Dynamic contrast enhanced optical imaging of cervix, in vivo: a paradigm for mapping neoplasia-related parameters.

We present a novel biophotonic method and imaging modality for estimating and mapping neoplasia-specific functional and structural parameters of the cervical precancerous epithelium. Estimations were based on experimental data obtained from dynamic contrast-enhanced optical imaging of cervix, in vivo. We have developed a pharmacokinetic, in silico, model of the optical tracer's uptake by the epithelium. We have identified that the kinetic parameters of the model correlate well with pathologic alterations in both metabolic and structural characteristics of the tissue, associated with the neoplasia progress. Global sensitivity analysis and global optimization methods were employed for identifying the key determinant set of biological parameters that dictate the model's output. Particularly, the shuffled complex evolution algorithm converged to a set of four parameters that can be estimated with an error of 7%, indicating a good accuracy and precision. These results are unique in the sense that for the first time functional and microstructural parameter maps can be estimated and displayed together, thus maximizing the diagnostic information. The quantity and the quality of this information are unattainable by other invasive and non invasive methods.

Estimation of neoplasia-related biological parameters through modeling and sensitivity analysis of optical molecular imaging data.

We combine system's biology approaches with in vivo optical molecular imaging of epithelial neoplasia for estimating disease-specific biological parameters. Molecular imaging measures and maps the dynamic optical effects, generated by the topical application of acetic acid diluted solution. The dynamic characteristics of the in vivo measured optical signal are governed by the epithelial transport effects of the biomarker. Nine biological parameters, both structural and functional, have been identified to be potentially correlated with the neoplasia growth and to be manifested to the measured data in a convoluted manner. A compartmental model of the cervical neoplastic epithelium has been developed, which predicts the dynamic optical effects in all possible parameter value combinations. We have performed global sensitivity analysis for the purpose of identifying the subset of the input parameters that are the key determinants of the model's output. Finally, we have for the first time shown that it is possible to estimate, from in vivo measured dynamic optical data, the following neoplasia related parameters: number of neoplastic layers, intracellular and extracellular space dimensions, functionality of tight junctions, and extracellular pH. These findings have been (in part) validated with optical data and biopsies obtained from 30 women with cervical neoplasia.

In vivo dynamic imaging, in silico modeling and global sensitivity analysis for the study and the diagnosis of epithelial neoplasia.

We present a method for detecting and studying neoplasia-specific functional and structural features through the combination of in vivo dynamic imaging, in silico modeling and global sensitivity analysis. We particularly present the case of cervical epithelium interacting with acetic acid solution, which is employed as an optical biomarker. The in vivo measured dynamic scattering characteristics are strongly correlated with the output of the biomarker's pharmacokinetic model that we have developed. Model global sensitivity analysis has shown that the measured/modeled bio-optical processes can be used for probing, in vivo, the number of neoplastic layers, the extracellular pH, the intracellular buffering efficiency and the size of the extracellular space.