Resonance-Based Frequency-Selective Amplification for Increased Photoacoustic Imaging Sensitivity

Photoacoustic (PA) imaging has attracted much attention as a new biomedical imaging modality due to its ultrasonic spatial resolution, optical contrast resolution, and deeper imaging depth than other optical imaging modalities. Exogenous PA contrast agents have been developed, with high optical absorbance at a desired wavelength, to improve their imaging sensitivity over background signal produced from endogenous nontargeted absorbers. However, the current approaches to PA imaging are based on a nonoptimal detection of PA signal, due to the fact that the PA signal contains a broad range of frequency components, whereas an ultrasound transducer is only capable of receiving signals within a certain frequency range. As a result, much of the signal generated by PA contrast agent is lost when received by an ultrasound transducer. In this study, we propose a new concept for PA contrast enhancement. This method uses chromophore-embedded microbubbles as selective resonance frequency amplifiers; only the PA signal energy within a desired spectral bandwidth can be selectively increased by adjusting the microbubble size. Therefore, the efficiency of the signal reception by an ultrasound transducer can be improved when the operating frequency of the transducer is similar to the amplified spectral bandwidth, thus allowing for more sensitive PA imaging. This new concept was validated using a porphyrin-phospholipid microbubble (p-MB) in vitro and in vivo experiments, which showed that the p-MBs increased the PA signals up to 40.94 times, compared with the PA signals from the freely dispersed porphyrin-embedded liposomes (i.e., porphysomes).