-
[show abstract]
[hide abstract]
ABSTRACT: Optical coherence tomography (OCT) and scanning laser ophthalmoscopy (SLO) are complementary imaging modalities, the combination of which can provide clinicians with a wealth of information to detect retinal diseases, monitor disease progression, or assess new therapies. Adaptive optics (AO) is a tool that enables correction of wavefront distortions from ocular aberrations. We have developed a multimodal adaptive optics system (MAOS) for high-resolution multifunctional use in a variety of research and clinical applications. The system integrates both OCT and SLO imaging channels into an AO beam path. The optics and hardware were designed with specific features for simultaneous SLO/OCT output, for high-fidelity AO correction, for use in humans, primates, and small animals, and for efficient location and orientation of retinal regions of interest. The MAOS system was tested on human subjects and rodents. The design, performance characterization, and initial representative results from the human and animal studies are presented and discussed.
Journal of the Optical Society of America A 12/2012; 29(12):2598-607. · 1.56 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Blood flow in murine epicardial and intra-myocardial coronary arteries was measured in vivo with spectral domain optical Doppler tomography (SD-ODT). Videos at frame rates up to 180 fps were collected and processed to extract phase shifts associated with moving erythrocytes in the coronary arteries. Radial averaging centered on the vessel lumen provided spatial smoothing of phase noise in a single cross-sectional frame for instantaneous peak velocity measurement without distortion of the flow profile. Temporal averaging synchronized to the cardiac cycle (i.e., gating) was also performed to reduce phase noise, although resulting in lower flow profiles. The vessel angle with respect to incident imaging beam was measured with three-dimensional raster scans collected from the same region as the high speed cross-sectional scans. The variability in peak phase measurement was 10-15% from cycle to cycle on a single animal but larger for measurements among animals. The inter-subject variability is attributed to factors related to real physiological and anatomical differences, instrumentation variables, and measurement error. The measured peak instantaneous flow velocity in a ~40-µm diameter vessel was 23.5 mm/s (28 kHz Doppler phase shift). In addition to measurement of the flow velocity, we observed several dynamic features of the vessel and surrounding myocardium in the intensity and phase sequences, including asymmetric vessel deformation and rapid flow reversal immediately following maximum flow, in confirmation of known coronary artery flow dynamics. SD-ODT is an optical imaging tool that can provide in vivo measures of structural and functional information on cardiac function in small animals.
Biomedical Optics Express 04/2012; 3(4):701-14. · 2.33 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: A multifunctional line scanning ophthalmoscope (mLSO) was designed, constructed, and tested on human subjects. The mLSO could sequentially acquire wide-field, confocal, near-infrared reflectance, fluorescein angiography (FA), and indocyanine green angiography (ICGA) retinal images. The system also included a retinal tracker (RT) and a photodynamic therapy laser treatment port. The mLSO was tested in a pilot clinical study on human subjects with and without retinal disease. The instrument exhibited robust retinal tracking and high-contrast line scanning imaging. The FA and ICGA angiograms showed a similar appearance of hyper- and hypo-pigmented disease features and a nearly equivalent resolution of fine capillaries compared to a commercial flood-illumination fundus imager. An mLSO-based platform will enable researchers and clinicians to image human and animal eyes with a variety of modalities and deliver therapeutic beams from a single automated interface. This approach has the potential to improve patient comfort and reduce imaging session times, allowing clinicians to better diagnose, plan, and conduct patient procedures with improved outcomes.
Journal of Biomedical Optics 02/2012; 17(2):026008. · 3.16 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: A new type of freeze-drying microscope based upon time-domain optical coherence tomography is presented here (OCT-FDM). The microscope allows for real-time, in situ 3D imaging of pharmaceutical formulations in vials relevant for manufacturing processes with a lateral resolution of <7 μm and an axial resolution of <5 μm. Correlation of volumetric structural imaging with product temperature measured during the freeze-drying cycle allowed investigation of structural changes in the product and determination of the temperature at which the freeze-dried cake collapses. This critical temperature is the most important parameter in designing freeze-drying processes of pharmaceutical products.
Biomedical Optics Express 01/2012; 3(1):55-63. · 2.33 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: A new concept for cancer screening has been preliminarily investigated. A cancer targeting agent loaded with a near-infrared (NIR) dye was topically applied on the tissue to highlight cancer-suspect locations and guide optical coherence tomography (OCT) imaging, which was used to further investigate tissue morphology at the micron scale. A pilot study on ApcMin mice has been performed to preliminarily test this new cancer screening approach. As a cancer-targeting agent, poly(epsilon-caprolactone) microparticles (PCLMPs), labeled with a NIR dye and functionalized with an RGD (argenine-glycine-aspartic acid) peptide, were used. This agent recognizes the α(ν)β(3) integrin receptor (ABIR), which is over-expressed by epithelial cancer cells. The contrast agent was administered topically in vivo in mouse colon. After incubation, the animals were sacrificed and fluorescence-guided high resolution optical coherence tomography (OCT) imaging was used to visualize colon morphology. The preliminary results show preferential staining of the abnormal tissue, as indicated by both microscopy and laser-induced fluorescence imaging, and OCT's capability to differentiate between normal mucosal areas, early dysplasia, and adenocarcinoma. Although very preliminary, the results of this study suggest that fluorescence-guided OCT imaging might be a suitable approach for cancer screening. If successful, this approach could be used by clinicians to more reliably diagnose early stage cancers in vivo.
Biomedical Optics Express 01/2012; 3(1):178-91. · 2.33 Impact Factor
-
Nicusor Iftimia,
Sevdenur Cizginer,
Vikram Deshpande,
Martha Pitman,
Servet Tatli,
Nicolae-Adrian Iftimia,
Daniel X Hammer,
Mircea Mujat,
Teoman Ustun, R Daniel Ferguson,
William R Brugge
[show abstract]
[hide abstract]
ABSTRACT: We demonstrate for the first time that optical coherence tomography (OCT) imaging can reliably distinguish between morphologic features of low risk pancreatic cysts (i.e., pseudocysts and serous cystadenomas) and high risk pancreatic cysts (i.e., mucinous cystic neoplasms and intraductal papillary mucinous neoplasms). In our study fresh pancreatectomy specimens (66) from patients with cystic lesions undergoing surgery were acquired and examined with OCT. A training set of 20 pathology-OCT correlated tissue specimens were used to develop criteria for differentiating between low and high risk cystic lesions. A separate (validation) set of 46 specimens were used to test the OCT criteria by three clinicians, blinded to histopathology findings. Histology was finally used as a 'gold' standard for testing OCT findings. OCT was able to reveal specific morphologic features of pancreatic cysts and thus to differentiate between low-risk and high-risk cysts with over 95% sensitivity and specificity. This pilot study suggests that OCT could be used by clinicians in the future to more reliably differentiate between benign and potentially malignant pancreatic cysts. However, in vivo use of OCT requires a probe that has to fit the bore of the pancreas biopsy needle. Therefore, we have developed such probes and planned to start an in vivo pilot study within the very near future.
Biomedical Optics Express 08/2011; 2(8):2372-82. · 2.33 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: We have developed a new, unified implementation of the adaptive optics scanning laser ophthalmoscope (AOSLO) incorporating a wide-field line-scanning ophthalmoscope (LSO) and a closed-loop optical retinal tracker. AOSLO raster scans are deflected by the integrated tracking mirrors so that direct AOSLO stabilization is automatic during tracking. The wide-field imager and large-spherical-mirror optical interface design, as well as a large-stroke deformable mirror (DM), enable the AOSLO image field to be corrected at any retinal coordinates of interest in a field of >25 deg. AO performance was assessed by imaging individuals with a range of refractive errors. In most subjects, image contrast was measurable at spatial frequencies close to the diffraction limit. Closed-loop optical (hardware) tracking performance was assessed by comparing sequential image series with and without stabilization. Though usually better than 10 μm rms, or 0.03 deg, tracking does not yet stabilize to single cone precision but significantly improves average image quality and increases the number of frames that can be successfully aligned by software-based post-processing methods. The new optical interface allows the high-resolution imaging field to be placed anywhere within the wide field without requiring the subject to re-fixate, enabling easier retinal navigation and faster, more efficient AOSLO montage capture and stitching.
Journal of the Optical Society of America A 11/2010; 27(11):A265-77. · 1.56 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: The goal of this research was to develop and preliminarily test a novel technology and instrumentation that could help to significantly increase the diagnostic yield of current colon cancer screening procedures. This technology is based on a combined fluorescence-optical coherence tomography (OCT) imaging, and topical delivery of a cancer-targeting agent.
Gold colloid-adsorbed poly(ε-caprolactone) microparticles were labeled with a near-infrared dye, and functionalized with argentine-glycine-aspartic acid (RGD peptide) to effectively target cancer tissue, and enhance fluorescence-imaging contrast. The RGD peptide recognizes the α(v)β(3)-integrin receptor, which is overexpressed by epithelial cancer cells. OCT was used under fluorescence guidance to visualize tissue morphology and, thus, to serve as a confirmatory tool for cancer presence.
A preliminary testing of this technology on human colon cancer cell lines, a mouse model of colon cancer, as well as human colon tissue specimens, was performed. Strong binding of microparticles to cancer cells and no binding to cells that do not significantly express integrins, such as mouse fibroblasts, was observed. Preferential binding to cancer tissue was also observed. Strong fluorescence signals were obtained from cancer tissue, owing to the efficient binding of the contrast agent. OCT imaging was capable of revealing clear differences between normal and cancer tissue.
A dual-modality imaging approach combined with topical delivery of a cancer-targeting contrast agent has been preliminarily tested for colon cancer diagnosis. Preferential binding of the contrast agent to cancer tissue allowed the cancer-suspicious locations to be highlighted and, thus, guided OCT imaging to visualize tissue morphology and determine tissue type. If successful, this multimodal approach might help to increase the sensitivity and the specificity of current colon cancer-screening procedures in the future.
Nanomedicine 11/2010; 5(9):1467-79. · 5.05 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: We developed a multimodal adaptive optics (AO) retinal imager which is the first to combine high performance AO-corrected scanning laser ophthalmoscopy (SLO) and swept source Fourier domain optical coherence tomography (SSOCT) imaging modes in a single compact clinical prototype platform. Such systems are becoming ever more essential to vision research and are expected to prove their clinical value for diagnosis of retinal diseases, including glaucoma, diabetic retinopathy (DR), age-related macular degeneration (AMD), and retinitis pigmentosa. The SSOCT channel operates at a wavelength of 1 microm for increased penetration and visualization of the choriocapillaris and choroid, sites of major disease activity for DR and wet AMD. This AO system is designed for use in clinical populations; a dual deformable mirror (DM) configuration allows simultaneous low- and high-order aberration correction over a large range of refractions and ocular media quality. The system also includes a wide field (33 deg.) line scanning ophthalmoscope (LSO) for initial screening, target identification, and global orientation, an integrated retinal tracker (RT) to stabilize the SLO, OCT, and LSO imaging fields in the presence of lateral eye motion, and a high-resolution LCD-based fixation target for presentation of visual cues. The system was tested in human subjects without retinal disease for performance optimization and validation. We were able to resolve and quantify cone photoreceptors across the macula to within approximately 0.5 deg (approximately 100-150 microm) of the fovea, image and delineate ten retinal layers, and penetrate to resolve features deep into the choroid. The prototype presented here is the first of a new class of powerful flexible imaging platforms that will provide clinicians and researchers with high-resolution, high performance adaptive optics imaging to help guide therapies, develop new drugs, and improve patient outcomes.
Optics Express 05/2010; 18(11):11607-21. · 3.59 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: We have developed a compact retinal imager that integrates adaptive optics (AO) into a line scanning ophthalmoscope (LSO). The bench-top AO-LSO instrument significantly reduces the size, complexity, and cost of research AO scanning laser ophthalmoscopes (AOSLOs), for the purpose of moving adaptive optics imaging more rapidly into routine clinical use. The AO-LSO produces high resolution retinal images with only one moving part and a significantly reduced instrument footprint and number of optical components. The AO-LSO has a moderate field of view (5.5 deg), which allows montages of the macula or other targets to be obtained more quickly and efficiently. In a preliminary human subjects investigation, photoreceptors could be resolved and counted within approximately 0.5 mm of the fovea. Photoreceptor counts matched closely to previously reported histology. The capillaries surrounding the foveal avascular zone could be resolved, as well as cells flowing within them. Individual nerve fiber bundles could be resolved, especially near the optic nerve head, as well as other structures such as the lamina cribrosa. In addition to instrument design, fabrication, and testing, software algorithms were developed for automated image registration and cone counting.
Optics Express 07/2009; 17(12):10242-58. · 3.59 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Real-time display of processed Fourier domain optical coherence tomography (FDOCT) images is important for applications that require instant feedback of image information, for example, systems developed for rapid screening or image-guided surgery. However, the computational requirements for high-speed FDOCT image processing usually exceeds the capabilities of most computers and therefore display rates rarely match acquisition rates for most devices. We have designed and developed an image processing system, including hardware based upon a field programmable gated array, firmware, and software that enables real-time display of processed images at rapid line rates. The system was designed to be extremely flexible and inserted in-line between any FDOCT detector and any Camera Link frame grabber. Two versions were developed for spectrometer-based and swept source-based FDOCT systems, the latter having an additional custom high-speed digitizer on the front end but using all the capabilities and features of the former. The system was tested in humans and monkeys using an adaptive optics retinal imager, in zebrafish using a dual-beam Doppler instrument, and in human tissue using a swept source microscope. A display frame rate of 27 fps for fully processed FDOCT images (1024 axial pixels x 512 lateral A-scans) was achieved in the spectrometer-based systems.
The Review of scientific instruments 12/2008; 79(11):114301. · 1.52 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: To describe the fine structure of the fovea in subjects with a history of mild retinopathy of prematurity (ROP) using adaptive optics-Fourier domain optical coherence tomography (AO-FDOCT).
High-speed, high-resolution AO-FDOCT videos were recorded in subjects with a history of ROP (n = 5; age range, 14-26 years) and in control subjects (n = 5; age range, 18-25 years). Custom software was used to extract foveal pit depth and volume from three-dimensional (3-D) retinal maps. The thickness of retinal layers as a function of retinal eccentricity was measured manually. The retinal vasculature in the parafoveal region was assessed.
The foveal pit was wider and shallower in ROP than in control subjects. Mean pit depth, defined from the base to the level at which the pit reaches a lateral radius of 728 microm, was 121 microm compared with 53 microm. Intact, contiguous inner retinal layers overlay the fovea in ROP subjects but were absent in the control subjects. Mean full retinal thickness at the fovea was greater in the subjects with ROP (279.0 microm vs. 190.2 microm). The photoreceptor layer thickness did not differ between ROP and control subjects. An avascular zone was not identified in the subjects with ROP but was present in all the control subjects.
The foveas of subjects with a history of mild ROP have significant structural abnormalities that are probably a consequence of perturbations of neurovascular development.
Investigative Ophthalmology & Visual Science 06/2008; 49(5):2061-70. · 3.60 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: We have developed a compact, multimodal instrument for simultaneous acquisition of en face quasi-confocal fundus images and adaptive-optics (AO) spectral-domain optical coherence tomography (SDOCT) cross-sectional images. The optical system including all AO and SDOCT components occupies a 60x60 cm breadboard that can be readily transported for clinical applications. The AO component combines a Hartmann-Shack wavefront sensor and a microelectromechanical systems-based deformable mirror to sense and correct ocular aberrations at 15 Hz with a maximum stroke of 4 microm. A broadband superluminescent diode source provides 4 mum depth resolution for SDOCT imaging. In human volunteer testing, we observed up to an 8 dB increase in OCT signal and a corresponding lateral resolution of <10 microm as a result of AO correction.
Journal of the Optical Society of America A 06/2007; 24(5):1327-36. · 1.56 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: We demonstrate in vivo measurements in human retinal vessels of an experimental parameter, the slope of the low coherence interferometry (LCI) depth reflectivity profile, which strongly correlates with the real value of blood hematocrit. A novel instrument that combines two technologies, spectral domain low coherence interferometry (SDLCI) and retinal tracking, has been developed and used for these measurements. Retinal tracking allows a light beam to be stabilized on retinal vessels, while SDLCI is used for obtaining depth-reflectivity profiles within the investigated vessel. SDLCI backscatter extinction rates are obtained from the initial slope of the A-scan profile within the vessel lumen. The differences in the slopes of the depth reflectivity profiles for different subjects are interpreted as the difference in the scattering coefficient, which is correlated with the number density of red blood cells (RBC) in blood. With proper calibration, it is possible to determine hematocrit in retinal vessels. Ex vivo measurements at various RBC concentrations were performed to calibrate the instrument. Preliminary measurements on several healthy volunteers show estimated hematocrit values within the normal clinical range.
Optics Express 05/2006; 14(8):3377-88. · 3.59 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: A retinal imaging instrument that integrates adaptive optics (AO), scanning laser ophthalmoscopy (SLO), and retinal tracking components was built and tested. The system uses a Hartmann-Shack wave-front sensor (HS-WS) and MEMS-based deformable mirror (DM) for AO-correction of high-resolution, confocal SLO images. The system includes a wide-field line-scanning laser ophthalmoscope for easy orientation of the high-magnification SLO raster. The AO system corrected ocular aberrations to <0.1 mum RMS wave-front error. An active retinal tracking with custom processing board sensed and corrected eye motion with a bandwidth exceeding 1 kHz. We demonstrate tracking accuracy down to 6 mum RMS for some subjects (typically performance: 10-15 mum RMS). The system has the potential to become an important tool to clinicians and researchers for vision studies and the early detection and treatment of retinal diseases.
Optics Express 04/2006; 14(8):3354-67. · 3.59 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: To develop an eye-motion-tracking optical coherence tomographic (OCT) method and assess its effect on image registration and nerve fiber layer (NFL) thickness measurement reproducibility.
A system capable of tracking common fundus features based on reflectance changes was integrated into a commercial OCT unit (OCT II; Carl Zeiss Meditec, Inc., Dublin, CA) and tested on healthy subjects and patients with glaucoma. Twenty successive peripapillary NFL scans were obtained with tracking and 20 without tracking, for 40 images in each session for each eye. Subjects participated in one session on three different days. Composite OCT scans and composite fundus images were generated for assessment of eye tracking. NFL thickness measurement reproducibility was also assessed.
Seven healthy and nine glaucomatous eyes of 16 subjects were recruited. A qualitative assessment of composite OCT scans and composite fundus images showed little motion artifact or blurring along edges and blood vessels during tracking; however, those structures were less clearly defined when tracking was disengaged. There was no significant reproducibility difference with and without tracking in both intra- and intersession NFL measurement SD calculations in any location. The mean retinal pixel SD was significantly smaller with tracking than without (490.9 +/- 19.3 microm vs. 506.4 +/- 31.8 microm, P = 0.005, paired t-test).
A retinal-tracking system was successfully developed and integrated into a commercial OCT unit. Tracking OCT improved the consistency of scan registration, but did not influence NFL thickness measurement reproducibility in this small sample study.
Investigative Ophthalmology & Visual Science 04/2006; 47(3):964-7. · 3.60 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: A novel instrument for real-time in vivo measurement of blood composition is presented. Two optical technologies are combined in this instrument: spectral domain low coherence interferometry (SD-LCI) and retinal tracking. Retinal tracking is used to stabilize the LCI beam on vessels. SD-LCI is used to get depth-reflectivity profiles within the vessels. Multiple signals are rapidly acquired, averaged and processed. Differences in the slopes of the depth reflectivity profiles for different subjects correspond to the difference in the scattering coefficient, which is proportional to the concentration of red blood cells per cubic mm of blood (hematocrit). Preliminary measurements on several healthy volunteers show a good correlation with the normal range of the hematocrit.
01/2006;
-
[show abstract]
[hide abstract]
ABSTRACT: An upgraded optical coherence tomography system with integrated retinal tracker (TOCT) was developed. The upgraded system uses improved components to extend the tracking bandwidth, fully integrates the tracking hardware into the optical head of the clinical OCT system, and operates from a single software platform. The system was able to achieve transverse scan registration with sub-pixel accuracy (~10 microm). We demonstrate several advanced scan sequences with the TOCT, including composite scans averaged (co-added) from multiple B-scans taken consecutively and several hours apart, en face images collected by summing the A-scans of circular, line, and raster scans, and three-dimensional (3D) retinal maps of the fovea and optic disc. The new system achieves highly accurate OCT scan registration yielding composite images with significantly improved spatial resolution, increased signal-to-noise ratio, and reduced speckle while maintaining well-defined boundaries and sharp fine structure compared to single scans. Precise re-registration of multiple scans over separate imaging sessions demonstrates TOCT utility for longitudinal studies. En face images and 3D data cubes generated from these data reveal high fidelity image registration with tracking, despite scan durations of more than one minute.
Optics Express 11/2005; 13(20):7937-47. · 3.59 Impact Factor
-
01/2005;
-
[show abstract]
[hide abstract]
ABSTRACT: We have designed, developed, and tested a three-dimensional tracking and imaging system that uses a novel optical layout to acquire both en-face confocal images by scanning laser imaging (e.g. scanning laser ophthalmoscopy, SLO) and high-resolution depth sections by optical coherence tomography (OCT). The present application for this system is retinal imaging. The instrument is capable of sequentially collecting OCT and SLO images with the simple articulation of an optic affixed to a flip-mount. In addition, we have extended our mature transverse tracking system for full three-dimensional motion stabilization. The tracking component employs an innovative optical and electronic design that encodes transverse and depth tracking information on a single beam. We have demonstrated en face SLO imaging with a resolution of ~25 µm and depth-resolved OCT imaging with a resolution of ~10 µm. On artificial targets, transverse tracking was robust up to 1 m/s with a bandwidth of ~1 kHz and depth tracking was robust up to a velocity of ~15 cm/sec, a range of ~1 mm, and a bandwidth of a few hundred Hz. The details of the instrument, including optical and electronic design, are discussed. The system has the potential to provide clinicians and researchers with a wide variety of diagnostic information for the early detection and treatment of retinal diseases.
01/2005;
