1. NIBIB Strategic Plan: Focus on Imaging Science Belinda Seto, Ph.D. Deputy Director National Institute of Biomedical Imaging and Bioengineering

2. Goal One  Improve human health through the development of emerging biomedical technologies at the interface of engineering and the physical and life sciences.  2 examples: represent the convergence of bioengineering, physical sciences, biology and clinical sciences

3. Molecularly-Targeted Fluorescent Cell Penetrating Peptides for Tumor and Nerve Quyen Nguyen et al. Nature Biotechnology (NIBIB K08 Awardee) Molecularly-Targeted Fluorescent Cell Penetrating Peptides for Tumor and Nerve Quyen Nguyen et al. Nature Biotechnology (NIBIB K08 Awardee) ©2004 by National Academy of Sciences Schematic diagram of activatable CPPs. Cellular uptake induced by a cationic peptide is blocked by a short stretch of acidic residues attached by a cleavable linker.

4. Surgery Guided with Molecularly-Targeted Fluorescence of Both Tumor and Nerve Quyen Nguyen et al. Nature Biotechnology (NIBIB K08 Awardee) Portion of nerve embedded within tumor visible with fluorescently labeled probe. Tumor and nerve both invisible in standard white light reflected image Deep red Cy5 fluorescence from tumor-targeting ACPP pseudocolored green and overlaid on standard white-light reflectance image Green FAM fluorescence from nerve imaging peptide pseudocolored aqua Buried nerve branch

5. clinical Diagram of the transcranial MRI–guided focused ultrasound surgery device for noninvasive brain tumor ablation being developed under R01EB003268, (PI: K. Hynynen). This work evaluated the clinical feasibility of transcranial magnetic resonance imaging–guided focused ultrasound surgery (McDannold et al, ). This work was also based on earlier funding by NCI grants: CA76550; CA089017; CA46627 Transcranial MRI–Guided Focused Ultrasound Surgery of Brain Tumors: Initial Findings in 3 Patients (Neurosurgery 66:323-332, 2010)

6. NIBIB Translation Research: World’s First MR- Guided HIFU Treatment for Essential Tremor  Helmet-like applicator developed with 512 phased-array HIFU transducers  Can be precisely focused within the brain.  Entering FDA clinical trials PI on this study: W. Jeffrey Elias, MD., U.Va. Funded by the Focused Ultrasound Foundation. K.Hynynen, U. Toronto, funded by NIBIB, collaborated with InSightec in adapting the design of the applicator and US delivery, based on research funded under R01EB 3268, ExAblateExAblate MR-guided High-Intensity Focused Ultrasound (Insightec, Inc.)

7. Magnetic Resonance Elastography

8. HardSoft In principle, the mechanical properties of tissue could be assessed if a method could be developed to visualize propagation of applied mechanical waves The challenge in visualizing such waves is that they are only microns in amplitude. How can such small motions be reliably imaged?

9. Magnetic resonance imaging is a remarkably versatile technology. A 1995 publication by Mayo Clinic researchers reported the discovery of a method to visualize propagating shear waves in tissue with amplitudes smaller than the wavelength of light…

10. MR Elastography Tissue-simulating gel phantom with stiff inclusions 80 0 40 -100+10 1. Driver 2. MRE Sequence 3. Inversion (30-500 Hz) 2.5cm 2.5cm Conventional MR Image Wave Images Wave Images Displacement (mm ) Shear Stiffness (kPa ) Elastogram

11. Importance of Chronic Liver Disease, Fibrosis, Cirrhosis  A leading cause of death world- wide  Increasing prevalence of conditions that cause hepatic fibrosis Hepatitis C - 170 M people globally Hepatitis B Obesity / Fatty liver disease  Fibrosis can be reversed, if diagnosed early and treated

12. Progression of Liver Disease  Risk of Complications  Potential Sampling Errors  Subjective Histology Grading Liver Biopsy Standard Diagnostic Procedure to rule-out Fibrosis Irreversible High Mortality Reversible Silent Normal Cirrhosis Fibrosis

13. Technology Developed for Hepatic MRE -90 0 +90 Displacement (  m) Shear Stiffness (kPa) 0 10 4 6 8 2 Elastogram Active Driver Acoustic waves at 60Hz Imaging time: 16 sec Passive Driver (EB001981)

14. +60-60 Amplitude (  m) 0 M, 21 yrs -60 -60 +60 Amplitude (  m) 0 F, 30 yrs 2.0 kPa 7.0 kPa Biopsy: Grade 3 Fibrosis Healthy Chronic Liver Disease

15. Goal Two  Enable Patient-centered health care through development of health informatics and mobile and point-of-care technologies  Example: Image sharing contracts

16. Image Data Sharing: NIBIB Activities  Contract awarded to Radiological Society of North America: Image Sharing Network, PI: Dr. David Mendelson  Grant awarded to Wake Forest University  Grant awarded to University of Alabama

17. Goal Three  Transform advances in medicine at the molecular and cellular levels into therapeutic and diagnostic technologies that target an individual’s personal state of health  Example: Mehmet Toner’s project on circulating tumor cells

18. Key dimensions of the CTC-chip 100  m 50  m 200  m 45  m

19. Biotinylated anti-EpCAM Avidin Capture Antibody Clinical Application EpCAMLung, Prostate, Colon, Pancreas, Breast EGFRLung, Brain, Colon HER-2Breast CD133Lung, Prostate CD44, CD44v6 Lymphangioleiomyomatosis NG2Angiomyolipoma, Melanoma OH

20. Native Signal Filter f (x,y) Quantify (x 3, y 3 ) (x 2, y 2 ) (x 1, y 1 ) Threshold DNA Classify CTC PSA Automated Image Processing Stott, et al. Science Translational Medicine, 2010  Enumerate  Report  Image database  Intensity-based  Brightest signals  Center of mass (x i,y i )  Area  Elongation factor  |(x 1,y 1 ) – (x 2,y 2 )| < 2.5µm  Elongation < 3.6  Area PSA > Area DNA  12-bit monochrome  Filter-based images

21. Taking Imaging Beyond Enumeration Novel classification schema for CTCs using cross- correlation image processing algorithms Ki67: Cell proliferation marker M30: Cell apoptosis marker

22. Questions to be addressed: 1.Can CTCs be detected in the blood of patients with EGFR- and ALK-mutant lung cancer? 2.Do CTC numbers change with treatment? Numbers 4.Can signaling be measured in CTCs (and does it change with targeted therapy)? 5.Do the signaling effects in CTCs match those of the primary tumor? 6.Does this predict clinical outcome? Signaling 3.Can tumor-specific mutations be detected in CTCs? Genotype

23. Dynamic Range of CTC Enumeration Lung Cancer Patient Responding Lung Cancer Patient Not Responding CTC Numbers Track with Disease Course Nagrath et al, Nature 2007

24. Goal Four  Develop medical technologies that are low-cost, effective, and accessible to everyone.  Example: GE Vcan  Transformative low cost mobile clinical Ultrasound system. A hand held portable $8K device that can be carried in a coat pocket and has the same functionality of conventional systems which cost ~$200K. Has been embraced by leading cardiologist as a major development to help realize mHealth and is described as tomorrow’s stethoscope.

25. GE V-scan: World’s smallest portable ultrasound V-scan offers a chance for physicians to make a move from stethoscopes to portable imaging devices, bringing advanced visualization to any examination room. V-scan can offer an immediate look beyond patient vital signs with the potential to identify critical issues, like fluid around the heart, which could be a sign of congestive heart failure. And for cardiologists, Vscan provides a dependable visual evaluation of how well the heart is pumping at a glance, so they can treat patients more efficiently. GE’s Chairman and CEO Jeff Immelt demonstrates the new V-scan The handheld ultrasound can reduce the need for specialist referrals, which in turn can lower healthcare costs. NIBIB Grant R01EB002485: Kai Thomenius, Ph.D.

26. Goal Five  Develop training programs to prepare a new generation of interdisciplinary engineers, scientists, and health care providers.  Examples: R25 program for residents

27. NIBIB Research Education Program for Residents and Fellows (R25)  Target groups: residents or fellows interested in developing research experience in interdisciplinary areas such as quantitative biology, biologically-inspired engineering, and/or imaging science.  12 month initial support, additional 12 months possible  75% effort  $70,000 direct costs including $10,000 research supplies and $1000 travel

28. Goal Six Expand public knowledge about the medical, social, and economic value of bioengineering, biomedical imaging, and biomedical informatics. Examples of start-ups