Browsing by Subject "Low coherence interferometry"

Cancer is a disease that affects millions of people each year. While methods for the prevention and treatment of the disease continue to advance, the early detection of precancerous development remains a key factor in reducing mortality and morbidity among patients. The current gold standard for cancer detection is the systematic biopsy. While this method has been used for decades, it is not without limitations. Fortunately, optical detection of cancer techniques are particularly well suited to overcome these limitations. This dissertation chronicles the development of one such technique called Fourier domain low coherence interferometry (fLCI).

The presented work first describes a detailed analysis of temporal and spatial coherence. The study shows that temporal coherence information in time frequency distributions contains valuable structural information about experimental samples. Additionally, the study of spatial coherence demonstrates the necessity of spatial resolution in white light interferometry systems. The coherence analysis also leads to the development of a new data processing technique that generates depth resolved spectroscopic information with simultaneously high depth and spectral resolution.

The development of two new fLCI optical systems is also presented. These systems are used to complete a series of controlled experiments validating the theoretical basis and functionality of the fLCI system and processing methods. First, the imaging capabilities of the fLCI system are validated through scattering standard experiments and animal tissue imaging. Next, the new processing method is validated by a series of absorption phantom experiments. Additionally, the nuclear sizing capabilities of the fLCI technique are validated by a study measuring the nuclear morphology of in vitro cell monolayers.

The validation experiments set the stage for two animal studies: an initial, pilot study and a complete animal trial. The results of these animal studies show that fLCI can distinguish between normal and dyplastic epithelial tissue with high sensitivity and specificity. The results of the work presented in this dissertation show that fLCI has great potential to develop into an effective method for early cancer detection.

Optical coherence tomography (OCT) is a non-invasive optical imaging modality that provides micron-scale resolution of tissue micro-structure over depth ranges of several millimeters. This imaging technique has had a profound effect on the field of ophthalmology, wherein it has become the standard of care for the diagnosis of many retinal pathologies. Applications of OCT in the anterior eye, as well as for imaging of coronary arteries and the gastro-intestinal tract, have also shown promise, but have not yet achieved widespread clinical use.

The usable imaging depth of OCT systems is most often limited by one of three factors: optical attenuation, inherent imaging range, or depth-of-focus. The first of these, optical attenuation, stems from the limitation that OCT only detects singly-scattered light. Thus, beyond a certain penetration depth into turbid media, essentially all of the incident light will have been multiply scattered, and can no longer be used for OCT imaging. For many applications (especially retinal imaging), optical attenuation is the most restrictive of the three imaging depth limitations. However, for some applications, especially anterior segment, cardiovascular (catheter-based) and GI (endoscopic) imaging, the usable imaging depth is often not limited by optical attenuation, but rather by the inherent imaging depth of the OCT systems. This inherent imaging depth, which is specific to only Fourier Domain OCT, arises due to two factors: sensitivity fall-off and the complex conjugate ambiguity. Finally, due to the trade-off between lateral resolution and axial depth-of-focus inherent in diffractive optical systems, additional depth limitations sometimes arises in either high lateral resolution or extended depth OCT imaging systems. The depth-of-focus limitation is most apparent in applications such as adaptive optics (AO-) OCT imaging of the retina, and extended depth imaging of the ocular anterior segment.

In this dissertation, techniques for extending the imaging range of OCT systems are developed. These techniques include the use of a high spectral purity swept source laser in a full-field OCT system, as well as the use of a peculiar phenomenon known as coherence revival to resolve the complex conjugate ambiguity in swept source OCT. In addition, a technique for extending the depth of focus of OCT systems by using a polarization-encoded, dual-focus sample arm is demonstrated. Along the way, other related advances are also presented, including the development of techniques to reduce crosstalk and speckle artifacts in full-field OCT, and the use of fast optical switches to increase the imaging speed of certain low-duty cycle swept source OCT systems. Finally, the clinical utility of these techniques is demonstrated by combining them to demonstrate high-speed, high resolution, extended-depth imaging of both the anterior and posterior eye simultaneously and in vivo.

Cervical cancer is one of the most common gynecologic malignancies with significant morbidity and mortality globally. However, most pre-cancers are easily treatable such that early detection of cervical abnormalities is critical in improving patient prognosis. Despite the success of current cervical cancer screening methodologies, these techniques are still limited in accuracy, leading to undetected cervical lesions or unnecessary biopsies.

This dissertation will focus on the development of two optical modalities for early detection of cervical dysplasia: angle-resolved low coherence interferometry (a/LCI) and multiplexed low coherence interferometry (mLCI). Originally, a/LCI was developed as a clinical technique for detecting esophageal dysplasia by detecting nuclear enlargement in the basal layer of the epithelium. To improve the clinical utility of a/LCI, a novel processing algorithm was developed using a continuous wavelet transform (CWT) based analysis of the a/LCI data which demonstrated significant improvement in processing speed compared to previous analysis techniques. Future development of this algorithm may open the possibility for real-time clinical analysis of a/LCI data, improving the clinical utility of the instrument.

In addition, the a/LCI instrument was adapted for cervical imaging, and a clinical feasibility study was performed to determine the effectiveness of using a/LCI nuclear morphology measurements for detecting cervical dysplasia. a/LCI optical biopsies were taken from 63 distinct tissue biopsy sites and compared to histopathological analysis of co-registered tissue biopsies. Analysis of the a/LCI nuclear morphology data found a significant increase in the nuclear diameter in the basal layer of dysplastic tissue sites and demonstrated high sensitivity and specificity (both >0.80) for detection of cervical dysplasia and high-grade squamous intraepithelial lesions.

Secondly, mLCI was adapted for collecting A-scans over the cervical epithelium. An mLCI cervical probe was designed and a clinical study was conducted to image 50 patients with the new device. Linear discriminant analysis was performed on the mLCI data to automatically classify the cervical A-scans as either endocervical or ectocervical tissue towards the goal of automatic delineation cervical transformation zone. This device can be combined with a/LCI to direct optical biopsy scans to areas on the cervix which are most likely to harbor tissue dysplasia.

Finally, the two technologies were incorporated into a single multimodal imaging system. First, a benchtop scanning a/LCI system was developed by incorporating an image rotator and 2D scanner into the system to enable radial scanning on the sample. This system was integrated into a handheld probe for cervical imaging. Volumetric imaging using sparse depth scans and the scanning a/LCI technology was validated with a polystyrene microsphere phantom, and a pilot study was conducted to demonstrate the feasibility of using this instrument for comprehensive screening of cervical tissue for precancerous cells.