Defintions:
A-scan: Interferometry works by splitting a light beam and comparing it with a reference beam. When the beams interfere, they create an interference pattern, which is then analyzed. The A-scan captures this interference pattern as a single depth profile, providing information about the features or reflections at that specific location. A-scans are commonly used in techniques like low-coherence interferometry (LCI) and optical coherence tomography (OCT) for various applications, including measuring axial length in the eye.
Beamsplitters: plate or cube beamsplitters can be used in OCT to split the light into two different paths: the reference and sample beams. The beamsplitter allows for the reference beam to be reflected to the reference mirror while the sample beam is focused into the sample using an optical lens.
Optical coherence tomography (OCT): is a non-invasive imaging technique that uses light waves to create detailed, cross-sectional images of internal structures, especially within the eye. It’s similar to ultrasound but uses light instead of sound, allowing for high-resolution visualization of tissue layers. OCT is commonly used in ophthalmology to diagnose and monitor a variety of eye conditions, including glaucoma, diabetic retinopathy, and age-related macular degeneration.
OCT employs low-coherence interferometry, a technique that uses interference patterns of light waves to create images. It sends a beam of light into the tissue and measures the reflected light, which is then used to create a cross-sectional image. OCT uses a light beam to scan the eye, similar to how ultrasound uses sound waves. The light beam is split into two paths. One path is directed towards the eye, and the other remains as a reference. As the light beam passes through the eye, it is reflected back by the various tissues and structures. The reflected light interferes with the reference beam, creating an image that can be analyzed by the eye doctor to see the different layers of the retina, optic nerve, and other structures.
The principal idea of OCT is that depth information is encoded in light that reflects from a sample. The depth information can be extracted via OCT in any of several methods. The methods fall into one of two broad categories. A Michelson type interferometer is utilized as the basis of any OCT system (Figure 2). The first implementation of OCT was called Time Domain OCT (TD-OCT). The fundamentals of TD-OCT rely on light from a broadband light source being split into two paths by a beamsplitter. After passing through the beamsplitter, one beam is directed to the sample and the other to a mobile reference mirror. The light from the reference arm will travel a specific optical distance as it moves, and because of the low coherence length of the source, will form an interference pattern only with light that travels the same optical distance in the sample arm. The intensity of the interference as the mirror moves provides a map of the depth profile (the “A-scan”). By rastering the location of the A-scan, the interference pattern can produce two-dimensional (2D) and three-dimensional (3D) images of tissues in the body.
Modern ultra-high resolution OCT has been demonstrated for evaluating the thickness of overall PCTF. With the sche of 2-axis scanning and fast image acquisition speed, OCT has the potential to measure the PCTF thickness at various depths across the ocular surface. However, the axial resolution of the OCT is limited down to 1 um. In contrast, traditional interferometric methods have better resoltuion, but they are limited to measuring a single, small spot about 30 um diameter on the ocular surface. (Nichols, “An imaging system integrating optical coherence tomography and interferometry for in vivo measurement of the thickness and dynamics of the tear film” BioMedical Engineering Online, 20108).
The output signal recorded by the detector is a depth scan or commonly referred to as an A-scan or 1D scan. The A-scan describes the axial resolution of the system and it is defined by the bandwidth, or coherence length, of the light source. As the bandwidth of the light source decreases, the axial resolution increases, increasing the system’s resolving power. After an A-scan is collected, the light beam moves laterally across the sample to collect B-scans. The B-scan provides cross-sectional structural information that will produce 2D images based on the magnitude, phase, frequency shift, and polarization of the interference light signal. 3D or volumetric images are formed by collecting multiple A-scans per B-scan and multiple B-scans per 3D volume.
OCT has allowed clinicians to better diagnose ophthalmic diseases such as age-related macular degeneration (AMD) which causes blurred vision. Two causes of AMD are deterioration of the retina due to tissue thinning (dry AMD) or the formation of leaky blood vessels under the retina (wet AMD). Another field that OCT has been adapted for is cardiology to diagnose the likelihood of a heart attack. One of the leading causes for heart attacks is athrosclerosis which occurs when ruptured fatty plaques and calcium build-up inside the lining of the artery wall, blocking blood flow. Clinicians have turned to utilizing OCT technologies to detect vulnerable plaques prior to rupture. OCT allows physicians to visualize plaque in the arterial wall with an image resolution of 5-7µm to determine the size, shape, and location of the plaque. The high sensitivity of OCT allows better axial penetration to view plaques pre-rupture compared to other diagnostic methods such as angiography and intravascular ultrasound, allowing for early diagnosis. Edmund Optics
Optical Lens: a standard plano-convex (PCX) can be used to focus the split beam paths into the sample and detector. To reduce potential spherical and chromatic aberrations, an aspheric or achromatic lens can be utilized. These lenses will focus the light into the sample at a smaller spot size with reduced aberrations, making a more precise OCT system.
A spectrometer is a scientific instrument that analyzes the spectral components of a physical phenomenon, like light, by separating it into its constituent wavelengths and measuring their intensity or other properties. It’s essentially a device that splits light (or other forms of radiation) into its different wavelengths and measures how much of each wavelength is present.
Introduction; Conventional Tests for Diagnosing Dry Eye Disease:
In clinical practice, the diagnosis and management of DED is often difficult because of its multifactorial nature, as well as discrepancy between dry eye signs and sumptoms. Moreover, conventional diagnostic tests for DED, such as the fluorescein tear film break-up time (TBUT) and Schimer test, often show unsatisfactory reliability and reprodudicibility, which also renders the diagnosis and monitroing of the condition challenging. (Mehta, “Objective Imaging Diagnostics for Dry Eye Disease” J. Opthalmology, 2020).
Measurement of Lipd and Aqueous Layer Thickness:
There is a correlation between the ocular tear film layer thicknesses and dry eye disease. Korb (US 2013/0308095). Accurate and precise determination of lipid and aqueous layer thicknesses are critical for proper diagnosis of dry eye sub categories.
–Optic Interferometry Devices:
Wavelength dependent optical interferometry has been used to simultaneously measure tear film lip and aqueous layer thickness at a single point at the apex of the cornea over a period of time. Such measurements can be used to diagnose sub categories of dry eye from (a) either lipid or aqueous deficiencies or (b) time-profile changes in lipid and aqueous layer thickness after a blink. Huth (US 2013/0141698)
Lipid and aqueous layer thickness calculation methods using interferometry data has been conducted separately. This is due to the large difference in layer thicknesses (aqeuous 1-5 microns; lipd 20-120 nanometers), basing aqueous thickness calculations upon spectral interference oscillations and absence of spectral oscillations form the lipid layer. Huth (US 2013/0141698)
Korb (US 2013/0308095) discloses apparatuses and methods employed for measuring tear film layer thickness (TFLT) of the ocular tear film, which includes lipid layer thickness (LLT) and/or aqueous layer thickness (ALT). Ab imaging device is focused on the lipid layer of the tear film to capture optical wave interfence interactions of specularly reflected light from the tear film combined with a background signal(s) in a first image. The imaging device is focused on the lipid layer of the tear film to capture a second image containing background signal(s) in the first image. The second image can be subtracted form the first image to reduce and/or eliminate background signal(s) in teh first image to produce a resulting image that can be analyzed to measure tear film layer thickness.
Grenon (US 2015/0138505) discloses ocular surface interferometry (OSI) devices, systems, and methods for mesuring a tear film layer thickness (TFLT) of the ocular tear film, including the lipid layer thickness (LLT) and/or the aqueous layer thickness (ALT). The TFLT can be used to diagnose dry eye syndrome (DES). In one embodiment, a control system is configured to spatially modulate light from a multi-wavelenght light source to project a first circular pattern onto the eye such that at least one first portion of the eye receives emititted light and at least one second protion does not, recieving at an imaging device the at least one first image containing at least one first signal, spatially modulate light from the multi-wavelenght light source to project a second circular pattern onto the eye such athat at least one first porition of the ye does not receive the emitted light and at least one second porition of the ye recieves the light and recieving at the imaging device the at least one second image and then subtracting the at elast one second image from the at elast one frist image to generate a resulting image the represents the ocuar property of the eye.
Huth (US 2013/0141698) discloses a method of measuring tear film lipid layer thickness by applying a mathematical method to simultaneous tear film lipid and aqueous layer thicknesses and corneal refractive index calculations form interferometry data. The method includes aligning an eye of the patient with light originating from a light source, measuring light reflectance from the eye, filtering the light reflectance to the mathematical construct and determing a parameter selected form the group of lipid layer thickness, aqueous layer thickness and corneal surface refractive index.
–Measurement of Lipid Layer thickness and tear film thickness:
—-Optical coherence tomography (OCT) and Thickness dependent fringes (TDF) interferometry:
The outermost layer of the term film consists of a thin lipid layer (LL) which serves as a barrier against evaporation of the aqueous component of the term film. Nichols, (“An imaging system integrating optical coherence tomography and interferometry for in vivo measurement of the thickness and dynamics of the tear film” BioMedical Engineering Online, 20108), discloses a system that combines simultaneous OCT and TDF intererometry for in vivo imaging of the tear film. The OCT possesses an axial resolution of 1.38 um in tear film, providing an accurate measurement of the thickness of the overall tear film. The TDF can detect a minimal change of about 15 hm in LL thickness. The ability to simultanteously image both the lipid layer thickness and overall tear film thickness is novel and helps understanding the mechanisms of how lipid layer assembles and interacts with the full tearm film thickness.
Accordingly Nichols (US 2020/0154999) disclsoes a multimodal interferometric tear film measnurement system that includes an optical coherence tomography (OCT) system and a thickness dependent fringe (TDR) system. The multimodal interferrement system can include a hot mirror dual focuometric tear film measusing system taht allows the OCT system’s light signals and the TDF system’s light signals to be individually focused while both are simultaneously directed towards the eye. The multimodal interferometry system can provide OCT and TDF measurements simultaneously. The OCT system can provide measurement of the thickness of the entire tear fim, while the TDF system can provide urements of the thickness of the lipid layer of the ter fim The multimodal interferometry system can provide in vivo measurements of both lipid layer and overall tear film.
Noninvasive Tear Break-Up time (NITBUT): reflects the stability and quality of the tear film, which is crucial for maintenance of ocular surface integrity and clear vision. Masurement of the TBUT has generally been performed after fluorescein dye instillation. However, the variability of the concentration and amount of the dye leads to reduced reliability and reproducibility. (Mehta, “Objective Imaging Diagnostics for Dry Eye Disease” J. Opthalmology, 2020).
Anterior Sigment Optical Coherence Tomography (AS-OCT): produces cross-sectional images of anterior segment structures by low-coherence interferometry. The technique enables measurement of tear meniscus parameters important for the diagnosis and monitoring of DED, such as the tear meniscus height (TMH) and tear meniscus area (TMA), without relfex tearing due to its noncontact nature and rapid image acquitition. (Mehta, “Objective Imaging Diagnostics for Dry Eye Disease” J. Opthalmology, 2020).
In vivo confocal microscopy (IVCM): is a noninvasive method that provides real time imaging of the ocular surface at the histologic level, which enables the evaluation of changes in cells reflecting ocular surface damage and inflammation, such as corneal epithelial cells, keratocytes and dendritic cells.
Infrared Meibography: has been widely used for teh evaluation of MG droput since its introduction in 2008, as it can provide improved image quality with a short acquisition time and minimal patient discomfort. In meibography, healthy meibum is visualized as a light area due to its autofluroescence. Dark areas in the MG conceivable indicate loss of acinal tissue or an altered meibum condition, which is detemriend as MG dropout. (Mehta, “Objective Imaging Diagnostics for Dry Eye Disease” J. Opthalmology, 2020).
Interferometry: Tear interferometry is a noninvasive method for the investigation of the tear lipid layer by visualization of the reflection of light at the lipd aqueous interface of the tear film. Interferometry allows objective evaluation of tear film properties such as lipid layer thickness, break-up characteristics and changes in thickness of the tear film, its distribution, and wetitng patterns with sequential blinking.
The LipiView II (LVII) ocular surface interferometer (TearScience, Johnson and Johnson Vision, Jacksonville, FL) is capable of providing quantiative information of the LLT, as well as images of MGs using a patetned Lid Everter and infrared diodes for eversion and illumination of the eyelid. (Mehta, “Objective Imaging Diagnostics for Dry Eye Disease” J. Opthalmology, 2020).
Anterior-segment optical coherence tomography: In a study deficient patients and 47 controls, researchers found that the cutoff value for an abnormal lower tear meniscus radius was 182 um and the value for an abnormal lower tear meniscus was 164 um. The LTMR diagnostic sensitivty and specificity were 092 and 0.87, respectively, and that the LTMH diagnostic sensitivity and specificity were 0.92 and 0.90. The tear meniscus was smaller in aqeous-deficient patients than in healthy subjects. Researchrs used OCT to image the upper and lwoer tear menisci in 14 consectuive dry eye patients. They then started the treatment group on daily cyclosporine adminstiraiton and repeated the measurements at one and two months. They found that, in the treatment group, measurements showed significant increases of both upper and lower tear menisci heights, after a month of cyclosporine. (Walter Bethke, “Dry-Eye Disease by the Numbers” October 4, 2012).
Commercial Tests:
Interferometry (LipiView -by TearScience -Morrisville, N.C.): is a daignostic for meibomian gland dysfunction. LipiView uses interferometry to measure the lipid layer’s thickness between blinks, and gives a quantiative assessment in interferometric olor units. One study of the lipid layer thicness found a connection between a patient’s lipid layer thickness and dry eye sympoms.
TearLab Osmolarity Testing: The TearLab system uses a small sample of a patient’s tears to test the concetnraiton of electrolytes in the ter film, which gives an osmolarity reading. Pateints with higher levels of osmolarity are likely to have dry-eye disease.
Inflammadry (Rapid Pathogen Screening, Sarasota, Florida) takes a sample of a patient’s tears and gives a positive (ocular surface disease) or negative (no ocular surface disease) result. The est is based on a quantifiable value of the amount of matrix metalloproteinase-9 in the tears. If the test is positive, then there is over 40 ng/ml for the elvel of MMP-9, which is a proteolytic enzyme that omes from stressed epithelial cells on the ocular surface.