1) Provide spectroscopic instrumentation and fiberoptic probes Update the existing OP and ESS """"""""boxes"""""""" - incorporate an internal micro-controller board to provide timing and A/D functions - update user-interface software Specify and contract with the industrial partners and other suppliers to fabricate and provide the duplicate instruments, which will be needed for the Primary Projects and, later on, for the Development Projects. Initially two existing instruments will be upgraded and two new instruments will be acquired, matching specifications of prototypes built in Dr. Bigio's laboratory.. Specify and acquire fiberoptic probes to meet the needs of the animal and clinical studies. Perform acceptance testing for all of the above. 2) Provide customized data analysis routines and mathematical tools for pharmacokinetics and diagnostic algorithms for ESS spectra Carry out spectrophotometry on each drug to be used in OP studies, so as to incorporate the intrinsic extinction coefficient into the data extraction routine. Also incorporate any known spectral shifts of drug spectra for in-vivo conditions. Generate and provide the drug-specific routines for the OP measurements and data analysis of the various studies in the Projects. Construct mathematical models of drug pharmacokinetics (PK) and pharmacodynamics (PD) (where appropriate) from OP measurement data collected by Project teams Assist in refinement of existing ESS diagnostic algorithms. Perform validating data analysis for OP and ESS. 3) Provide the software tools to incorporate real-time data extraction Develop and provide the mathematical and computational tools to incorporate real-time analysis into the system-control software, so as to provide drug concentrations in real time, rather than waiting for offline analysis of the spectral data. Extend the on-line analysis software to include recommended changes in PDT treatment based on the PK and PD relationships developed in 2), above, thereby providing the opportunity to individualize therapy in real-time on a patient-specific basis. Develop the software tools to incorporate the diagnostic algorithms of ESS applications into the operating system so as to provide instant detection/diagnostic output. 4) Develop new fiber probe designs For applications of OP to measurement of drug concentrations in subcutaneous tumors (and also for other tissue sites that are expected to be irregularly vascularized and otherwise heterogeneous) multiple-element probes will be developed (details provided below) to measure concentrations averaged over multiple adjacent tissue volumes, thus averaging mm-scale inhomogeneities that are common for this type of xenograft tumors in immune-suppressed mice. Develop new ESS probe designs to be specific to the type of epithelium being studied. Probes incorporating polarizing elements will be developed for sizing of epithelial nuclei. Care will be taken to avoid statistically-incompatible data sets with spectra from different probe specifications. 5) Design, test and provide enhancements of instrumentation for years 2-5 of this program: Through discussions with the Project investigators about the operation of the instruments in the clinical and animal studies, improvements and upgrades will be implemented to instruments in the field. These might include: - a foot pedal for triggering the measurements in the clinical setting. - application-specific new specifications for fiberoptic probes. - changes in interface design and information availability/presentation to clarify results for investigators during pre-clinical/clinical studies 6) Develop new mathematical tools for new sensing capabilities for Development Projects Develop mathematical methods to treat OP spectra for fiber separations that are smaller or larger than the """"""""optimum"""""""" separation, to permit probing different depths, while still accommodating variable scattering properties. Develop the analytical method to permit determination of the concentration depth-profile for topically-applied drugs, taking advantage of spectral data taken with probes with multiple fiber separations. Explore, in collaboration with new Associate Members, an imaging version of ESS to scan tissue surface area, with a field-of-view of 1-2 cm.
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