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Electrical impedance spectroscopy (EIS) and high-frequency ultrasound (HFU) have been evaluated in various in vivo and in vitro models as potential methods to monitor biological changes induced by photodynamic therapy (PDT). EIS was assessed in tumor-bearing rat leg in vivo, in multicell tumor spheroids in vitro, and in normal rat liver tissue in vivo. HFU measurements, both imaging and backscatter frequency scanning, were tested in normal rat brain and skin treated in vivo. Marked changes in the EIS spectra were seen in all 3 models following PDT, depending on the photosensitizer and treatment parameters. With HFU, significant increases in echogenicity of the PDT-treated tissues were observed, with evidence of dose dependency and correlation with apoptotic cell death in vivo. While the results are encouraging for both modalities, a number of technical problems remain, particularly in the case of EIS, before these methods can be used reliably in mechanistic and clinical PDT applications.

Electrical impedance spectroscopy (EIS) has been evaluated as a non- or minimally-invasive technique to monitor the acute tissue response to photodynamic therapy (PDT). In this study the EIS spectra of normal muscle tissue in the rat hind leg were monitored immediately before and at time intervals up to 96 hours post-PDT treatment with different photosensitizers (Photofrin, ALA-induced PpIX, BenzoPorphyrin Derivative), at varying photosensitizer and light doses. EIS measurements were made using a pair of solid matrix Ag-AgCl electrodes placed parallel to one another on either side of the muscle mass and interfaced to a precision LCR impedance meter scanning the frequency range 1 - 1000 KHz. Independent histological grading of tissue injury was performed on tissue sections from treated and untreated legs at the 96 hour end point. Significant and PDT dose-dependent changes in the EIS spectra following treatment were observed, including increases in conductivity which correlated with the immediate post-PDT edematous response with Photofrin and ALA and which resolved or partially-resolved over the measurement time course. Photofrin treatments exhibited a clear drug dose response at 96 hours that was evident in both the EIS spectra and the histological sections. These changes included significant tissue necrosis as well as edema, inflammation and early fibroplasia. The BPD data were less clear, but potentially quite interesting. Most striking were below unity ratios of treated-to-untreated muscle spectra components at 24 hours which reversed to above unity by 96 hours in the through skin measurements. This phenomenon is indicative of a tissue response distinctly different than that observed with Photofrin or ALA. These data also suggest that EIS measured changes are sensitive enough to detect differences in PDT-initiated tissue damage that may be photosensitize-specific. While the data are derived from a small number of animals, the findings are quite encouraging in terms of the potential for EIS to track PDT-induced changes in tissue.

Electrical properties of tissues in the 10 KHz to 10 MHz range are known to be temperature sensitive making the monitoring and assessment of thermal insult delivered for therapeutic purposes possible through imaging schemes which spatially resolve these changes. We have been developing electrical impedance imaging technology from both the hardware data acquisition and software image reconstruction perspectives in order to realize the capability of spectroscopically examining the electrical property response of tissues undergoing hyperthermia therapy. Results from simulations, in vitro phantom experiments and in vivo studies including in human patients are presented. Specifically, a new prototype multi-frequency data acquisition system which is functional to 1 MHz in both voltage and current modes is described. In addition, recent advances in image reconstruction methods which include the enhancement techniques of total variation minimization, dual meshing and spatial filtering are discussed. It is also clear that the electrical impedance spectrum of tissue has the potential to monitor other types of treatment-induced injury. Preliminary in vivo electrical impedance measurements in a rat leg model suggest that the tissue damage from radiation therapy can be tracked with this technique. Both dose and time-dependent responses have been observed in the electrical impedance data when compared to measurements recorded in an untreated control. Correlations with histological examination have also been performed and indicate that electrical impedance spectroscopy may provide unique information regarding tissue functional status and cellular morphology. Representative results from these studies are reported.