Up to 20% of breast cancer patients who undergo presurgical (neoadjuvant) chemotherapy have no response to treatment. Standard-of-care imaging modalities, including MRI, CT, mammography, and ultrasound, measure anatomical features and tumor size that reveal response only after months of treatment. Recently, non-invasive, near-infrared optical markers have shown promise in indicating the efficacy of treatment at the outset of the chemotherapy treatment. For example, frequency domain Diffuse Optical Spectroscopic Imaging (DOSI) can be used to characterize the optical scattering and absorption properties of thick tissue, including breast tumors. These parameters can then be used to calculate tissue concentrations of chromophores, including oxyhemoglobin, deoxyhemoglobin, water, and lipids. Tumors differ in hemoglobin concentration, as compared with healthy background tissue, and changes in hemoglobin concentration during neoadjuvant chemotherapy have been shown to correlate with efficacy of treatment. Using DOSI early in treatment to measure chromophore concentrations may be a powerful tool for guiding neoadjuvant chemotherapy treatment. Previous frequency-domain DOSI systems have been limited by large device footprints, complex electronics, high costs, and slow acquisition speeds, all of which complicate access to patients in the clinical setting. In this work a new digital DOSI (dDOSI) system has been developed, which is relatively inexpensive and compact, allowing for use at the bedside, while providing unprecedented measurement speeds. The system builds on, and significantly advances, previous dDOSI setups developed by our group and, for the first time, utilizes hardware-integrated custom board-level direct digital synthesizers (DDS) and analog to digital converters (ADC) to generate and directly measure signals utilizing undersampling techniques. The dDOSI system takes high-speed optical measurements by utilizing wavelength multiplexing while sweeping through hundreds of modulation frequencies in tens of milliseconds. The new dDOSI system is fast, inexpensive, and compact without compromising accuracy and precision.

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Neoadjuvant chemotherapy (NAC) is a common breast cancer treatment that involves administering chemotherapy for 3-6 months prior to surgery. This treatment enables more breast-conserving surgeries and even allows for the omission of surgery in some cases. However, about 31% of patients receiving NAC do not respond to the treatment. Therefore, there is a need for real-time methods to predict treatment response and improve patient outcomes. Over the last two decades, diffuse optical imaging has been investigated as a potential solution to this problem. This noninvasive and inexpensive technology uses near or shortwave infrared (NIR or SWIR) light to illuminate tissue, and detects multiply-scattered photons. However, bulky instrumentation and complicated imaging procedures have limited the clinical adoption of this technology. Furthermore, measured biomarkers including oxy- and deoxy-hemoglobin (HbO2 and HHb, respectively), water, and lipid, have had mixed results in terms of prognostic capability. To address these limitations, a new wearable optical probe technology was developed and validated in this project, including a high-optode density NIR probe for monitoring hemodynamics and a first-generation SWIR probe for quantifying water and lipid. Measurements on tissue-mimicking channel flow phantoms confirmed the ability of the NIR probe to quantify absorption contrast in vitro, and a cuff occlusion measurement demonstrated sensitivity to HbO2 and HHb in vivo. Hemodynamic oscillations at the respiratory rate were also explored in healthy volunteers and breast cancer patients as a potential new biomarker. It was demonstrated that traditional and novel breathing-related hemodynamic metrics provide tumor contrast and can potentially track treatment response. A deep-learning algorithm was developed to extract water and lipid concentrations from multi-distance SWIR measurements. The SWIR probe was validated by comparing measured water and lipid concentrations against ground truth values in emulsion phantoms. This work represents a significant step toward the development of technologies for frequent breast cancer treatment monitoring in the clinic and potentially at home.

Fluorescence diffuse optical tomography provides non-invasive, in vivo imaging of molecular targets in small animals. While standard fluorescence microscopy is limited to shallow depths and small fields of view, tomographic methods allows recovery of the distribution of fluorescent probes throughout the small animal body. In this thesis, we present novel reconstruction algorithms for the tomographic separation of optical parameters using time-domain (TD) measurements. These technique are validated using simulations and with experimental phantom and mouse imaging studies. We outline the contributions of each chapter of the thesis below. First, we explore the TD fluorescence tomography reconstruction problem for single and multiple fluorophores with discrete lifetimes. We focus on late arriving photons and compare a direct inversion approach with a two-step, asymptotic approach operating on the same TD data. We show that for lifetime multiplexing, the two methods produce fundamentally different kinds of solutions. The direct inversion is computationally inefficient and results in poor separation but has overall higher resolution while the asymptotic approach provides better separation, relative quantitation of lifetime components and localization but has overall lower resolution. We verify these results with simulation and experimental phantoms. Second, we introduce novel high resolution lifetime multiplexing algorithms which combine asymptotic methods for separation of fluorophores with the high resolving power of early photon tomography. We show the effectiveness of such methods to achieve high resolution reconstructions of multiple fluorophores in simulations with complex-shaped phantoms, a digital mouse atlas and also experimentally in fluorescent tube phantoms. Third, we compare the performance of tomographic spectral and lifetime multiplexing. We show that both of these techniques involve a two-step procedure, consisting of a diffuse propagation step and a basis-function mixing step. However, in these two techniques, the order of the two steps is switched, which leads to a fundamental difference in imaging performance. As an illustration of this difference, we show that the relative concentrations of three colocalized fluorophores in a diffuse medium can accurately be retrieved with lifetime methods but cannot be retrieved with spectral methods. Fourth, we address the long standing challenge in diffuse optical tomography (DOT) of cross-talk between absorption and scattering. We extend the ideas developed from lifetime multiplexing algorithms by using a constrained optimization approach for separation of absorption and scattering in DOT. Using custom designed phantoms, we demonstrate a novel technique allows better separation of absorption and scattering inclusions compared to existing algorithms for CW and TD diffuse optical tomography. Finally, we show experimental validation of the lifetime multiplexing algorithms developed in this thesis using three experimental models. First, we show the reconstruction of overlapping complex shapes in a dish phantom. Second, we demonstrate the localization accuracy of lifetime based methods using fluorescent pellets embedded in a sacrificed mouse. Third, we show using planar imaging and tomography, the in vivo recovery of multiple anatomically targeted near-infrared fluorophores. In summary, we have presented novel reconstruction algorithms and experimental methods that extend the capability of time-domain fluorescence diffuse optical tomography systems. The methods developed in this thesis should also have applicability for general multi-parameter image reconstruction problems. / Engineering and Applied Sciences

La possibilité de déterminer précisément et de quantifier la composition des milieux biologiques est un défi pour l'imagerie médicale qui permettrait de diagnostiquer certaines maladies ou de mieux étudier les processus physiologiques. La tomographie optique diffuse (DOT) est une technique d'imagerie attrayante qui permet de façon non invasive, non-ionisante et potentiellement avec une grande spécificité de sonder les milieux en profondeur en utilisant la lumière dans le proche infrarouge et de reconstruire en trois dimensions leur composition. Pour obtenir les caractéristiques des chromophores endogènes (oxy- et désoxy-hémoglobine) enfouis dans un milieu très diffusant, une instrumentation optique dans le domaine temporel et multi-longueurs d'onde combinée à un algorithme de reconstruction en trois dimensions a été développée. Des mesures expérimentales ont été menées en géométrie de réflectance en éclairant avec un laser picoseconde un milieu perturbé (contenant une hétérogénéité) et en récupérant, pour plusieurs longueurs d'onde et multi-positions, la lumière rétrodiffusée via deux fibres optiques connectées à deux détecteurs dédiés et couplés à un système de comptage de photon unique. Le traitement des données de ces mesures résolues en temps a été réalisé en supposant que la propagation de la lumière est gouvernée par l'approximation de la diffusion et en utilisant une méthode basée sur la transformée de Mellin-Laplace. Des simulations et des expériences sur une gamme de milieux imitant les milieux biologiques ont démontré que cette technique médicale a le potentiel pour donner des images médicales quantitatives. Nous avons montré que l'on peut déterminer correctement la composition d'objets à 10 mm de profondeur absorbant faiblement. Pour de plus fortes profondeurs et des absorptions plus élevées, la valeur du coefficient d'absorption ou de la concentration est sous-estimée. En outre, l'imagerie multimodale apporte des améliorations dans la précision de la quantification en profondeur et donc peut être une bonne opportunité pour les futures applications cliniques de la DOT. / In medical imaging, the ability to accurately retrieve and quantify the composition of turbid media is challenging and would enable to diagnose some diseases or to better study physiological processes. Diffuse optical tomography (DOT) is an attractive medical imaging technique which permits to probe in depth using near-infrared light and to reconstruct in three dimensions the composition of biological tissues non-invasively, non-ionizing and with potentially high specificity. To obtain endogenous chromophore (oxy- and desoxy-hemoglobin) features in the depth of a highly scattering medium, a multiwavelength time domain optical setup combined to a three-dimensional reconstruction algorithm was developed. Experimental measurements were conducted in reflectance geometry by illuminating a perturbed medium (with a heterogeneity) with a picosecond laser and by collecting, for several wavelengths and multi-positions, the backscattered light via two fibers connected to two dedicated detectors and coupled to a time-correlated single photon counting system. The data processing of these time-resolved measurements and those of a known reference medium was performed by supposing that the propagation of light is governed by the diffusion approximation and using a method based on Mellin-Laplace transform. Numerical and phantom experiments on series of objects similar to biological media demonstrate that this technique has the potential to give quantitative medical images. We have highlighted a correct quantification for the less absorbing objects at 10 mm depth while underestimation results at deeper depths and higher absorptions. Furthermore, the multimodal imaging brings improvements in quantification in depth and thus it can be a good opportunity to DOT for its future clinical applications.

Chemo-radiation therapy is a principal modality for the treatment of head and neck cancers, and its efficacy depends on the interaction of tumor oxygen with free radicals. In this study, we adopted a novel hybrid diffuse optical instrument combining a commercial frequency-domain tissue oximeter (Imagent) and a custom-made diffuse correlation spectroscopy (DCS) flowmeter, which allowed for simultaneous measurements of tumor blood flow and blood oxygenation. Using this hybrid instrument we continually measured tumor hemodynamic responses to chemo-radiation therapy over the treatment period of 7 weeks. We also explored monitoring dynamic tumor hemodynamic changes during radiation delivery. Blood flow data analysis was improved by simultaneously extracting multiple parameters from one single autocorrelation function curve measured by DCS. Patients were classified into two groups based on clinical outcomes: a complete response (CR) group and an incomplete response (IR) group with remote metastasis and/or local recurrence within one year. Interestingly, we found human papilloma virus (HPV-16) status largely affected tumor homodynamic responses to therapy. Significant differences in tumor blood flow index (BFI) and reduced scattering coefficient (μs’) between the IR and CR groups were observed in HPV-16 negative patients at Week 3. Significant differences in oxygenated hemoglobin concentration ([HbO2]) and blood oxygen saturation (StO2) between the two groups were found in HPV-16 positive patients at Week 1 and Week 3, respectively. Receiver operating characteristic curves were constructed and results indicated high sensitivities and specificities of these hemodynamic parameters for early (within the first three weeks of the treatment) prediction of one-year treatment outcomes. Measurement of tumor hemodynamics may serve as a predictive tool allowing treatment selection based on biologic tumor characteristics. Ultimately, reduction of side effects in patients not benefiting from radiation treatment may be feasible.