The ability to diagnose the early onset of disease, rapidly, non-invasively and unequivocally has multiple benefits. These include the early intervention of therapeutic strategies leading to a reduction in morbidity and mortality, and the releasing of economic resources within overburdened health care systems. Some of the routine clinical tests currently in use are known to be unsuitable or unreliable. In addition, these often rely on single disease markers which are inappropriate when multiple factors are involved. Many diseases are a result of metabolic disorders, therefore it is logical to measure metabolism directly. One of the strategies employed by the emergent science of metabolomics is metabolic fingerprinting; which involves rapid, high-throughput global analysis to discriminate between samples of different biological status or origin. This review focuses on a selective number of recent studies where metabolic fingerprinting has been forwarded as a potential tool for disease diagnosis using infrared and Raman spectroscopies.

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Metabolic fingerprinting in disease diagnosis: biomedical applications of infrared and Raman spectroscopy.

Spectroscopy is carried out in almost every field of science, whenever light interacts with matter. Although sophisticated instruments with impressive performance characteristics are available, much effort continues to be invested in the development of miniaturized, cheap and easy-to-use systems. Current microspectrometer designs mostly use interference filters and interferometric optics that limit their photon efficiency, resolution and spectral range. Here we show that many of these limitations can be overcome by replacing interferometric optics with a two-dimensional absorptive filter array composed of colloidal quantum dots. Instead of measuring different bands of a spectrum individually after introducing temporal or spatial separations with gratings or interference-based narrowband filters, a colloidal quantum dot spectrometer measures a light spectrum based on the wavelength multiplexing principle: multiple spectral bands are encoded and detected simultaneously with one filter and one detector, respectively, with the array format allowing the process to be efficiently repeated many times using different filters with different encoding so that sufficient information is obtained to enable computational reconstruction of the target spectrum. We illustrate the performance of such a quantum dot microspectrometer, made from 195 different types of quantum dots with absorption features that cover a spectral range of 300 nanometres, by measuring shifts in spectral peak positions as small as one nanometre. Given this performance, demonstrable avenues for further improvement, the ease with which quantum dots can be processed and integrated, and their numerous finely tuneable bandgaps that cover a broad spectral range, we expect that quantum dot microspectrometers will be useful in applications where minimizing size, weight, cost and complexity of the spectrometer are critical.

A colloidal quantum dot spectrometer

Within the framework of systems biology, functional analyses at all ’omic levels have seen an intense level of activity during the first decade of the twenty-first century. These include genomics, transcriptomics, proteomics, metabolomics and lipidomics. It could be said that metabolomics offers some unique advantages over the other ’omics disciplines and one of the core approaches of metabolomics for disease diagnostics is metabolic fingerprinting. This review provides an overview of the main metabolic fingerprinting approaches used for disease diagnostics and includes: infrared and Raman spectroscopy, Nuclear magnetic resonance (NMR) spectroscopy, followed by an introduction to a wide range of novel mass spectrometry-based methods, which are currently under intense investigation and developmental activity in laboratories worldwide. It is hoped that this review will act as a springboard for researchers and clinicians across a wide range of disciplines in this exciting era of multidisciplinary and novel approaches to disease diagnostics.

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Metabolic fingerprinting as a diagnostic tool

The intensive investment in optical microelectromechanical systems (MEMS) in the last decade has led to many successful components that satisfy the requirements of lightwave communication networks. In this paper, we review the current state of the art of MEMS devices and subsystems for lightwave communication applications. Depending on the design, these components can either be broadband (wavelength independent) or wavelength selective. Broadband devices include optical switches, crossconnects, optical attenuators, and data modulators, while wavelength-selective components encompass wavelength add/drop multiplexers, wavelength-selective switches and crossconnects, spectral equalizers, dispersion compensators, spectrometers, and tunable lasers. Integration of MEMS and planar lightwave circuits, microresonators, and photonic crystals could lead to further reduction in size and cost

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Optical MEMS for Lightwave Communication

(IEEE Transactions on Electron Devices,36(12):2816-2820)Field-Drifting Resonant Tunneling Through a-Si:H/a-Sil-xCx:H Quantum Wells at Different Locations of the i-Layer of a p-i-n Structure

We report a novel, miniature Fourier transform spectrometer with a linear architecture that works by sampling a standing wave. The spectrometer consists of an electrostatically actuated microelectromechanical mirror with on-resonance displacement of up to 65 /spl mu/m, a thin-film photodetector, and an electrical back plane for actuating the mirror. The integrated device offers mirror stability and fixed relative alignment of the three components. The spectrometer has better than 32-nm resolution at 633 nm.

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Standing-wave Fourier transform spectrometer based on integrated MEMS mirror and thin-film photodetector

A novel Fourier spectrometer based on a partly transparent thin-film detector in combination with a tunable silicon micromachined mirror was developed. The operation principle based on the detection of an intensity profile of a standing-wave by introducing a partly transparent detector in the standing-wave. Varying the position of the mirror results in a phase shift of the standing-wave and thus in a change of the optical intensity profile within the detector. The photoelectric active region of the sensor is thinner than the wavelength of the incoming light, so that the modulation of the intensity leads to the modulation of the photocurrent. The spectral information of the incoming light can be determined by the Fourier transform of the sensor signal. Based on the linear arrangement of the sensor and the mirror, the spectrometer facilitates the realization of one- and two-dimensional arrays of spectrometers combining spectral and spatial resolution. The operation principle of the spectrometer will be described and the influence of the detector design on the spectrometer performance will be discussed. A spectral resolution of down to 6 nm was achieved under real-time imaging conditions.

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Silicon-based micro-Fourier spectrometer

We demonstrate a compact transform spectrometer based on measuring the periodicity of Talbot self-images. The system has no moving parts; it contains only a tilted absorption grating that is imaged onto a CCD camera. The linear architecture of the system makes it possible to use this design in imaging arrays of spectrometers. Unlike other transform spectrometers, its resolution is independent of wavelength.

Transform spectrometer based on measuring the periodicity of Talbot self-images

An interferometric sensor based on a partly transparent amorphous silicon n–i–p diode was realized. The combination of the sensor with a tunable micromirror facilitates the realization of a novel microspectrometer. The working principle of the sensor based on the sampling of a standing wave created in front of the tunable mirror. To sample a standing wave the active region of the sensor has to be thinner than the wavelength of the incoming light. Varying the position of the mirror results in a shift of the phase of the standing wave, in a variation of the generation profile within the diode and, thus, in a modulation of the photocurrent. The spectral information of the incoming light can be determined by the Fourier transform of the sensor signal. The spectral resolution of the integrated spectrometer scales reciprocally with the displacement of the mirror. A spectrometer resolution down to 6 nm was achieved. © 2004 Elsevier B.V. All rights reserved.

Interferometric Sensors for Spectral Imaging

A transform spectrometer determines the spectrum of light based on the Talbot effect. Light to be analyzed is passed through a spatially periodic object, thereby generating a series of Talbot images. The intensities of these Talbot images at different optical distances from the spatially periodic object are then detected, and Fourier transformed to determine the spectrum of the light. Preferably, the detector comprises a spatial masking pattern such that the intensities detected are maximized at Talbot planes or at the midpoints between Talbot planes. In one embodiment, the optical distance between the spatially periodic object and the detector is changed in order to detect image intensities at different Talbot planes. In another embodiment, the detector and the spatially periodic object are positioned along a common optical axis at relative angle θ such that different detector rows detect intensities at different Talbot planes. In yet another embodiment, the spatially periodic object is both a grating and a detector, and the Talbot images generated by the grating are reflected off a mirror back to the detector.

H.L. Kung

Papers

Standing-wave Fourier transform spectrometer based on integrated MEMS mirror and thin-film photodetector

Silicon-based micro-Fourier spectrometer

Transform spectrometer based on measuring the periodicity of Talbot self-images

Interferometric Sensors for Spectral Imaging

Miniaturized talbot spectrometer