Multimodal 3D Imaging of Cells and Tissue, Bridging the Gap Between Clinical and Research Microscopy

Absorption dyes are widely used in traditional cytology and pathology clinical practice, while fluorophores and nanoparticles are more often used in biologic research. Optical projection tomographic microscopy (OPTM) is a platform technology that can image the same specimen in multiple modes in 3D, providing morphologic and molecular information concurrently and in exact co-registration. The depth-of-field of a high numerical aperture objective is extended by scanning the focal plane through the sample to generate an optical projection image. Samples of cells or tissue are brought into the OPTM instrument through a microcapillary tube filled with optical index-matching gel. Multiple optical projection images are taken from different perspectives by rotating the tube. Computed tomography (CT) algorithms are applied to these optical projection images to reconstruct 3D structure of the sample. Image segmentation and analysis based on these 3D images provide quantitative biosignatures for cancer diagnosis that represents a clear improvement over conventional 2D image analysis. In this article, we introduce the OPTM platform, optical Cell-CT, and Tissue-CT instruments, and some applications using these OPTM instruments.

[1]  Sulabha K. Kulkarni,et al.  Plasmon-assisted photonics at the nanoscale , 2007 .

[2]  Timothy C Y Chan,et al.  Accounting for range uncertainties in the optimization of intensity modulated proton therapy , 2007, Physics in medicine and biology.

[3]  Thomas Neumann,et al.  Three-dimensional imaging of single isolated cell nuclei using optical projection tomography. , 2005, Optics express.

[4]  Eric J. Seibel,et al.  Dual-modal optical projection tomography microscopy for cancer diagnosis , 2010, BiOS.

[5]  Kort Travis,et al.  Polarization microscopy with stellated gold nanoparticles for robust, in-situ monitoring of biomolecules , 2008 .

[6]  Deirdre Meldrum,et al.  Quantitative characterization of preneoplastic progression using single‐cell computed tomography and three‐dimensional karyometry , 2011, Cytometry. Part A : the journal of the International Society for Analytical Cytology.

[7]  James Sharpe,et al.  Tomographic molecular imaging and 3D quantification within adult mouse organs , 2007, Nature Methods.

[8]  Eric J Seibel,et al.  Dual-mode optical projection tomography microscope using gold nanorods and hematoxylin-stained cancer cells. , 2010, Optics letters.

[9]  R. Weissleder,et al.  Imaging in the era of molecular oncology , 2008, Nature.

[10]  Eric J. Seibel,et al.  High resolution optical projection tomographic microscopy for 3D tissue imaging , 2011, BiOS.

[11]  Leopold G. Koss,et al.  Kosss diagnostic cytology and its histopathologic bases , 2017 .

[12]  Eric J. Seibel,et al.  Automated cell analysis in 2D and 3D: A comparative study , 2009, Pattern Recognit..

[13]  James W. Reagan,et al.  The Manual of cytotechnology , 1983 .

[14]  Rebecca Richards-Kortum,et al.  Widefield and high-resolution reflectance imaging of gold and silver nanospheres. , 2007, Journal of biomedical optics.

[15]  Eric J Seibel,et al.  Resolution improvement in optical projection tomography by the focal scanning method. , 2010, Optics letters.

[16]  W. Denk,et al.  Two-photon laser scanning fluorescence microscopy. , 1990, Science.

[17]  X. Zhuang,et al.  Whole cell 3D STORM reveals interactions between cellular structures with nanometer-scale resolution , 2008, Nature Methods.

[18]  C. A. Glasbey,et al.  Multimodal microscopy by digital image processing , 1996 .

[19]  C. Murphy,et al.  Gold nanoparticles are taken up by human cells but do not cause acute cytotoxicity. , 2005, Small.

[20]  Adam Wax,et al.  Molecular imaging and quantitative measurement of epidermal growth factor receptor expression in live cancer cells using immunolabeled gold nanoparticles. , 2009, AJR. American journal of roentgenology.

[21]  M. Glas,et al.  Principles of Computerized Tomographic Imaging , 2000 .

[22]  T. Wilson,et al.  Method of obtaining optical sectioning by using structured light in a conventional microscope. , 1997, Optics letters.

[23]  Anna Moore,et al.  In vivo imaging of siRNA delivery and silencing in tumors , 2007, Nature Medicine.

[24]  Elodie Boisselier,et al.  Gold nanoparticles in nanomedicine: preparations, imaging, diagnostics, therapies and toxicity. , 2009, Chemical Society reviews.

[25]  James Sharpe,et al.  Resolution improvement in emission optical projection tomography , 2007, Physics in medicine and biology.

[26]  J. Conchello,et al.  Three-dimensional imaging by deconvolution microscopy. , 1999, Methods.

[27]  D L Farkas,et al.  Multimode light microscopy and the dynamics of molecules, cells, and tissues. , 1993, Annual review of physiology.

[28]  Stephen S Raab,et al.  Quality in Cancer Diagnosis , 2010, CA: a cancer journal for clinicians.

[29]  J. Hecksher-Sørensen,et al.  Optical Projection Tomography as a Tool for 3D Microscopy and Gene Expression Studies , 2002, Science.

[30]  Boris N. Khlebtsov,et al.  Observation of Extra-High Depolarized Light Scattering Spectra from Gold Nanorods , 2008 .

[31]  Anthony P. Reeves,et al.  Nuclear cytoplasmic cell evaluation from 3D optical CT microscope images , 2012, Medical Imaging.

[32]  Adam Wax,et al.  Molecular imaging and darkfield microspectroscopy of live cells using gold plasmonic nanoparticles , 2009 .

[33]  J. Mulshine,et al.  Purification and Characterization of a Protein That Permits Early Detection of Lung Cancer , 1996, The Journal of Biological Chemistry.

[34]  Victor Horodincu,et al.  Nucleic acid and protein mass mapping by live-cell deep-ultraviolet microscopy , 2007, Nature Methods.

[35]  Eric J Seibel,et al.  Dual-modal three-dimensional imaging of single cells with isometric high resolution using an optical projection tomography microscope. , 2009, Journal of biomedical optics.

[36]  Rimas Juskaitis,et al.  Real-time extended depth of field microscopy. , 2008, Optics express.

[37]  Graeme I Murray,et al.  The roles of heterogeneous nuclear ribonucleoproteins in tumour development and progression. , 2006, Biochimica et biophysica acta.

[38]  F. Del Bene,et al.  Optical Sectioning Deep Inside Live Embryos by Selective Plane Illumination Microscopy , 2004, Science.

[39]  S. Hell,et al.  Fluorescence microscopy with diffraction resolution barrier broken by stimulated emission. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[40]  T Smitha,et al.  Morphometry of the basal cell layer of oral leukoplakia and oral squamous cell carcinoma using computer-aided image analysis , 2011, Journal of oral and maxillofacial pathology : JOMFP.

[41]  Xiaoping P. Hu,et al.  Functionalization and peptide-based delivery of magnetic nanoparticles as an intracellular MRI contrast agent , 2004, JBIC Journal of Biological Inorganic Chemistry.

[42]  E de Kerviler,et al.  Contrast agents in magnetic resonance imaging of the liver: present and future. , 1998, Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie.

[43]  J. Pawley,et al.  Handbook of Biological Confocal Microscopy , 1990, Springer US.

[44]  Eric J. Seibel,et al.  Simultaneous 3D imaging of morphology and nanoparticle distribution in single cells with the Cell-CT™ technology , 2008, 2008 30th Annual International Conference of the IEEE Engineering in Medicine and Biology Society.

[45]  J. Umen,et al.  The elusive sizer. , 2005, Current opinion in cell biology.

[46]  Igor Meglinski,et al.  Application of gold nanoparticles as contrast agents in confocal laser scanning microscopy , 2008 .

[47]  B. Bonnemain,et al.  Superparamagnetic agents in magnetic resonance imaging: physicochemical characteristics and clinical applications. A review. , 1998, Journal of drug targeting.

[48]  H. Fujiki,et al.  Heterogeneous nuclear ribonucleoprotein B1 as early cancer biomarker for occult cancer of human lungs and bronchial dysplasia. , 2001, Cancer research.