Colin M. Carpenter

Structural information within regularization matrices improves near infrared diffuse optical tomography

Near-Infrared (NIR) tomographic image reconstruction is a non-linear, ill-posed and ill-conditioned problem, and so in this study, different ways of penalizing the objective function with structural information were investigated. A simple framework to incorporate structural priors is presented, using simple weight matrices that have either Laplacian or Helmholtz-type structures. Using both MRI-derived breast geometry and phantom data, a systematic and quantitative comparison was performed with and without spatial priors. The Helmholtz-type structure can be seen as a more generalized approach for incorporating spatial priors into the reconstruction scheme. Moreover, parameter reduction (i.e. hard prior information) in the imaging field through the enforcement of spatially explicit regions may lead to erroneous results with imperfect spatial priors.

Image-guided optical spectroscopy provides molecular-specific information in vivo: MRI-guided spectroscopy of breast cancer hemoglobin, water, and scatterer size

A multimodality instrument that integrated optical or near-infrared spectroscopy into a magnetic resonance imaging (MRI) breast coil was used to perform a pilot study of image-guided spectroscopy on cancerous breast tissue. These results are believed to be the first multiwavelength spectroscopic images of breast cancer using MRI-guided constraints, and they show the cancer tumor to have high hemoglobin and water values, decreased oxygen saturation, and increased subcellular granularity. The use of frequency-domain diffuse tomography methods at many wavelengths provides the spectroscopy required for recovering maps of absorbers and scattering spectra, but the integration with MRI allows these data to be recovered on an image field that preserves high resolution and fuses the two data sets together. Integration of molecular spectroscopy into standard clinical MRI can be achieved with this approach to spectral tomography.

Evaluation of Breast Tumor Response to Neoadjuvant Chemotherapy with Tomographic Diffuse Optical Spectroscopy: Case Studies of Tumor Region-of-Interest Changes

PURPOSE To evaluate two methods of summarizing tomographic diffuse optical spectroscopic (DOS) data through region-of-interest (ROI) analysis to differentiate complete from incomplete responses in patients with locally advanced breast cancer undergoing neoadjuvant treatment and to estimate the standard deviations of these methods for power analysis of larger study designs in the future. MATERIALS AND METHODS Subjects participating in the HIPAA-compliant imaging study, approved by the institutional review board, provided written informed consent and were compensated for their examination participation. Seven of 16 cases in women with complete study data were analyzed by using both fixed- and variable-size (full-width-at-half-maximum) ROI measures of the DOS total hemoglobin concentration (Hb(T)), blood oxygen saturation, water fraction, optical scattering amplitude, and scattering power in the ipsilateral and contralateral breasts. Postsurgical histopathologic analysis was used to categorize patients as having a complete or incomplete treatment response. RESULTS Average normalized change in Hb(T) was the only DOS parameter to show significant differences (P < or = .05) in the pathologic complete response (pCR) and pathologic incomplete response (pIR) outcomes in seven patients. Mean values of the changes for fixed-size ROIs were -64.2% +/- 50.8 (standard deviation) and 16.9% +/- 38.2 for the pCR and pIR groups, respectively, and those for variable-size ROIs were -96.7% +/- 91.8, and 14.1% +/- 26.7 for the pCR and pIR groups, respectively. CONCLUSION Tomographic DOS may provide findings predictive of therapeutic response, which could lead to superior individualized patient treatment. SUPPLEMENTAL MATERIAL http://radiology.rsnajnls.org/cgi/content/full/2522081202/DC1.

X-Ray Luminescence Computed Tomography via Selective Excitation: A Feasibility Study

X-ray luminescence computed tomography (XLCT) is proposed as a new molecular imaging modality based on the selective excitation and optical detection of X-ray-excitable phosphor nanoparticles. These nano-sized particles can be fabricated to emit near-infrared (NIR) light when excited with X-rays, and, because because both X-rays and NIR photons propagate long distances in tissue, they are particularly well suited for in vivo biomedical imaging. In XLCT, tomographic images are generated by irradiating the subject using a sequence of programmed X-ray beams, while sensitive photo-detectors measure the light diffusing out of the subject. By restricting the X-ray excitation to a single, narrow beam of radiation, the origin of the optical photons can be inferred regardless of where these photons were detected, and how many times they scattered in tissue. This study presents computer simulations exploring the feasibility of imaging small objects with XLCT, such as research animals. The accumulation of 50 nm phosphor nanoparticles in a 2-mm-diameter target can be detected and quantified with subpicomolar sensitivity using less than 1 cGy of radiation dose. Provided sufficient signal-to-noise ratio, the spatial resolution of the system can be made as high as needed by narrowing the beam aperture. In particular, 1 mm spatial resolution was achieved for a 1-mm-wide X-ray beam. By including an X-ray detector in the system, anatomical imaging is performed simultaneously with molecular imaging via standard X-ray computed tomography (CT). The molecular and anatomical images are spatially and temporally co-registered, and, if a single-pixel X-ray detector is used, they have matching spatial resolution.

Synthesis and Radioluminescence of PEGylated Eu3+-doped Nanophosphors as Bioimaging Probes

Lanthanide-doped nanophosphors have received significant attention for use in biological sensing and imaging due to their unique optical properties. Much like semiconductor quantum dots (QDs), these luminescent nanocrystals offer several advantages over conventional organic fluorophores, including high photochemical stability, large Stokes shift, and tunable fluorescence emission. [1] Up-conversion nanophosphors, which are capable of absorbing two or more low-energy photons to emit a higher-energy photon, also exhibit favorable characteristics such as long fluorescence lifetimes, no photoblinking, and reduced autofluorescence. [2] The recent development of lanthanide-doped nanophosphors that function in the near-infrared (NIR) spectral range optimal for optical transmission through biological tissues (650–900 nm) has attracted great interest towards in vivo bioim-aging probes. [3–5] Alternatively, high-energy radiation, currently employed in medical imaging modalities, such as X-ray computed tomography (CT) or positron emission tomo graphy (PET), may also be used to excite NIR-emitting radioluminescent nanophosphors (RLNPs) for bioimaging.

Tomographic molecular imaging of x-ray-excitable nanoparticles

X-ray luminescence computed tomography (XLCT) is proposed as a new dual molecular/anatomical imaging modality. XLCT is based on the selective excitation and optical detection of x-ray-excitable nanoparticles. As a proof of concept, we built a prototype XLCT system and imaged near-IR-emitting Gd(2)O(2)S:Eu phosphors in various phantoms. Imaging in an optically diffusive medium shows that imaging performance is not affected by optical scatter; furthermore, the linear response of the reconstructed images suggests that XLCT is capable of quantitative imaging.

Intraoperative Imaging of Tumors Using Cerenkov Luminescence Endoscopy: A Feasibility Experimental Study

Cerenkov luminescence imaging (CLI) is an emerging new molecular imaging modality that is relatively inexpensive, easy to use, and has high throughput. CLI can image clinically available PET and SPECT probes using optical instrumentation. Cerenkov luminescence endoscopy (CLE) is one of the most intriguing applications that promise potential clinical translation. We developed a prototype customized fiberscopic Cerenkov imaging system to investigate the potential in guiding minimally invasive surgical resection. Methods: All experiments were performed in a dark chamber. Cerenkov luminescence from 18F-FDG samples containing decaying radioactivity was transmitted through an optical fiber bundle and imaged by an intensified charge-coupled device camera. Phantoms filled with 18F-FDG were used to assess the imaging spatial resolution. Finally, mice bearing subcutaneous C6 glioma cells were injected intravenously with 18F-FDG to determine the feasibility of in vivo imaging. The tumor tissues were exposed, and CLI was performed on the mouse before and after surgical removal of the tumor using the fiber-based imaging system and compared with a commercial optical imaging system. Results: The sensitivity of this particular setup was approximately 45 kBq (1.21 μCi)/300 μL. The 3 smallest sets of cylindric holes in a commercial SPECT phantom were identifiable via this system, demonstrating that the system has a resolution better than 1.2 mm. Finally, the in vivo tumor imaging study demonstrated the feasibility of using CLI to guide the resection of tumor tissues. Conclusion: This proof-of-concept study explored the feasibility of using fiber-based CLE for the detection of tumor tissue in vivo for guided surgery. With further improvements of the imaging sensitivity and spatial resolution of the current system, CLE may have a significant application in the clinical setting in the near future.

Hybrid x-ray/optical luminescence imaging: characterization of experimental conditions.

PURPOSE The feasibility of x-ray luminescence imaging is investigated using a dual-modality imaging system that merges x-ray and optical imaging. This modality utilizes x-ray activated nanophosphors that luminesce when excited by ionizing photons. By doping phosphors with lanthanides, which emit light in the visible and near infrared range, the luminescence is suitable for biological applications. This study examines practical aspects of this new modality including phosphor concentration, light emission linearity, detector damage, and spectral emission characteristics. Finally, the contrast produced by these phosphors is compared to that of x-ray fluoroscopy. METHODS Gadolinium and lanthanum oxysulfide phosphors doped with terbium (green emission) or europium (red emission) were studied. The light emission was imaged in a clinical x-ray scanner with a cooled CCD camera and a spectrophotometer; dose measurements were determined with a calibrated dosimeter. Using these properties, in addition to luminescence efficiency values found in the literature for a similar phosphor, minimum concentration calculations are performed. Finally, a 2.5 cm agar phantom with a 1 cm diameter cylindrical phosphor-filled inclusion (diluted at 10 mg/ml) is imaged to compare x-ray luminescence contrast with x-ray fluoroscopic contrast at a superficial location. RESULTS Dose to the CCD camera in the chosen imaging geometry was measured at less than 0.02 cGy/s. Emitted light was found to be linear with dose (R(2)= 1) and concentration (R(2)= 1). Emission peaks for clinical x-ray energies are less than 3 nm full width at half maximum, as expected from lanthanide dopants. The minimum practical concentration necessary to detect luminescent phosphors is dependent on dose; it is estimated that subpicomolar concentrations are detectable at the surface of the tissue with typical mammographic doses, with the minimum detectable concentration increasing with depth and decreasing with dose. In a reflection geometry, x-ray luminescence had nearly a 430-fold greater contrast to background than x-ray fluoroscopy. CONCLUSIONS X-ray luminescence has the potential to be a promising new modality for enabling molecular imaging within x-ray scanners. Although much work needs to be done to ensure biocompatibility of x-ray exciting phosphors, the benefits of this modality, highlighted in this work, encourage further study.

A boundary element approach for image-guided near-infrared absorption and scatter estimation

Multimodality NIR spectroscopy systems offer the possibility of region-based vascular and molecular characterization of tissue in vivo. However, computationally efficient 3D image reconstruction algorithms specific to these image-guided systems currently do not exist. Image reconstruction is often based on finite-element methods (FEMs), which require volume discretization. Here, a boundary element method (BEM) is presented using only surface discretization to recover the optical properties in an image-guided setting. The reconstruction of optical properties using BEM was evaluated in a domain containing a 30 mm inclusion embedded in two layer media with different noise levels and initial estimates. For 5% noise in measurements, and background starting values for reconstruction, the optical properties were recovered to within a mean error of 6.8%. When compared with FEM for this case, BEM showed a 28% improvement in computational time. BEM was also applied to experimental data collected from a gelatin phantom with a 25 mm inclusion and could recover the true absorption to within 6% of expected values using less time for computation compared with FEM. When applied to a patient-specific breast mesh generated using MRI, with a 2 cm ductal carcinoma, BEM showed successful recovery of optical properties with less than 5% error in absorption and 1% error in scattering, using measurements with 1% noise. With simpler and faster meshing schemes required for surface grids as compared with volume grids, BEM offers a powerful and potentially more feasible alternative for high-resolution 3D image-guided NIR spectroscopy.

Radioluminescent nanophosphors enable multiplexed small-animal imaging

We demonstrate the ability to image multiple nanoparticle-based contrast agents simultaneously using a nanophosphor platform excited by either radiopharmaceutical or X-ray irradiation. These radioluminescent nanoparticles emit optical light at unique wavelengths depending on their lanthanide dopant, enabling multiplexed imaging. This study demonstrates the separation of two distinct nanophosphor contrast agents in gelatin phantoms with a recovered phosphor separation correlation of −0.98. The ability to distinguish the two nanophosphors and a Cerenkov component is then demonstrated in a small animal phantom. Combined with the high-resolution potential of low-scattering X-ray excitation, this imaging technique may be a promising method to probe molecular processes in living organisms.