Photothermal Optical Coherence Tomography of Anti-Angiogenic Treatment in the Mouse Retina Using Gold Nanorods as Contrast Agents.

PURPOSE: Optical coherence tomography (OCT) is widely used for ocular imaging in clinical and research settings. OCT natively provides structural information based on the reflectivity of the tissues it images. We demonstrate the utility of photothermal OCT (PTOCT) imaging of gold nanorods (GNR) in the mouse retina in vivo in the laser-induced choroidal neovascularization (LCNV) model to provide additional image contrast within the lesion. METHODS: Wild-type C57BL/6 mice were imaged following the intravenous injection of ICAM2-targeted or untargeted GNR. Mice were also imaged following the injection of ICAM2-targeted GNR with or without the additional ocular delivery of a neutralizing monoclonal anti-vascular endothelial growth factor (anti-VEGF) antibody. RESULTS: Mice cohorts injected with untargeted or ICAM2-targeted GNR demonstrated increased lesion-associated photothermal signal during subsequent imaging relative to phosphate-buffered saline (PBS)-injected controls. Additionally, intravitreal injection of anti-VEGF antibody caused a detectable reduction in the extent of anatomic laser damage and lesion-associated photothermal signal density in mice treated in the LCNV model and injected with ICAM2-targeted GNR. CONCLUSIONS: These experiments demonstrate the ability of PTOCT imaging of GNR to detect anti-VEGF-induced changes in the mouse retina using the LCNV model. TRANSLATIONAL RELEVANCE: This study shows that PTOCT imaging of GNR in the LCNV model can be used to detect clinically relevant, anti-VEGF-induced changes that are not visible using standard OCT systems. In the future this technology could be used to aid in early detection of disease, monitoring disease progress, and assessing its response to therapies.

In vivo photothermal optical coherence tomography of endogenous and exogenous contrast agents in the eye.

Optical coherence tomography (OCT) has become a standard-of-care in retinal imaging. OCT allows non-invasive imaging of the tissue structure but lacks specificity to contrast agents that could be used for in vivo molecular imaging. Photothermal OCT (PT-OCT) is a functional OCT-based technique that has been developed to detect absorbers in a sample. We demonstrate in vivo PT-OCT in the eye for the first time on both endogenous (melanin) and exogenous (gold nanorods) absorbers. Pigmented mice and albino mice (n = 6 eyes) were used to isolate the photothermal signal from the melanin in the retina. Pigmented mice with laser-induced choroidal neovascularization lesions (n = 7 eyes) were also imaged after a systemic injection of gold nanorods to observe their passive accumulation in the retina. This experiment demonstrates the feasibility of PT-OCT to image the distribution of both endogenous and exogenous absorbers in the mouse retina.

Nanoengineering of therapeutics for retinal vascular disease.

Retinal vascular diseases, including diabetic retinopathy, neovascular age related macular degeneration, and retinal vein occlusion, are leading causes of blindness in the Western world. These diseases share several common disease mechanisms, including vascular endothelial growth factor (VEGF) signaling, hypoxia, and inflammation, which provide opportunities for common therapeutic strategies. Treatment of these diseases using laser therapy, anti-VEGF injections, and/or steroids has significantly improved clinical outcomes. However, these strategies do not address the underlying root causes of pathology, and may have deleterious side effects. Furthermore, many patients continue to progress toward legal blindness despite receiving regular therapy. Nanomedicine, the engineering of therapeutics at the 1-100 nm scale, is a promising approach for improving clinical management of retinal vascular diseases. Nanomedicine-based technologies have the potential to revolutionize the treatment of ophthalmology, through enabling sustained release of drugs over several months, reducing side effects due to specific targeting of dysfunctional cells, and interfacing with currently "undruggable" targets. We will discuss emerging nanomedicine-based applications for the treatment of complications associated with retinal vascular diseases, including angiogenesis and inflammation.

Spectral fractionation detection of gold nanorod contrast agents using optical coherence tomography.

We demonstrate the proof of concept of a novel Fourier-domain optical coherence tomography contrast mechanism using gold nanorod contrast agents and a spectral fractionation processing technique. The methodology detects the spectral shift of the backscattered light from the nanorods by comparing the ratio between the short and long wavelength halves of the optical coherence tomography signal intensity. Spectral fractionation further divides the halves into sub-bands to improve spectral contrast and suppress speckle noise. Herein, we show that this technique can detect gold nanorods in intralipid tissue phantoms. Furthermore, cellular labeling by gold nanorods was demonstrated using retinal pigment epithelial cells in vitro.

Engineering of Nanoscale Contrast Agents for Optical Coherence Tomography.

Optical coherence tomography has emerged as valuable imaging modalityin ophthalmology and other fields by enabling high-resolution three-dimensional imaging of tissue. In this paper, we review recent progress in the field of contrast-enhanced optical coherence tomography (OCT). We discuss exogenous and endogenous sources of OCT contrast, focusing on their use with standard OCT systems as well as emerging OCT-based imaging modalities. We include advances in the processing of OCT data that generate improved tissue contrast, including spectroscopic OCT (SOCT), as well as work utilizing secondary light sources and/or detection mechanisms to create and detect enhanced contrast, including photothermal OCT (PTOCT) and photoacoustic OCT (PAOCT). Finally, we conclude with a discussion of the translational potential of these developments as well as barriers to their clinical use.

Molecular imaging of retinal disease.

Imaging of the eye plays an important role in ocular therapeutic discovery and evaluation in preclinical models and patients. Advances in ophthalmic imaging instrumentation have enabled visualization of the retina at an unprecedented resolution. These developments have contributed toward early detection of the disease, monitoring of disease progression, and assessment of the therapeutic response. These powerful technologies are being further harnessed for clinical applications by configuring instrumentation to detect disease biomarkers in the retina. These biomarkers can be detected either by measuring the intrinsic imaging contrast in tissue, or by the engineering of targeted injectable contrast agents for imaging of the retina at the cellular and molecular level. Such approaches have promise in providing a window on dynamic disease processes in the retina such as inflammation and apoptosis, enabling translation of biomarkers identified in preclinical and clinical studies into useful diagnostic targets. We discuss recently reported and emerging imaging strategies for visualizing diverse cell types and molecular mediators of the retina in vivo during health and disease, and the potential for clinical translation of these approaches.