In Vivo 3D Imaging of Retinal Neovascularization Using Multimodal Photoacoustic Microscopy and Optical Coherence Tomography Imaging

The pathological process of neovascularization of the retina plays a critical role in causing vision loss in several diseases, including diabetes, retinal vein occlusion, and sickle cell disease. Retinal neovascularization can lead to vitreous hemorrhage and retinal detachment, yet the pathological process of neovascularization is a complex phenomenon under active investigation. Understanding and monitoring retinal neovascularization is critically important in clinical ophthalmology. This study describes a novel multimodal ocular imaging system which combines photoacoustic microscopy (PAM) and a spectral domain optical coherence tomography (SD-OCT) to improve the visualization of retinal neovascularization (RNV), their depth, and the surrounding anatomy in living rabbits. RNV was induced in New Zealand rabbits by intravitreal injection of vascular endothelial growth factor (VEGF). The retinal vasculature before and after injection at various times was monitored and evaluated using multimodal imaging including color fundus photography, fluorescein angiography (FA), OCT, and PAM. In vivo experiments demonstrate that PAM imaging distinctly characterized the location as well as the morphology of individual RNV with high contrast at a safe laser energy of 80 nJ. SD-OCT was used to identify a cross-sectional structure of RNV. In addition, dynamic changes in the retinal morphology and retinal neovascularization were observed at day 4, 5, 6, 7, 9, 11, 14, 28, and day 35 after VEGF injection. PAM demonstrated high-resolution optical absorption of hemoglobin and vascular imaging of the retina and choroid with increased depth of penetration. With the current multimodal imaging system, RNV can be easily visualized in both 2D and 3D angiography. This multimodal ocular imaging system provides improved characterization of the microvasculature in a safe manner in larger rabbit eyes.

[1]  Gabriel Coscas,et al.  Optical Coherence Tomography Angiography in Retinal Vein Occlusion: Evaluation of Superficial and Deep Capillary Plexa. , 2016, American journal of ophthalmology.

[2]  Paul Kumar Upputuri,et al.  Broadband Absorbing Semiconducting Polymer Nanoparticles for Photoacoustic Imaging in Second Near-Infrared Window. , 2017, Nano letters.

[3]  Jeehyun Kim,et al.  Feasibility study on photoacoustic guidance for high-intensity focused ultrasound-induced hemostasis , 2014, Journal of biomedical optics.

[4]  Kai Wang,et al.  Contrast-enhanced photoacoustic imaging in the second near-infrared window using semiconducting polymer nanoparticles , 2018, Journal of biomedical optics.

[5]  Hans E. Grossniklaus,et al.  Animal models of choroidal and retinal neovascularization , 2010, Progress in Retinal and Eye Research.

[6]  Sohan Singh Hayreh,et al.  Ocular vascular occlusive disorders: Natural history of visual outcome , 2014, Progress in Retinal and Eye Research.

[7]  Fanting Kong,et al.  High-resolution photoacoustic imaging of ocular tissues. , 2010, Ultrasound in medicine & biology.

[8]  Yannis M Paulus,et al.  Photoacoustic ocular imaging. , 2010, Optics letters.

[9]  David H Sliney,et al.  Maximum permissible exposures for ocular safety (ANSI 2000), with emphasis on ophthalmic devices. , 2007, Journal of the Optical Society of America. A, Optics, image science, and vision.

[10]  Tsutomu Kume,et al.  In vivo corneal neovascularization imaging by optical-resolution photoacoustic microscopy , 2014, Photoacoustics.

[11]  P. Campochiaro,et al.  Retinal and choroidal neovascularization , 2000, Journal of cellular physiology.

[12]  Yannis M. Paulus,et al.  Novel Retinal Imaging Technologies , 2017 .

[13]  Michael W. Berns,et al.  Intravitreal VEGF and bFGF produce florid retinal neovascularization and hemorrhage in the rabbit , 2001, Current eye research.

[14]  D. Robinson.  The mechanics of human saccadic eye movement , 1964, The Journal of physiology.

[15]  Van Phuc Nguyen,et al.  Feasibility of photoacoustic evaluations on dual‐thermal treatment of ex vivo bladder tumors , 2017, Journal of biophotonics.

[16]  Al Borseghini.  The National Advisory Eye Council Vision Research: A National Plan 1987 Evaluation and Update , 1988 .

[17]  Qifa Zhou,et al.  Photoacoustic ophthalmoscopy for in vivo retinal imaging , 2010, Optics express.

[18]  Lihong V. Wang,et al.  Integrated optical- and acoustic-resolution photoacoustic microscopy based on an optical fiber bundle. , 2013, Optics letters.

[19]  Shuliang Jiao,et al.  Integrated photoacoustic ophthalmoscopy and spectral-domain optical coherence tomography. , 2013, Journal of visualized experiments : JoVE.

[20]  Andreas Ebneter,et al.  Investigation of Retinal Morphology Alterations Using Spectral Domain Optical Coherence Tomography in a Mouse Model of Retinal Branch and Central Retinal Vein Occlusion , 2015, PloS one.

[21]  Hao F. Zhang,et al.  Photoacoustic imaging of the eye: A mini review , 2016, Photoacoustics.

[22]  Shuliang Jiao,et al.  Optical coherence photoacoustic microscopy for in vivo multimodal retinal imaging. , 2015, Optics letters.

[23]  Yannis M Paulus,et al.  Novel Photoacoustic Microscopy and Optical Coherence Tomography Dual-modality Chorioretinal Imaging in Living Rabbit Eyes. , 2018, Journal of visualized experiments : JoVE.

[24]  D. K. Vaughan,et al.  Retinal light damage: Mechanisms and protection , 2010, Progress in Retinal and Eye Research.

[25]  Bo Ning,et al.  Dynamic, heterogeneous endothelial Tie2 expression and capillary blood flow during microvascular remodeling , 2017, Scientific Reports.

[26]  Peng Liu,et al.  IR-780 dye loaded tumor targeting theranostic nanoparticles for NIR imaging and photothermal therapy. , 2013, Biomaterials.

[27]  I. Constable,et al.  Induced chorioretinal venous anastomosis in experimental retinal branch vein occlusion. , 1992, The British journal of ophthalmology.

[28]  Jean-Pierre Hubschman,et al.  Ultra wide-field angiographic characteristics of branch retinal and hemicentral retinal vein occlusion. , 2010, Ophthalmology.

[29]  Wolfgang Drexler,et al.  Visualization of micro-capillaries using optical coherence tomography angiography with and without adaptive optics. , 2017, Biomedical optics express.

[30]  T. Hebert,et al.  Adaptive optics scanning laser ophthalmoscopy. , 2002, Optics express.

[31]  Lihong V. Wang,et al.  Photoacoustic tomography imaging and estimation of oxygen saturation of hemoglobin in ocular tissue of rabbits. , 2015, Experimental eye research.

[32]  Mark S. Humayun,et al.  Natural course of experimental retinal vein occlusion in rabbit; arterial occlusion following venous photothrombosis , 2008, Graefe's Archive for Clinical and Experimental Ophthalmology.

[33]  J. Fujimoto,et al.  IMAGE ARTIFACTS IN OPTICAL COHERENCE TOMOGRAPHY ANGIOGRAPHY , 2015, Retina.

[34]  Chen-Yuan Dong,et al.  Multiple release kinetics of targeted drug from gold nanorod embedded polyelectrolyte conjugates induced by near-infrared laser irradiation. , 2010, Journal of the American Chemical Society.

[35]  J. Zubeldia,et al.  Fluorescein-induced allergic reaction. , 1998, Annals of allergy, asthma & immunology : official publication of the American College of Allergy, Asthma, & Immunology.

[36]  Wei Zhang,et al.  Noninvasive chorioretinal imaging in living rabbits using integrated photoacoustic microscopy and optical coherence tomography. , 2017, Optics express.

[37]  Paul Kumar Upputuri,et al.  Recent advances toward preclinical and clinical translation of photoacoustic tomography: a review , 2016, Journal of biomedical optics.

[38]  Ji Yi,et al.  A combined method to quantify the retinal metabolic rate of oxygen using photoacoustic ophthalmoscopy and optical coherence tomography , 2014, Scientific Reports.

[39]  Chulhong Kim,et al.  In Vivo Photoacoustic Imaging of Anterior Ocular Vasculature: A Random Sample Consensus Approach , 2017, Scientific Reports.

[40]  Yannis M. Paulus,et al.  Photoacoustic Imaging in Ophthalmology , 2015 .

[41]  Shuliang Jiao,et al.  Photoacoustic ophthalmoscopy for in vivo retinal imaging: current status and prospects. , 2011, Ophthalmic surgery, lasers & imaging : the official journal of the International Society for Imaging in the Eye.

[42]  Omer Faruk Sahin,et al.  Imaging in Ophthalmology , 2014 .

[43]  Lihong V. Wang,et al.  Label-free photoacoustic ophthalmic angiography. , 2010, Optics letters.

[44]  J. Edelman,et al.  Corticosteroids inhibit VEGF-induced vascular leakage in a rabbit model of blood-retinal and blood-aqueous barrier breakdown. , 2004, Experimental eye research.

[45]  Hyun Wook Kang,et al.  Doxorubicin-fucoidan-gold nanoparticles composite for dual-chemo-photothermal treatment on eye tumors , 2017, Oncotarget.

[46]  Xiao Shu,et al.  Optical coherence tomography angiography of retinal vascular occlusions produced by imaging-guided laser photocoagulation. , 2017, Biomedical optics express.

[47]  Andreas Wenzel,et al.  In vivo confocal imaging of the retina in animal models using scanning laser ophthalmoscopy , 2005, Vision Research.

[48]  Lihong V. Wang,et al.  Optical-resolution photoacoustic microscopy for in vivo imaging of single capillaries. , 2008, Optics letters.

[49]  Paul Kumar Upputuri,et al.  Fast photoacoustic imaging systems using pulsed laser diodes: a review , 2018, Biomedical Engineering Letters.

[50]  Chuanqing Zhou,et al.  In vivo time-serial evaluation of laser-induced choroidal neovascularization in rats simultaneously using photoacoustic microscopy and optical coherence tomography , 2018, BiOS.

[51]  Lihong V. Wang,et al.  In vivo dark-field reflection-mode photoacoustic microscopy. , 2005, Optics letters.

[52]  James G. Fujimoto,et al.  Image Artifacts in Optical Coherence Angiography , 2016 .

[53]  Rodney H. B. Grey.  Vascular Disorders of the Ocular Fundus: A Colour Manual of Diagnosis , 1991 .

[54]  Akitoshi Yoshida,et al.  Characteristics of Retinal Neovascularization in Proliferative Diabetic Retinopathy Imaged by Optical Coherence Tomography Angiography. , 2016, Investigative ophthalmology & visual science.

[55]  Shuliang Jiao,et al.  Fundus Camera Guided Photoacoustic Ophthalmoscopy , 2013, Current eye research.