Automatic And Robust Calibration of Optical Detector Arrays for Biomedical Diffuse Optical Spectroscopy

The design and testing of a new, fully automated, calibration approach is described. The process was used to calibrate an image-guided diffuse optical spectroscopy system with 16 photomultiplier tubes (PMTs), but can be extended to any large array of optical detectors and associated imaging geometry. The design goals were accomplished by developing a routine for robust automated calibration of the multi-detector array within 45 minutes. Our process was able to characterize individual detectors to a median norm of the residuals of 0.03 V for amplitude and 4.4 degrees in phase and achieved less than 5% variation between all the detectors at the 95% confidence interval for equivalent measurements. Repeatability of the calibrated data from the imaging system was found to be within 0.05 V for amplitude and 0.2 degrees for phase, and was used to evaluate tissue- simulating phantoms in two separate imaging geometries. Spectroscopic imaging of total hemoglobin concentration was recovered to within 5% of the true value in both cases. Future work will focus on streamlining the technology for use in a clinical setting with expectations of achieving accurate quantification of suspicious lesions in the breast

Review of tissue simulating phantoms with controllable optical, mechanical and structural properties for use in optical coherence tomography

We review the development of phantoms for optical coherence tomography (OCT) designed to replicate the optical, mechanical and structural properties of a range of tissues. Such phantoms are a key requirement for the continued development of OCT techniques and applications. We focus on phantoms based on silicone, fibrin and poly(vinyl alcohol) cryogels (PVA-C), as we believe these materials hold the most promise for durable and accurate replication of tissue properties

Criteria for the design of tissue-mimicking phantoms for the standardization of biophotonic instrumentation

A lack of accepted standards and standardized phantoms suitable for the technical validation of biophotonic instrumentation hinders the reliability and reproducibility of its experimental outputs. In this Perspective, we discuss general criteria for the design of tissue-mimicking biophotonic phantoms, and use these criteria and state-of-the-art developments to critically review the literature on phantom materials and on the fabrication of phantoms. By focusing on representative examples of standardization in diffuse optical imaging and spectroscopy, fluorescence-guided surgery and photoacoustic imaging, we identify unmet needs in the development of phantoms and a set of criteria (leveraging characterization, collaboration, communication and commitment) for the standardization of biophotonic instrumentation

Artery phantoms for intravascular optical coherence tomography: healthy arteries

We present a method to make phantoms of coronary arteries for intravascular optical coherence tomography (IV-OCT). The phantoms provide a calibrated OCT response similar to the layered structure of arteries. The optical properties of each layer are achieved with specific concentrations of alumina and carbon black in a silicone matrix. This composition insures high durability and also approximates the elastic properties of arteries. The phantoms are fabricated in a tubular shape by the successive deposition and curing of liquid silicone mixtures on a lathe setup

Deformable and durable phantoms with controlled density of scatterers

We have developed deformable and durable optical tissue phantoms with a simple and well-defined microstructure including a novel combination of scatterers and a matrix material. These were developed for speckle and elastography investigations in optical coherence tomography, but should prove useful in many other fields. We present in detail the fabrication process which involves embedding silica microspheres in a silicone matrix. We also characterize the resulting phantoms with scanning electron microscopy and optical measurements. To our knowledge, no such phantoms were proposed in the literature before. Our technique has a wide range of applicability and could also be adapted to fabricate phantoms with various optical and mechanical properties.Peer reviewed: YesNRC publication: Ye

NONCONTACT DIFFUSE CORRELATION TOMOGRAPHY OF BREAST TUMOR

Since aggressive cancers are frequently hypermetabolic with angiogenic vessels, quantification of blood flow (BF) can be vital for cancer diagnosis. Our laboratory has developed a noncontact diffuse correlation tomography (ncDCT) system for 3-D imaging of BF distribution in deep tissues (up to centimeters). The ncDCT system employs two sets of optical lenses to project source and detector fibers respectively onto the tissue surface, and applies finite element framework to model light transportation in complex tissue geometries. This thesis reports our first step to adapt the ncDCT system for 3-D imaging of BF contrasts in human breast tumors. A commercial 3-D camera was used to obtain breast surface geometry which was then converted to a solid volume mesh. An ncDCT probe scanned over a region of interest on the breast mesh surface and the measured boundary data were used for 3-D image reconstruction of BF distribution. This technique was tested with computer simulations and in 28 patients with breast tumors. Results from computer simulations suggest that relatively high accuracy can be achieved when the entire tumor was within the sensitive region of diffuse light. Image reconstruction with a priori knowledge of the tumor volume and location can significantly improve the accuracy in recovery of tumor BF contrasts. In vivo ncDCT imaging results from the majority of breast tumors showed higher BF contrasts in the tumor regions compared to the surrounding tissues. Reconstructed tumor depths and dimensions matched ultrasound imaging results when the tumors were within the sensitive region of light propagation. The results demonstrate that ncDCT system has the potential to image BF distributions in soft and vulnerable tissues without distorting tissue hemodynamics. In addition to this primary study, detector fibers with different modes (i.e., single-mode, few-mode, multimode) for photon collection were experimentally explored to improve the signal-to-noise ratio of diffuse correlation spectroscopy flow-oximeter measurements

Spatially-Dense, Multi-Spectral, Frequency-Domain Diffuse Optical Tomography of Breast Cancer

Diffuse optical tomography (DOT) employs near-infrared light to image the concentration of chromophores and cell organelles in tissue and thereby providing access to functional parameters that can differentiate cancerous from normal tissues. This thesis describes research at the bench and in the clinic that explores and identifies the potential of DOT breast cancer imaging. The bench and clinic instrumentation differ but share important features: they utilize a very large, spatially dense, set of source-detector pairs (10E7) for imaging in the parallel-plate geometry. The bench experiments explored three-dimensional (3D) image resolution and fidelity as a function of numerous parameters and also ascertained the effects of a chest wall phantom. The chest wall is always present but is typically ignored in breast DOT. My experiments clarified chest wall influences and developed schemes to mitigate these effects. Mostly, these schemes involved selective data exclusion, but their efficacy also depended on reconstruction approach. Reconstruction algorithms based on analytic (fast) Fourier inversion and linear algebraic techniques were explored. The clinical experiments centered around a DOT instrument that I designed, constructed, and have begun to test (in-vitro and in-vivo). This instrumentation offers many features new to the field. Specifically, the imager employs spatially-dense, multi-spectral, frequency-domain data; it possesses the world\u27s largest optical source-detector density yet reported, facilitated by highly-parallel CCD-based frequency-domain imaging based on gain-modulation heterodyne detection. The instrument thus measures both phase and amplitude of the diffusive light waves. Other features include both frontal and sagittal breast imaging capabilities, ancillary cameras for measurement of breast boundary profiles, real-time data normalization, and mechanical improvements for patient comfort. The instrument design and construction is my most significant contribution, but first imaging experiments with tissue phantoms and of cancer bearing breasts were also carried out. A parallel effort with simulated data has yielded important information about new reconstruction regularization issues that arise when phase and amplitude are measured. With these gains in device implementation and DOT reconstruction, my research takes valuable steps towards bringing this novel imaging technique closer to clinical utilization

Towards clinical optical elastography: high-speed 3D imaging using volumetric phase detection

Tese de mestrado integrado em Engenharia Biomédica e Biofísica, apresentada à Universidade de Lisboa, através da Faculdade de Ciências, 2014Dada a existência de diferenças nas propriedades elásticas de um tecido num estado saudável e patológico, a medição destas propriedades pode ser importante no diagnóstico de algumas doenças. A elastografia é uma técnica de imagiologia que dá informação objetiva sobre as propriedades elásticas de um tecido. Nesta técnica, o tecido é comprimido, o deslocamento do tecido é medido usando uma técnica de imagiologia (ex: ressonância magnética, CT ou ultrassons), e as medições de deslocamento são usadas para estimar uma propriedade elástica, como o Módulo de Young ou a Deformação, e formar então uma imagem médica – elastograma. As primeiras técnicas de elastografia usavam ultrassons e ressonância magnética nas medições de deslocamento. Mais recentemente, a tomografia de coerência ótica foi também aplicada à elastografia, numa técnica chamada elastografia de coerência ótica, trazendo melhor resolução espacial e sensibilidade, apesar de ser incapaz de obter imagens tão profundas no tecido. A elastografia de coerência ótica apresenta uma resolução na ordem dos 2-10 micrómetros, pelo menos uma ordem de grandeza inferior à elastografia usando as técnicas referidas anteriormente. A avaliação das margens de tumores em cirurgias de remoção de cancro da mama ou o diagnóstico de doenças musculares como a Distrofia Muscular de Duchenne são exemplos de aplicações de elastografia que requerem uma resolução microscópica ao nível que só a variante da coerência ótica consegue oferecer. Em tomografia de coerência ótica de domínio espectral, o sinal medido pode ser dividido em amplitude e fase. A amplitude do sinal é usada para formar as imagens normais de tomografia de coerência ótica enquanto a fase é aleatória. Contudo, quando adquiridas duas imagens de uma amostra que se desloca (entre a aquisição da primeira e da segunda imagem) paralelamente à direção de propagação do feixe de luz, gera-se um desvio na fase proporcional ao deslocamento. Em elastografia de coerência ótica de compressão quasi-estática sensível à fase, são adquiridas duas imagens com a amostra em dois estados diferentes de compressão e o desvio de fase em cada ponto é calculado. O desvio é posteriormente convertido em deslocamento que por sua vez é usado na estimação da Deformação em cada ponto da amostra. No projeto desenvolvido durante o estágio realizado no Optical and Biomedical Engineering Laboratory (OBEL) da University of Western Australia (UWA), a técnica de elastografia de coerência ótica usada pelo grupo foi modificada/adaptada de forma a adquirir imagens 3D de forma mais rápida e eficiente. Para o fazer, foi necessário modificar as instruções fornecidas ao software de aquisição, testar e otimizar diferentes parâmetros, assim como alterar todo o processamento de dados relativo à construção das imagens. Na técnica originalmente usada pelo grupo, a compressão e a descompressão são aplicadas alternadamente ao fantoma após a aquisição de cada uma das “fatias” (B-scans) do volume total (C-scan). A diferença de fase entre B-scans consecutivos (par comprimido-descomprimido) corresponde ao deslocamento da amostra, que era de seguida usada para calcular a Deformação em cada ponto. A velocidade de aquisição de cada B-scan é limitada pela frequência da compressão-descompressão da amostra, que em regimes quasi-estáticos não pode ultrapassar os 5 Hz. Desta forma, a aquisição de B-scans não pode ser feita a um ritmo superior a 10 Hz (0.1 segundos por B-scan). Num C-scan com 5000 B-scans (2500 B-scans comprimidos e 2500 B-scans descomprimidos), o tempo total de aquisição corresponde a 500 segundos. Na técnica desenvolvida durante o projeto, o volume total da amostra (C-scan) é adquirido com a amostra descomprimida, de seguida a compressão é aplicada e é adquirido um segundo volume com a amostra comprimida. Desta forma, o deslocamento é calculado diretamente através da diferença de fase entre os 2 C-scans. O novo esquema de aquisição permite eliminar a necessidade de efetuar oversampling, reduzindo o volume de dados (número de B-scans) em 10 vezes. A frequência a que é aplicada a compressão-descompressão continua a estar limitada a 5 Hz, mas como esta é aplicada entre C-scans, é a aquisição de C-scans que não pode ser efetuada a um ritmo superior a 10 Hz (0.1 segundos por C-scan). Levando a frequência de aquisição de B-scans ao limite do sistema (100 Hz), em 2 C-scans, um com 500 B-scans comprimidos e outro com 500 B-scans descomprimidos, o tempo total de aquisição corresponde a 5 segundos. Com um sistema de aquisição mais rápido, o tempo total de aquisição poderia ser reduzido a 0.2 segundos. O desempenho do novo esquema de aquisição foi comparado com o esquema anterior através da medição da sensibilidade de fase e da sensibilidade de deformação em imagens de fantomas obtidas com as duas técnicas. O tempo de aquisição de um volume de 5 mm × 5 mm × 2 mm foi reduzido de 500 segundos para 5 segundos, sendo que as sensibilidades se mantiveram na mesma ordem de grandeza. A grande diminuição do tempo de aquisição abre portas a futuras aplicações clínicas com base na elastografia de coerência ótica. Durante a realização do projeto houve a possibilidade de testar a técnica e o novo esquema de aquisição em amostras de tecidos musculares de ratazanas nos laboratórios do grupo e em amostras de tecido mamário cancerígeno no Hospital de Royal Perth. Alguns destes resultados estão contidos nesta dissertação. Com o trabalho desenvolvido neste projeto, foi escrito em conjunto com o meu orientador externo e um outro membro do OBEL, um artigo intitulado “Three-dimensional optical coherence elastography by phase-sensitive comparison of C-scans”, que foi submetido ao Journal of Biomedical Optics e aguarda revisão.As the mechanical properties of healthy and pathological tissue are often different, measuring these properties can be useful in the diagnosis of disease. Elastography is an imaging technique that provides information about the mechanical properties of tissue. In elastography, a mechanical load is applied to the tissue, the resulting displacement is measured using medical imaging, and a mechanical property of the sample is calculated and mapped into an image, known as an elastogram. Elastography was initially developed using ultrasound and magnetic resonance imaging (MRI). More recently, optical coherence tomography-based elastography, referred to as optical coherence elastography (OCE), has been developed providing greater spatial resolution and sensitivity although with lower penetration of 1-2 mm. In this project, a new and high speed acquisition method for three-dimensional (3D) OCE is presented and compared with a previously reported OCE method. In this new method, based on compression elastography, the mechanical load applied to the sample is altered between the acquisition of two OCT volume scans (C-scans), differing from the previous method in which the load is altered between the acquisition of every B-scan. The new acquisition scheme partially overcomes the low acquisition speed limitations imposed by the quasi-static requirements and eliminates the need for oversampling, resulting in faster acquisition rates and the acquisition of less data. Both methods are characterized and compared using tissue-mimicking phantoms. The acquisition method developed in this project improved the acquisition speed of a 3D-OCE data volume with dimensions (x × y × z) of 5 mm × 5 mm × 2 mm from 500 s to 5 s with similar sensitivity. This dramatic improvement in acquisition speed opens the possibility for future clinical applications of the technology. Within this project, to demonstrate the performance of this new method, OCE scans of rat muscle and freshly excised human breast cancer tissue are also presented