Method for the estimation and compensation of attenuating tissue layers by the acoustic observation of microbubbles for sonoporation therapy

The success of sonoporation, the transient increase of cell membrane permeability due to the interaction with microbubbles (MB), strongly depends on the parameters of the acoustic excitation. Low pressure amplitudes result in a low sonoporation rate, whereas high pressure amplitudes cause high numbers of dead cells. However, due to tissue attenuation the pressure at the therapy site cannot be predicted reliably. Consequently, we present a new method for the estimation and compensation of attenuating tissue by the acoustic observation of MB destruction. Repetitive MB insonification during sonoporation causes successive MB destruction. A simplified model for MB destruction is fitted to the subharmonic power decay to extract characteristic time constants for MB destruction. For a range of focal pressures, these time constants are generated from calibration measurements to obtain a characteristic curve. This characteristic curve can be employed to estimate and compensate the attenuation of intermediate tissue layers. To validate this method, the focus of a single element transducer is placed on a flow channel with Sonovue MB solution. In a first step, the characteristic curve is generated by varying the focal pressure between 150 kPa and 760 kPa with a central frequency of 3.3 MHz. These excitation parameters have been employed for successful sonoporation therapy before. In a second step, attenuating latex layers (2.4 dB and 3.8 dB) were placed between transducer and MB. Based on the characteristic curve, the attenuation was estimated to be 2.2 dB and 4.6 dB, resulting in a root mean squared error (RMSE) of 7.1%. The attenuation was compensated by increasing the initial pressure amplitude by the inverse estimated attenuation factor in order to obtain the desired MB behavior. Comparing the desired and the resulting characteristic time constant, a RMSE of 22.9% was obtained. The results verify the proposed method. Errors are caused by inconstant MB concentration in the flow channel and an altered therapy pulse due to the frequency dependency of the attenuation. By employing the proposed method, the excitation amplitude for sonoporation therapy can be adaptively increased to compensate tissue attenuation, yielding the desired MB behavior for the optimal sonoporation rate. Further online monitoring during sonoporation therapy would allow the adjustment of excitation parameters.