Development of In Vivo Optical Imaging

34 12 Vol. 34, No. 12 2008 12 ACTA AUTOMATICA SINICA December, 2008 1, 2 2.,,.,, R319 Development of In Vivo Optical Imaging LI Hui 1, 2 DAI Ru-Wei 2 Abstract With the emergence of in vivo optical imaging, bioluminescence imaging and fluorescence imaging can be used to non-invasively monitor the activities and responses of cells marked with optical signals in real time, which are considered to be promising tools for tumor detection, gene expression profiling, protein molecular detection, drug receptor localization, drug screening, and therapeutic evaluation. In this paper, the features, imaging systems, and applications of in vivo bioluminescence imaging and in vivo fluorescence imaging have been introduced and compared in detail. The basic theories, application fields, and development of in vivo optical imaging in future are reviewed. Key words In vivo optical imaging, bioluminescence imaging (BLI), fluorescence imaging (FI), (In vivo optical imaging),, (Bioluminescence imaging, BLI) (Fluorescence imaging) [1 2]. (Luciferase) DNA,, (Green fluorescent protein, GFP) (Red fluorescent protein, RFP) [3]., (Charge coupled device camera, CCD camera), 2007-08-08 2007-11-19 Received August 8, 2007; in revised form November 19, 2007 (30500131), (20061D0501600216), (20070410146) Supported by National Natural Science Foundation of China (30500131), Research Fund for Beijing Distinguished Specialists (20061D0501600216), Chinese Postdoctoral Science Foundation (20070410146), and Chinese Academy of Sciences K. C. Wong Postdoctoral Fellowships 1. 100048 2. 100190 1. Department of Education Technology, Capital Normal University, Beijing 100048 2. Key Laboratory of Complex Systems and Intelligence Science, Institute of Automation, Chinese Academy of Sciences, Beijing 100190 DOI: 10.3724/SP.J.1004.2008.01449, [4 8]., (Magnetic resonance imaging, MRI) (Computed tomography, CT) (Ultrasonic imaging) (Positron emission tomography, PET) (Single photon emission computed tomography, SPECT),,. : / ; / ;, ; ;.,. 1 2 ( ) [5, 9],,.,, [4 8].

1450 34 Table 1 (MRI) (CT) (PET) (SPECT) (FRI) (FMT) (BLI) (BLT) 1 Primary uses of different imaging techniques,, 2 Table 2 Parameters of imaging techniques (MRI) 10 100 m min/h, $$$ (CT) 50 m min $$ 50 m min mm $$ (PET) 1 2 mm min 18F, 11C, 15O $$$ (SPECT) 1 2 mm min 99mTc, 111In $$ (FRI) 1 2 mm s/min < 1 cm, $ (FMT) 1 2 mm s/min < 10 cm $$ (BLI) mm min cm $$ (BLT) mm min cm $$ : $ < 10 ; $$ 10 30 ; $$$ > 30,. 1 1995, Contag [3] Lux ( ),,. 1997, Fluc, (Luciferin), Mg 2+ ATP,.,.,, [10 11]., ( CCD camera).,, 590 1 500 nm., 600 nm,., (Bioluminescent imaging, BLI) (Bioluminescent tomography, BLT)., BLI,.,, [11 12].,, (Xenogen) IVIS. BLT,, [13 15] (

12 : 1451 BLT ),., BLT,,. BLT University of Iowa Bioluminescence Tomography Laboratory [16 18]. 2 20 80,,. 1994, Chalfie [19].,, [20]. ( ),,,,.,.,,,., (Fluorescence imaging, FI) (Fluorescence molecular tomography, FMT)., FI,. Xenogen IVIS, 400 950 nm. (< 5 mm),., 20 90 ( ) (FMT). ;,,, ( ). FMT [21 22], 2002 Ntziachristos [23] FMT B.,,.,, :, ;,, ;.,,.,,.,. 3 3.1 (Reporter gene)., : Firefly luciferase, Luciferin, ; Renilla luciferase, Coelenterazine,..,,.,.,, : 1) ; 2), ; 3), ; 4),,,., [6, 24 28]. [29] ( 3) :, (BLI BLT),

1452 34 Table 3 3 Comparison of in vivo optical imaging based on luciferase and GFP GFP Milliseconds (200 300 ms) Luciferase Luciferin Minute (10 min),,,, (FI FMT)., : 1), ; 2),,, ; 3) ; 4).,.,,.,,,,, CCD ( ),. 3.2 (BLI BLT), ; (FI FMT),,, 1. University of Iowa Bioluminescence Tomography Laboratory, CCD ( ).,,, CCD.. (a) (a) In vivo fluorescence imaging Fig. 1 1 (b) (b) In vivo bioluminescence imaging Schematics of in vivo optical imaging Xenogen IVIS, CCD (Living imaging)., CCD,,,,.,., (Multispectral imaging) (Time domain optical imaging, TDOI)., ;,,,. 3.3 ( )

12 : 1453,., ( ), [30 31] : [D(r) Φ(r, t)] µ a (r)φ(r, t) = 1 Φ(r, t) S(r, t) (1) c t, Φ(r, t) r t ; µ a (r) ; c ; S(r, t) ; D(r) : 1 D(r) = (2) 3[µ a (r) + µ s(r)] µ s(r) = (1 g)µ s (r), g, µ a (r)..., ( ), Cong [32].,,. : ; : Monte Carlo. [33],,,,.,, [34 37] [38 41] ; ( ), ( ). Monte Carlo, [11 12],,,., : 1), ( ); 2) ;,,. CCD,,,,,,. (Perturbation-based method) [42 46] [41, 47 48] (Gradient-based method) [13 15]., Born Rytov Newton, [42 45]. : Cong [46] BLT CCD, Born,.,. Arridge [41], (Method of conjugate gradients, CGD) (Method of steepest descent, SD) (Algebraic reconstruction technique, ART), CGD., UCL BORG (Biomedical Optical Research Group) TOAST (Time-resolved optical absorption and scattering tomography),. Hielscher,. University of Iowa Bioluminescent Tomography Laboratory BLT, Cong [15],,. Lv [13]. : 1),,, ; 2),,,.

1454 34 ; 3),,,,,. 4,, :. 4.1,,. Contag [20],,,,. Yang [49 50],. Jenkins [51],. [49 50, 52 53]. 4.2, AIDS.,,,., [54]. McCaffrey [55], sirna shrna sirna. [56 57] ( ),,,. 4.3,,., Wang [58] (Hematopoietic stem cells, HSC),,, HSC, HSC. Kim [59] (Neural progenitor cell, NPC),,. :,,.,. Paulmurugan [60] Renilla,. 4.4,. ( ),,,. Zhang [61], NO,. GFP [7],

12 : 1455 (http://www.metamouse.com)., [20]. 5,,., 10 cm [7], 12 cm 6 cm 5 cm [62],. 1). ( ),,,. ;,,,. 2).,,,.,,.. 3). X-ray,.,. References 1 Choy G, Choyke P, Libutti S K. Current advances in molecular imaging: noninvasive in vivo bioluminescent and fluorescent optical imaging in cancer research. Molecular Imaging, 2003, 2(4): 303 312 2 Contag C H, Fraser S, Weissleder R. Strategies in in vivo molecular imaging. Neoreviews, 2000, 1(12): 225 232 3 Contag P R, Olomu I N, Stevenson D K, Contag C H. Bioluminescent indicators in living mammals. Nature Medicine, 1998, 4(2): 245 247 4 Weissleder R, Mahmood U. Molecular imaging. Radiology, 2001, 219(2): 316 333 5 Ntziachristos V, Ripoll J, Wang L V, Weissleder R. Looking and listening to light: the evolution of whole-body photonic imaging. Nature Biotechnology, 2005, 23(3): 313 320 6 Maggi A, Ciana P. Reporter mice and drug discovery and development. Nature Reviews Drug Discovery, 2005, 4(3): 249 255 7 Hoffman R M. Green fluorescent protein imaging of tumour growth, metastasis, and angiogenesis in mouse models. The Lancet Oncology, 2002, 3(9): 546 556 8 Yang M, Baranov E, Moossa A R, Penman S, Hoffman R M. Visualizing gene expression by whole-body fluorescence imaging. Proceedings of the National Academy of Sciences of the United States of America, 2000, 97(22): 12278 12282 9 Weissleder R. Scaling down imaging: molecular mapping of cancer in mice. Nature Review Cancer, 2002, 2(1): 11 18 10 Li H, Tian J, Luo J, Lv Y J, Cong W X, Wang G. Design and implementation of an optical simulation environment for bioluminescent tomography studies. Progress in Natural Science, 2007, 17(1): 87 94 11 Li H, Tian J, Zhu F P, Cong W X, Wang L V, Hoffman E A. A mouse optical simulation environment (MOSE) to investigate bioluminescent phenomena in the living mouse with the Monte Carlo method. Academic Radiology, 2004, 11(9): 1029 1038 12 Li Hui, Tian Jie, Wang Ge. Photon propagation model of in vivo bioluminescent imaging based on Monte Carlo. Journal of Software, 2004, 15(11): 1709 1719 (,,. Monte Carlo., 2004, 15(11): 1709 1719) 13 Lv Y J, Tian J, Cong W X, Wang G, Luo J, Yang W. A multilevel adaptive finite element algorithm for bioluminescence tomography. Optics Express, 2006, 14(18): 8211 8223 14 Jiang M, Wang G. Image reconstruction for bioluminescence tomography. In: Proceedings of the 49th Annual Meetingthe International Symposium on Optical Science and Technology. Denver, USA: SPIE, 2004. 335 351 15 Cong W X, Wang G, Kumar D, Liu Y, Jiang M, Wang L V. Practical reconstruction method for bioluminescence tomography. Optics Express, 2005, 13(18): 6756 6771 16 Wang G, Hoffman E A, McLennan G, Wang L V, Suter M, Meinel J F. Development of the first bioluminescence CT scanner. Radiology, 2003, 229(Z): 566 17 Wang G, Li Y, Jiang M. Uniqueness theorems in bioluminescence tomography. Medical Physics, 2004, 31(8): 2289 2299 18 Wang G, Qian X, Cong W X, Shen H, Li Y, Han W M. Recent development in bioluminescence tomography. Current Medical Imaging Reviews, 2006, 2(4): 453 457 19 Chalfie M, Tu Y, Euskirchen G, Ward W W, Prasher D C. Green fluorescent protein as a marker for gene expression. Science, 1994, 263(5148): 802 805 20 Contag C H, Jenkins D, Contag P R, Negrin R S. Use of reporter genes for optical measurements of neoplastic disease in vivo. Neoplasia, 2000, 2(1-2): 41 52 21 Ntziachristos V, Bremer C, Graves E E, Ripoll J, Weissleder R. In vivo tomographic imaging of near-infrared fluorescent probes. Molecular Imaging, 2002, 1(2): 82 88

1456 34 22 Ntziachristos V, Tung C H, Bremer C, Weissleder R. Fluorescence molecular tomography resolves protease activity in vivo. Nature Medicine, 2002, 8(7): 757 760 23 Graves E E, Ripoll J, Weissleder R, Ntziachristos V. A submillimeter resolution fluorescence molecular imaging system for small animal imaging. Medical Physics, 2003, 30(5): 901 911 24 Minn A J, Gupta G P, Siegel P M, Bos P D, Shu W P, Giri D D. Genes that mediate breast cancer metastasis to lung. Nature, 2005, 436(7050): 518 524 25 Shachaf C M, Kopelman A M, Arvanitis C, Karlsson A, Beer S, Mandl S. MYC inactivation uncovers pluripotent differentiation and tumour dormancy in hepatocelluar cancer. Nature, 2004, 431(7012): 1112 1117 26 Walenskv L D, Kung A L, Escher I, Malia T J, Barbuto S, Wright R D. Activation of apoptosis in vivo by a hydrocarbon-stapled BH3 helix. Science, 2004, 305(5689): 1466 1470 27 Morizono K, Xie Y M, Ringpis G E, Johnson M, Nassanian H, Lee B. Lentiviral vector retargeting to P-glycoprotein on metastatic melanoma through intravenous injection. Nature Medicine, 2005, 11(3): 346 352 28 Gross S, Piwnica-Worms D. Real-time imaging of ligandinduced IKK activation in intact cells and in living mice. Nature Methods, 2005, 2(8): 607 614 29 Choy G, O Connor S, Diehn F E, Costouros N, Alexander H R, Choyke P. Comparison of noninvasive fluorescent and bioluminescent small animal optical imaging. Biotechniques, 2003, 35(5): 1022 1030 30 Ishimaru A. Wave Propagation and Scattering in Random Media. New York: IEEE Press, 1978. 175 190 31 Wilson B C, Sevick E M, Patterson M S, Chance B. Timedependent optical spectroscopy and imaging for biomedical applications. Proceedings of the IEEE, 1992, 80(6): 918 930 32 Cong W X, Wang L V, Wang G. Formulation of photon diffusion from spherical bioluminescent sources in an infinite homogeneous medium. BioMedical Engineering Online, 2004, 3: 12 33 Arridge S R, Hebdn J C. Optical imaging in medicine II: modeling and reconstruction. Physics in Medicine and Biology, 1997, 42(5): 841 853 34 Arridge S R, Schweiger M. Photon-measurement density functions, Part II: finite-element-method calculations. Applied Optics, 1995, 34(34): 8026 8037 35 Schweiger M, Arridge S R, Hiraoka M, Delpy D T. The finite element method for the propagation of light in scattering media: boundary and source conditions. Medical Physics, 1995, 22(11): 1779 1792 36 Schweiger M, Arridge S R. The finite element method for the propagation of light in scattering media: frequency domain case. Medical Physics, 1997, 24(6): 895 902 37 Arridge S R, Dehghani H, Schweiger M, Okada E. The finite element model for the propagation of light in scattering media: a direct method for domains with nonscattering regions. Medical Physics, 2000, 27(1): 252 264 38 Schweiger M, Arridge S R, Delpy D T. Application of the finite element method for the forward and inverse problem in optical tomography. Journal of Mathematical Imaging and Vision, 1993, 3(3): 263 283 39 Schweiger M. Application of the Finite Element Method in Infrared Image Reconstruction of Scattering Media [Ph. D. dissertation], University College London, 1994 40 Arridge S R. Forward and inverse problems in time-resolved infrared imaging. In: Proceedings of Medical Optical Tomography: Functional Imaging and Monitoring. Bellingham, Washington, USA: SPIE, 1992. 283 316 41 Arridge S R, Schweiger M. A gradient-based optimization scheme for optical tomography. Optics Express, 1998, 2(6): 213 226 42 Yao Y Q, Wang Y, Pei Y L, Zhu W W, Barbour R L. Simultaneous reconstruction of absorption and scattering distributions in turbid media using a born iterative method. In: Proceedings of the 40th Annual Meeting Experimental and Numerical Methods for Solving Ill-Posed Inverse Problems: Medical and Nonmedical Applications. San Diego, USA: SPIE, 1995. 254 266 43 Roy R, Sevick-Muraca E M. Truncated Newton s optimization scheme for absorption and fluorescence optical tomography: Part I theory and formulation. Optics Express, 1999, 4(10): 353 371 44 Ntziachristos V, Weissleder R. Experimental threedimensional fluorescence reconstruction of diffuse media by use of a normalized born approximation. Optics Letters, 2001, 26(12): 893 895 45 Jiang H B. Frequency-domain fluorescent diffusion tomography: a finite-element-based algorithm and simulations. Applied Optics, 1998, 37(22): 5337 5343 46 Cong W X, Durairaj K, Wang L V, Wang G. A borntype approximation method for bioluminescence tomography. Medical Physics, 2006, 33(3): 679 686 47 Hielscher A H, Klose A D, Hanson K M. Gradient-based iterative image-reconstruction scheme for time-resolved optical tomography. IEEE Transactions on Medical Imaging, 1999, 18(3): 262 271 48 Bluestone A Y, Abdoulaev G, Schmitz C H, Barbour R L, Hielscher A H. Three-dimensional optical tomography of hemodynamics in the human head. Optics Express, 2001, 9(6): 272 286 49 Yang M, Baranov E, Jiang P, Sun F X, Li X M, Li L. Whole-body optical imaging of green fluorescent proteinexpressing tumors and metastases. Proceedings of the National Academy of Sciences of the United States of America, 2000, 97(3): 1206 1211 50 Yang M, Baranov E, Wang J W, Jiang P, Wang X, Sun F X. Direct external imaging of nascent cancer, tumor progression, angiogenesis, and metastasis on internal organs in the fluorescent orthotopic model. Proceedings of the National Academy of Sciences of the United States of America, 2002, 99(6): 3824 3829 51 Jenkins D E, Yu S F, Hornig Y S, Purchio T, Contag P R. In vivo monitoring of tumor relapse and metastasis using bioluminescent PC-3M-luc-C6 cells in murine models of human prostate cancer. Clinical and Experimental Metastasis, 2003, 20(8): 745 756 52 Hasegawa S, Yang M, Chishima T, Miyagi Y, Shimada H, Moossa A R. In vivo tumor delivery of the green fluorescent protein gene to report future occurrence of metastasis. Cancer Gene Therapy, 2000, 7(10): 1336 1340

12 : 1457 53 Bouvet M, Wang J W, Nardin S R, Yang M, Baranov E, Jiang P. Real-time optical imaging of primary tumor growth and multiple metastatic events in a pan creatic cancer orthotopic model. Cancer Research, 2002, 62(5): 1534 1540 54 Vassaux G, Groot-Wassink T. In vivo noninvasive imaging for gene therapy. Journal of Biomedicine and Biotechnology, 2003, 2003(2): 92 101 55 McCaffrey A P, Meuse L, Pham T T, Conklin D S, Hannon G J, Kay M A. RNA interference in adult mice. Nature, 2002, 418(6893): 38 39 56 Sato M, Johnson M, Zhang L Q, Zhang B, Le K, Gambhir S S. Optimization of adenoviral vectors to direct highly amplified prostate-specific expression for imaging and gene therapy. Molecular Therapy, 2003, 8(5): 726 737 57 Tseng J C, Levin B, Hunado A, Yee H, de Castro I P, Jimenez M. Systemic tumor targeting and killing by Sindbis viral vectors. Nature Biotechnology, 2004, 22(1): 70 77 58 Wang X, Rosol M, Ge S, Peterson D, McNamara G, Pollack H. Dynamic tracking of human hematopoietic stem cell engraftment using in vivo bioluminescence imaging. Blood, 2003, 102(10): 3478 3482 59 Kim D E, Schellingerhout D, Ishii K, Shah K, Weissleder R. Imaging of stem cell recruitment to ischemic infarcts in a murine model. Stroke, 2004, 35(4): 952 957 60 Paulmurugan R, Gambhir S S. Monitoring protein-protein interactions using split synthetic renilla luciferase proteinfragment-assisted complementation. Analytical Chemistry, 2003, 75(7): l584 1589 61 Zhang N, Weber A, Li B, Lyons R, Contag P R, Purchio A F. An inducible nitric oxide synthase-luciferase reporter system for in vivo testing of anti-inflammatory compounds in transgenic mice. The Journal of Immunology, 2003, 170(12): 6307 6319 62 Ntziachristos V, Ripoll J, Weissleder R. Would near-infrared fluorescence signals propagate through large human organs for clinical studies? Optics Letters, 2002, 27(5): 333 335,... E-mail: lihuisd@gmail.com (LI Hui Lecturer in the Department of Education Technology, Capital Normal University, postdoctor at the Institute of Automation, Chinese Academy of Sciences. Her research interest covers image processing, pattern recognition, and complexity science. Corresponding author of this paper.),.. E-mail: ruwei.dai@mail.ia.ac.cn (DAI Ru-Wei Academician of Chinese Academy of Sciences, professor at the Institute of Automation, Chinese Academy of Sciences. His research interest covers pattern recognition, artificial intelligence, and complexity science.)