Monodisperse Microbubbles for Noninvasive Pressure Estimation

项目摘要 当前用于量化流体压力的临床标准依赖于压力的侵入性放置。 导管或针。这些措施成本高昂，并非没有风险，因此减少了数据传输的频率。 收集。超声造影剂（UCA）是一种充满气体的微泡，当以一定的速度超声时， 基频（f0）充当非线性振荡器，产生范围从 次谐波（f0/2）到高次谐波。UCA的次谐波幅值呈线性关系 与静水压力，导致亚谐波辅助压力估计（SHAPE）的技术。 迄今为止，SHAPE优化主要依赖于经验证据来确定最佳声学特性。 参数并选择市售的UCA。目前，SHAPE可将噪声降低高达14 dB， 压力增加180 mmHg（0.6 dB/kPa）时的次谐波振幅。使用SHAPE进行的临床试验 在治疗过程中，门静脉压力、心脏压力和间质肿瘤压力的诊断都 显示成功。然而，在较低的流体压力下观察到SHAPE的大的变化，表明 需要提高技术的整体灵敏度。使用Rayleigh-Plesset方程的变体，我们 小组和其他人已经模拟了单个商业泡沫的形状响应，并确定了潜在的 灵敏度> 2 dB/kPa，使用优化的声学参数。因此，潜在的可能性是三倍以上， SHAPE的电流灵敏度，从而大大降低了与较低压力相关的总体误差 测量. 单分散微泡可以使用现有UCA的浮力分离或微流体分离来产生。 技术.我们假设这些代理将使我们能够更好地完善以前的建模工作，同时也 通过调整UCA以适应其应用，大大提高了SHAPE的整体灵敏度。支持这一 假设，我们最近表明，单分散UCA几乎是SHAPE灵敏度的两倍（甚至 没有完全的声学优化）。这一建议将是实现翻译长期目标的第一步。 SHAPE特异性UCA进入临床试验，以提高SHAPE作为非侵入性 压力估计技术作为该应用的一部分，我们建议测试SHAPE的体外敏感性 使用单分散UCA，使用两种制造方法，以改进和验证我们先前的SHAPE模型 与来自单分散UCA的经验证据，最后，为了确定定制的， 单分散UCA，以提高SHAPE在心脏压力和门静脉压力的体内模型中的灵敏度。 高血压在这个项目结束时，我们将开发和验证一个形状特定的UCA， 能够提高SHAPE的灵敏度。这些发现有望减少SHAPE的变异性 作为流体压力的非侵入性临床测量，实现更安全和更可用的临床护理。

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.