The concept of relieving vascular stenoses by inflating a balloon mounted on the tip of a catheter was a major breakthrough in the treatment of cardiovascular disease when it was initiated in the late 1970s by Gruentzig in Zurich, Switzerland.1 The latter took advantage of the earlier concept by Dotter in the 1960s, who thought that passing a catheter through a vessel stenosis could enlarge the lumen, thus restablishing an adequate flow distal to the lesion. It took 15 more years to build up a catheter with an inflatable balloon that could push aside the obstructing material and compact it against the vessel wall to restore an adequate lumen.

Grating-coupled, thin-film integrated optical waveguide (IOW) structures were fabricated using standard transmission photolithography and employed in a fluoro-affinity assay for the trace detection of analyte. Using a ruled chrome-on-quartz mask with a 0.7 m repeat, gratings of three etch depths—0.6, 0.8, and 1.0 mm—were ion milled into 0.5-mm-thick quartz substrates. Silicon oxynitride (SiON) guiding films (1.5 mm) were deposited on the etched substrates by plasma-enhanced chemical vapor deposition (PECVD). Coupling efficiencies for the first diffracted grating orders into the zero-order IOW-guided modes were evaluated at 632.8 nm. The deepest gratings coupled the most light; however, their efficiency was less than half that of prisms. Binding isotherms for fluorescently labeled avidin (Cy5-Av) binding to a biotinylated bovine serum albumin (BSA) adlayer were generated from both prism- and grating-coupled SiON sensor data. Both techniques discriminated the binding of avidin from a 10215 M solution; however run-to-run (intraassay) and between-sensor (interassay) variability reduced reliability of the measurements.

The laser Doppler technique is used to assess tissue perfusion. Traditionally an integrated, v-weighted (firstorder filter) power spectrum is used to estimate perfusion. In order to be able to obtain selective information about the flow in vessels with different blood cell velocities, higher order filters have been implemented, investigated, and evaluated. Theoretical considerations show that the output of the signal processor will depend on the flow speed, for a given concentration of blood cells, according to Sout}vn where v is the average blood cell speed and n is the spectral filter order. An implementation of filters using zero-, first-, second-, and third-order spectral moments was utilized to experimentally verify the theory by using a laser Doppler perfusion imager. Two different flow models were utilized: A Plexiglas model was used to demonstrate the various signatures of the power spectrum for different flow speeds and filter orders, whereas a Delrin model was used to study the relationship between the flow velocity and the output of the signal processor for the different filters. The results show good agreement with theory and also good reproducibility. Recordings made on the skin of the wrist area demonstrated that the flow in small veins can be visualized by the use of higher spectral orders.

Gene expression can be quantitatively analyzed by hybridizing fluor-tagged mRNA to targets on a cDNA microarray. Comparison of gene expression levels arising from cohybridized samples is achieved by taking ratios of average expression levels for individual genes. A novel method of image segmentation is provided to identify cDNA target sites and a hypothesis test and confidence interval is developed to quantify the significance of observed differences in expression ratios. In particular, the probability density of the ratio and the maximum-likelihood estimator for the distribution are derived, and an iterative procedure for signal calibration is developed.

The image quality of pseudophakic eyes with intraocular lenses in high myopia was studied by applying geometric and wave optics. Two types of intraocular lenses (IOL) were compared—one that was meniscus shaped and the other either planoconcave or planoconvex [bending factor (X)511]. A geometric study of image quality was used to analyze the transverse spherical aberration (TA) and the chromatic aberration (chromatic difference of the blur circles, CDBC). The loss of image quality and visual acuity increases as the TA and CDBC increase. The polychromatic modulation transfer function (MTF) was obtained using the point-spread function (PSF), taking into account spherical aberration and defocus coefficients. Finally, for chromatic and spherical aberrations and polychromatic MTF, the type of IOL that would best improve image quality for a given patient can be established.

A system has been developed based on the measurement of skin surface vibration that can be used to detect the underlying vascular wall motion of superficial arteries and the chest wall. Data obtained from tissue phantoms suggested that the detected signals were related to intravascular pressure, an important clinical and physiological parameter. Unlike the conventional optical Doppler techniques that have been used to measure blood perfusion in skin layers and blood flow within superficial arteries, the present system was optimized to pick up skin vibrations. An optical interferometer with a 633-nm He:Ne laser was utilized to detect micrometer displacements of the skin surface. Motion velocity profiles of the skin surface near each superficial artery and auscultation points on a chest for the two heart valve sounds exhibited distinctive profiles. The theoretical and experimental results demonstrated that the system detected the velocity of skin movement, which is related to the time derivative of the pressure. The system also reduces the loading effect on the pulsation signals and heart sounds produced by the conventional piezoelectric vibration sensors. The system's sensitivity, which could be optimized further, was 366.2 mm/s for the present research. Overall, optical cardiovascular vibrometry has the potential to become a simple noninvasive approach to cardiovascular screening.

For integrated optical immunosensors, a much more reliable interpretation of the sensor output signal can be achieved by introducing reference pads near the sensing pads, in order to separate specific from nonspecific effects. The results of theoretical and experimental investigations are reported for immunosensors based on measuring changes of the effective refractive index due to the binding of analyte molecules. The emphasis is on the correction for variations of the light wavelength, the angle of incidence, and the temperature for integrated optical grating coupler chips. Using the binding of rabbit immunoglobulin to immobilized protein A as a regenerable model bioaffinity system, the influence of consecutive assay cycles on the two pads has been investigated. Experiments have been performed using sensor chips consisting of TiO2 waveguiding films on fused silica and on replicated polycarbonate substrates.

Theoretical and computer modeling approaches, such as Mie theory, radiative transfer theory, diffusion wave correlation spectroscopy, and Monte Carlo simulation were used to analyze tissue optics during a process of optical clearing due to refractive index matching. Continuous wave transmittance and forward scattering measurements as well as intensity correlation experiments were used to monitor tissue structural and optical properties. As a control, tissue samples of the human sclera were taken. Osmotically active solutions, such as Trazograph, glucose, and polyethylene glycol, were used as chemicals. A characteristic time response of human scleral optical clearing the range 3 to 10 min was determined. The diffusion coefficients describing the permeability of the scleral samples to Trazograph were experimentally estimated; the average value was DT'(0.960.5)31025 cm2/s. The results are general and can be used to describe many other fibrous tissues.

Spectroscopic measurement of light that is reflected from biological tissue in vivo is being investigated for various clinical applications. One special object of investigation using optical methods is the human ocular fundus. A fundus reflectometer that enables the simultaneous acquisition of up to 192 spectra arranged in a horizontal line across the fundus is described. The underlying optical principle of the device is the confocal imaging of an illuminated narrow, slitlike field at the fundus to the entrance slit of a spectrograph. This is imaged by the grating of the spectrograph onto a two-dimensional CCD chip that records the local distribution of ocular fundus reflectance spectra within a wavelength range of 400 up to 710 nm with a resolution better than 2 nm and a local resolution of 23 mm in a field dimension of 1.5 mm. The performance of the device was investigated, the effects of confocal and nonconfocal imaging are discussed, and some representative measurements are presented.

An image reconstruction algorithm based on a Wentzel–Kramers–Brillouin (WKB) approximation in the frequency domain in terms of path integration is tested with both simulated and experimental data. The algorithm can be used with full frequency domain data (amplitude modulation and phase shift), or partial data (amplitude or phase shift). This algorithm reconstructs an image of photon density wave propagation factor k without knowing the optical parameters of the background medium. Reconstruction was performed for data sets of different modulation frequencies and different detector geometries. The reconstruction time on a SUN-SPARC 5 station was about 5 min for images with a 1283128 pixel size.

The use of reflected light confocal microscopy is proposed to rapidly observe unfixed, unstained biopsy specimens of human skin. Reflected light laser scanning confocal microscopy was used to compare a freshly excised, unfixed, unstained biopsy specimen, and in vivo human skin. Optical sections from the ex vivo biopsy specimen of human skin and in vivo human skin were converted to red-green anaglyphs for threedimensional visualization. Contrast was derived from intrinsic differences in the scattering properties of the organelles and cells within the tissue. Individual cellular layers were observed in both tissues from the surface to the papillary dermis. Confocal microscopy of an unfixed, unstained biopsy specimen showed cells and cell nuclei of the stratum spinosum. Confocal microscopy of in vivo human skin demonstrated optical sectioning through a hair shaft on the upper hand. The combination of reflected light confocal microscopy and threedimensional visualization with red-green anaglyphs provides a rapid technique for observing fresh biopsies of human skin.