Strong nanoscale light-matter interaction is often accompanied by ultra-confined photonic modes and large momentum polaritons existing far beyond the light cone. A direct probe of such phenomena is difficult due to the momentum mismatch of these modes with free space light however, fast electron probes can reveal the fundamental quantum and spatially dispersive behavior of these excitations.Here, we use momentum-resolved electron energy loss spectroscopy (q-EELS) in a transmission electron microscope to explore the optical response of plasmonic thin films including momentum transfer up to wavevectors (q) significantly exceeding the light line wave vector. We show close agreement between experimental q-EELS maps, theoretical simulations of fast electrons passing through thin films and the momentum-resolved photonic density of states (q-PDOS) dispersion. Although a direct link between q-EELS and the q-PDOS exists for an infinite medium, here we show fundamental differences between q-EELS measurements and the q-PDOS that must be taken into consideration for realistic finite structures with no translational invariance along the direction of electron motion. Our work paves the way for using q-EELS as the preeminent tool for mapping the q-PDOS of exotic phenomena with large momenta (high-q) such as hyperbolic polaritons and spatially-dispersive plasmons.

We demonstrate the in vivo reconstruction of all fluorescence resonance energy transfer (FRET) parameters, including the nanometer donor-acceptor distance, in a mouse. The FRET chemical targets cancer cells, and on internalization, the acceptor is released, in lieu of a targeted anticancer drug in chemotherapy. Our method provides a new vehicle for studying disease by imaging FRET parameters in deep tissue.

Fluorescence resonance energy transfer (FRET) is a nonradiative energy transfer process based on dipole-dipole interaction between donor and acceptor fluorophores that are spatially separated by a distance of a few nanometers. FRET has proved to be of immense value in the study of cellular function and the underlying cause of disease due to, for example, protein misfolding (of consequence in Alzheimer's disease). The standard parameterization in intramolecular FRET is the lifetime and yield, which can be related to the donor-acceptor (DA) distance. FRET imaging has thus far been limited to in vitro or near-surface microscopy because of the deleterious effects of substantial scatter. We show that it is possible to extract the microscopic FRET parameters in a highly scattering environment by incorporating the FRET kinetics of an ensemble of DA molecules connected by a flexible or rigid linker into an optical diffusion tomography (ODT) framework. We demonstrate the efficacy of our approach for extracting the microscopic DA distance through simulations and an experiment using a phantom with scattering properties similar to tissue. Our method will allow the in vivo imaging of FRET parameters in deep tissue, and hence provide a new vehicle for the fundamental study of disease.

An approach for the fast localization and detection of an absorbing inhomogeneity in a tissue-like scattering medium is presented. The probability of detection as a function of the size, location, and absorptive properties of the inhomogeneity is investigated. The detection sensitivity in relation to the source and detector location serves a basis for instrument design. c 2007 Optical Society of America OCIS codes: 170.3010, 290.7050, 100.3010, 100.3190 Optical imaging in scattering media provides important opportunities for clinical imaging and environmental sensing, among others [1]. In the near-infrared wavelength range, soft tissue has both high scatter and low absorption, allowing use of a diffusion equation model for photon transport [2,3], which with exp(jωt) time dependence iswhere φ is the photon flux density, ω is the circular modulation frequency, β is the modulation amplitude, c is the speed of light in the intervening medium between the scatterers, µ a is the absorption coefficient, D is the diffusion coefficient, and a Dirac delta function excitation is assumed. Reconstruction of the unknown optical parameters µ a (r) and D(r) requires inversion of measured data, which is formulated as an optimization problem [1,4]. This is a computationally intensive process, in large part due to the nonlinear relationship between the cost function and the image parameters. Another difficulty is caused by physical limitations of a practical measurement system, which may result in insufficient information for accurate volumetric imaging. These issues motivate interest in simpler, efficient approaches for detecting and localizing a heterogeneity in a scattering medium instead of quantitative three-dimensional reconstruction. Methods have been studied for localizing injected fluorophores. Chen et al. used least squares curve fitting to compare a diffusion equation model for expected fluorescence with measurements based on the perturbation on a cancellation plane, formed by dual-interfering sources [5], to localize a fluorophore in a mouse model [6]. Gannot et al. used the Levenberg-Marquardt method to fit measured data with a forward model based on random-walk theory for three-dimensional 1

Many cancer cells over-express folate receptors, and this provides an opportunity for both folate-targeted fluorescence imaging and the development of targeted anti-cancer drugs. We present an optical imaging modality that allows for the monitoring and evaluation of drug delivery and release through disulfide bond reduction inside a tumor in vivo for the first time. A near-infrared folate-targeting fluorophore pair was synthesized and used to image a xenograft tumor grown from KB cells in a live mouse. The in vivo results are shown to be in agreement with previous in vitro studies, confirming the validity and feasibility of our method as an effective tool for preclinical studies in drug development.