Three-dimensional calibration targets for optical coherence tomography

The recent expansion of clinical applications for optical coherence tomography (OCT) is driving the development of approaches for consistent image acquisition. There is a simultaneous need for time-stable, easy-to-use imaging targets for calibration and standardization of OCT devices. We present calibration targets consisting of three-dimensional structures etched into nanoparticle-embedded resin. Spherical iron oxide nanoparticles with a predominant particle diameter of 400 nm were homogeneously dispersed in a two part polyurethane resin and allowed to harden overnight. These samples were then etched using a precision micromachining femtosecond laser with a center wavelength of 1026 nm, 100kHz repetition rate and 450 fs pulse duration. A series of lines in depth were etched, varying the percentage of inscription energy and speed of the translation stage moving the target with respect to the laser. Samples were imaged with a dual wavelength spectral-domain OCT system and point-spread function of nanoparticles within the target was measured.

Optical coherence tomography confirmed resolution of macular edema in a diabetic patient after hemodialysis

Purpose: The authors report the first case, to their knowledge, of resolution of diffuse macular edema after hemodialysis, which has been confirmed by optical coherence tomography. Methods: A 53-year-old white woman with type 2 diabetes developed worsening macular edema and was examined in the ophthalmology clinic and scheduled for macular grid laser photocoagulation. The laser, however, was deferred for 4 weeks because she had also developed end-stage renal failure and required hemodialysis. Results: When she was reviewed in the ophthalmology clinic 4 weeks later for laser therapy, it was found that her macular edema had resolved, vision had improved, and laser was unnecessary. Review at 6 months showed that the macular edema remains resolved. Conclusion: Ophthalmologists should be aware that hemodialysis may reduce macular edema in such patients. Copyright © by Ophthalmic Communications Society Inc.

Three-dimensional calibration targets for optical coherence tomography

The recent expansion of clinical applications for optical coherence tomography (OCT) is driving the development of approaches for consistent image acquisition. There is a simultaneous need for time-stable, easy-to-use imaging targets for calibration and standardization of OCT devices. We present calibration targets consisting of three-dimensional structures etched into nanoparticle-embedded resin. Spherical iron oxide nanoparticles with a predominant particle diameter of 400 nm were homogeneously dispersed in a two part polyurethane resin and allowed to harden overnight. These samples were then etched using a precision micromachining femtosecond laser with a center wavelength of 1026 nm, 100kHz repetition rate and 450 fs pulse duration. A series of lines in depth were etched, varying the percentage of inscription energy and speed of the translation stage moving the target with respect to the laser. Samples were imaged with a dual wavelength spectral-domain OCT system and point-spread function of nanoparticles within the target was measured.

Advances in characterisation, calibration and data processing speed of optical coherence tomography systems

This thesis describes advances in the characterisation, calibration and data processing of optical coherence tomography (OCT) systems. Femtosecond (fs) laser inscription was used for producing OCT-phantoms. Transparent materials are generally inert to infra-red radiations, but with fs lasers material modification occurs via non-linear processes when the highly focused light source interacts with the materials. This modification is confined to the focal volume and is highly reproducible. In order to select the best inscription parameters, combination of different inscription parameters were tested, using three fs laser systems, with different operating properties, on a variety of materials. This facilitated the understanding of the key characteristics of the produced structures with the aim of producing viable OCT-phantoms. Finally, OCT-phantoms were successfully designed and fabricated in fused silica. The use of these phantoms to characterise many properties (resolution, distortion, sensitivity decay, scan linearity) of an OCT system was demonstrated. Quantitative methods were developed to support the characterisation of an OCT system collecting images from phantoms and also to improve the quality of the OCT images. Characterisation methods include the measurement of the spatially variant resolution (point spread function (PSF) and modulation transfer function (MTF)), sensitivity and distortion. Processing of OCT data is a computer intensive process. Standard central processing unit (CPU) based processing might take several minutes to a few hours to process acquired data, thus data processing is a significant bottleneck. An alternative choice is to use expensive hardware-based processing such as field programmable gate arrays (FPGAs). However, recently graphics processing unit (GPU) based data processing methods have been developed to minimize this data processing and rendering time. These processing techniques include standard-processing methods which includes a set of algorithms to process the raw data (interference) obtained by the detector and generate A-scans. The work presented here describes accelerated data processing and post processing techniques for OCT systems. The GPU based processing developed, during the PhD, was later implemented into a custom built Fourier domain optical coherence tomography (FD-OCT) system. This system currently processes and renders data in real time. Processing throughput of this system is currently limited by the camera capture rate. OCTphantoms have been heavily used for the qualitative characterization and adjustment/ fine tuning of the operating conditions of OCT system. Currently, investigations are under way to characterize OCT systems using our phantoms. The work presented in this thesis demonstrate several novel techniques of fabricating OCT-phantoms and accelerating OCT data processing using GPUs. In the process of developing phantoms and quantitative methods, a thorough understanding and practical knowledge of OCT and fs laser processing systems was developed. This understanding leads to several novel pieces of research that are not only relevant to OCT but have broader importance. For example, extensive understanding of the properties of fs inscribed structures will be useful in other photonic application such as making of phase mask, wave guides and microfluidic channels. Acceleration of data processing with GPUs is also useful in other fields.

Fiber optically integrated cost-effective spectrometer for optical coherence tomography

A tilted fiber Bragg grating (TFBG) was integrated as the dispersive element in a high performance biomedical imaging system. The spectrum emitted by the 23 mm long active region of the fiber is projected through custom designed optics consisting of a cylindrical lens for vertical beam collimation and successively by an achromatic doublet onto a linear detector array. High resolution tomograms of biomedical samples were successfully acquired by the frequency domain OCT-system. Tomograms of ophthalmic and dermal samples obtained by the frequency domain OCT-system were obtained achieving 2.84 μm axial and 10.2 μm lateral resolution. The miniaturization reduces costs and has the potential to further extend the field of application for OCT-systems in biology, medicine and technology. © 2014 SPIE.

Quantitative optical coherence tomography for characterization of microscopic structures with varying refractive index

In this paper we have done back to back comparison of quantitive phase and refractive index from a microscopic image of waveguide previously obtained by Allsop et al. Paper also shows microscopic image of the first 3 waveguides from the sample. Tomlins et al. have demonstrated use of femtosecond fabricated artefacts as OCT calibration samples. Here we present the use of femtosecond waveguides, inscribed with optimized parameters, to test and calibrate the sensitivity of the OCT systems.

A program to analyse optical coherence tomography images of the ciliary muscle

Purpose: To describe and validate bespoke software designed to extract morphometric data from ciliary muscle Visante Anterior Segment Optical Coherence Tomography (AS-OCT) images. Method: Initially, to ensure the software was capable of appropriately applying tiered refractive index corrections and accurately measuring orthogonal and oblique parameters, 5 sets of custom-made rigid gas-permeable lenses aligned to simulate the sclera and ciliary muscle were imaged by the Visante AS-OCT and were analysed by the software. Human temporal ciliary muscle data from 50 participants extracted via the internal Visante AS-OCT caliper method and the software were compared. The repeatability of the software was also investigated by imaging the temporal ciliary muscle of 10 participants on 2 occasions. Results: The mean difference between the software and the absolute thickness measurements of the rigid gas-permeable lenses were not statistically significantly different from 0 (t = -1.458, p = 0.151). Good correspondence was observed between human ciliary muscle measurements obtained by the software and the internal Visante AS-OCT calipers (maximum thickness t = -0.864, p = 0.392, total length t = 0.860, p = 0.394). The software extracted highly repeatable ciliary muscle measurements (variability ≤6% of mean value). Conclusion: The bespoke software is capable of extracting accurate and repeatable ciliary muscle measurements and is suitable for analysing large data sets.

Cost-effective optical coherence tomography spectrometer based on a tilted fiber Bragg grating

A compact, fiber-based spectrometer for biomedical application utilizing a tilted fiber Bragg grating (TFBG) as integrated dispersive element is demonstrated. Based on a 45° UV-written PS750 TFBG a refractive spectrometer with 2.06 radiant/μm dispersion and a numerical aperture of 0.1 was set up and tested as integrated detector for an optical coherence tomography (OCT) system. Featuring a 23 mm long active region at the fiber the spectrum is projected via a cylindrical lens for vertical beam collimation and focused by an achromatic doublet onto the detector array. Covering 740 nm to 860 nm the spectrometer was optically connected to a broadband white light interferometer and a wide field scan head and electronically to an acquisition and control computer. Tomograms of ophthalmic and dermal samples obtained by the frequency domain OCT-system were obtained achieving 2.84 μm axial and 7.6 μm lateral resolution. © 2014 SPIE.

Measurement of scleral thickness in humans using anterior segment optical coherent tomography

Anterior segment optical coherent tomography (AS-OCT, Visante; Zeiss) is used to examine meridional variation in anterior scleral thickness (AST) and its association with refractive error, ethnicity and gender. Scleral cross-sections of 74 individuals (28 males; 46 females; aged between 18-40 years (27.7±5.3)) were sampled twice in random order in 8 meridians: [superior (S), inferior (I), nasal (N), temporal (T), superior-temporal (ST), superior-nasal (SN), inferior-temporal (IT) and inferior-nasal (IN)]. AST was measured in 1mm anterior-toposterior increments (designated the A-P distance) from the scleral spur (SS) over a 6mm distance. Axial length and refractive error were measured with a Zeiss IOLMaster biometer and an open-view binocular Shin-Nippon autorefractor. Intra- And inter-observer variability of AST was assessed for each of the 8 meridians. Mixed repeated measures ANOVAs tested meridional and A-P distance differences in AST with refractive error, gender and ethnicity. Only right eye data were analysed. AST (mean±SD) across all meridians and A-P distances was 725±46μm. Meridian SN was the thinnest (662±57μm) and I the thickest (806 ±60μm). Significant differences were found between all meridians (p<0.001), except S:ST, IT:IN, IT:N and IN:N. Significant differences between A-P distances were found except between SS and 6 mm and between 2 and 4mm. AST measurements at 1mm (682±48 μm) were the thinnest and at 6mm (818±49 μm) the thickest (p<0.001); a significant interaction occurred between meridians and A-P distances (p<0.001). AST was significantly greater (p<0.001) in male subjects but no significant differences were found between refractive error or ethnicity. Significant variations in AST occur with regard to meridian and distance from the SS and may have utility in selecting optimum sites for pharmaceutical or surgical intervention.

Improving the economic value of photographic screening for optical coherence tomography-detectable macular oedema:a prospective, multicentre, UK study

Objectives: To determine the best photographic surrogate markers for detecting sight-threatening macular oedema (MO) in people with diabetes attending UK national screening programmes. Design: A multicentre, prospective, observational cohort study of 3170 patients with photographic signs of diabetic retinopathy visible within the macular region [exudates within two disc diameters, microaneurysms/dot haemorrhages (M/DHs) and blot haemorrhages (BHs)] who were recruited from seven study centres. Setting: All patients were recruited and imaged at one of seven study centres in Aberdeen, Birmingham, Dundee, Dunfermline, Edinburgh, Liverpool and Oxford. Participants: Subjects with features of diabetic retinopathy visible within the macular region attending one of seven diabetic retinal screening programmes. Interventions: Alternative referral criteria for suspected MO based on photographic surrogate markers; an optical coherence tomographic examination in addition to the standard digital retinal photograph. Main outcome measures: (1) To determine the best method to detect sight-threatening MO in people with diabetes using photographic surrogate markers. (2) Sensitivity and specificity estimates to assess the costs and consequences of using alternative strategies. (3) Modelled long-term costs and quality-adjusted life-years (QALYs). Results: Prevalence of MO was strongly related to the presence of lesions and was roughly five times higher in subjects with exudates or BHs or more than two M/DHs within one disc diameter. Having worse visual acuity was associated with about a fivefold higher prevalence of MO. Current manual screening grading schemes that ignore visual acuity or the presence of M/DHs could be improved by taking these into account. Health service costs increase substantially with more sensitive/less specific strategies. A fully automated strategy, using the automated detection of patterns of photographic surrogate markers, is superior to all current manual grading schemes for detecting MO in people with diabetes. The addition of optical coherence tomography (OCT) to each strategy, prior to referral, results in a reduction in costs to the health service with no decrement in the number of MO cases detected. Conclusions: Compared with all current manual grading schemes, for the same sensitivity, a fully automated strategy, using the automated detection of patterns of photographic surrogate markers, achieves a higher specificity for detecting MO in people with diabetes, especially if visual acuity is included in the automated strategy. Overall, costs to the health service are likely to increase if more sensitive referral strategies are adopted over more specific screening strategies for MO, for only very small gains in QALYs. The addition of OCT to each screening strategy, prior to referral, results in a reduction in costs to the health service with no decrement in the number of MO cases detected. © Queen's Printer and Controller of HMSO 2013.

The design and validation of an optical coherence tomography-based classification system for focal vitreomacular traction

PurposeTo develop and validate a classification system for focal vitreomacular traction (VMT) with and without macular hole based on spectral domain optical coherence tomography (SD-OCT), intended to aid in decision-making and prognostication.MethodsA panel of retinal specialists convened to develop this system. A literature review followed by discussion on a wide range of cases formed the basis for the proposed classification. Key features on OCT were identified and analysed for their utility in clinical practice. A final classification was devised based on two sequential, independent validation exercises to improve interobserver variability.ResultsThis classification tool pertains to idiopathic focal VMT assessed by a horizontal line scan using SD-OCT. The system uses width (W), interface features (I), foveal shape (S), retinal pigment epithelial changes (P), elevation of vitreous attachment (E), and inner and outer retinal changes (R) to give the acronym WISPERR. Each category is scored hierarchically. Results from the second independent validation exercise indicated a high level of agreement between graders: intraclass correlation ranged from 0.84 to 0.99 for continuous variables and Fleiss' kappa values ranged from 0.76 to 0.95 for categorical variables.ConclusionsWe present an OCT-based classification system for focal VMT that allows anatomical detail to be scrutinised and scored qualitatively and quantitatively using a simple, pragmatic algorithm, which may be of value in clinical practice as well as in future research studies.

Enhancing the Visualization of the Peripheral Retina with Wide Field-of-View Optical Coherence Tomography

The goal of my Ph.D. thesis is to enhance the visualization of the peripheral retina using wide-field optical coherence tomography (OCT) in a clinical setting.

OCT has gain widespread adoption in clinical ophthalmology due to its ability to visualize the diseases of the macula and central retina in three-dimensions, however, clinical OCT has a limited field-of-view of 300. There has been increasing interest to obtain high-resolution images outside of this narrow field-of-view, because three-dimensional imaging of the peripheral retina may prove to be important in the early detection of neurodegenerative diseases, such as Alzheimer's and dementia, and the monitoring of known ocular diseases, such as diabetic retinopathy, retinal vein occlusions, and choroid masses.

Before attempting to build a wide-field OCT system, we need to better understand the peripheral optics of the human eye. Shack-Hartmann wavefront sensors are commonly used tools for measuring the optical imperfections of the eye, but their acquisition speed is limited by their underlying camera hardware. The first aim of my thesis research is to create a fast method of ocular wavefront sensing such that we can measure the wavefront aberrations at numerous points across a wide visual field. In order to address aim one, we will develop a sparse Zernike reconstruction technique (SPARZER) that will enable Shack-Hartmann wavefront sensors to use as little as 1/10th of the data that would normally be required for an accurate wavefront reading. If less data needs to be acquired, then we can increase the speed at which wavefronts can be recorded.

For my second aim, we will create a sophisticated optical model that reproduces the measured aberrations of the human eye. If we know how the average eye's optics distort light, then we can engineer ophthalmic imaging systems that preemptively cancel inherent ocular aberrations. This invention will help the retinal imaging community to design systems that are capable of acquiring high resolution images across a wide visual field. The proposed model eye is also of interest to the field of vision science as it aids in the study of how anatomy affects visual performance in the peripheral retina.

Using the optical model from aim two, we will design and reduce to practice a clinical OCT system that is capable of imaging a large (800) field-of-view with enhanced visualization of the peripheral retina. A key aspect of this third and final aim is to make the imaging system compatible with standard clinical practices. To this end, we will incorporate sensorless adaptive optics in order to correct the inter- and intra- patient variability in ophthalmic aberrations. Sensorless adaptive optics will improve both the brightness (signal) and clarity (resolution) of features in the peripheral retina without affecting the size of the imaging system.

The proposed work should not only be a noteworthy contribution to the ophthalmic and engineering communities, but it should strengthen our existing collaborations with the Duke Eye Center by advancing their capability to diagnose pathologies of the peripheral retinal.

Development of Swept Source Optical Coherence Tomography and Adaptive Optics Scanning Laser Ophthalmoscopy: Improved Imaging Speed and Handheld Applications

Optical coherence tomography (OCT) is a noninvasive three-dimensional interferometric imaging technique capable of achieving micrometer scale resolution. It is now a standard of care in ophthalmology, where it is used to improve the accuracy of early diagnosis, to better understand the source of pathophysiology, and to monitor disease progression and response to therapy. In particular, retinal imaging has been the most prevalent clinical application of OCT, but researchers and companies alike are developing OCT systems for cardiology, dermatology, dentistry, and many other medical and industrial applications.

Adaptive optics (AO) is a technique used to reduce monochromatic aberrations in optical instruments. It is used in astronomical telescopes, laser communications, high-power lasers, retinal imaging, optical fabrication and microscopy to improve system performance. Scanning laser ophthalmoscopy (SLO) is a noninvasive confocal imaging technique that produces high contrast two-dimensional retinal images. AO is combined with SLO (AOSLO) to compensate for the wavefront distortions caused by the optics of the eye, providing the ability to visualize the living retina with cellular resolution. AOSLO has shown great promise to advance the understanding of the etiology of retinal diseases on a cellular level.

Broadly, we endeavor to enhance the vision outcome of ophthalmic patients through improved diagnostics and personalized therapy. Toward this end, the objective of the work presented herein was the development of advanced techniques for increasing the imaging speed, reducing the form factor, and broadening the versatility of OCT and AOSLO. Despite our focus on applications in ophthalmology, the techniques developed could be applied to other medical and industrial applications. In this dissertation, a technique to quadruple the imaging speed of OCT was developed. This technique was demonstrated by imaging the retinas of healthy human subjects. A handheld, dual depth OCT system was developed. This system enabled sequential imaging of the anterior segment and retina of human eyes. Finally, handheld SLO/OCT systems were developed, culminating in the design of a handheld AOSLO system. This system has the potential to provide cellular level imaging of the human retina, resolving even the most densely packed foveal cones.

Live volumetric (4D) visualization and guidance of in vivo human ophthalmic surgery with intraoperative optical coherence tomography.

Minimally-invasive microsurgery has resulted in improved outcomes for patients. However, operating through a microscope limits depth perception and fixes the visual perspective, which result in a steep learning curve to achieve microsurgical proficiency. We introduce a surgical imaging system employing four-dimensional (live volumetric imaging through time) microscope-integrated optical coherence tomography (4D MIOCT) capable of imaging at up to 10 volumes per second to visualize human microsurgery. A custom stereoscopic heads-up display provides real-time interactive volumetric feedback to the surgeon. We report that 4D MIOCT enhanced suturing accuracy and control of instrument positioning in mock surgical trials involving 17 ophthalmic surgeons. Additionally, 4D MIOCT imaging was performed in 48 human eye surgeries and was demonstrated to successfully visualize the pathology of interest in concordance with preoperative diagnosis in 93% of retinal surgeries and the surgical site of interest in 100% of anterior segment surgeries. In vivo 4D MIOCT imaging revealed sub-surface pathologic structures and instrument-induced lesions that were invisible through the operating microscope during standard surgical maneuvers. In select cases, 4D MIOCT guidance was necessary to resolve such lesions and prevent post-operative complications. Our novel surgical visualization platform achieves surgeon-interactive 4D visualization of live surgery which could expand the surgeon's capabilities.