CMUT as a Transmitter for Microbubble-Assisted Blood-Brain Barrier Opening

Focused ultrasound (FUS) combined with microbubbles (MBs) has emerged as a promising strategy for transiently opening the blood-brain barrier (BBB) to enhance drug permeability in the brain. Current FUS systems for BBB opening use piezoelectric transducers as transmitters and receivers. While capacitive micromachined ultrasonic transducers (CMUTs) have been suggested as an FUS receiver alternative due to their broad bandwidth, their capabilities as transmitters have not been investigated. This is mainly due to the intrinsic nonlinear behavior of CMUTs, which complicates the detection of MB generated harmonic signals and their low-pressure output at FUS frequencies. Various methods have been proposed to mitigate CMUT nonlinearity; however, these approaches have primarily targeted contrast enhanced ultrasound imaging. In this study, we propose the use of polyphase modulation (PM) technique to isolate MB emissions when CMUTs are employed as transmitters for BBB opening. Our calculations for a human scale FUS system with multiple CMUT transmitters show that 10-kPa peak negative pressure (PNP) at 150-mm focal distance will be sufficient for MB excitation for BBB opening. Experimental findings indicate that this pressure level can be easily generated at 400-800 kHz using a readily available CMUT. Furthermore, more than 50-dB suppression of the fundamental harmonic signal is obtained in free field and transcranial hydrophone measurements by processing receive signals in response to phase-modulated transmit waveforms. In vitro validation of PM is also conducted using Definity MB flowing through a tube phantom. MB-filled tube phantoms show adequate nonlinear signal isolation and SNR for MB harmonic detection. Together our findings indicate that PM can effectively mitigate CMUT harmonic generation, thereby creating new opportunities for wideband transmission and receive operation for BBB opening in clinical and preclinical applications.