Time-domain geometrical localization of point-like fluorescence inclusions in turbid media with early photon arrival times

Abstract

We introduce a novel approach for localizing a plurality of discrete point-like fluorescent inclusions embedded in a thick turbid medium using time-domain measurements. The approach uses early photon information contained in measured time-of-flight distributions originating from fluorescence emission. Fluorescence time point-spread functions (FTPSFs) are acquired with ultrafast time-correlated single photon counting after short pulse laser excitation. Early photon arrival times are extracted from the FTPSFs obtained from several source-detector positions. Each source-detector measurement allows defining a geometrical locus where an inclusion is to be found. These loci take the form of ovals in 2D or ovoids in 3D. From these loci a map can be built, with the maxima thereof corresponding to positions of inclusions. This geometrical approach is supported by Monte Carlo simulations performed for biological tissue-like media with embedded fluorescent inclusions. To validate the approach, several experiments are conducted with a homogeneous phantom mimicking tissue optical properties. In the experiments, inclusions filled with indocyanine green are embedded in the phantom and the fluorescence response to a short pulse of excitation laser is recorded. With our approach, several inclusions can be localized with low millimeter positional error. Our results support the approach as an accurate, efficient, and fast method for localizing fluorescent inclusions embedded in highly turbid media mimicking biological tissues. Further Monte Carlo simulations on a realistic mouse model show the feasibility of the technique for small animal imaging.

Prospects on Time-Domain Diffuse Optical Tomography Based on Time-Correlated Single Photon Counting for Small Animal Imaging

“…The first-generation scanner has recently allowed developing entirely new techniques for imaging the scattering properties of turbid media mimicking biological tissues [33] and for localizing fluorescent point-like inclusions therein [34]. These techniques critically rely on the high temporal resolution and exquisite timing accuracy and stability of TCSPC which is at the core of our scanner.…”

“…Such photons are, however, too few to be used for any practical purposes in tissue imaging as soon as the propagation distance exceeds a few millimeters (≈2-3 mm), beyond which practically all photons have suffered a scattering event [32]. Second are the so-called snake or early photons which suffer few scattering events and can be considered to propagate along nearly straight paths [33,34]. These are the photons appearing early in a measurement and contribute to the rising edge of a TPSF (Figure 4).…”

Diffuse photon density wavefront speed as a contrast for tomographic imaging of heterogeneous diffusive media

“…We will thus consider, in our model detailed below, that early photons travel along this ray; this is what makes this approximate model linear. The second fact is that, as we have shown both experimentally and with Monte Carlo simulations for a homogeneous medium, the speed of snake photons is a well-defined quantity very well approximated by a constant [12,14]. Thus, by partitioning a nonhomogeneous medium into small elements, we may assume the speed along the EPAT rays to be constant within each element (as similarly done in x ray CT for the attenuation coefficient).…”

“…An ultrashort collimated laser pulse injected into such a medium rapidly develops as a diffusive wavefront expanding in all directions [12]. The speeds of points on such wavefronts ultimately depend on the absorption and scattering properties of the diffusive medium.…”

“…With TD measurements made at the boundary of a medium, these are the photons detected early and contribute to the rising edge of the TPSF. The time of arrival of that rising edge will be taken as the time of arrival of these early photons (i.e., the EPAT), which can be obtained from measured TPSFs using numerical constant fraction discrimination (NCFD) as previously reported [12,14]. The propagation of snake photons inside a medium defines an expanding diffusive wavefront (DPDWF) (we hereby distinguish between DPDWs and DPDWFs, as the former are defined for frequency-domain measurements, whereas here, TD measurements are considered).…”