Angle-resolved Low Coherence Interferometry Research Articles

Next-generation endoscopic probe for detection of esophageal dysplasia using combined OCT and angle-resolved low-coherence interferometry.

Angle-resolved low-coherence interferometry (a/LCI) is an optical technique that enables depth-specific measurements of nuclear morphology, with applications to detecting epithelial cancers in various organs. Previous a/LCI setups have been limited by costly fiber-optic components and large footprints. Here, we present a novel a/LCI instrument incorporating a channel for optical coherence tomography (OCT) to provide real-time image guidance. We showcase the system's capabilities by acquiring imaging data from in vivo Barrett's esophagus patients. The main innovation in this geometry lies in implementing a pathlength-matched single-mode fiber array, offering substantial cost savings while preserving signal fidelity. A further innovation is the introduction of a specialized side-viewing probe tailored for esophageal imaging, featuring miniature optics housed in a custom 3D-printed enclosure attached to the tip of the endoscope. The integration of OCT guidance enhances the precision of tissue targeting by providing real-time morphology imaging. This novel device represents a significant advancement in clinical translation of an enhanced screening approach for esophageal precancer, paving the way for more effective early-stage detection and intervention strategies.

Advanced endoscopic imaging for detecting and guiding therapy of early neoplasias of the esophagus.

Esophageal cancers, largely adenocarcinoma in Western countries and squamous cell cancer in Asia, present a significant burden of disease and remain one of the most lethal of cancers. Key to improving survival is the development and adoption of new imaging modalities to identify early neoplastic lesions, which may be small, multifocal, subsurface, and difficult to detect by standard endoscopy. Such advanced imaging is particularly relevant with the emergence of ablative techniques that often require multiple endoscopic sessions and may be complicated by bleeding, pain, strictures, and recurrences. Assessing the specific location, depth of involvement, and features correlated with neoplastic progression or incomplete treatment may optimize treatments. While not comprehensive of all endoscopic imaging modalities, we review here some of the recent advances in endoscopic luminal imaging, particularly with surface contrast enhancement using virtual chromoendoscopy, highly magnified subsurface imaging with confocal endomicroscopy, optical coherence tomography, elastic scattering spectroscopy, angle-resolved low-coherence interferometry, and light scattering spectroscopy. While there is no single ideal imaging modality, various multimodal instruments are also being investigated. The future of combining computer-aided assessments, molecular markers, and improved imaging technologies to help localize and ablate early neoplastic lesions shed hope for improved disease outcome.

Prospective detection of cervical dysplasia with scanning angle-resolved low coherence interferometry.

We present a prospective clinical study using angle-resolved low-coherence interferometry (a/LCI) to detect cervical dysplasia via depth resolved nuclear morphology measurements. The study, performed at the Jacobi Medical Center, compares 80 a/LCI optical biopsies taken from 20 women with histopathological tissue diagnosis of co-registered physical biopsies. A novel instrument was used for this study that enables 2D scanning across the cervix without repositioning the probe. The main study goal was to compare performance with a previous clinical a/LCI point-probe instrument [Int. J. Cancer140, 1447 (2017)] and use the same diagnostic criteria as in that study. Tissue was classified in two schemes: non-dysplastic vs. dysplastic and low-risk vs. high-risk, with the latter classification aligned with clinically actionable diagnosis. High sensitivity (non-dysplastic vs. dysplastic: 0.903, low-risk vs. high-risk: 1.000) and NPV (0.930 and 1.000 respectively) were obtained when using the previously established decision boundaries, showing the success of the scanning a/LCI instrument and reinforcing the clinical viability of a/LCI in disease detection.

Spatial scanning of a sample with two-dimensional angle-resolved low-coherence interferometry for analysis of anisotropic scatterers.

Angle-resolved low-coherence interferometry (a/LCI) measures depth-resolved angular scattering for cell nuclear morphology analysis. 2D a/LCI, developed to collect across two scattering planes, is currently limited by the lack of spatial scanning. Here we demonstrate 2D a/LCI scanning across a three-dimensional volume using an image rotation scheme and a scanning mirror. Validation using various optical phantoms demonstrated excellent scatterer size determination over a 7.5 mm linear range, for a total accessible area of ∼44 mm2. Measurements from anisotropic scatterers allowed accurate determination of sizes and computation of aspect ratios. This scanning system will facilitate analysis of scatterer structure across wider tissue areas.

Multimodal Coherent Imaging of Retinal Biomarkers of Alzheimer\u2019s Disease in a Mouse Model

We acquired depth-resolved light scattering measurements from the retinas of triple transgenic Alzheimer’s Disease (3xTg-AD) mice and wild type (WT) age-matched controls using co-registered angle-resolved low-coherence interferometry (a/LCI) and optical coherence tomography (OCT). Angle-resolved light scattering measurements were acquired from the nerve fiber layer, outer plexiform layer, and retinal pigmented epithelium using image guidance and segmented thicknesses provided by co-registered OCT B-scans. Analysis of the OCT images showed a statistically significant thinning of the nerve fiber layer in AD mouse retinas compared to WT controls. The a/LCI scattering measurements provided complementary information that distinguishes AD mice by quantitatively characterizing tissue heterogeneity. The AD mouse retinas demonstrated higher mean and variance in nerve fiber layer light scattering intensity compared to WT controls. Further, the difference in tissue heterogeneity was observed through short-range spatial correlations that show greater slopes at all layers of interest for AD mouse retinas compared to WT controls. A greater slope indicates a faster loss of spatial correlation, suggesting a loss of tissue self-similarity characteristic of heterogeneity consistent with AD pathology. Use of this combined modality introduces unique tissue texture characterization to complement development of future AD biomarker analysis.

Angular range, sampling and noise considerations for inverse light scattering analysis of nuclear morphology.

In recent years, significant work has been devoted to the use of angle-resolved elastic scattering for the extraction of nuclear morphology in tissue. By treating the nucleus as a Mie scattering object, techniques such as angle-resolved low-coherence interferometry (a/LCI) have demonstrated substantial success in identifying nuclear alterations associated with dysplasia. Because optical biopsies are inherently noninvasive, only a small, discretized portion of the 4π scattering field can be collected from tissue, limiting the amount of information available for diagnostic purposes. In this work, we comprehensively characterize the diagnostic impact of variations in angular sampling, range and noise for inverse light scattering analysis of nuclear morphology, using a previously reported dataset from 40 patients undergoing a/LCI optical biopsy for cervical dysplasia. The results from this analysis are applied to a benchtop scanning a/LCI system which compromises angular range for wide-area scanning capability. This work will inform the design of next-generation optical biopsy probes by directing optical design towards parameters which offer the most diagnostic utility.

Scanning system for angle-resolved low-coherence interferometry.

Angle-resolved low-coherence interferometry (a/LCI) detects precancer by enabling depth-resolved measurements of nuclear morphology in vivo. A significant limitation of a/LCI is the point-probe nature of the method, sampling <0.5 mm2 before probe relocation is necessary. In this work, we demonstrate a scanning method capable of assessing an area >100 mm2 without repositioning. By utilizing a reflection-only three-optic rotator prism and a two-axis scanning mirror, we demonstrate radial scans of a sample with a linear range of 12mm and a full rotational range of 180°. Use of this design will improve the diagnostic utility of a/LCI for wide-area screening of tissue health.

Analyzing spatial correlations in tissue using angle-resolved low coherence interferometry measurements guided by co-located optical coherence tomography.

Angle-resolved low coherence interferometry (a/LCI) is an optical technique used to measure nuclear morphology in situ. However, a/LCI is not an imaging modality and can produce ambiguous results when the measurements are not properly oriented to the tissue architecture. Here we present a 2D a/LCI system which incorporates optical coherence tomography imaging to guide the measurements. System design and characterization are presented, along with example cases which demonstrate the utility of the combined measurements. In addition, future development and applications of this dual modality approach are discussed.

Non-invasive diagnostic techniques in the diagnosis of squamous cell carcinoma.

Squamous cell carcinoma is the second most common cutaneous malignancy after basal cell carcinoma. Although the gold standard of diagnosis for squamous cell carcinoma is biopsy followed by histopathology evaluation, optical non-invasive diagnostic tools have obtained increased attention. Dermoscopy has become one of the basic diagnostic methods in clinical practice. The most common dermoscopic features of squamous cell carcinoma include clustered vascular pattern, glomerular vessels and hyperkeratosis. Under reflectance confocal microscopy, squamous cell carcinoma shows an atypical honeycomb or disarranged pattern of the spinous-granular layer of the epidermis, round nucleated bright cells in the epidermis and round vessels in the dermis. High frequency ultrasound and optical coherence tomography may be helpful in predominantly in pre-surgical evaluation of tumor size. Emerging non-invasive or minimal invasive techniques with possible application in the diagnosis of squamous cell carcinoma of the skin, lip, oral mucosa, vulva or other tissues include high-definition optical coherence tomography, in vivo multiphoton tomography, direct oral microscopy, electrical impedance spectroscopy, fluorescence spectroscopy, Raman spectroscopy, elastic scattering spectroscopy, differential path-length spectroscopy, nuclear magnetic resonance spectroscopy, and angle-resolved low coherence interferometry.

Evaluation of hybrid algorithm for analysis of scattered light using ex vivo nuclear morphology measurements of cervical epithelium.

We evaluate a new hybrid algorithm for determining nuclear morphology using angle-resolved low coherence interferometry (a/LCI) measurements in ex vivo cervical tissue. The algorithm combines Mie theory based and continuous wavelet transform inverse light scattering analysis. The hybrid algorithm was validated and compared to traditional Mie theory based analysis using an ex vivo tissue data set. The hybrid algorithm achieved 100% agreement with pathology in distinguishing dysplastic and non-dysplastic biopsy sites in the pilot study. Significantly, the new algorithm performed over four times faster than traditional Mie theory based analysis.

Inverse scattering solutions using low-coherence light.

We present a new wave-vector-space approach for solving inverse scattering problems. In our formulation, the theories for diffraction tomography and coherence gating are combined to explain 3D reconstruction with low-coherence light. Specifically, we apply this method to solve the scattering problem with broadband fields for transmission and reflection measurements. Our results can be applied to any interferometric measurements with low-coherence light, including optical coherence tomography, angle-resolved low-coherence interferometry, and white-light diffraction tomography.

A scattering phantom for observing long range order with two-dimensional angle-resolved Low-Coherence Interferometry

Angle-resolved low coherence interferometry (a/LCI) is an approach for assessing tissue structure based on light scattering data. Recent advances in a/LCI have extended the analysis to study scattering distributions in two dimensions. In order to provide suitable scattering phantoms for 2D a/LCI, we have developed phantoms based on soft lithography which can provide a range of structures including long range order. Here we characterize these phantoms and demonstrate their utility for providing standardized multi-scale structural information for light scattering measurements.

Spectroscopic Applications in Gastrointestinal Endoscopy

One of the major frontiers in biomedical optics has been as an adjunct to gastrointestinal endoscopy. In particular, spectroscopy of elastic light scattering has the potential of addressing many of the vexing challenges confronting endoscopists. This review discusses the principles of spectroscopy and critically evaluates performance in clinically significant scenarios. One of the best established applications is optical biopsy (in situ histological determination), and a number of techniques such as elastic scattering spectroscopy have demonstrated the ability to discriminate between neoplastic and non-neoplastic polyps. For flat dysplasia detection in Barrett's esophagus, some of the most promising spectroscopic technologies are angle-resolved low-coherence interferometry and endoscopic polarized scanning spectroscopy (the next generation light scattering spectroscopy). A new and exciting biological approach involves optical detection of field carcinogenesis. This can be exploited to reduce colonoscopic adenoma miss rate by assessing microcirculatory augmentation in the mucosa in the vicinity of the polyp using polarization-gatedspectroscopy. Furthermore, there are nano/micro-architectural correlates with diffuse field carcinogenesis throughout the colon. Indeed, technologies such as low coherence enhanced backscattering spectroscopy and partial wave spectroscopic microscopy have demonstrated that the detection of the nano-architectural alterations in the rectal mucosa can accurately sense advanced adenomas elsewhere in the colon. This may lend itself to a minimally intrusive risk stratification to identify patients who are most likely to harbor neoplasia and thus benefit from colonoscopy. Bridging these advances into the endoscopy suite requires pragmatic future development. Future studies need to focus on efficacy, cost, practicality (time required, etc), and particularly developing the paradigms that will impact upon clinical decision making.

Angle-resolved low-coherence interferometry: an optical biopsy technique for clinical detection of dysplasia in Barrett’s esophagus

Angle-resolved low-coherence interferometry (a/LCI) is an optical biopsy technique that measures scattered light from tissue to determine nuclear size with submicron-level accuracy. The a/LCI probe can be deployed through the accessory channel of a standard endoscope and provides feedback to physicians to guide physical biopsies. The technique has been validated in animal and ex vivo human studies, and has been used to detect dysplasia in Barrett’s esophagus patients in vivo. In a recent clinical study of 46 Barrett’s esophagus patients, a/LCI was able to detect dysplasia with 100% sensitivity and 84% specificity. This report reviews the technique and discusses its potential clinical utility.

Angle-Resolved Low Coherence Interferometry for Detection of Dysplasia in Barrett's Esophagus

Barrett’s esophagus (BE) is a metaplastic change of the esophagus which is associated with an increased risk of esophageal adenocarcinoma (EAC)1. The incidence of this cancer has risen dramatically in the U.S. in the last 40 years,2 and prognosis for subjects presenting with symptomatic EAC is dismal, with less than a 15% 5-year survival.3 For this reason, strategies aimed at prevention figure prominently in societal guidelines for the care of BE.4

Detection of intestinal dysplasia using angle-resolved low coherence interferometry

Angle-resolved low coherence interferometry (a/LCI) is an optical biopsy technique that allows for depth-resolved, label-free measurement of the average size and optical density of cell nuclei in epithelial tissue to assess the tissue health. a/LCI has previously been used clinically to identify the presence of dysplasia in Barrett's Esophagus patients undergoing routine surveillance. We present the results of a pilot, ex vivo study of tissues from 27 patients undergoing partial colonic resection surgery, conducted to evaluate the ability of a/LCI to identify dysplasia. Performance was determined by comparing the nuclear morphology measurements with pathological assessment of co-located physical biopsies. A statistically significant correlation between increased average nuclear size, reduced nuclear density, and the presence of dysplasia was noted at the basal layer of the epithelium, at a depth of 200 to 300 μm beneath the tissue surface. Using a decision line determined from a receiver operating characteristic, a/LCI was able to separate dysplastic from healthy tissues with a sensitivity of 92.9% (13/14), a specificity of 83.6% (56/67), and an overall accuracy of 85.2% (69/81). The study illustrates the extension of the a/LCI technique to the detection of intestinal dysplasia, and demonstrates the need for future in vivo studies.

Design and validation of an angle-resolved low-coherence interferometry fiber probe for in vivo clinical measurements of depth-resolved nuclear morphology

We present a novel Fourier-domain angle-resolved low-coherence interferometry (a /LCI) fiber probe designed for in vivo clinical application in gastrointestinal endoscopy. The a/LCI technique measures the depth-resolved angular scattering distribution to determine the size distribution and optical density of cell nuclei for assessing the health of epithelial tissues. Clinical application is enabled by an endoscopic fiber-optic probe that employs a 2.3-m-long coherent fiber bundle and is compatible with the standard 2.8-mm-diam biopsy channel of a gastroscope. The probe allows for real-time data acquisition by collecting the scattering from multiple angles in parallel, enabled by the Fourier domain approach. The performance of the probe is characterized through measurement of critical parameters. The depth-resolved sizing capability of the system is demonstrated using single- and double-layer microsphere phantoms with subwavelength sizing precision and accuracy achieved. Initial results from a clinical feasibility test are also presented to show in vivo application in the human esophagus.

Nuclear morphology measurements with angle-resolved low coherence interferometry for application to cell biology and early cancer detection.

The study of intact, living cells using non-invasive optical spectroscopic methods offers the opportunity to assess cellular structure and organization in a way that is not possible with commonly used cell biology imaging techniques. We have developed a novel spectroscopic technique for diagnosing disease at the cellular level based on using low-coherence interferometry (LCI) to detect the angular distribution of scattered light. Angle-resolved LCI (a/LCI) combines the ability of LCI to isolate scattering from sub-surface tissue layers with the ability of light scattering spectroscopy to obtain structural information on sub-wavelength scales. In application to examining cellular structure, a/LCI enables quantitative measurements of changes in the size and texture of cell nuclei. These quantitative measurements are characteristic of different pathological states. The capabilities of a/LCI were demonstrated using a clinical system that can be applied in endoscopic surveillance of esophageal tissue, producing high sensitivity and specificity for detecting dysplastic tissues in vivo. Experiments with in vitro cell samples also show the utility of a/LCI in observing structural changes due to environmental stimuli as well as detecting apoptosis due to chemotherapeutic agents.

Nuclear Morphology Measurements with Angle-Resolved Low Coherence Interferometry For Application To Cell Biology And Early Cancer Detection

The study of intact, living cells using non-invasive optical spectroscopic methods offers the opportunity to assess cellular structure and organization in a way that is not possible with commonly used cell biology imaging techniques. We have developed a novel spectroscopic technique for diagnosing disease at the cellular level based on using low-coherence interferometry (LCI) to detect the angular distribution of scattered light. Angle-resolved LCI (a/LCI) combines the ability of LCI to isolate scattering from sub-surface tissue layers with the ability of light scattering spectroscopy to obtain structural information on sub-wavelength scales. In application to examining cellular structure, a/LCI enables quantitative measurements of changes in the size and texture of cell nuclei. These quantitative measurements are characteristic of different pathological states. The capabilities of a/LCI were demonstrated using a clinical system that can be applied in endoscopic surveillance of esophageal tissue, producing high sensitivity and specificity for detecting dysplastic tissuesin vivo. Experiments within vitrocell samples also show the utility of a/LCI in observing structural changes due to environmental stimuli as well as detecting apoptosis due to chemotherapeutic agents.

Development of angle-resolved low coherence interferometry for clinical detection of dysplasia

This review covers the development of angle-resolved low coherence interferometry (a/LCI) from initial development through clinical application. In the first applications, the approach used a time-domain interferometry scheme and was validated using animal models of carcinogenesis to assess the feasibility of detecting dysplasia in situ. Further development of the approach led to Fourier-domain interferometry schemes with higher throughput and endoscope-compatible probes to enable clinical application. These later implementations have been applied to clinical studies of dysplasia in Barrett's esophagus tissues, a metaplastic tissue type that is associated with an increased risk of esophageal adenocarcinoma. As an alternative to systematic biopsy, the a/LCI approach offers high sensitivity and specificity for detecting dysplasia in these tissues while avoiding the need for tissue removal or exogenous contrast agents. Here, the various implementations of a/LCI are discussed and the results of the preliminary animal experiments and ex vivo human tissue studies are reviewed. A review of a recent in vivo clinical study is also presented.