Optical and X-Ray Technology Synergies Enabling Diagnostic and Therapeutic Applications in Medicine

X-ray and optical technologies are the two central pillars for human imaging and therapy. The strengths of x-rays are deep tissue penetration, effective cytotoxicity, and the ability to image with robust projection and computed-tomography methods. The major limitations of x-ray use are the lack of molecular specificity and the carcinogenic risk. In comparison, optical interactions with tissue are strongly scatter dominated, leading to limited tissue penetration, making imaging and therapy largely restricted to superficial or endoscopically directed tissues. However, optical photon energies are comparable with molecular energy levels, thereby providing the strength of intrinsic molecular specificity. Additionally, optical technologies are highly advanced and diversified, being ubiquitously used throughout medicine as the single largest technology sector. Both have dominant spatial localization value, achieved with optical surface scanning or x-ray internal visualization, where one often is used with the other. Therapeutic delivery can also be enhanced by their synergy, where radio-optical and optical-radio interactions can inform about dose or amplify the clinical therapeutic value. An emerging trend is the integration of nanoparticles to serve as molecular intermediates or energy transducers for imaging and therapy, requiring careful design for the interaction either by scintillation or Cherenkov light, and the nanoscale design is impacted by the choices of optical interaction mechanism. The enhancement of optical molecular sensing or sensitization of tissue using x-rays as the energy source is an important emerging field combining x-ray tissue penetration in radiation oncology with the molecular specificity and packaging of optical probes or molecular localization. The ways in which x-rays can enable optical procedures, or optics can enable x-ray procedures, provide a range of new opportunities in both diagnostic and therapeutic medicine. Taken together, these two technologies form the basis for the vast majority of diagnostics and therapeutics in use in clinical medicine

Contrast-Detail Analysis Characterizing Diffuse Optical Fluorescence Tomography Image Reconstruction

Contrast-detail analysis is used to evaluate the imaging performance of diffuse optical fluorescence tomography (DOFT), characterizing spatial resolution limits, signal-to-noise limits, and the trade-off between object contrast and size. Reconstructed images of fluorescence yield from simulated noisy data were used to determine the contrast-to-noise ratio (CNR). A threshold of CNR=3 was used to approximate a lowest acceptable noise level in the image, as a surrogate measure for human detection of objects. For objects 0.5 cm inside the edge of a simulated tissue region, the smallest diameter that met this criteria was approximately 1.7 mm, regardless of contrast level, and test field diameter had little impact on this limit. Object depth had substantial impact on object CNR, leading to a limit of 4 mm for objects near the center of a 51-mm test field and 8.5 mm for an 86-mm test field. Similarly, large objects near the edge of both test fields required a minimum contrast of 50% to achieve acceptable image CNR. The minimum contrast for large, centered objects ranged between 50% and 100%. Contrast-detail analysis using human detection of lower contrast limits provides fundamentally important information about the performance of reconstruction algorithms, and can be used to compare imaging performance of different systems

Optimization of Fluorescent Imaging in the Operating Room through Pulsed Acquisition and Gating to Ambient Background Cycling

The design of fluorescence imaging instruments for surgical guidance is rapidly evolving, and a key issue is to efficiently capture signals with high ambient room lighting. Here, we introduce a novel time-gated approach to fluorescence imaging synchronizing acquisition to the 120 Hz light of the room, with pulsed LED excitation and gated ICCD detection. It is shown that under bright ambient room light this technique allows for the detection of physiologically relevant nanomolar fluorophore concentrations, and in particular reduces the light fluctuations present from the room lights, making low concentration measurements more reliable. This is particularly relevant for the light bands near 700nm that are more dominated by ambient lights

White Light-Informed Optical Properties Improve Ultrasound-Guided Fluorescence Tomography of Photoactive Protoporphyrin IX

Subsurface fluorescence imaging is desirable for medical applications, including protoporphyrin-IX (PpIX)-based skin tumor diagnosis, surgical guidance, and dosimetry in photodynamic therapy. While tissue optical properties and heterogeneities make true subsurface fluorescence mapping an ill-posed problem, ultrasound-guided fluorescence-tomography (USFT) provides regional fluorescence mapping. Here USFT is implemented with spectroscopic decoupling of fluorescence signals (auto-fluorescence, PpIX, photoproducts), and white light spectroscopy-determined bulk optical properties. Segmented US images provide a priori spatial information for fluorescence reconstruction using region-based, diffuse FT. The method was tested in simulations, tissue homogeneous and inclusion phantoms, and an injected-inclusion animal model. Reconstructed fluorescence yield was linear with PpIX concentration, including the lowest concentration used, 0.025  μg/ml . White light spectroscopy informed optical properties, which improved fluorescence reconstruction accuracy compared to the use of fixed, literature-based optical properties, reduced reconstruction error and reconstructed fluorescence standard deviation by factors of 8.9 and 2.0, respectively. Recovered contrast-to-background error was 25% and 74% for inclusion phantoms without and with a 2-mm skin-like layer, respectively. Preliminary mouse-model imaging demonstrated system feasibility for subsurface fluorescence measurement in vivo. These data suggest that this implementation of USFT is capable of regional PpIX mapping in human skin tumors during photodynamic therapy, to be used in dosimetric evaluations

Fluorescence Tomography Characterization for Sub-Surface Imaging with Protoporphyrin IX

Optical imaging of fluorescent objects embedded in a tissue simulating medium was characterized using non-contact based approaches to fluorescence remittance imaging (FRI) and sub-surface fluorescence diffuse optical tomography (FDOT). Using Protoporphyrin IX as a fluorescent agent, experiments were performed on tissue phantoms comprised of typical in-vivo tumor to normal tissue contrast ratios, ranging from 3.5:1 up to 10:1. It was found that tomographic imaging was able to recover interior inclusions with high contrast relative to the background; however, simple planar fluorescence imaging provided a superior contrast to noise ratio. Overall, FRI performed optimally when the object was located on or close to the surface and, perhaps most importantly, FDOT was able to recover specific depth information about the location of embedded regions. The results indicate that an optimal system for localizing embedded fluorescent regions should combine fluorescence reflectance imaging for high sensitivity and sub-surface tomography for depth detection, thereby allowing more accurate localization in all three directions within the tissue

Spectroscopic Separation of Čerenkov Radiation in High-Resolution Radiation Fiber Dosimeters

We have investigated Čerenkov radiation generated in phosphor-based optical fiber dosimeters irradiated with clinical electron beams. We fabricated two high-spatial resolution fiber-optic probes, with 200 and 400  μm core diameters, composed of terbium-based phosphor tips. A generalizable spectroscopic method was used to separate Čerenkov radiation from the transmitted signal by the fiber based on the assumption that the recorded signal is a linear superposition of two basis spectra: characteristic luminescence of the phosphor medium and Čerenkov radiation. We performed Monte Carlo simulations of the Čerenkov radiation generated in the fiber and found a strong dependence of the recorded Čerenkov radiation on the numerical aperture of the fiber at shallow phantom depths; however, beyond the depth of maximum dose that dependency is minimal. The simulation results agree with the experimental results for Čerenkov radiation generated in fibers. The spectroscopic technique used in this work can be used for development of high-spatial resolution fiber micro dosimeters and for optical characterization of various scintillating materials, such as phosphor nanoparticles, in ionizing radiation fields of high energy

Multichannel Diffuse Optical Raman Tomography for Bone Characterization In Vivo: a Phantom Study

Raman spectroscopy is used to gather information on the mineral and organic components of bone tissue to analyze their composition. By measuring the Raman signal of bone through spatially offset Raman spectroscopy the health of the bone can be determined. We’ve customized a system with 8 collection channels that consist of individual fibers, which are coupled to separate spectrometers and cooled CCDs. This parallel detection system was used to scan gelatin phantoms with Teflon inclusions of two sizes. Raman signals were decoupled from the autofluorescence background using channel specific polynomial fitting. Images with high contrast to background ratios of Raman yield and accurate spatial resolution were recovered using a model-based diffuse tomography approach