cid:138) Distribution limited to U.S. Government agencies only; report contains proprietary information The views, opinions and/or findings contained in this report are those of the author(s) and should not be construed as an official Department of the Army position, policy or decision unless so designated by other documentation. 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REPORT DATE (DD-MM-YYYY) 2. REPORT TYPE 3. DATES COVERED (From - To) 01/31/10 Annual Summary 1 Jan 2009 – 31 Dec 2009 4. TITLE AND SUBTITLE 5a. CONTRACT NUMBER A Novel Hand-Held Optical Imager with Real-Time Co-registration (cid:1)(cid:2)(cid:3)(cid:4)(cid:1)(cid:5)(cid:6)(cid:7)(cid:8)(cid:6)(cid:3)(cid:6)(cid:7)(cid:7)(cid:7)(cid:9) 5b. GRANT NUMBER Facilities toward Diagnostic Mammography BC083282 5c. PROGRAM ELEMENT NUMBER 6. AUTHOR(S) 5d. PROJECT NUMBER Sarah J. Erickson E mail: [email protected] 5e. TASK NUMBER 5f. WORK UNIT NUMBER 7. PERFORMING ORGANIZATION NAME(S) AND ADDRESS(ES) 8. PERFORMING ORGANIZATION REPORT NUMBER AFNlDo rAiDdDaR ESISn(tEeSr) national University MARC 430 11200 SW 8th Street Miami, FL 33199 9. SPONSORING / MONITORING AGENCY NAME(S) AND ADDRESS(ES) 10. SPONSOR/MONITOR’S ACRONYM(S) U.S. Army Medical Research and Materiel Command Fort Detrick, Maryland 21702-5012 11. SPONSOR/MONITOR’S REPORT NUMBER(S) 12. DISTRIBUTION / AVAILABILITY STATEMENT Approved for public release; distribution unlimited 13. SUPPLEMENTARY NOTES 14. ABSTRACT Hand-held based optical imaging devices using near-infrared (NIR) light are currently developed toward clinical translation of the technology. However, none of the NIR devices developed to date have attempted 3D tomography since they are not able to coregister the image to the tissue geometry. The objective for the work described herein is the clinical translation of a hand-held optical imager with automated coregistration facilities toward 3D tomography. Studies were performed in vivo with normal human subjects to demonstrate fast (near real-time) 2D fluorescence imaging for target detection prior to 3D tomography. The results showed that 0.23 cm3 and 0.45 cm3 fluorescent targets placed behind the breast tissue were detected through ~2.5 cm deep tissue. Parallely, studies were performed on phantoms composed of minced chicken breast and 1% Liposyn solution to demonstrate coregistered imaging in vitro. The results showed that the 3D tracking system was able to track the position of the probe in real-time and accurately coregister the image to the geometry of the object. Additionally, deeper targets can be detected upon summation of multiple coregistered images. These results demonstrate the potential of the device to perform 3D tomographic imaging in human subjects via coregistered imaging on complex breast geometries. 15. SUBJECT TERMS Diffuse optical imaging, near-infrared, breast cancer, hand-held device, fluorescence, coregistration, in-vivo 16. SECURITY CLASSIFICATION OF: 17. LIMITATION 18. NUMBER 19a. NAME OF RESPONSIBLE PERSON OF ABSTRACT OF PAGES USAMRMC a. REPORT b. ABSTRACT c. THIS PAGE UU 19b. TELEPHONE NUMBER (include area U U U 29 code) Standard Form 298 (Rev. 8-98) Prescribed by ANSI Std. Z39.18 Table of Contents Page Introduction…………………………………………………………….………..…….. 4 Body……………………………………………………………………………………… 4 Key Research Accomplishments………………………………………….………. 8 Reportable Outcomes……………………………………………………………….. 9 Conclusion…………………………………………………………………………….. 10 References…………………………………………………………………………….. 10 Appendices……………………………………………………………………………. 11 A Novel Hand-Held Optical Imager with real-Time Coregistration Facilities toward Diagnostic Mammography Annual Report (Year 1, Jan 2009-Dec 2009) PI: Sarah J. Erickson ([email protected]) Contact Details: Doctoral Student, Department of Biomedical Engineering College of Engineering and Computing, Florida International University, Miami, FL Grant No. BC083282 Mentor: Dr. Anuradha Godavarty ([email protected]) INTRODUCTION Optical imaging using near-infrared (NIR) light is an emerging technique toward non-invasive breast cancer diagnosis. Hand-held based optical imaging devices are currently developed toward clinical translation of the technology.1 However, the NIR devices developed to date have not attempted three-dimensional (3D) tomography since they are not able to accurately coregister the image to the geometry of the object. The overall goal of the research is to implement and test a novel hand-held based optical imager with capabilities of automated coregistration on any tissue curvature for real-time surface imaging and 3D tomographic analysis, on tissue phantoms and in vivo with human subjects. The purpose for this research is to translate the device to the clinical setting for breast cancer imaging. The scope of the research involves experimental studies on tissue phantoms and in vitro, and in vivo studies with normal human subjects prior to clinical studies with breast cancer patients. BODY The tasks that were completed in Year-1 of the proposed projects are described herein. The tasks were categorized according to three specific aims as outlined in the statement of work: Specific Aim# 1: Demonstrate imaging and 3-D tomography using hand-held probe on different curved tissue phantoms. Work Completed to Date: Proposed Task A: Modify probe design to achieve uniform source intensity. The current design of the hand-held device (shown in Figure 1) utilizes a single laser diode source and a custom built collimator package which divides the laser light among six optical fibers attached to the probe face. The limitation of this design is that the output intensity of the laser light is not divided equally among the six fibers. The goal of this task was to modify the 4 collimator package in order to achieve the desired uniform source intensity distribution. However, during the course of this task, it was found that achieving uniform intensity distribution is difficult using a single laser diode. Hence, a new design was developed to use six laser diodes individually attached to the six optical fibers which can be adjusted individually to the desired intensity. This design is currently carried out in a parallel project by a team of graduate and undergraduate students in our lab and will be implemented with the second generation of the optical imaging system. Figure 1. The three major components of the hand-held device (left) are the hand-held probe, the intensified charge-coupled device (ICCD) camera detector, and the laser diode source. The light from the single laser diode source is divided via a collimator package into six source fibers at the probe face (right). Proposed Task B: Perform experiments using the hand-held probe in the curved position on curved tissue phantoms. Experiments were carried out using the probe in the maximum curved position (45° curvature of each wing) on octagonal phantoms designed to fit the curvature of the probe with full contact. During these studies, it was found that there was interference in the collected signal due to the sharp edges of the octagonal phantom. These studies were discontinued. Further studies focused directly on human breast tissues to demonstrate imaging of curved geometries in the realistic case. In vivo studies were performed on normal human subjects to demonstrate the feasibility of using the hand-held device to perform fast 2D imaging toward target detection prior to 3D tomography studies. The device was used to collect images of a fluorescent target with a background of real human breast tissue. Fast imaging was performed in near real time (~5 sec). All human subject studies were approved by the Florida International University Institutional Review Board. Healthy female volunteers age 21 and above were recruited for the studies. A fluorescent target (acrylic sphere filled with 1 µM indocyanine green) was used to simulate a tumor and was placed underneath the flap of the breast tissue (i.e. between breast tissue and chest wall, underneath the tissue). Table 1 gives a summary of the in vivo experimental cases performed. 5 Table 1 Summary of experimental cases performed for in vivo fast 2D imaging studies. Figure 2 shows the results of images (i.e. 2D surface contour plots of fluorescence intensity) collected with the probe in both the flat (Figure 2A) and curved (Figure 2B) position. When the probe was in the flat position, it was placed with gentle compression against the tissue surface to allow full contact with the probe face, whereas in the curved position it was able to contour around the tissue in its natural shape. Figure 2. Results for in vivo studies with normal human subjects. (A) 0.23 cc target was placed at the 4 o’clock position and imaged with the probe in the flat position. (B) 0.45 cc target was placed at the 8 o’clock position and imaged with the probe in the curved position. The results show that a fluorescent target was detectable through ~2.5 cm of actual human breast tissue using the probe in both the flat and curved positions. The results for these studies were published in Translational Oncology2 and the article in press is attached in Appendix A. 6 Specific Aim # 2: Implement 3-D automated co-registration using acoustic-based tracking system in order to perform real-time in-vivo optical imaging. Work Completed to Date: Proposed Task A: Implement a 3D motion tracking device in order to randomly track the movement of the hand-held probe. Coregistered imaging is required in order to perform 3D tomography since the 2D image must be located in the exact position of the hand-held probe on the tissue surface. A 3D tracking system was implemented on the probe in order to perform coregistered imaging using MATLAB/LabView software developed by a master’s student in house. Experimental studies using an exogenous fluorescent contrast agent Indocyanine Green (ICG) were performed to demonstrate the feasibility of coregistered imaging using the hand-held probe based optical imager. The contrast agent is placed in a small spherical target and embedded within the phantom to represent a tumor within a tissue background. Successful implementation of the coregistered tracking method would be indicated by the ability to track the actual location of the target as the probe is moved to different positions with respect to the phantom surface. Coregistered imaging was demonstrated in slab tissue phantoms (composed of 1% Liposyn) and the results published in Review of Scientific Instruments3 (article in press is attached in Appendix B). Additional experiments were performed in phantoms composed of minced chicken breast combined with 1% Liposyn to demonstrate coregistered imaging in vitro, and the results were published in Review of Scientific Instruments (Appendix B).3 The results showed that the 3D tracking system was able to track the position of the probe in real-time and accurately coregister the image to the geometry of the object in tissue phantoms and in vitro. During these coregistered imaging studies, it was found that by collecting multiple coregistered images and applying a post-processing summation technique, a target can be detected at greater depths than with a single image alone. A 0.45 cm3 target was detected at a depth of 3.0 cm in the slab tissue phantom, and a 0.45 cm3 target was detected at a depth of 2.5 cm in the in vitro phantom.3 These results show that by summating multiple coregistered images, deeper targets can be detected. Ongoing studies are currently performed to determine the deepest and smallest size target that can be detected using this technique. Proposed Task B: Adapt and improve 3D reconstruction tools for optical tomography studies. This task is part of ongoing research to be completed in subsequent years. 7 Specific Aim # 3: Perform feasibility in-vivo studies using diffuse optical imaging on normal subjects to demonstrate real-time co-registered imaging. Proposed Task A: Perform in-vivo studies with ~5 normal human subjects at Florida International University. This task is part of ongoing research to be completed in subsequent years. Proposed Task B: Implement the tracking system to obtain real-time surface images of the human breast tissues using the hand-held optical imager. This task is part of ongoing research to be completed in subsequent years. Training Plan: Instrumentation and Phantom Studies: The P.I. trained under a previous doctoral student to learn how to operate the imaging system and carry out experiments using tissue phantoms. In Vivo Studies The P.I. received training from Sylvester Cancer Center under Dr. Richard Kiszonas. The training involved observing breast imaging (i.e. x-ray mammography and breast ultrasound) and interacting with doctors and technicians in the clinical setting. Mentoring During Year-1 the P.I. mentored two undergraduate students in performing in vivo studies, a third undergraduate student in instrumentation, and a master’s student in coregistered imaging and instrumentation. KEY RESEARCH ACCOMPLISHMENTS (cid:1) Demonstrated fast 2D imaging using the hand-held device on curved tissue geometries in normal human subjects. (Specific Aim #1) (cid:1) Detected fluorescent targets in vivo within actual human breast tissue. (Specific Aim #1) (cid:1) Implemented 3D tracking system and demonstrated coregistered imaging using the hand- held device on tissue phantoms and in vitro. (Specific Aim #2) (cid:1) Detected deeper targets by applying multi-scan summation technique using coregistered images. (Specific Aim #2 8 REPORTABLE OUTCOMES Peer-reviewed Journal Publications (1) S.J. Erickson, J. Ge, A. Sanchez, and A. Godavarty. “Two-dimensional fast surface imaging using a hand-held optical device: in-vitro and in-vivo fluorescence studies,” Translational Oncology (in press, 2009). (2) S. Regalado, S. J. Erickson, B. Zhu, J. Ge, and A. Godavarty. “Automated coregistered imaging using a hand-held probe-based optical imager,” Review of Scientific Instruments (in press, 2009). (3) J. Ge, S.J. Erickson, and A. Godavarty. “Fluorescence tomographic imaging using a hand-held probe based optical imager: extensive phantom studies,” Applied Optics 48(33), 6408-6416 (2009). National Conference Proceedings (* presenter) (1) S.J. Erickson*, J. Ge, and A. Godavarty. “Clinical Translation of a Novel Hand-Held Based Optical Imager: In Vitro and In Vivo Studies,” IFMBE Proceedings 25th Southern Biomedical Engineering Conference 2009, 15 -- 17 May 2009, Miami, Florida, USA; 24: 3-4; A.J. McGoron, C.Z. Li, and W.C. Lin, eds. ISBN: 978-3-642-01696-7 (2009). (2) J. Ge, S.J. Erickson*, and A. Godavarty. “Fluorescence Tomographic Imaging Using a Hand-Held Optical Imager: Extensive Phantom Studies,” IFMBE Proceedings 25th Southern Biomedical Engineering Conference 2009, 15 -- 17 May 2009, Miami, Florida, USA; 24: 1-2; A.J. McGoron, C.Z. Li, and W.C. Lin, eds. ISBN: 978-3-642-01696-7; 2009. Abstracts (accepted) (1) S.J. Erickson, S. Martinez, J. DeCerce, L. Caldera, A. Godavarty. “Fast coregistered imaging in vivo using a hand-held optical imager,” SPIE Photonics West, San Francisco, CA, Jan. 23-28, paper #7555-25 (2010). Awards (1) Lydia I. Pickup Scholarship, Society of Women Engineers, 2009 (2) 1st Place Doctoral Student Award, SBEC 2009 Paper Competition, 25th Southern Biomedical Engineering Conference, Miami, FL (3) 3rd Place Best Student Poster Award 2009 NIH-SPIE Workshop, Bethesda, MD (4) 3rd Place Paper Competition Award, Engineering Division, 2009 Scholarly Forum, Florida International University Funding Received (1) Coulter Early Career Translational Award (to PI’s mentor): The initial in-vivo results from the PI’s work served as strong preliminary results in the proposal to Coulter Foundation, leading to the funding of a 2-year project for the PI’s mentor. 9 CONCLUSION The objectives outlined in the statement of work that have been completed to date are Specific Aim #1 and part of Specific Aim #2. The major outcomes from these tasks are: (i) demonstration of fast 2D imaging using the hand-held device on curved tissue geometries and detection of a fluorescent target in actual human breast tissue, (ii) implementation of a 3D tracking system and demonstration of coregistered imaging using the hand-held device on tissue phantoms and in vitro, and (iii) detection of deeper targets using summation of multiple coregistered images. The results obtained were published in the peer-reviewed journals Translational Oncology and Review of Scientific Instruments and presented at the national meetings SPIE Photonics West and Southeastern Biomedical Engineering Conference. The results from these tasks demonstrate the ability of the hand-held device to image in human breast tissues which have complex geometries, whereas previous studies used slab phantoms with simple geometries. A fluorescent target was detected in vivo through human breast tissue which demonstrates the potential of the device to detect a tumor in the clinical setting. A tracking system was implemented with the hand-held device and coregistered imaging was demonstrated on tissue phantoms and in vitro. These results demonstrate the ability of the device to accurately coregister the image to the geometry of the object and hence the potential of the device to perform 3D tomographic imaging in human subjects via coregistered imaging on complex geometries. REFERENCES (1) S.J. Erickson and A. Godavarty. “Hand-Held Based Near-Infrared Optical Imaging Systems: A Review” Medical Engineering and Physics 31, 495-509 (2009). (2) S.J. Erickson, J. Ge, A. Sanchez, and A. Godavarty. “Two-dimensional fast surface imaging using a hand-held optical device: in-vitro and in-vivo fluorescence studies,” Translational Oncology (in press, 2009). (3) S. Regalado, S. J. Erickson, B. Zhu, J. Ge, and A. Godavarty. “Automated coregistered imaging using a hand-held probe-based optical imager,” Review of Scientific Instruments (in press, 2009). 10