Evaluation of Contrast Agents for Enhanced
Visualization in Optical Coherence Tomography
Justis P. Ehlers,1,2Preeya K. Gupta,2Sina Farsiu,2Ramiro Maldonado,2Terry Kim,2
Cynthia A. Toth,2and Prithvi Mruthyunjaya2
PURPOSE. To identify and evaluate the use of contrast agents in
optical coherence tomography (OCT) for ophthalmic applica-
METHODS. Three agents—prednisolone acetate (PA), triamcin-
olone 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 cham-
ber. 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 re-
view board approval was obtained for imaging in human sub-
jects undergoing cataract surgery. PA was applied to the cor-
neal surface, and SD-OCT imaging was performed of the
corneal surface and wound interface immediately after cataract
All agents provided increased reflectivity. PA and
LBAT showed a smooth bright reflectivity profile, whereas TA
had a granular profile. Improved visualization of tissue inter-
faces 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 applica-
tions of OCT contrast agents might include evaluation of
wound stability, intraocular fluidics, and ocular surface
disease. (Invest Ophthalmol Vis Sci. 2010;51:6614–6619)
in ophthalmology and in multiple other fields, including cardi-
ology, dermatology, gastroenterology, and urology.2–5Oph-
thalmology 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 disor-
irst described in 1991,1optical coherence tomography
(OCT) has improved ultrastructural imaging and diagnosis
OCT image quality and acquisition have improved with the
development of spectral domain OCT (SD-OCT),9–11allowing
greater tissue resolution and anatomic detail compared with
time-domain OCT.12Despite these significant advances, the
use and study of contrast agents to enhance ophthalmic OCT
imaging has been lacking. Historically, common imaging mo-
dalities, such as magnetic resonance imaging (MRI) and com-
puted tomography (CT), have used agents such as gadolinium
or iodinated contrast to further improve diagnostic capabilities
and visualization of pathology and tissue structure.13,14The
usefulness for contrast enhancement in OCT is likely no differ-
ent 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 sys-
tems are very promising.15–19OCT contrast enhancements can
be achieved through exogenous or endogenous methods.20
Endogenous methods of contrast enhancement use the inher-
ent wavelength-dependent absorption patterns of the imaged
tissues to enhance image contrast, such as with spectroscopic
OCT.20Exogenous 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, lipo-
somes), magnetomotive agents, and near-infrared absorbing
reviewed with a focus on molecular OCT contrast enhance-
ment.16Gold15and magnetomotive21nanoparticle 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.18However,
acute exposure to nanoparticles is a relatively recent phenom-
enon; the systemic and ocular safety of nanomaterial-based
drugs for human studies is still under debate.22Any substance
that exhibits high backscattering properties resulting in in-
creased reflectivity may function as a useful OCT contrast
agent through its scattering properties.21
In this study, we investigated novel use of common oph-
thalmic medications as potential OCT contrast agents and de-
scribed 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 en-
hancement in human subjects.
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
From the1Cole Eye Institute, The Cleveland Clinic Foundation,
Cleveland, Ohio; and the2Duke Eye Center, Duke University, Durham,
Supported by a grant from Research to Prevent Blindness.
Submitted for publication July 12, 2010; revised August 1, 2010;
accepted August 1, 2010.
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
Corresponding author: Justis P. Ehlers, Cole Eye Institute, The
Cleveland Clinic Foundation, 9500 Euclid Avenue, Mail Code i-20,
Cleveland, OH 44195; email@example.com.
Multidisciplinary Ophthalmic Imaging
Investigative Ophthalmology & Visual Science, December 2010, Vol. 51, No. 12
Copyright © Association for Research in Vision and Ophthalmology
ture of the contrast agents might allow for evaluation of in-
traocular 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 patho-
logic conditions could lead to a greater role for OCT in evalu-
ating 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 pat-
terns of these agents limit the contrast enhancement of inter-
faces 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 en-
hancement 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, struc-
tures, 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 con-
trast agents will further enhance our ability to image ocular
structures as well as our understanding of ophthalmic disease
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