The statistical evaluation of molecular imaging approaches for detecting, diagnosing, and monitoring molecular response to treatment are required prior to their adoption. The assessment of fluorescence-enhanced optical imaging is particularly challenging since neither instrument nor agent has been established. Small animal imaging does not address the depth of penetration issues adequately and the risk of administering molecular optical imaging agents into patients remains unknown. Herein, we focus upon the development of a framework for OAIQ which includes a lumpy-object model to simulate natural anatomical tissue structure as well as the non-specific distribution of fluorescent contrast agents. This work is required for adoption of fluorescence-enhanced optical imaging in the clinic. Herein, the imaging system is simulated by the diffusion approximation of the time-dependent radiative transfer equation, which describes near infra-red light propagation through clinically relevant volumes. We predict the time-dependent light propagation within a 200 cc breast interrogated with 25 points of excitation illumination and 128 points of fluorescent light collection. We simulate the fluorescence generation from Cardio-Green at tissue target concentrations of 1, 0.5, and 0.25 µM with backgrounds containing 0.01 µM. The fluorescence boundary measurements for 1 cc spherical targets simulated within lumpy backgrounds of (i) endogenous optical properties (absorption and scattering), as well as (ii) exogenous fluorophore crosssection are generated with lump strength varying up to 100% of the average background. The imaging data are then used to validate a PMBF/CONTN tomographic reconstruction algorithm. Our results show that the image recovery is sensitive to the heterogeneous background structures. Further analysis on the imaging data by a Hotelling observer affirms that the detection capability of the imaging system is adversely affected by the presence of heterogeneous background structures. The above issue is also addressed using the human-observer studies wherein multiple cases of randomly located targets superimposed on random heterogeneous backgrounds are used in a “double-blind” situation. The results of this study show consistency with the outcome of above mentioned analyses. Finally, the Hotelling observer’s analysis is used to demonstrate (i) the inverse correlation between detectability and target depth, and (ii) the plateauing of detectability with improved excitation light rejection.

A new optical imaging modality has been developed for small animal in vivo imaging of near-infrared fluorescence resulting from fluorescent contrast agents specifically targeted to molecular markers of cancer. The imaging system is comprised of an intensified charge-coupled device (ICCD) for the detection of ultra-low levels of re-emitted fluorescence following the delivery of an expanded beam of excitation light. The design of the ICCD detection system allows for both continuous wave (CW) and frequency-domain modes of operation. Since the accurate acquisition of frequency-domain photon migration (FDPM) data is important for tomographic imaging, the imaging system was also validated using experimentally obtained FDPM measurements of homogenous turbid media and diffusion theory to obtain estimates of the optical properties characteristic of the media. The experiments demonstrated that the absorption and reduced scattering coefficients are determined least accurately when relative rel measurements of average light intensity IDC are employed either alone or in a rel combination with relative modulation amplitude data IAC and/or relative phase shift data rel . However, when FDPM measurements of are employed either alone or in rel combination with IAC data, the absorption and reduced scattering coefficients may be found accurate to within 15% and 11%, respectively, of the values obtained from standard single-pixel measurements; a result that suggests that FDPM data obtained from an ICCD detection system may in fact be useful in tomographic imaging. Furthermore, intensified-detection allows for sub-second exposure times, permitting the acquisition of dynamic fluorescence images immediately following administration of the contrast agent. Experimental results demonstrate that when coupled with a suitable pharmacokinetic model describing targeted dye distribution throughout the body, dynamic fluorescence imaging may be used to discriminate spontaneous canine adenocarcinoma from normal mammary tissue. A separate experiment demonstrates that pharmacokinetic analysis of dynamic fluorescence images enables one to estimate the rate constant governing Kaposi's sarcoma tumor uptake of an integrin-targeted dye and integrin receptor turnover rate. The rate constant for uptake was calculated to be 0.16-sec-1 while the turnover rate of the integrin receptor was estimated to occur within 24-hours.

This work mainly focuses on signal processing issues related to continuous-wave, polarization-based direct imaging schemes. Here, we present a mathematical framework to analyze the performance of the Polarization Difference Imaging (PDI) and Polarization Modulation Imaging (PMI). We have considered three visualization parameters, namely, the polarization intensity (PI), Degree of Linear Polarization (DOLP) and polarization orientation (PO) for comparing these schemes. The first two parameters appear frequently in literature, possibly under different names. The last parameter, polarization orientation, has been introduced and elaborated in this thesis. We have also proposed some extensions/alternatives for the existing imaging and processing schemes and analyzed their advantages. Theoretically and through Monte-Carlo simulations, we have studied the performance of these schemes under white and coloured noise conditions, concluding that, in general, the PMI gives better estimates of all the parameters. Experimental results corroborate our theoretical arguments. PMI is shown to give asymptotically efficient estimates of these parameters, whereas PDI is shown to give biased estimates of the first two and is also shown to be incapable of estimating PO. Moreover, it is shown that PDI is a particular case of PMI. The property of PDI, that it can yield estimates at lower variances has been recognized as its major strength. We have also shown that the three visualization parameters can be fused to form a colour image, giving a holistic view of the scene. We report the advantages of analyzing chunks of data and bootstrapped data under various circumstances. Experiments were conducted to image objects through calibrated scattering media and natural media like mist, with successful results. Scattering media prepared with polystyrene microspheres of diameters 2.97m, 0.06m and 0.13m dispersed in water were used in our experiments. An intensified charge coupled device (CCD) camera was used to capture the images. Results showed that imaging could be performed beyond optical thickness of 40, for particles with 0.13m diameter. For larger particles, the depth to which we could image was much lesser. An experiment using an incoherent source yielded better results than with coherent sources, which we attribute to the speckle noise induced by coherent sources. We have suggested a harmonic based imaging scheme, which can perhaps be used when we have a mixture of scattering particles. We have also briefly touched upon the possible post processing that can be performed on the obtained results, and as an example, shown segmentation based on a PO imaging result.

The scientific applications and engineering aspects of multispectral and hyperspectral imaging systems have been studied extensively. The traditional geometric spectral imaging system model is specifically developed aiming at spectral sensors with spectrally non-overlapping bands. Spectral imaging systems with overlapping bands also exist. For example, the quantum-dot infrared photodetectors (QDIPs) for midwave- and longwave-infrared (IR) imaging systems exhibit highly overlapping spectral responses tunable through the bias voltages applied. This makes it possible to build spectrally tunable imaging system in IR range based on single QDIP. Furthermore, the QDIP based system can be operated as being adaptive to scenes. Other optical imaging systems like the human eye and some polarimetric sensing systems also have overlapping bands. To analyze such sensors, a functional analysis-based framework is provided in this dissertation. The framework starts from the mathematical description of the interaction between sensor and the radiation from scene reaching it. A geometric model of the spectral imaging process is provided based on the framework. The spectral response functions and the scene spectra are considered as vectors inside an 1-dimensional spectral space. The spectral imaging process is abstracted to represent a projection of scene spectrum onto sensor. The projected spectrum, which is the least-square error reconstruction of the scene vectors, contains the useful information for image processing. Spectral sensors with arbitrary spectral response functions are can be analyzed with this model. The framework leads directly to an image pre-processing algorithm to remove the data correlation between bands. Further discussion shows that this model can also serve the purpose of sensor evaluation, and thus facilitates comparison between different sensors. The spectral shapes and the Signal-to-Noise Ratios (SNR) of different bands are seen to influence the sensor's imaging ability in different manners, which are discussed in detail. With the newly defined SNR in spectral space, we can quantitatively characterize the photodetector noise of a spectral sensor with overlapping bands. The idea of adaptive imaging with QDIP based sensor is proposed and illustrated.

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Porphyrins represent one of the oldest, most widely studied chemical structures, both in nature and in biomedical applications. Due to their tumor avidity and favorable photophysical properties, such as long wavelength absorption and emission, easy derivatization, high singlet oxygen quantum yield and low in vivo toxicity, porphyrins have found particular success for photodynamic therapy and fluorescence imaging of cancer. Additionally, they are excellent metal chelators, forming highly stable metallo-complexes, making porphyrins an efficient delivery vehicle for radioisotopes. Thus, there is great potential in the applications of these multi-modal porphyrin-based agents for cancer imaging and therapy. I have investigated the characteristics of various porphyrin-based probes and their potential application in different clinically relevant models. Here, I will discuss three types of porphyrin-based agents: 1) photodynamic molecular beacons (PPMMPB), 2) targeted peptide porphyrins (PPF) and 3) porphyrin-lipid nanovesicles, porphysomes. I will demonstrate that all of these porphyrin-based agents have potential clinical applications in various fields of cancer imaging and therapy. Although these three agents differ greatly, they all aim to increase the signal-to-background ratio of tumor to healthy tissue uptake of porphyrins, thereby increasing our ability to detect tumor tissue and better preserve healthy tissue during therapy.

Porphyrins represent one of the oldest, most widely studied chemical structures, both in nature and in biomedical applications. Due to their tumor avidity and favorable photophysical properties, such as long wavelength absorption and emission, easy derivatization, high singlet oxygen quantum yield and low in vivo toxicity, porphyrins have found particular success for photodynamic therapy and fluorescence imaging of cancer. Additionally, they are excellent metal chelators, forming highly stable metallo-complexes, making porphyrins an efficient delivery vehicle for radioisotopes. Thus, there is great potential in the applications of these multi-modal porphyrin-based agents for cancer imaging and therapy. I have investigated the characteristics of various porphyrin-based probes and their potential application in different clinically relevant models. Here, I will discuss three types of porphyrin-based agents: 1) photodynamic molecular beacons (PPMMPB), 2) targeted peptide porphyrins (PPF) and 3) porphyrin-lipid nanovesicles, porphysomes. I will demonstrate that all of these porphyrin-based agents have potential clinical applications in various fields of cancer imaging and therapy. Although these three agents differ greatly, they all aim to increase the signal-to-background ratio of tumor to healthy tissue uptake of porphyrins, thereby increasing our ability to detect tumor tissue and better preserve healthy tissue during therapy.

Quantum Dot (QD) nanobeacons distinguish themselves from molecular beacons with the promise of non-linear activation, tunability, and multi-functionality. These unique features make them highly attractive for cancer detection imaging with opportunities for increased signal-to-background ratio and tunable sensitivity. In this thesis, a nanobeacon was designed to target matrix metalloproteinase-7 (MMP-7), known to be over-expressed by a wide array of tumours. The nanobeacon is normally dark until specifically activated by MMP-7. The overall design strategy links single QDs to multiple energy acceptors by GPLGLARK peptides that can be cleaved specifically by MMP-7. However, design details such as the choice of energy acceptor and conjugation method was found to drastically alter the function of the nanobeacon. Studies of nanobeacons synthesized with Black Hole Quencher-1 or Rhodamine Red by either covalent conjugation or electrostatic self-assembly revealed that peptide conformation and bonding flexibility are both important considerations in nanobeacon design due to QD sterics.

Quantum Dot (QD) nanobeacons distinguish themselves from molecular beacons with the promise of non-linear activation, tunability, and multi-functionality. These unique features make them highly attractive for cancer detection imaging with opportunities for increased signal-to-background ratio and tunable sensitivity. In this thesis, a nanobeacon was designed to target matrix metalloproteinase-7 (MMP-7), known to be over-expressed by a wide array of tumours. The nanobeacon is normally dark until specifically activated by MMP-7. The overall design strategy links single QDs to multiple energy acceptors by GPLGLARK peptides that can be cleaved specifically by MMP-7. However, design details such as the choice of energy acceptor and conjugation method was found to drastically alter the function of the nanobeacon. Studies of nanobeacons synthesized with Black Hole Quencher-1 or Rhodamine Red by either covalent conjugation or electrostatic self-assembly revealed that peptide conformation and bonding flexibility are both important considerations in nanobeacon design due to QD sterics.