Irving J. Bigio

Predictions and measurements of scattering and absorption over broad wavelength ranges in tissue phantoms

Predictions from Mie theory regarding the wavelength dependence of scattering in tissue from the near UV to the near IR are discussed and compared with experiments on tissue phantoms. For large fiber separations it is shown that rapid, simultaneous measurements of the elastic scatter signal for several fiber separations can yield the absorption coefficient and reduced scattering coefficient. With this information, the size of the scattering particles can be estimated, and this is done for Intralipid. Measurements made at smaller source detector separations support Mie theory calculations, demonstrating that the sensitivity of elastic scatter measurements to morphological features, such as scatterer size, is enhanced when the distance between the source and detector fibers is small.

Ultraviolet and visible spectroscopies for tissue diagnostics: fluorescence spectroscopy and elastic-scattering spectroscopy

We review the application of fluorescence spectroscopy and elastic-scattering spectroscopy, over the ultraviolet-to-visible wavelength range, to minimally invasive medical diagnostics. The promises and hopes, as well as the difficulties, of these developing techniques are discussed.

Influence of particle size and concentration on the diffuse backscattering of polarized light from tissue phantoms and biological cell suspensions

We present experimental results that show the spatial variations of the diffuse-backscattered intensity when linearly polarized light is incident upon highly scattering media. Experiments on polystyrene-sphere and Intralipid suspensions demonstrate that the radial and azimuthal variations of the observed pattern depend on the concentration, size, and anisotropy factor g of the particles that constitute the scattering medium. Measurements performed on biological-cell suspensions show the potential of this method for cell characterization.

Diffuse backscattering Mueller matrices of highly scattering media

We report on the development of a method that records spatially dependent intensity patterns of polarized light that is diffusely backscattered from highly scattering media. It is demonstrated that these intensity patterns can be used to differentiate turbid media, such as polystyrene-sphere and biological-cell suspensions. Our technique employs polarized light from a He-Ne laser (l=543nm), which is focused onto the surface of the scattering medium. A surface area of approximately 4x4 cm centered on the light input point is imaged through polarization-analysis optics onto a CCD camera. One can observe a large variety of intensity patterns by varying the polarization state of the incident laser light and changing the analyzer configuration to detect different polarization components of the backscattered light. Introducing the Mueller-matrix concept for diffusely backscattered light, a framework is provided to select a subset of measurements that comprehensively describe the optical properties of backscattering media.

Measuring absorption coefficients in small volumes of highly scattering media: source-detector separations for which path lengths do not depend on scattering properties.

The noninvasive measurement of variations in absorption that are due to changes in concentrations of biochemically relevant compounds in tissue is important in many clinical settings. One problem with such measurements is that the path length traveled by the collected light through the tissue depends on the scattering properties of the tissue. We demonstrate, using both Monte Carlo simulations and experimental measurements, that for an appropriate separation between light-delivery and light-collection fibers the path length of the collected photons does not depend on scattering parameters for the range of parameters typically found in tissue. This is important for developing rapid, noninvasive, and inexpensive methods for measuring absorption changes in tissue.

Influence of the scattering phase function on light transport measurements in turbid media performed with small source–detector separations

Many methods of optical tissue diagnosis require that measurements be performed with small source-detector separations in a backscatter geometry. Monte Carlo simulations are used to demonstrate that for these situations light transport depends on the exact form of the angular scattering probability distribution, P(theta). Simulations performed with different forms of P(theta) with the same value of ?cos theta? result in the collection of significantly different fractions of the incident photons, particularly when small-numerical-aperture delivery and collection fibers are employed. More photons are collected for the distribution that has a higher probability of scattering events with theta > 125 degrees . For the clinically relevant optical parameters employed here, the differences in light collection are >60%.

Analytical model of light reflectance for extraction of the optical properties in small volumes of turbid media

Monte Carlo simulations and experiments in tissue phantoms were used to empirically develop an analytical model that characterizes the reflectance spectrum in a turbid medium. The model extracts the optical properties (scattering and absorption coefficients) of the medium at small source-detector separations, for which the diffusion approximation is not valid. The accuracy of the model and the inversion algorithm were investigated and validated. Four fiber probe configurations were tested for which both the source and the detector fibers were tilted at a predetermined angle, with the fibers parallel to each other. This parallel-fiber geometry facilitates clinical endoscopic applications and ease of fabrication. Accurate extraction of tissue optical properties from in vivo spectral measurements could have potential applications in detecting, noninvasively and in real time, epithelial (pre)cancers.

Spectroscopic sensing of cancer and cancer therapy - Current status of translational research

Various types of optical spectroscopy have been investigated as methods to effect a noninvasive, real-time in-situ assessment of tissue pathology. All of these methods have one basic principle in common: the optical spectrum of a tissue contains information about the biochemical composition and/or the structure of the tissue, and that information conveys diagnostic information. The biochemical information can be obtained by measuring absorption, fluorescence, or Raman scattering signals. Structural and morphological information may be obtained by techniques that assess the elastic-scattering properties of tissue. These basic approaches are useful for the detection of cancer as well as for other diagnostic applications such as hemoglobin saturation, intra-luminal detection of atherosclerosis, and simply the identification of different tissue types during procedures. Optical spectroscopic measurements can also be employed in the management of disease treatment. The site-specific pharmacokinetics of chemotherapy and photodynamic therapy agents can be used to customize dosage to the patient, and diagnostic spectroscopy can be used to monitor response to treatment. In recent years clinical studies have provided indications of potential efficacy, and some of these modalities are now entering a translational research stage, with an eye to approval and commercialization. A benefit of these methods is their inherent low cost and ease of implementation, generally mediated with small portable instruments, not requiring any specialized facilities, and eventually not requiring expert interpretation. This paper reviews briefly the most common methods of diagnostic optical spectroscopy, and reviews in greater depth recent clinical translational research invoking scattering spectroscopy as the enabling technology, which has been the experience of the authors.

Elastic scattering spectroscopy accurately detects high grade dysplasia and cancer in Barrett's oesophagus

Background and aims: Endoscopic surveillance of Barrett’s oesophagus currently relies on multiple random biopsies. This approach is time consuming, has a poor diagnostic yield, and significant interobserver variability. Elastic scattering spectroscopy is a real time in vivo optical technique which detects changes in the physical properties of cells. The aim of this study was to assess the potential for elastic scattering to detect high grade dysplasia or cancer within Barrett’s oesophagus. Methods: Elastic scattering spectroscopy measurements collected in vivo were matched with histological specimens taken from identical sites within Barrett’s oesophagus. All biopsies were reviewed by three gastrointestinal pathologists and defined as either “low risk” (non-dysplastic or low grade dysplasia) or “high risk” (high grade dysplasia or cancer). Two different statistical approaches (leave one out and block validation) were used to validate the model. Results: A total of 181 matched biopsy sites from 81 patients, where histopathological consensus was reached, were analysed. There was good pathologist agreement in differentiating high grade dysplasia and cancer from other pathology (kappa = 0.72). Elastic scattering spectroscopy detected high risk sites with 92% sensitivity and 60% specificity and differentiated high risk sites from inflammation with a sensitivity and specificity of 79%. If used to target biopsies during endoscopy, the number of low risk biopsies taken would decrease by 60% with minimal loss of accuracy. A negative spectroscopy result would exclude high grade dysplasia or cancer with an accuracy of >99.5%. Conclusions: These preliminary results show that elastic scattering spectroscopy has the potential to target conventional biopsies in Barrett’s surveillance saving significant endoscopist and pathologist time with consequent financial savings. This technique now requires validation in prospective studies.

Non-invasive measurement of chemotherapy drug concentrations in tissue: preliminary demonstrations of in vivo measurements

Measurements of the tissue concentrations of two chemotherapy agents have been made in vivo on an animal tumour model. The method used is based on elastic scattering spectroscopy (ESS) and utilizes a fibre-optic probe spectroscopic system. A broadband light source is used to acquire data over a broad range of wavelengths and, therefore, to facilitate the separation of absorptions from various chromophores. The results of the work include measurements of the time course of the drug concentrations as well as a comparison of the optical measurements with high performance liquid chromatography (HPLC) analysis of the drug concentrations at the time of sacrifice. It is found that the optical measurements correlate linearly with HPLC measurements, but give lower absolute values.