Abstract
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.
Highlights
The focus of this work was to develop and test an optimized system for image-guided fluorescence tomography of subsurface skin lesions, with the goal of providing region-based quantification of protoporphyrin IX (PpIX) fluorescence in vivo
This paper presents the validation of a combined high frequency ultrasound imaging (US)-guided reflectance-mode-fluorescence tomography (FT) system, with spectral fitting to decouple multiple signals and novel use of white light spectroscopy to inform optical models for accurate reconstruction of regional, subsurface fluorescence yield in vivo
While it is possible to estimate a linear metric of fluorescence from reconstructions with assumed background optical property values, the overall reconstruction accuracy of fluorescence estimates are improved significantly when sample-specific optical properties are measured by white light spectroscopy and used to inform reconstruction models
Summary
The focus of this work was to develop and test an optimized system for image-guided fluorescence tomography of subsurface skin lesions, with the goal of providing region-based quantification of protoporphyrin IX (PpIX) fluorescence in vivo. Photodynamic therapy (PDT) based upon PpIX as the photosensitizer is an established, noninvasive dermatologic treatment for actinic keratosis in the US, and is commonly used ‘off label’ for cosmetic treatments, and treatment of squamous cell carcinoma (SCC) and superficial basal cell carcinoma (BCC).[1,2,3,4,5] PpIXbased PDT involves the administration of a precursor molecule, either aminolevulinic acid (ALA) in the form of Levulan, or methyl aminolevulinate (MAL) in the form of Metvix. The induced PpIX accumulates preferentially in epithelial pathologies including SCC and BCC, with tumor-to-background contrast from 2:1 to 9:1 depending on the pathology and the preparation of ALA used.[4,5,6] The photophysically active form of PpIX is fluorescent, and so the effective fluorescent yield is an indirect measurement of the active concentration available for a fixed light delivery.[7].
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