Project Summary The current clinical standard for quantifying fluid pressures relies on the invasive placement of pressure catheters or needles. These measures are costly and not without risk, thereby reducing how often data is collected. Ultrasound contrast agents (UCA) are gas-filled microbubbles that, when insontated at a fundamental frequency (f0), act as nonlinear oscillators, generating signal components ranging from the subharmonic (f0/2) through higher harmonics. The subharmonic amplitude of UCA exhibits a linear relationship with hydrostatic pressure, leading to the technique of subharmonic-aided pressure estimation (SHAPE). SHAPE optimizations to date have relied primarily on empirical evidence to identify optimal acoustic parameters and select a commercially available UCA. Currently, SHAPE provides up to 14 dB reduction in the subharmonic amplitude over a pressure increase of 180 mmHg (0.6 dB/kPa). Clinical trials using SHAPE for the diagnosis of portal pressures, cardiac pressures, and interstitial tumoral pressures during therapy have all shown success. However, large variations in SHAPE have been observed at lower fluid pressures, indicating a need to improve the technique's overall sensitivity. Using a variation of the Rayleigh–Plesset equation, our group and others have modeled the SHAPE response of individual commercial bubbles and identified potential sensitivities > 2 dB/kPa using optimized acoustic parameters. Thus, the potential exists to more than triple the current sensitivity of SHAPE, thereby greatly reducing the overall errors associated with lower pressure measurements. Monodisperse microbubbles can be created using either buoyancy separation of existing UCAs or microfluidic techniques. We hypothesize these agents will allow us to better refine previous modeling efforts, while also greatly improving the overall sensitivity of SHAPE by tailoring the UCA to its application. To support this hypothesis, we recently showed that monodisperse UCA nearly doubled the sensitivity of SHAPE (even without full acoustic optimization). This proposal will be a first step towards the long-term goal of translating SHAPE-specific UCA into clinical trials for improving the overall sensitivity of SHAPE as a noninvasive pressure estimation technique. As part of this application, we propose to test the in vitro sensitivity of SHAPE using monodisperse UCA using two fabrication approaches, to refine and validate our prior models of SHAPE with empirical evidence from monodisperse UCA, and finally, to determine the ability of a customized, monodisperse UCA to improve the sensitivity of SHAPE in in vivo models of cardiac pressures and portal hypertension. At the conclusion of this project, we will have developed and validated a SHAPE-specific UCA, capable of improving the sensitivity of SHAPE. These findings are expected to reduce the variability of SHAPE as a noninvasive clinical measure of fluid pressures, enabling safer and more available clinical care.

Project Narrative Although costly and invasive, hydrostatic pressure measurements are required for the diagnosis and management of a wide variety of clinical diseases. An ultrasound contrast agent (UCA) based technique termed subharmonic aided pressure estimation (SHAPE) has shown promise in several clinical trials, but the sensitivity of the technique is currently limited due to polydisperse nature of commercial UCA. Thus, we propose to develop a monodisperse, clinically translatable, SHAPE-specific UCA to improve overall sensitivity and to reconcile theoretical modeling work with empirical data.