December 2010
Volume 51, Issue 12
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Multidisciplinary Ophthalmic Imaging  |   December 2010
Evaluation of Contrast Agents for Enhanced Visualization in Optical Coherence Tomography
Author Affiliations & Notes
  • Justis P. Ehlers
    From the Cole Eye Institute, The Cleveland Clinic Foundation, Cleveland, Ohio; and
    the Duke Eye Center, Duke University, Durham, North Carolina.
  • Preeya K. Gupta
    the Duke Eye Center, Duke University, Durham, North Carolina.
  • Sina Farsiu
    the Duke Eye Center, Duke University, Durham, North Carolina.
  • Ramiro Maldonado
    the Duke Eye Center, Duke University, Durham, North Carolina.
  • Terry Kim
    the Duke Eye Center, Duke University, Durham, North Carolina.
  • Cynthia A. Toth
    the Duke Eye Center, Duke University, Durham, North Carolina.
  • Prithvi Mruthyunjaya
    the Duke Eye Center, Duke University, Durham, North Carolina.
  • Corresponding author: Justis P. Ehlers, Cole Eye Institute, The Cleveland Clinic Foundation, 9500 Euclid Avenue, Mail Code i-20, Cleveland, OH 44195; justis.p.ehlers@alumni.nd.edu
Investigative Ophthalmology & Visual Science December 2010, Vol.51, 6614-6619. doi:10.1167/iovs.10-6195
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      Justis P. Ehlers, Preeya K. Gupta, Sina Farsiu, Ramiro Maldonado, Terry Kim, Cynthia A. Toth, Prithvi Mruthyunjaya; Evaluation of Contrast Agents for Enhanced Visualization in Optical Coherence Tomography. Invest. Ophthalmol. Vis. Sci. 2010;51(12):6614-6619. doi: 10.1167/iovs.10-6195.

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      © ARVO (1962-2015); The Authors (2016-present)

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Abstract

Purpose.: To identify and evaluate the use of contrast agents in optical coherence tomography (OCT) for ophthalmic applications.

Methods.: Three agents—prednisolone acetate (PA), triamcinolone acetonide (TA), and lipid-based artificial tears (LBAT)—were tested in cadaveric porcine eyes imaged with hand-held spectral-domain OCT (SD-OCT). Anterior segment imaging was performed in triplicate with each agent at three sites: corneal epithelial surface, corneal wound interface, and anterior chamber. OCT characteristics of the three agents at each ocular site were analyzed. Quantitative intensity (i.e., brightness) analysis was performed with image analysis software. Institutional review board approval was obtained for imaging in human subjects undergoing cataract surgery. PA was applied to the corneal surface, and SD-OCT imaging was performed of the corneal surface and wound interface immediately after cataract surgery.

Results.: All agents provided increased reflectivity. PA and LBAT showed a smooth bright reflectivity profile, whereas TA had a granular profile. Improved visualization of tissue interfaces was noted. Maximum and mean intensity of reflectance were higher for all agents compared with controls (P < 0.05). PA showed topical and wound interface contrast enhancement in human subjects after cataract surgery.

Conclusions.: Significant OCT contrast enhancement was achieved with improved visualization of tissue interfaces. Each agent had a unique reflectivity profile. Future applications of OCT contrast agents might include evaluation of wound stability, intraocular fluidics, and ocular surface disease.

First described in 1991, 1 optical coherence tomography (OCT) has improved ultrastructural imaging and diagnosis in ophthalmology and in multiple other fields, including cardiology, dermatology, gastroenterology, and urology. 2 5 Ophthalmology has been an early adopter of OCT technology, and many of the clinical applications of OCT were first described for ophthalmic diseases, including glaucoma and retinal disorders. 1,6 8  
OCT image quality and acquisition have improved with the development of spectral domain OCT (SD-OCT), 9 11 allowing greater tissue resolution and anatomic detail compared with time-domain OCT. 12 Despite these significant advances, the use and study of contrast agents to enhance ophthalmic OCT imaging has been lacking. Historically, common imaging modalities, such as magnetic resonance imaging (MRI) and computed tomography (CT), have used agents such as gadolinium or iodinated contrast to further improve diagnostic capabilities and visualization of pathology and tissue structure. 13,14 The usefulness for contrast enhancement in OCT is likely no different and has the potential to provide the clinician with more detailed in vivo information. Recent reports on making use of contrast agents to enhance the target selectivity of OCT systems are very promising. 15 19 OCT contrast enhancements can be achieved through exogenous or endogenous methods. 20 Endogenous methods of contrast enhancement use the inherent wavelength-dependent absorption patterns of the imaged tissues to enhance image contrast, such as with spectroscopic OCT. 20 Exogenous methods seek to achieve improved contrast through the addition of a material or an agent to the tissue of interest to improve imaging contrast. Exogenous contrast agents include scattering agents (e.g., gold microspheres, liposomes), magnetomotive agents, and near-infrared absorbing dyes. 20 The different classes of OCT contrast agents were recently reviewed with a focus on molecular OCT contrast enhancement. 16 Gold 15 and magnetomotive 21 nanoparticle contrast agents have been shown to be useful in OCT imaging in animals. Gold nanoparticle antibody conjugates have been examined for in vivo imaging of human subjects. 18 However, acute exposure to nanoparticles is a relatively recent phenomenon; the systemic and ocular safety of nanomaterial-based drugs for human studies is still under debate. 22 Any substance that exhibits high backscattering properties resulting in increased reflectivity may function as a useful OCT contrast agent through its scattering properties. 21  
In this study, we investigated novel use of common ophthalmic medications as potential OCT contrast agents and described their application in anterior segment SD-OCT with improved visualization of tissue interfaces. According to our literature review, this study provides the first examination of these OCT contrast agents and provides the first description of the feasibility of ophthalmic OCT imaging with contrast enhancement in human subjects. 
Methods
Human subjects and cadaveric porcine eyes were used for this study. Institutional review board approval was obtained for all portions of this research pertaining to human subjects, and all research adhered to the tenets of the Declaration of Helsinki. Informed consent was obtained from all human subjects. Cadaveric porcine eyes were obtained fresh and used rapidly for imaging. Putative contrast agents that were selected for testing were as follows: prednisolone acetate 1% (PA; Econopred Plus; Alcon, Fort Worth, TX), triamcinolone acetonide 40 mg/mL (TA; Kenalog-40; Bristol-Myers Squibb, Pennington, NJ), and lipid-based emollient artificial tears (LBAT; Soothe XP Emollient Lubricant Eye Drops; Bausch & Lomb, Rochester, NY). 
OCT scanning was performed using a handheld 3D SD-OCT system (Bioptigen; Research Triangle Park, Durham, NC) with the anterior segment imaging head for all cadaveric porcine eye imaging. 23 The handheld probe was placed on a fixed mount to optimize image quality and consistency of image acquisition. Distance of the probe from the eye was adjusted to optimize image focus based on depth of imaging interest (e.g., corneal surface, anterior chamber). Contrast enhancement of anterior segment structures was examined by the introduction of the various agents at the following locations: external corneal surface (topical), in the anterior chamber (intracameral), and within a surgically constructed clear corneal wound (intracorneal). Imaging was performed in triplicate in fresh eyes. Non-lipid–based artificial tears were used to maintain corneal clarity and integrity throughout imaging, except while a topical contrast agent was applied. 
Topical application was performed by placing three drops of the selected test agent (PA, TA, or LBAT) onto the corneal surface and then immediately imaging with the OCT device. Intracameral application was performed with delivery of 0.1 mL of the selected test agent (PA, TA, or LBAT) with a 30-gauge needle that entered the anterior chamber at the limbus. Real-time image OCT image capture was initiated at the time of injection of the contrast agent. Intracorneal application, a 2.7-mm keratome blade was used to make a uniplanar clear corneal incision. The wound interface was then lightly irrigated with 0.1 mL of the selected test agent (PA, TA, or LBAT). For all locations and agents imaged, a 10 × 10-mm volume scan was performed with 1 B-scan/0.1 mm before and after contrast agent application. Additionally, a linear scan was performed with 40 B-scans in the selected area. 
Anterior segment SD-OCT imaging was performed in human subjects immediately after cataract surgery. Immediately after discharge from the postoperative recovery area, subjects were imaged with anterior segment SD-OCT (Cirrus OCT; Zeiss, Thornwood, NY). Volume scanning was performed while centered over the corneal incision. Scans were taken before PA application and immediately after topical application. To administer the topical PA, 1 drop was applied to the inferior fornix after which the patient was instructed to gently close his or her eyes. After 1 minute, an additional drop of PA was applied, and imaging was immediately performed. Scans were evaluated for increased contrast enhancement/reflectivity above the corneal surface and within the corneal wound. 
Qualitative assessment for increased contrast through increased reflectivity in OCT imaging was performed. Intensity is used throughout this article to describe the amount of reflectivity present. Brightness on OCT is synonymous here with intensity, but, for consistency, intensity is used throughout. Application of the agents resulting in relative increased reflectivity/intensity/brightness reflects contrast enhancement. Description of the reflectance patterns of each agent was recorded. Quantitative analysis using ImageJ software (developed by Wayne Rasband, National Institutes of Health, Bethesda, MD; available at http://rsb.info.nih.gov/ij/ index.html) was performed. The polygon measurement tool was used to determine intensity characteristics on a continuous scale from 0 to 256 U (0 = black, 256 = white), for the OCT signal in the area of interest both with and without contrast agents, as measured in three randomly selected scans for each of the triplicate porcine eyes. Measurements of mean, maximum, and SD were obtained for intensity values. Control values were obtained from images of the eyes before any contrast administration. Control measurements were obtained from the area superficial to the corneal epithelium, corneal stroma, corneal wound tract, and anterior chamber fluid, as appropriate. In human eyes, qualitative comparative assessment of the reflectivity patterns of the tear/corneal interface and the wound interface were performed before and after PA application. Quantitative analysis was performed of the wound reflectivity changes after PA application using the polygon tool in the ImageJ software package. Mean intensity was obtained for the area of the wound interface both before and after PA application. Additionally, quantitative intensity measurements of the corneal stroma anterior to the wound interface were obtained to allow for calculation of a correction factor for any interscan intensity variability. A mean intensity increase of 10% at the wound interface was selected as a threshold for increased contrast. This threshold was based on preliminary evaluation and correlation of visible changes in the reflectivity of the wound interface and associated quantitative measurements of increased intensity of the reflectivity within the wound interface. Statistical analysis was performed with the Student's t-test (Excel; Microsoft, Redmond, WA). 
Results
Anatomic Localization
Topical Application.
All three agents provided variable enhanced reflectivity at the corneal surface once applied (Fig. 1). Each of the agents provided variable blockage of the intrastromal details and endothelium. The interface between the agent used and the corneal epithelium was prominent because of the reflectivity difference between the corneal epithelium and the agent examined. PA provided a bright, smooth reflectivity profile across the corneal surface (Fig. 1B). LBAT had a smooth reflectivity profile with minimal granularity. A hyporeflective cleft was variably present at the junction of the hyperreflective portion of the LBAT and the corneal epithelial surface (Fig. 1C). TA appeared to have a coarser and more speckled reflectivity profile on the ocular surface (Fig. 1D). 
Figure 1.
 
SD-OCT images of topically applied contrast agents. (A) Control. (B) PA. (C) LBAT. (D) TA. (A) Corneal epithelium (white arrow), corneal stroma (asterisk), and corneal endothelium (white arrowhead) are labeled. (BD, white arrow) Increased reflectivity associated with the applied contrast agent. (B, C) Increased blockage (e.g., decreased visualization of the deep tissues, such as the endothelium) is seen beneath the contrast agents, particularly with prednisolone and triamcinolone. (C) A thin hyporeflective interface cleft (black arrow) is seen with the LBAT.
Figure 1.
 
SD-OCT images of topically applied contrast agents. (A) Control. (B) PA. (C) LBAT. (D) TA. (A) Corneal epithelium (white arrow), corneal stroma (asterisk), and corneal endothelium (white arrowhead) are labeled. (BD, white arrow) Increased reflectivity associated with the applied contrast agent. (B, C) Increased blockage (e.g., decreased visualization of the deep tissues, such as the endothelium) is seen beneath the contrast agents, particularly with prednisolone and triamcinolone. (C) A thin hyporeflective interface cleft (black arrow) is seen with the LBAT.
Intracameral Application.
Increased reflectivity compared with baseline was seen within the anterior chamber after injection of all three agents (Fig. 2). PA and LBAT coated the undersurface of the corneal endothelium, resulting in improved visualization of the endothelial/aqueous interface (Fig. 2). PA and LBAT exhibited a smooth reflectivity profile within the anterior chamber. TA in the anterior chamber showed a speckled reflectivity profile with granular characteristics. Dynamic visualization of the contrast agent injection was obtained through acquisition of the volume scan during injection (Movie S1
Figure 2.
 
SD-OCT images of intracameral administration of contrast agents. (A) Control image without contrast agent. (B) PA (asterisk) is seen at the interface of the endothelium and anterior chamber (white arrowhead). (C) Lipid-based artificial tears (asterisk) are visualized at the endothelium and anterior chamber interface (white arrowhead). (D) TA (asterisk) is seen in the anterior chamber. The granular nature of the contrast agent is apparent. K, cornea; AC, anterior chamber.
Figure 2.
 
SD-OCT images of intracameral administration of contrast agents. (A) Control image without contrast agent. (B) PA (asterisk) is seen at the interface of the endothelium and anterior chamber (white arrowhead). (C) Lipid-based artificial tears (asterisk) are visualized at the endothelium and anterior chamber interface (white arrowhead). (D) TA (asterisk) is seen in the anterior chamber. The granular nature of the contrast agent is apparent. K, cornea; AC, anterior chamber.
Clear Corneal Wound Enhancement.
Improved visualization of the corneal wound architecture across the length of the incision was seen after application of each of the three agents (Fig. 3). Contrast agent on the ocular surface did not preclude visualization of the contrast material within the wound interface (Movies S2, S3). 
Figure 3.
 
SD-OCT images of a clear corneal incision with and without contrast agent. The wound entry point (white arrow), termination point (arrowhead), and track are visualized without contrast, but visualization is improved with the contrast agents (A, C, E). Once the contrast agent is applied, the agent (PA, B; LBAT, D; TA, F) is seen throughout the wound interface. K, cornea; AC, anterior chamber.
Figure 3.
 
SD-OCT images of a clear corneal incision with and without contrast agent. The wound entry point (white arrow), termination point (arrowhead), and track are visualized without contrast, but visualization is improved with the contrast agents (A, C, E). Once the contrast agent is applied, the agent (PA, B; LBAT, D; TA, F) is seen throughout the wound interface. K, cornea; AC, anterior chamber.
Reflectivity Patterns and Properties of Contrast Agents
Each of the three tested agents showed increased reflectivity on OCT scanning (Fig. 4). LBAT provided a smooth reflectivity profile with a minimal granular appearance. A hyporeflective cleft was variably present in the interface between the corneal epithelial surface and the layer of LBAT (Fig. 4A). PA also provided a smooth reflectivity profile, similar to the appearance of LBAT. The hyporeflective cleft seen with LBAT with topical application was not present in those eyes imaged with PA (Fig. 4B). TA showed a speckled and granular heterogeneous reflectivity profile in all locations (Fig. 4C). 
Figure 4.
 
High-magnification images of reflectivity characteristics of topical contrast agents. (A) LBAT reveals a slightly granular appearance (black asterisk) with a hyporeflective interface stripe at the tear/corneal interface (black arrow) and cornea (white asterisk). (B) PA reveals a smooth and fairly homogeneous highly reflective stripe (black asterisk) over the tear/corneal interface and cornea (white asterisk). (C) TA provides a heterogeneous speckled reflectivity pattern (black asterisk) over the tear/corneal interface and cornea (white asterisk).
Figure 4.
 
High-magnification images of reflectivity characteristics of topical contrast agents. (A) LBAT reveals a slightly granular appearance (black asterisk) with a hyporeflective interface stripe at the tear/corneal interface (black arrow) and cornea (white asterisk). (B) PA reveals a smooth and fairly homogeneous highly reflective stripe (black asterisk) over the tear/corneal interface and cornea (white asterisk). (C) TA provides a heterogeneous speckled reflectivity pattern (black asterisk) over the tear/corneal interface and cornea (white asterisk).
Quantitative Reflectivity Analysis
Comparative analysis was performed of the intensity of the contrast agents compared with the surrounding tissues and baseline physiologic reflectivity. All the contrast agents, when used topically, had significantly increased mean intensity compared with standard non-lipid–based artificial tears (P < 0.01; Fig. 5A). Mean intensity values for artificial tears, PA, LBAT, and TA were 54 U, 143 U, 150 U, and 117 U, respectively. Additionally, maximum intensity was significantly increased compared with control (P < 0.05). When compared with each other, topical PA and LBAT both had higher mean intensity than TA (P < 0.01). There were no differences between the maximum intensity of the topical agents. Intracameral contrast agents had significantly increased mean and maximum intensity compared with aqueous and corneal stroma (P < 0.001; Fig. 5B). Mean intensity values for aqueous, corneal stroma, PA, LBAT, and TA were 42 U, 52 U, 106 U, 89 U, and 106 U, respectively. Intracameral comparison of the contrast agents revealed that PA had a higher mean intensity than LBAT and TA (P < 0.05). Both TA and PA had a higher maximum intensity than LBAT (P < 0.05). Each of the test agents also significantly increased the mean intensity of the wound interface (P < 0.02; Fig. 5C) and increased maximum intensity of the wound interface (P < 0.001). Mean intensity of the PA control and PA were 70 U and 103 U, respectively. Mean intensity of LBAT-control and LBAT were 74 U and 101 U, respectively. Mean intensity of the TA control and TA were 82 U and 107 U, respectively. No significant differences were found between the agents when used within the wound interface. 
Figure 5.
 
Comparison of mean intensity levels (U, arbitrary) between control (non-lipid–based artificial tears) and test agents of interest at various locations. *P < 0.05; statistically significant compared with control (AT, aqueous, corneal stroma, and no intracorneal contrast).
Figure 5.
 
Comparison of mean intensity levels (U, arbitrary) between control (non-lipid–based artificial tears) and test agents of interest at various locations. *P < 0.05; statistically significant compared with control (AT, aqueous, corneal stroma, and no intracorneal contrast).
Contrast-Enhanced SD-OCT Imaging of Clear Corneal Cataract Wounds in Human Subjects
Ten subjects underwent uncomplicated clear corneal cataract surgery with 2.2 mm clear corneal biplanar incisions. The corneal wound stoma was hydrated, and the eye was left at physiologic pressure; no wounds were sutured. No wound burns were noted at the end of the case. OCT imaging of the corneal wound was successfully achieved in all subjects. After topical PA, a hyperreflective layer was noted above the corneal surface in all patients. The reflectivity of PA in human imaging was similar, with a smooth, bright profile. With the reduced volume of PA applied, the height of the hyperreflective layer appeared shorter than the layer obtained in ex vivo imaging. In six eyes, quantitative analysis revealed an increased reflectivity of ≥10% within the corneal wound interface after PA application with improved contrast enhancement of the corneal wound (Fig. 6). 
Figure 6.
 
SD-OCT of a clear corneal incision immediately after cataract surgery, before (A) and after (B) prednisolone acetate application. Corneal surface shows (A, dotted arrow) absence of precorneal hyperreflective stripe before prednisolone and (B, dotted arrow) presence of stripe after prednisolone. Internal extent of incision with wound gape is noted (A, B, solid arrows). Wound interface is difficult to visualize in the mid-corneal stroma before prednisolone application (A, arrowhead), but visualization is improved by the contrast enhancement provided after prednisolone application (B, arrowhead).
Figure 6.
 
SD-OCT of a clear corneal incision immediately after cataract surgery, before (A) and after (B) prednisolone acetate application. Corneal surface shows (A, dotted arrow) absence of precorneal hyperreflective stripe before prednisolone and (B, dotted arrow) presence of stripe after prednisolone. Internal extent of incision with wound gape is noted (A, B, solid arrows). Wound interface is difficult to visualize in the mid-corneal stroma before prednisolone application (A, arrowhead), but visualization is improved by the contrast enhancement provided after prednisolone application (B, arrowhead).
Discussion
In this study, we describe the use of contrast agents in anterior segment OCT imaging. The agents used in this study are all commonly used for ophthalmic conditions, such as dry eye and inflammation. PA is approved by the United States Food and Drug Administration (FDA) for ophthalmic use, and TA is used off label for ophthalmic applications. LBAT is an over-the-counter medication indicated for dry eye syndrome. These commercially available compounds were selected because of their optical characteristics of variable translucency and light scattering from particulate or droplet reflectors, suggesting a possible effect on reflectivity with OCT imaging. Additionally, these agents were selected because of the ease of availability and for their current clinical use in ophthalmology both on and off label. In human subjects, topical PA was used as a possible contrast agent because of its frequent use in postoperative care. When used topically, intracamerally, and within the corneal stroma, the agents exhibited increased reflectivity and improved visualization of tissue interfaces. 
PA provided excellent contrast in human subjects. When applied topically, increased reflectivity was noted above the corneal surface in all subjects, and in 6 of 10 patients increased contrast enhancement was noted at the wound interface. The presence of contrast enhancement within the corneal wound suggested an influx of PA. With this contrast-enhanced method of SD-OCT, it may be possible to study functional wound dynamics in vivo. 
The present study shows that reflectivity patterns are varied between the chosen contrast agents. TA was granular and had a heterogeneous pattern compared with PA, which had a smooth, homogeneous, hyperreflective pattern. The pattern seen may be related to differences between TA and PA in particle size/area and the reflectance at the interfaces within the agents. TA particles have a mean area of 177 μm2 24 ; assuming a circular configuration for the particles, the mean diameter of the triamcinolone particles would be 15 μm. PA particles have a median particle size of approximately 2 μm, with 90% of particles smaller than 4 μm. 25 We hypothesize that the difference between TA and PA particle size dictates the reflectivity patterns given the maximum resolution of 6 μm for the OCT unit used in this study. The reflectivity pattern seen with LBAT showed a superficial hyperreflective layer with a variable underlying hyporeflective stripe above the corneal epithelium. The hyperreflectivity likely depended on the emulsion droplet size and reflectance at the droplet interfaces within LBAT. The underlying hyporeflective layer may be attributed to the bilayer film created by the constituents of the LBAT solution, including a mixture of oils and water, with the more hyporeflective aqueous layer located deep to the more superficial lipid layer. 26,27  
Historically, imaging modalities have often been improved by the use of contrast agents. As early as 1948, iodinated compounds were described for use in radiographic studies. 13 Similarly, MRI has been greatly enhanced by the development of paramagnetic compounds, such as gadolinium. 14 The use of contrast agents can improve visualization of anatomy and pathology, inform diagnosis, and guide therapeutic intervention. 
In other areas of clinical medicine, OCT contrast agents are being studied to improve diagnosis and to expand the potential of OCT technology. Enhanced OCT imaging of oral dysplasia has been described using antibody-conjugated gold nanoparticles in a hamster model. 28 The application of OCT contrast agents to dermatology and cutaneous imaging has also been reported. 29 Improved OCT contrast and visualization has been reported for the gastrointestinal tract using a hyperosmotic agent (i.e., propylene glycol). 17 Using time-domain OCT, microbubbles have been found to provide contrast in murine femoral blood vessels and the anterior chambers of harvested rabbit eyes. 30  
The possible clinical usefulness of an OCT contrast agent in ophthalmology is broad and wide ranging. Contrast agents could potentially be used on the corneal surface to highlight superficial corneal pathology. Additionally, the particulate nature of the contrast agents might allow for evaluation of intraocular fluidics if used intraocularly. As in this study, wound integrity and architecture could be analyzed based on the ingress of contrast agents from the ocular surface into the wound interface after surgical intervention. Targeted agents for various ophthalmic locations, molecular targets, or pathologic conditions could lead to a greater role for OCT in evaluating ongoing function, making it a dynamic imaging tool. In effect, targeted contrast agents could result in a functional OCT that guides ongoing clinical management. Clearly, a strong safety profile and a low toxicity risk of any possible agents would be necessary to allow for ocular or intraocular use of a contrast agent for imaging purposes. 
The present study has some limitations. None of these agents is approved by the FDA for intraocular use in the formulations evaluated in this study. The hyperreflectivity patterns of these agents limit the contrast enhancement of interfaces within ocular tissues that are hyperreflective on OCT (e.g., sclera). For increasing image contrast in hyperreflective tissues, a hyporeflective contrast agent might be of value. The agents evaluated in this study provided contrast enhancement of tissue interfaces rather than increased resolution within the tissue. This is an important differentiation from other contrast agents used in medicine (e.g., gadolinium, iodinated contrast) in which specific tissues may actually enhance with contrast. It is unclear whether these agents might provide improved enhancement of tissue in various disease states (e.g., increased contrast at the epithelium in corneal surface abnormalities, chronic inflammatory conditions). Imaging and evaluation of contrast agents for posterior segment tissue interfaces, structures, and pathologic conditions were not evaluated. 
This study provides a foundation for further study of OCT contrast agents in ophthalmology. Importantly, the contrast agents used in this study are frequently used both on label and off label for ophthalmic applications. This report confirms the feasibility of enhancing reflectivity and improving visualization of tissue interfaces through the use of contrast agents. Further study regarding the clinical applications of OCT contrast agents and research into the development of posterior segment contrast agents will further enhance our ability to image ocular structures as well as our understanding of ophthalmic disease processes. 
Supplementary Materials
Movie S1 - (.mov) - Intracameral injection of prednisolone acetate. Video shows volume scan with spectral domain optical coherence tomography obtained while actively injection prednisolone acetate. Anterior segment structures, including the cornea, iris, and anterior chamber, are well visualized during the scan. The prednisolone acetate appears as a highly reflective wave in the anterior chamber. The needle is also visualized during the scan. 
Movie S2 - (.mov) - Intracorneal wound visualization, control. Video shows volume scan with spectral domain optical coherence tomography of control eye following construction of a clear corneal wound. The wound interface is visualized as a slightly hyperreflective band in the corneal stroma. 
Movie S3 - (.mov) - Intracorneal wound visualization with prednisolone acetate. Video shows volume scan with spectral domain optical coherence tomography of control eye following construction of a clear corneal wound with application of prednisolone acetate to the wound interface. The wound interface is visualized as a highly reflective band in the corneal stroma. 
Footnotes
 Supported by a grant from Research to Prevent Blindness.
Footnotes
 Disclosure: J.P. Ehlers, None; P.K. Gupta, None; S. Farsiu, None; R. Maldonado, None; T. Kim, None; C.A. Toth, Bioptigen (C); P. Mruthyunjaya, None
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Figure 1.
 
SD-OCT images of topically applied contrast agents. (A) Control. (B) PA. (C) LBAT. (D) TA. (A) Corneal epithelium (white arrow), corneal stroma (asterisk), and corneal endothelium (white arrowhead) are labeled. (BD, white arrow) Increased reflectivity associated with the applied contrast agent. (B, C) Increased blockage (e.g., decreased visualization of the deep tissues, such as the endothelium) is seen beneath the contrast agents, particularly with prednisolone and triamcinolone. (C) A thin hyporeflective interface cleft (black arrow) is seen with the LBAT.
Figure 1.
 
SD-OCT images of topically applied contrast agents. (A) Control. (B) PA. (C) LBAT. (D) TA. (A) Corneal epithelium (white arrow), corneal stroma (asterisk), and corneal endothelium (white arrowhead) are labeled. (BD, white arrow) Increased reflectivity associated with the applied contrast agent. (B, C) Increased blockage (e.g., decreased visualization of the deep tissues, such as the endothelium) is seen beneath the contrast agents, particularly with prednisolone and triamcinolone. (C) A thin hyporeflective interface cleft (black arrow) is seen with the LBAT.
Figure 2.
 
SD-OCT images of intracameral administration of contrast agents. (A) Control image without contrast agent. (B) PA (asterisk) is seen at the interface of the endothelium and anterior chamber (white arrowhead). (C) Lipid-based artificial tears (asterisk) are visualized at the endothelium and anterior chamber interface (white arrowhead). (D) TA (asterisk) is seen in the anterior chamber. The granular nature of the contrast agent is apparent. K, cornea; AC, anterior chamber.
Figure 2.
 
SD-OCT images of intracameral administration of contrast agents. (A) Control image without contrast agent. (B) PA (asterisk) is seen at the interface of the endothelium and anterior chamber (white arrowhead). (C) Lipid-based artificial tears (asterisk) are visualized at the endothelium and anterior chamber interface (white arrowhead). (D) TA (asterisk) is seen in the anterior chamber. The granular nature of the contrast agent is apparent. K, cornea; AC, anterior chamber.
Figure 3.
 
SD-OCT images of a clear corneal incision with and without contrast agent. The wound entry point (white arrow), termination point (arrowhead), and track are visualized without contrast, but visualization is improved with the contrast agents (A, C, E). Once the contrast agent is applied, the agent (PA, B; LBAT, D; TA, F) is seen throughout the wound interface. K, cornea; AC, anterior chamber.
Figure 3.
 
SD-OCT images of a clear corneal incision with and without contrast agent. The wound entry point (white arrow), termination point (arrowhead), and track are visualized without contrast, but visualization is improved with the contrast agents (A, C, E). Once the contrast agent is applied, the agent (PA, B; LBAT, D; TA, F) is seen throughout the wound interface. K, cornea; AC, anterior chamber.
Figure 4.
 
High-magnification images of reflectivity characteristics of topical contrast agents. (A) LBAT reveals a slightly granular appearance (black asterisk) with a hyporeflective interface stripe at the tear/corneal interface (black arrow) and cornea (white asterisk). (B) PA reveals a smooth and fairly homogeneous highly reflective stripe (black asterisk) over the tear/corneal interface and cornea (white asterisk). (C) TA provides a heterogeneous speckled reflectivity pattern (black asterisk) over the tear/corneal interface and cornea (white asterisk).
Figure 4.
 
High-magnification images of reflectivity characteristics of topical contrast agents. (A) LBAT reveals a slightly granular appearance (black asterisk) with a hyporeflective interface stripe at the tear/corneal interface (black arrow) and cornea (white asterisk). (B) PA reveals a smooth and fairly homogeneous highly reflective stripe (black asterisk) over the tear/corneal interface and cornea (white asterisk). (C) TA provides a heterogeneous speckled reflectivity pattern (black asterisk) over the tear/corneal interface and cornea (white asterisk).
Figure 5.
 
Comparison of mean intensity levels (U, arbitrary) between control (non-lipid–based artificial tears) and test agents of interest at various locations. *P < 0.05; statistically significant compared with control (AT, aqueous, corneal stroma, and no intracorneal contrast).
Figure 5.
 
Comparison of mean intensity levels (U, arbitrary) between control (non-lipid–based artificial tears) and test agents of interest at various locations. *P < 0.05; statistically significant compared with control (AT, aqueous, corneal stroma, and no intracorneal contrast).
Figure 6.
 
SD-OCT of a clear corneal incision immediately after cataract surgery, before (A) and after (B) prednisolone acetate application. Corneal surface shows (A, dotted arrow) absence of precorneal hyperreflective stripe before prednisolone and (B, dotted arrow) presence of stripe after prednisolone. Internal extent of incision with wound gape is noted (A, B, solid arrows). Wound interface is difficult to visualize in the mid-corneal stroma before prednisolone application (A, arrowhead), but visualization is improved by the contrast enhancement provided after prednisolone application (B, arrowhead).
Figure 6.
 
SD-OCT of a clear corneal incision immediately after cataract surgery, before (A) and after (B) prednisolone acetate application. Corneal surface shows (A, dotted arrow) absence of precorneal hyperreflective stripe before prednisolone and (B, dotted arrow) presence of stripe after prednisolone. Internal extent of incision with wound gape is noted (A, B, solid arrows). Wound interface is difficult to visualize in the mid-corneal stroma before prednisolone application (A, arrowhead), but visualization is improved by the contrast enhancement provided after prednisolone application (B, arrowhead).
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