Predictive value of ex vivo biodynamic imaging in determining response to chemotherapy in dogs with spontaneous non-Hodgkin's lymphomas: a preliminary study.

Biodynamic imaging (BDI) is a novel phenotypic cancer profiling technology which optically characterizes changes in subcellular motion within living tumor tissue samples in response to ex vivo treatment with cancer chemotherapy drugs. The purpose of this preliminary study was to assess the ability of ex vivo BDI to predict in vivo clinical response to chemotherapy in ten dogs with naturally-occurring non-Hodgkin's lymphomas. Pre-treatment tumor biopsy samples were obtained from all dogs and treated ex vivo with doxorubicin (10 µM). BDI measured six dynamic biomarkers of subcellular motion from all biopsy samples at baseline and at regular intervals for 9 h following drug application. All dogs subsequently received doxorubicin to treat their lymphomas. Best overall response to and progression-free survival time following chemotherapy were recorded for all dogs. Receiver operating characteristic (ROC) curves were used to determine accuracy and identify possible cut-off values for the BDI-measured biomarkers which could accurately predict those dogs' cancers that would and would not respond to doxorubicin chemotherapy. One biomarker (designated 'MEM') showed 100% discriminative capability for predicting clinical response to doxorubicin (area under the ROC curve = 1.00, 95% CI 0.692-1.000), while other biomarkers also showed promising predictive capability. These preliminary findings suggest that ex vivo BDI can accurately predict treatment outcome following doxorubicin chemotherapy in a spontaneous animal cancer model, and is worthy of further investigation as a technology for personalized cancer medicine.

Three-dimensional holographic imaging of living tissue using a highly sensitive photorefractive polymer device.

Photorefractive materials are dynamic holographic storage media that are highly sensitive to coherent light fields and relatively insensitive to a uniform light background. This can be exploited to effectively separate ballistic light from multiply-scattered light when imaging through turbid media. We developed a highly sensitive photorefractive polymer composite and incorporated it into a holographic optical coherence imaging system. This approach combines the advantages of coherence-domain imaging with the benefits of holography to form a high-speed wide-field imaging technique. By using coherence-gated holography, image-bearing ballistic light can be captured in real-time without computed tomography. We analyzed the implications of Fourier-domain and image-domain holography on the field of view and image resolution for a transmission recording geometry, and demonstrate holographic depth-resolved imaging of tumor spheroids with 12 microm axial and 10 microm lateral resolution, achieving a data acquisition speed of 8 x 10(5) voxels/s.

Combined fluorescent and interferometric detection of protein on a BioCD.

We perform simultaneous interferometric and fluorescent detection of molecular protein layers on a BioCD. The 488 nm excitation wavelength of fluorescein also provides the interferometric detection channel that operates in a common-path in-line configuration in the condition of phase quadrature set by a thermal oxide on silicon. The simultaneous acquisition of both channels enables a direct correlation between bound mass and fluorescent surface density, which we compare in forward- and reverse-phase immunoassays. Scaling mass sensitivities for immunoassays measured in the interferometric and fluorescent channels are 15 pg/mm and 1.5 pg/mm, respectively, when applied to gel-printed periodic antibody patterns detected in the frequency domain from the spinning disc. These sensitivities are limited by the inhomogeneities of the print. While fluorescence is subject to bleaching, the interferometry signal is robust under long-term laser illumination.

Common-path interferometric detection of protein monolayer on the BioCD.

The bio-optical compact disk (BioCD) is an optical biosensor that performs common-path molecular interferometry of patterned proteins on a disk spinning at high speed. The common-path configuration makes it ultrastable and allows surface height precision below 10 pm. In this paper we show that two complementary interferometric quadrature conditions exist simultaneously that convert the modulus and phase of the reflection coefficient, modulated by protein patterns on the disk surface, into intensity modulation at the detector. In the far field they separate into spatially symmetric and antisymmetric intensity modulation in response to the local distribution of protein. The antisymmetric response is equivalent to differential phase-contrast detection, and the symmetric response is equivalent to in-line (IL) common-path interferometry. We measure the relative sensitivities of these orthogonal channels to printed protein patterns on disk structures that include thermal oxide on silicon and Bragg dielectric stacks. The scaling mass sensitivity of the IL channel on oxide on silicon was measured to be 0.17 pg/mm.

Spinning-disk self-referencing interferometry of antigen-antibody recognition.

A gold ridge microstructure fabricated to a height of lambda/8 on a high-reflectivity substrate behaves as a wave-front-splitting self-referencing interferometer in phase quadrature when illuminated by a Gaussian laser beam and observed in the far field along the optic axis. When immuno-gammaglobulin (IgG) antibodies are selectively immobilized on the gold microstructure, they recognize and bind to a specific antigen, which shifts the relative optical phase of the interferometer and modifies the far-field diffracted intensity. We detect bound antigen interferometrically on spinning disks at a sampling rate of 100 kHz and verify the interferometric nature of the signal by using two quadratures of opposite sign to rule out effects of dynamic light scattering. Strong molecular recognition is demonstrated by the absence of binding to nontarget molecules but strong signal change in response to a specific antigen. This BioCD has the potential to be applied as a spinning-disk interferometric immunoassay and biosensor.

Time-dependent speckle in holographic optical coherence imaging and the health of tumor tissue.

Holographic optical coherence imaging acquires en face images from successive depths inside scattering tissue. In a study of multicellular tumor spheroids the holographic features recorded from a fixed depth are observed to be time dependent, and they may be classified as variable or persistent. The ratio of variable to persistent features, as well as speckle correlation times, provides quantitative measures of the health of the tissue. Studies of rat osteogenic sarcoma tumor spheroids that have been subjected to metabolic and cross-polymerizing poisons provide quantitative differentiation among healthy, necrotic, and poisoned tissue. Organelle motility in healthy tissue appears as super-Brownian laser speckle, whereas chemically fixed tissue exhibits static speckle.

Ultrasound detection through turbid media.

Optical coherence-domain reflectometry and laser-based ultrasound detection have been combined with the use of adaptive optics to detect ultrasound through turbid media. The dynamic hologram in a photorefractive quantum-well device performs as a coherence gate that eliminates multiply scattered background. Quadrature homodyne detection conditions are selected by the choice of center wavelength of the pulse spectrum, requiring no active stabilization or feedback. A depth resolution of 30 microm was achieved, with a pulse duration of nominally 120 fs for ultrasound detection through turbid media up to optical thicknesses of 11 mean free scattering lengths.

High-speed adaptive interferometer for optical coherence-domain reflectometry through turbid media.

Two-wave mixing in a dynamic holographic film acts as the adaptive beam combiner in a short-coherence interferometer that performs optical coherence-domain reflectometry (OCDR) through turbid media. This approach combines the high spatial resolution and sensitivity of coherence-domain reflectometry with photorefractive quantum-well-based adaptive homodyne detection. A depth resolution of 28 microm and penetration through 16 mean free paths in a turbid medium have been obtained in this adaptive OCDR application.

Elimination of beam walk-off in low-coherence off-axis photorefractive holography.

Whole-field photorefractive holography can be combined with low-coherence interferometry for three-dimensional imaging and other applications, including imaging through turbid media, but the off-axis holographic recording geometry results in a limited field of view when light of low temporal coherence is used. We show that tilting the energy fronts with respect to the wave fronts by use of prisms can eliminate this problem and point out that this approach will be useful for many linear and nonlinear wave-mixing experiments.

Enhanced responsivity of non-steady-state photoinduced electromotive force sensors using asymmetric interdigitated contacts.

The responsivity at a constant detection area of non-steady-state photoinduced electromotive force (photo-emf) detectors is improved by a factor equal to the number of contact pairs contained in asymmetric interdigitated surface contacts. The polar nature of photo-emf current generation requires contact asymmetry in which one increases the total signal by blocking the illumination between alternate contact pairs, in distinct contrast to the behavior of conventional interdigitated contacts fabricated upon isotropic photoconductors.

Oscillatory mode coupling and electrically strobed gratings in photorefractive quantum-well diodes.

Oscillatory mode coupling between two coherent laser beams is produced when an interference pattern moves against a quasi-static electrically strobed grating in a photorefractive AlGaAs/GaAs multiple-quantum-well diode operated in the quantum-confined Stark geometry. The oscillation frequency is equal to the frequency difference between the two laser beams and provides a method to measure high-frequency Doppler shifts or large surface displacements for laser-based ultrasound. Combined photorefractive gains (normally forbidden by symmetry in the Stark geometry) and absorptive gains approach 1200cm(-1)during two-wave mixing using moving gratings.

Direct-to-video holographic readout in quantum wells for three-dimensional imaging through turbid media.

Customized photorefractive quantum-well devices have been developed for real-time video acquisition of coherence-gated, three-dimensional images in turbid media. Large-field-of-view holographic imaging with direct video capture is now possible. We have evaluated the role of intensity-limited device performance in Fourier-plane and image-plane holography in such devices and, using near-infrared light, have imaged through turbid phantoms of 13 mean free paths' scattering depth with 50-microm transverse and 60-microm depth resolution.

Real-time edge enhancement of femtosecond time-domain images by use of photorefractive quantum wells.

Dynamic holograms written in a photorefractive multiple quantum well placed inside a Fourier femtosecond pulse shaper convert a space-domain image into the time domain. We demonstrate that edge-enhancement processing of the time-domain image can be performed by controlling hologram-writing intensities.

Femtosecond pulse shaping by dynamic holograms in photorefractive multiple quantum wells.

Femtosecond pulses can be shaped in the time domain by diffraction from dynamic holograms in a photorefractive multiple quantum well placed inside a Fourier pulse shaper. We present several examples of shaped pulses obtained by controlling the amplitude or the phase of the hologram writing beams, which modifies the complex spectrum of the femtosecond output.

Reflection-geometry photorefractive quantum wells.

We present what is to our knowledge the first demonstration of photorefractive AlGaAs/GaAs quantum wells operated in the reflection geometry, using the quantum-confined Stark effect. This photorefractive geometry relies on volume reflection gratings of a small number of periods written in a nonstoichiometric multiple-quantum-well layer with counterpropagating beams. Combined absorptive and photorefractive twowave mixing gains as large as 1500 cm(-1) are observed under reverse bias of the diode.

Optical phase conjugation in a magnetic photorefractive semiconductor CdMnTe.

Magneto-optical phase conjugation was performed in a diluted magnetic photorefractive semiconductor crystal CdMnTe under an applied magnetic field. The magnetic field removes time-reversal symmetry and quenches orthogonal components of the phase-conjugate signal for selected field strengths. The experimental results as functions of magnetic field and incident polarization angle are in good agreement with coupled-mode theory with transmission gratings during magneto-photorefractive mixing.

Dynamic holographic phase gratings in multiple-quantum-well asymmetric Fabry-Perot reflection modulators.

Dynamic holographic pi-phase gratings can be written in a multiple-quantum-well asymmetric Fabry-Perot reflection modulator by spatial modulation of the quantum-confined exciton absorption. Operating near the Fabry-Perot resonance, the phase grating quenches the zero-order reflection and enhances the first-order diffraction efficiency. The diffraction efficiency of these structures as diffractive optics elements is not sensitive to the contrast ratio, which eases the constraints for device fabrication. Numerical simulations for multiple-quantum-well structures are presented that fully include refractive-index changes in response to a spatial modulation of the exciton absorption, which can be caused by any of several techniques, including free-carrier gratings, absorption bleaching, electro-optic effects, and photorefractive effects.

Photorefractive phase shift induced by nonlinear electronic transport.

A photorefractive phase shift can be generated under dc applied fields if the dominant photocarriers have a nonlinear velocity-field dependence with a vanishing differential mobility. Phase shifts as large as pi/2 are possible when velocity saturation disables dielectric relaxation while still permitting large drift rates. The inability of the space-charge field to relax leads to a saturated trap density that mimics trap-limited behavior. All direct-gap photorefractive semiconductors have strong velocity saturation from hot-electron transport effects, most widely known for the origin of the Gunn effect. Previous photorefractive trap-limited-field studies may have to be reevaluated in the context of transport nonlinearity.