Changes in the noninvasive, in vivo electrical impedance of three xenografts during the necrotic cell-response sequence.

PURPOSE To investigate the noninvasive, in vivo use of electrical impedance spectroscopy (EIS) as a method for observing the real-time, cellular-level responses of a volume of tissue to therapies. Here, we studied the EIS response during the development and progression of hyperthermia-induced coagulative necrosis in three diverse human xenografts. METHODS AND MATERIALS A necrotic cell response sequence was selectively induced in three types of subcutaneously-grown human tumor xenografts by applying hyperthermia at 44.5 degrees C. The electrical impedance of the tumors was measured from 100 Hz to 10 MHZ, noninvasively, in vivo during the treatments. From the full spectrum EIS, ratios between resistivities at selected frequencies (p-ratios) were used as indicators of the changes in the electrical impedance spectra of each tumor's cell population. RESULTS The rho-ratios consistently demonstrated characteristic, early, rapid increases which coincided with cell and organelle swelling typical of early necrosis. These increases subsequently slowed, but no decrease began before the end of treatment, unlike previous, similarly treated, thermo-sensitive EMT6 mouse tumors. This was consistent with the xenograft histology, which revealed ubiquitous, early-stage coagulative necrosis, with no gross plasma membrane damage at the end of treatment. The extent of both the necrosis and p-ratio changes were similar to those seen early in the EMT6 tumor treatment. Within several days after treatment, the xenograft volumes regressed nearly completely, suggesting completion of the cell populations' necrotic response (lysing) during this period. Consistent with this, extended EIS measurements over a 24-h posttreatment period allowed tracking of the necrotic response sequence through this lysing phase for one type of xenograft. CONCLUSION The change in the electrical impedance of a volume of tumor tissue which occurs during and/or after a hyperthermia treatment can be correlated with the extent of necrosis observed histologically in the cell population.

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