Cancer treatment often includes chemotherapy drugs that prevent cancer cell growth through a variety of biochemical mechanisms, but are not target specific and kill other cells. Consequently, the dosage has a narrow range of safe and effective use. Furthermore, because of the dangerous side-effects of these drugs, clinical trials are not performed, and dosage is based on the limited statistics of the response of previously treated patients and administered according to body surface area. Monitoring dosage during administration would clearly improve patient outcome. Unfortunately current practices require 10-20 milliliters of blood per analysis, and multiple samples to profile pharmacokinetics may further jeopardize the patient's health. Saliva analysis has long been considered an attractive alternative, but the large sample volumes are difficult to obtain. In an effort to overcome this limitation we have been investigating metal-doped sol-gels to both separate drugs and their metabolites from saliva and generate surface-enhanced Raman spectra. We have incorporated the sol-gel in a disposable pipette format, and generally no more than two drops (100 microL) of sample are required to perform analysis. The detailed molecular vibrational information allows chemical identification, while the increase in Raman scattering by six orders of magnitude or more allows detection of nanomolar concentrations. Measurements of chemotherapy drugs at relevant concentration are presented.

The phototrophic cyanobacterium Acaryochloris marina discovered in 1996 has a unique composition of the light harvesting system. The chlorophyll (Chl) antenna contains mainly Chl d instead of the usually dominant Chl a and the Phycobiliprotein (PBP) antenna has a simpler rod shaped structure than in typical cynobacteria [1]. The interaction of the photosynthetic subunits and especially the mechanisms regulating the energy transfer under different stress conditions are presently interesting and open fields in photosynthesis research. In this study we use time- and wavelength-resolved single photon counting to investigate the excited states dynamics in living cells of A.marina. The fluorescence dynamics is synchronistically monitored in the visible and near infrared spectrum with high signal to noise ratio and short data acquisition times while using low excitation light intensities. These attributes are necessary to investigate photosynthetic processes in sensitive biological samples, when the light emission varies due to metabolic changes. The results suggest a fast excitation energy transfer kinetics of 20-30 ps along the PBP antenna of A.marina followed by a transfer of about 60 ps to the Chl d antenna. Cells of A. marina which are stored at 0°C for some time show a decoupling of the PBP antenna, which is partially reversible when the sample is kept at 25 °C for a short time. Decoupling effects appearing after strong illumination with white light (1600 W/m²) suggest a mechanism which removes the PBP antenna at different stress conditions to avoid photo damage of the reaction center of Photosystem II (PS II).

These authors have been developing for some years a variety of morphological classifiers, which analyse images, extract descriptors by FOURIER analysis, fractal analysis and spatial differentiation, fuse these descriptors by means of multivariate statistics. Classifiers have been trained, validated and applied to recognizing patterns belonging to new classes. One of the most relevant application has been the quantitative morphology of microtubule organisation. Results, which have been described in a number of publications, have consisted of: a) the quantitative assessment of structural damage caused by xenobiotics and the ensueing recovery, and b) the estimation of dose- and time- response relations. This paper, in addition to presenting a survey of the classification methods and the related results, will focus on some instructive class-wide and cell-wise statistical properties deduced from the first principal component only. These properties lead to three questions about the dose-response behaviour of microtubules which are still open.

In order to evaluate the potential hematotoxicity of xenobiotics, including candidate anti-cancer drugs, in vitro models of hematopoiesis are used, which involve clonogenic assays on CFU-GM (Colony Forming Unit-Granulocyte-Macrophage). These assays require live and unstained colonies to be counted. Most laboratories still rely on visual scoring, which is time consuming and error prone. As a consequence automated scoring is highly desired. A classification algorithm aimed at emulating the colony recognition and scoring capabilities of a human expert has been developed. A first account will be given herewith. Assays were carried out on CFU-GM progenitors derived from human umbilical cord blood cells and grown in methylcellulose. A three-dimensional (3-D) medium is essential for these assays to simulate the clonogenetic process which takes place in bone marrow. Stacks of images representing slices of a 3-D domain were acquired. Structure and texture information was extracted from each image. Classifier training was based on a 3-D colony model applied to the image stack. The number of scored colonies (assigned class) was required to match the count supplied by the human expert (class of belonging). Successful applications to scoring colonies, which partially overlap and/or are masked by caustics, are described. Whereas the industry's scoring methods all rely on image structure alone and process 2-D data, the classifier described herewith takes texture into account and fuses 3-D dtat from a whole stack.

Breast cancer cells and normal cells were grown on glass substrates and investigated via laser generated speckles. The optical speckle pattern of a layer was investigated via angular correlation and fractal dimension analysis. A porous silicate slab with various water contents was used as calibration. The angular correlation and its associated Fourier transform results were consistent with the property of the cells. The speckle intensity data can be treated as a random series and the Higuchi method was used to explore the fractal property of the random series. The fractal dimension results differentiated the cancer cells (fractal dimension about 1.5) from the normal cells (fractal dimension about 1.8). The Fourier transformed series showed fractal dimension results consistent with cell functions. A composite of breast cancer/normal cell matrix was built with cancer cell layers embedded within normal cell layers. The optical speckle pattern of a composite was investigated and computer modeling was used to extract the embedded cancer cell fractal dimension information. The measurement of the efficacy of a drug was simulated with the monitoring of the effect of added chemicals in the growth media. Laboratory optical speckle pattern monitoring of the effect of added chemicals was discussed. The extension for early cancer detection in mammography was also discussed and an example of the application of the anisotropic spatial variation of the fractal dimension via the Higuchi fractal method was presented.

Electroluminescence from self-assembled InAs quantum dots in cascade-like unipolar heterostructures is demonstrated. Initial results show weak luminescence signals in the mid-infrared from such structures, though more recent designs exhibit significantly stronger luminescence with improved designs of the active region of these devices. Further studies of mid-infrared emitting quantum dot structures have shown anisotropically polarized emission at multiple wavelengths. A qualitative explanation of such luminescence is developed and used to understand the growth morphology of buried quantum dots grown on AlAs layers. Finally, a novel design for future mid-infrared quantum dot emitters, intended to increase excited state scattering times and, at the same time, more efficiently extract carriers from the lowest states of our quantum dots, is presented.

A planar waveguide design is studied for the mid-infrared wavelengths from 2.5μm to 4.5μm by simulation. Lithium-niobate and silicon are integrated to increase functionality. Silicon as a higher index material is introduced on behalf of its transparency to the infrared spectrum. Power transfer from a buried lithium-niobate waveguide to silicon is simulated using field mode matching software for several wavelengths and taper dimensions. In addition, bend losses and mode mismatch losses to a quantum cascade laser are evaluated by simulation.

Significant recent advances in the high-temperature, high-power performance of type-II antimonide interband cascade lasers (ICLs) operating in the mid-infrared are reported. A 5-stage ICL with a 12μm ridge width and Au electroplating for improved epitaxial-side-up heat sinking operates cw to a maximum temperature of 257 K, where the emission wavelength is 3.7 μm. A similar device with a ridge width of 22 μm emits > 260 mW per facet for cw operation at 80 K (λ = 3.4 μm) and 100 mW at 200 K (λ = 3.6 μm). Beam qualities for the narrowest ridges approach the diffraction limit. The recent development of type-II "W" photodiodes for the long-wave infrared is also reviewed. A "W" photodiode with an 11.3 μm cutoff displayed a 34% external quantum efficiency (at 8.6 μm) operating at 80 K. A graded-gap design of the depletion region is shown to strongly suppress dark currents due to tunneling and generation-recombination processes. The median dynamic impedance-area product of 216 Ω-cm² for 33 devices with 10.5 μm cutoff at 78 K is comparable to that for state-of-the-art HgCdTe-based photodiodes. The sidewall resistivity of ≈70 kΩ-cm for untreated mesas is also considerably higher than previous reports for passivated or unpassivated type-II LWIR photodiodes, apparently indicating self-passivation by the graded bandgap.

We report the realisation of spectroscopic broadband transmission experiments on quantum cascade lasers (QCLs) under continuous wave operating conditions for drive currents up to laser threshold. This technique allows, for the first time, spectroscopic study of light transmission through the waveguide of QCLs in a very broad spectral range (λ~1.5-12 μm), limited only by the detector response and by interband absorption in the materials used in the QCL cladding regions. Waveguide transmittance spectra have been studied for both TE and TM polarization, for InGaAs/InAlAs/InP QCLs with different active region designs emitting at 7.4 and 10μm. The transmission measurements clearly show the depopulation of the lower laser levels as bias is increased, the onset and growth of optical amplification at the energy corresponding to the laser transitions as current is increased towards threshold, and the thermal filling of the second laser level and decrease of material gain at high temperatures. This technique also allows direct determination of key parameters such as the exact temperature of the laser core region under operating conditions, as well as the modal gain and waveguide loss coefficients.

We present a study of the spectral characteristics of Fabry-Perot quantum cascade lasers in pulsed mode operation applying a time resolution of 3 ns in combination with a high spectral resolution of 0.02 cm^-1. With this technique the laser spectra were investigated applying pulse lengths ranging between 100 ns and 20 μs and duty cycles between 0.01% and 10%. Depending on the current density and operation temperature, the spectra exhibit complex line patterns, which indicate mode competition caused by gain saturation effects.

We propose a new design of quantum cascade lasers integrated with resonant intersubband nonlinearities, in which the laser is divided into two separately contacted and biased sections along the cavity length. One section operates as a laser active medium while another section serves as a nonlinear element. We show that such schemes turn out to be surprisingly flexible and efficient in implementing various resonant optical nonlinearities.

We report second-harmonic and sum-frequency generation in GaAs based quantum cascade lasers. Different waveguide designs and active regions were investigated as well as a doping dependence study of the second-order susceptibility in one of the investigated structures is shown. We present farfield measurements which give information about the modal behavior depending on the waveguide design and dimensions. We also demonstrate that grating-coupled surface emission is a highly efficient way to couple out the second-harmonic radiation.

A laser sensor realised at ENEA Frascati (Italy) based on photoacoustic spectroscopy (PAS), able to detect gas concentrations down to sub-ppb level, was applied for revealing ethylene traces emitted in the exhaled breath by human subjects, before as well as after an antioxidant treatment. In the present work, the changes in breath ethylene detected by PAS, compared to a direct analysis of reactive oxygen species detected in the blood by a spectrophotometric method (d- ROMs), were investigated in each patient. The sensorial system, the methods, the experiment and the results are discussed in the paper.

Acetone is a good marker of metabolic stress as it is the most volatile and rapidly equilibrated of the ketone bodies produced by human metabolism. If the body utilizes predominately fat to meet its energy requirements, blood and breath acetone concentrations will increase. Elevated concentrations of breath acetone can indicate a normal response to caloric imbalances in the diet, or a diseased state such as untreated diabetes. This paper describes a novel method of acetone detection that uses a gas-solid chemical reaction of acetone with a hydroxylamine hydrochloride (HA) to produce an easily detectable chemical species, HCl. Breath samples are passed through a reactor filled with solid HA and the amount of HCl gas released is measured by sensitive near infrared diode laser spectroscopy. The breath acetone instrument described is compact, low power and portable.

We are developing a mid-IR ICL-based sensor for field measurements of ambient CH₄. We describe some of the design considerations for this sensor. Our sensor uses a Type II Quantum Cascade Laser (or Interband Cascade Laser, ICL) operating near 3.3 μm to monitor a well-isolated line in the υ₃ fundamental band of CH₄. The ICL operates in cw mode at cryogenic temperature. The sensor consists of two major components, an optical breadboard containing the laser, transfer optics, sample cell, and detectors, and an instrumentation module containing power supplies and system control computer. Light from the laser is collimated using a reflective microscope objective and transported to a multipass cell via a simple optics train. The multipass cell provides an optical path of ~7 meters in an 0.25 m base path. The spectrometer uses TE-cooled InAs detectors along with our Balanced Ratiometric Detection. Our measured precision for CH₄ is 15 ppbv for a 60 sec integration time. We report on additional sensor characterization and data from recent field trials at two facilities maintained by the University of New Hampshire.

We demonstrate the performance of a novel long-wave infrared photoacoustic laser absorbance spectrometer for gas-phase species using an amplitude modulated (AM) quantum cascade (QC) laser and a quartz tuning fork microphone. Photoacoustic signal was generated by focusing the output of a Fabry-Perot QC laser operating at 8.41 μm between the legs of a quartz tuning fork which served as a transducer for the transient acoustic pressure wave. The QC laser was modulated at the resonant frequency of the tuning fork (32.8 kHz). This sensor was calibrated using the infrared absorber Freon-134a by performing a simultaneous absorption measurement using a 35 cm absorption cell. The NEAS of this instrument was determined to be 2 x 10^-8 W • cm / √Hz, and the fundamental sensitivity of this technique is limited by the noise floor of the tuning fork itself.

We report a new highly efficient source of frequency-tunable (0.5-3.5 THz) narrow-bandwidth terahertz wave packets with up to 1 mW average power, based on parametric down-conversion in quasi-phase-matched GaAs. Different lasers were employed as a pump source, including femtosecond OPA/DFG system (wavelength range 2-4μm), Tm-fiber femtosecond laser (wavelength ~2μm), and near-degenerate synchronously-pumped picosecond OPO system with extra- and intracavity THz generation. We prove experimentally that the optical-to-terahertz conversion efficiency is fluence-dependent, with the scaling factor being the same for femtosecond (optical rectification) and picosecond (difference frequency generation) pump pulses, with optical-to-terahertz conversion efficiency on the order of 0.1% per μJ.

Microcirculatory changes, such as vascular shutdown, may be a predictor to the therapeutic efficacy of photodynamic therapy (PDT). The aim of this study was to measure the tumour vascular response to varying irradiance rates during PDT deep within prostate tumour xenograft, via interstitial Doppler optical coherence tomography (DOCT). DOCT provides micron-scale spatial resolution allowing visualization of structures at near histological levels, and yields flow velocity resolution of ~20 μm/s. Current in vivo DOCT imaging probes are limited to intraluminal and near-surface sites. To improve the accessibility of DOCT to anatomically relevant sites deep within the body (e.g., prostate), an interstitial (IS) needle (~700μm diameter) probe was developed for minimally invasive monitoring of the microvascular response to PDT (irradiance administered superficially) within tumour tissue. Rats were given a photosensitizer drug, Photofrin, and 20-24 h later the tumours were exposed to light (635nm) with an irradiance rate of 8-133 mW/cm2 for 25 minutes to a total irradiance of 12-200 J/cm². Results illustrated different rates of vascular shutdown within the tumour as imaged by IS-DOCT, related to the administered PDT irradiance rate and total irradiance. Controls (probe only, probe + light) showed no significant microvascular changes. IS-DOCT was able to detect and monitor microvascular changes during PDT. Microvascular shutdown occurred at different rates and showed correlation with PDT light dose and irradiance rate. These dependencies may play an important role in PDT treatment planning, feedback control for treatment optimization, and post treatment assessment.

Two families of photonic crystal based Terahertz Quantum Cascade Laser structures are demonstrated. The first one uses Bragg mirrors that relies on a two-dimensional photonic lattice. Single mode lasing emission is observed from the edge of the structure for particular lattice constants. Moreover mode pinning of the laser is obtained along the whole dynamic range. In the second part a vertically emitting THz Quantum Cascade Laser device that exploits in-plane resonator based on a two-dimensional photonic crystal is demonstrated. Stable single mode lasing is reported. Simulations based on block-iterative frequency-domain methods on a plane wave basis account for the observed results.

We have developed a portable terahertz pulsed imaging system (TPI Imaga1000) for use in a clinical environment. The system uses photoconduction to generate and detect terahertz radiation with frequency content from 0.1-4 THz. Here, we report on a study using TPI for imaging breast tumours ex vivo. Several breast samples were imaged and parameters from the time domain impulse functions were used to provide contrast. The size and shape of tumour regions in the terahertz images were compared with the corresponding histology section. Good correlation was found for area and shape of tumour in the THz images compared to that of histology. In addition, we have also performed spectroscopy study comparing the terahertz properties (absorption coefficient and refractive index) of excised normal breast skin and breast tumor. Both the absorption coefficient and refractive index were higher for tissue containing tumor compared to normal. These changes are consistent with higher water content and structural changes, like increased cell and protein density. This study demonstrates the potential of TPI to image both invasive breast carcinomas and ductal carcinoma in situ using THz and encourages further studies.

We report on the progress of devices and applications of quantum-well photodetectors (QWIP) for the terahertz (~ 1-10 THz) spectrum region. We discuss device design and show that the device dark current can by effectively reduced by employing wider quantum barriers. We demonstrate several GaAs/AlGaAs QWIPs for different peak wavelength with background limited infrared performance (BLIP). We report experimental results on intersubband absorption spectra, measured using multi-pass waveguide geometry. We show that the experimentally measured intersubband energy levels agree excellently with the theoretical simulations, provided that many-body effects are taken into consideration, including exchange-correlation and depopulation effects. We report the results of QWIP photo-current spectra and detector responsivity. We discuss the high frequency capability of THz-QWIP and present experimental results of device time response measured using microwave rectification technique. We discuss its application in free space terahertz communication in combination with a terahertz quantum cascade laser (QCL). We discuss the terahertz to near infrared (THz-to-NIR) optical upconversion using a monolithic integration of THz GaAs/AlGaAs QWIP and NIR GaAs/AlGaAs LED, and its potential applications in terahertz imaging.