Simultaneous transrectal ultrasound and photoacoustic human prostate imaging
Science Translational Medicine • 28 Aug 2019 • Vol 11, Issue 507 • DOI: 10.1126/scitranslmed.aav2169
Probing the prostate
Molecular imaging can help improve detection of cancer, but some modalities require ionizing radiation, making them nonideal for repeated imaging. Kothapalli et al. developed a probe that could perform ultrasound and photoacoustic imaging simultaneously, two modalities that do not require ionizing radiation. Testing the transrectal ultrasound and photoacoustic device in vitro, in mouse models, and using excised human prostates demonstrated the ability to view anatomical features within tissue and vascular contrast within tumors. Administering a dye improved photoacoustic contrast when imaging the prostates of human subjects with cancer. This device allows for real-time anatomical, functional, and molecular imaging of the human prostate and could be easily adopted into clinical workflows.
Abstract
Imaging technologies that simultaneously provide anatomical, functional, and molecular information are emerging as an attractive choice for disease screening and management. Since the 1980s, transrectal ultrasound (TRUS) has been routinely used to visualize prostatic anatomy and guide needle biopsy, despite limited specificity. Photoacoustic imaging (PAI) provides functional and molecular information at ultrasonic resolution based on optical absorption. Combining the strengths of TRUS and PAI approaches, we report the development and bench-to-bedside translation of an integrated TRUS and photoacoustic (TRUSPA) device. TRUSPA uses a miniaturized capacitive micromachined ultrasonic transducer array for simultaneous imaging of anatomical and molecular optical contrasts [intrinsic: hemoglobin; extrinsic: intravenous indocyanine green (ICG)] of the human prostate. Hemoglobin absorption mapped vascularity of the prostate and surroundings, whereas ICG absorption enhanced the intraprostatic photoacoustic contrast. Future work using the TRUSPA device for biomarker-specific molecular imaging may enable a fundamentally new approach to prostate cancer diagnosis, prognostication, and therapeutic monitoring.
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Supplementary Material
Summary
Materials and Methods
Fig. S1. Description of the TRUSPA imaging system next to the patient bed in the urology clinic.
Fig. S2. Schematics and images that describe the TRUSPA device, operating principle, and its data acquisition.
Fig. S3. Images of the CMUT array and ASIC.
Fig. S4. Simulated output pressure of a CMUT cell and experimental impedance measurements of a single CMUT element.
Fig. S5. Design and characterization of PDMS lens on the CMUT array.
Fig. S6. Time sequence used for simultaneous US and PAI of the TRUSPA device.
Fig. S7. Characterizing the US field of the TRUSPA device using simulations and experiments.
Fig. S8. Output pressure of the TRUSPA device, recorded by hydrophone in immersion, as a function of different DC and AC bias voltage settings.
Fig. S9. Characterization of TRUSPA system SNR as a function of depth and wavelength.
Fig. S10. Multiwavelength PA images of the mouse prostate tumor imaged with intravenous ICG.
Fig. S11. Multi-ROI time activity of ICG for the patient case presented in Fig. 7.
Fig. S12. Multiwavelength PA images of human prostate for the patient case presented in Fig. 7.
Fig. S13. Analysis of ICG activity during in vivo TRUSPA imaging of a human patient with PCa intravenously administered 75 mg of ICG at a concentration of 2.5 mg/ml.
Fig. S14. Analysis of ICG activity during in vivo TRUSPA imaging of a human patient with PCa intravenously administered 5 mg of ICG at a concentration of 2.5 mg/ml.
Table S1. 1D (linear) CMUT array parameters.
Table S2. Typical deep-tissue imaging parameters of the TRUSPA device.
Table S3. Intravenous ICG dose given to 10 human subjects at a concentration of 2.5 mg/ml.
Movie S1. In vivo TRUSPA imaging of human prostate in clinic (without administering contrast agent).
Resources
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Science Translational Medicine
Volume 11 | Issue 507
August 2019
August 2019
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Copyright © 2019 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.
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Received: 25 August 2018
Accepted: 26 July 2019
Acknowledgments
We thank J. Rosenberg for the statistical analysis of ICG patient data. We thank laboratory members of S.S.G. and P.T.K.-Y. for their help and discussions. We thank the Stanford Nanofabrication Facility for their support in the fabrication of capacitive micromachined ultrasonic arrays. Part of the TRUSPA integration design and fabrication work was done in the Stanford Nano Shared Facilities (supported by the NSF, ECCS-1542152). We also extend our thanks to the National Semiconductors for their support in the fabrication of ASICs. We thank K. Merkle and his team in the physics machine shop at Stanford for the fabrication of polycarbonate housing of the TRUSPA device. We thank summer undergraduate interns A. Lei and R. Singh for their assistance in some phantom and mice experiments with TRUSPA. We thank laboratory members of J.C.L. for their assistance in experiments with surgically removed prostates. We thank K. Rupnarayan for help with consenting the PCa patients. We thank A. Karanany for assistance with intravenous ICG experiments and J. Schwimmer for help with proofreading the manuscript. Funding: We acknowledge funding support from NCI ICMIC P50CA114747 (S.S.G.), NCI CCNE-T U54 U54CA151459 (S.S.G.), the Canary Foundation (S.S.G.), RO1HL117740 (P.T.K.-Y.), NIBIB-K99EB017729 (S.-R.K.), NIBIB-R00EB017729-04 (S.-R.K.), the Sir Peter Michael Foundation (S.S.G. and S.-R.K.), Philips Medical (S.S.G.), and T32-CA118681 (D.M.H.). This work was supported in part from a grant by Philips Healthcare (S.S.G.). Author contributions: S.S.G. conceived the idea of PAI of the human prostate and supervised the entire bench-to-bedside clinical translation of the project. S.-R.K. designed the integrated TRUSPA device, including the fiber optic cable, the polycarbonate housing, and the PCB cable for CMUT and ASIC bonding; A.N. and P.T.K.-Y. contributed to the PCB design. J.W.C. and M.F.R. developed the real-time imaging software on Verasonics platform. S.-R.K. developed the beamforming code for the raw RF data reconstruction used in all the data analysis, the spectral unmixing code, the spectral analysis approach, and the control sequence for synchronizing the laser firing with the data acquisition system. K.K.P. and P.T.K.-Y. designed and fabricated the CMUT array. A.B. and P.T.K.-Y. developed ASICs. S.-R.K., T.E.C., and P.T.K.-Y. designed the PDMS lens mold. S.-R.K. and T.E.C. integrated all components of the TRUSPA device with PDMS encapsulation. S.-R.K., A.B., B.C.L., P.C., A.N., and A.M. performed the characterization of the CMUT arrays, ASICs, and the TRUSPA US field distribution using the hydrophone. S.-R.K. performed Field II simulations and all validation experiments in phantoms, mice models of cancer, and surgically removed human prostates. S.-R.K. set up all the in vivo TRUSPA experiments in the urology clinic and assisted in the data acquisition, whereas G.A.S. and L.S. performed transrectal imaging in men using the TRUSPA device and prepared the ICG solutions for intravenous injection. S.-R.K., S.S.G., G.A.S., J.W., J.D.B., J.C.L., and R.F. contributed to the protocols for the patient imaging. D.T. and J.C.L. provided surgically removed human prostates and contributed to the interpretation and analysis. S.-R.K., G.A.S., J.D.B., J.C.L., and S.S.G. interpreted TRUSPA imaging results. I.S. and D.M.H. assisted in the last five ICG experiments. S.-R.K. wrote the main and supplementary manuscripts, and all authors provided comments and suggestions to further improve the clarity of the manuscript. Competing interests: S.S.G. serves on the board of Endra Inc. (a manufacturer of small-animal PA instruments and RF-acoustic instruments), is a founding member, and has stock options. S.S.G. also served as a paid consultant to VisualSonics (a developer of US and PA products) up to late 2017. Data and materials availability: All data associated with this study are present in the paper and/or the Supplementary Materials. The software associated with US and PA beamforming using the raw RF data, and spectral unmixing using the multispectral PA data is available at http://doi.org/10.5281/zenodo.3347969.
Authors
Funding Information
National Institutes of Health: P50CA114747
National Institutes of Health: U54CA151459 (SSG)
National Institutes of Health: RO1HL117740 (PKY)
National Institutes of Health: NIBIB-K99EB017729
National Institute of Biomedical Imaging and Bioengineering: R00EB017729-04
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