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Am J Nucl Med Mol Imaging 2013;3(4):336-349
Original Article
In vivo validation and 3D visualization of broadband ultrasound molecular imaging
Xiaowen Hu, Charles F Caskey, Lisa M Mahakian, Dustin E Kruse, Julie R Beegle, Anne-Emilie Declèves, Joshua J Rychak, Patrick L
Sutcliffe, Kumar Sharma, Katherine W Ferrara
Department of Biomedical Engineering, University of California, Davis, One Shields Ave, Davis, CA 95616, USA; Center for Renal
Translational Medicine, Division of Nephrology-Hypertension, Department of Medicine, University of California, San Diego, La Jolla,
CA 92093, USA; Targeson Inc., 3550 General Atomics Court, MS 02-444, San Diego, CA 92121, USA. These authors contributed
equally to this manuscript.
Received March 7, 2013; Accepted April 11, 2013; Epub July 10, 2013; Published July 15, 2013
Abstract: Ultrasound can selectively and specifically visualize upregulated vascular receptors through the detection of bound
microbubbles. However, most current ultrasound molecular imaging methods incur delays that result in longer acquisition times and
reduced frame rates. These delays occur for two main reasons: 1) multi-pulse imaging techniques are used to differentiate
microbubbles from tissue and 2) acquisition occurs after free bubble clearance (>6 minutes) in order to differentiate bound from
freely circulating microbubbles. In this paper, we validate tumor imaging with a broadband single pulse molecular imaging method
that is faster than the multi-pulse methods typically implemented on commercial scanners. We also combine the single pulse
method with interframe filtering to selectively image targeted microbubbles without waiting for unbound bubble clearance, thereby
reducing acquisition time from 10 to 2 minutes. The single pulse imaging method leverages non-linear bubble behavior by
transmitting at low and receiving at high frequencies (TLRH). We implemented TLRH imaging and visualized the accumulation of
intravenously administrated integrin-targeted microbubbles in a phantom and a Met-1 mouse tumor model. We found that the TLRH
contrast imaging has a ~2-fold resolution improvement over standard contrast pulse sequencing (CPS) imaging. By using interframe
filtering, the tumor contrast was 24.8±1.6 dB higher after the injection of integrin-targeted microbubbles than non-targeted control
MBs, while echoes from regions lacking the target integrin were suppressed by 26.2±2.1 dB as compared with tumor echoes. Since
real-time three-dimensional (3D) molecular imaging provides a more comprehensive view of receptor distribution, we generated 3D
images of tumors to estimate their volume, and these measurements correlated well with expected tumor sizes. We conclude that
TLRH combined with interframe filtering is a feasible method for 3D targeted ultrasound imaging that is faster than current
multi-pulse strategies. (ajnmmi1303004).
Keywords: Targeted microbubbles, ultrasound molecular imaging, angiogenesis, 3D visualization
Address correspondence to: Katherine Ferrara, Department of Biomedical Engineering, University of California, Davis, 451 E Health
Sciences Dr, Davis, CA 95616. Phone: 530-754-9436; Fax: 530-754-5739; E-mail: kwferrara@ucdavis.edu
Original Article
In vivo validation and 3D visualization of broadband ultrasound molecular imaging
Xiaowen Hu, Charles F Caskey, Lisa M Mahakian, Dustin E Kruse, Julie R Beegle, Anne-Emilie Declèves, Joshua J Rychak, Patrick L
Sutcliffe, Kumar Sharma, Katherine W Ferrara
Department of Biomedical Engineering, University of California, Davis, One Shields Ave, Davis, CA 95616, USA; Center for Renal
Translational Medicine, Division of Nephrology-Hypertension, Department of Medicine, University of California, San Diego, La Jolla,
CA 92093, USA; Targeson Inc., 3550 General Atomics Court, MS 02-444, San Diego, CA 92121, USA. These authors contributed
equally to this manuscript.
Received March 7, 2013; Accepted April 11, 2013; Epub July 10, 2013; Published July 15, 2013
Abstract: Ultrasound can selectively and specifically visualize upregulated vascular receptors through the detection of bound
microbubbles. However, most current ultrasound molecular imaging methods incur delays that result in longer acquisition times and
reduced frame rates. These delays occur for two main reasons: 1) multi-pulse imaging techniques are used to differentiate
microbubbles from tissue and 2) acquisition occurs after free bubble clearance (>6 minutes) in order to differentiate bound from
freely circulating microbubbles. In this paper, we validate tumor imaging with a broadband single pulse molecular imaging method
that is faster than the multi-pulse methods typically implemented on commercial scanners. We also combine the single pulse
method with interframe filtering to selectively image targeted microbubbles without waiting for unbound bubble clearance, thereby
reducing acquisition time from 10 to 2 minutes. The single pulse imaging method leverages non-linear bubble behavior by
transmitting at low and receiving at high frequencies (TLRH). We implemented TLRH imaging and visualized the accumulation of
intravenously administrated integrin-targeted microbubbles in a phantom and a Met-1 mouse tumor model. We found that the TLRH
contrast imaging has a ~2-fold resolution improvement over standard contrast pulse sequencing (CPS) imaging. By using interframe
filtering, the tumor contrast was 24.8±1.6 dB higher after the injection of integrin-targeted microbubbles than non-targeted control
MBs, while echoes from regions lacking the target integrin were suppressed by 26.2±2.1 dB as compared with tumor echoes. Since
real-time three-dimensional (3D) molecular imaging provides a more comprehensive view of receptor distribution, we generated 3D
images of tumors to estimate their volume, and these measurements correlated well with expected tumor sizes. We conclude that
TLRH combined with interframe filtering is a feasible method for 3D targeted ultrasound imaging that is faster than current
multi-pulse strategies. (ajnmmi1303004).
Keywords: Targeted microbubbles, ultrasound molecular imaging, angiogenesis, 3D visualization
Address correspondence to: Katherine Ferrara, Department of Biomedical Engineering, University of California, Davis, 451 E Health
Sciences Dr, Davis, CA 95616. Phone: 530-754-9436; Fax: 530-754-5739; E-mail: kwferrara@ucdavis.edu
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