Nondestructive Ultrasound Molecular Imaging With Higher Order Singular Value Decomposition

Ultrasound molecular imaging (UMI) uses targeted microbubbles (MBs) to detect disease-associated biomarkers. For UMI, distinguishing the acoustic signals produced by bound MBs from those by free MBs and tissue is critical. Currently, the main approach, known as differential targeted enhancement (DTE), is time-intensive and requires MB destruction. Here, we introduce a novel, rapid, and nondestructive UMI technique utilizing higher order singular value decomposition (HOSVD). HOSVD decomposes the signals of an acoustic contrast sequence, separating them owing to their nonlinear content and temporal coherence. The nonlinear separation enables distinction between tissue and MBs, while the temporal separation enables distinction between free and bound MBs. From the HOSVD output, we defined a bound MB indicator $\chi $ , which indicates the presence of bound MBs. In our in vitro experiments, $\chi $ was lower for free MBs and tissue ( $0.04~\pm ~0.03$ ) compared to bound MBs ( $0.31~\pm ~0.11$ without free MBs, decreasing with concentration down to $0.11~\pm ~0.07$ at $20\times 10^{{3}}$ free MBs/mL). In addition, the molecular signal determined from $\chi $ correlated well with a DTE ground truth acquisition. The method was compared to other nondestructive techniques such as low-pass filtering and normalized singular spectrum area, demonstrating an average molecular signal enhancement of 12 dB. Furthermore, when used as a binary classifier, our method achieved a detection of up to $1.81\times $ more true positives while reducing false positives by up to $1.78\times $ . These findings suggest that HOSVD could pave the way to rapid, nondestructive UMI.