Quantitative viscoelastic parameters measured by harmonic motion imaging.

Quantifying the mechanical properties of soft tissues remains a challenging objective in the field of elasticity imaging. In this work, we propose an ultrasound-based method for quantitatively estimating viscoelastic properties, using the amplitude-modulated harmonic motion imaging (HMI) technique. In HMI, an oscillating acoustic radiation force is generated inside the medium by using focused ultrasound and the resulting displacements are measured using an imaging transducer. The proposed approach is a two-step method that uses both the properties of the propagating shear wave and the phase shift between the applied stress and the measured strain in order to infer to the shear storage (G') and shear loss modulus (G''), which refer to the underlying tissue elasticity and viscosity, respectively. The proposed method was first evaluated on numerical phantoms generated by finite-element simulations, where a very good agreement was found between the input and the measured values of G' and G''. Experiments were then performed on three soft tissue-mimicking gel phantoms. HMI measurements were compared to rotational rheometry (dynamic mechanical analysis), and very good agreement was found at the only overlapping frequency (10 Hz) in the estimate of the shear storage modulus G' (14% relative error, averaged p-value of 0.34), whereas poorer agreement was found in G'' (55% relative error, averaged p-value of 0.0007), most likely due to the significantly lower values of G'' of the gel phantoms, posing thus a greater challenge in the sensitivity of the method. Nevertheless, this work proposes an original model-independent ultrasound-based elasticity imaging method that allows for direct, quantitative estimation of tissue viscoelastic properties, together with a validation against mechanical testing.

A mechanical model to compute elastic modulus of tissues for harmonic motion imaging.

Numerous experimental and computational methods have been developed to estimate tissue elasticity. The existing testing techniques are generally classified into in vitro, invasive in vivo and non-invasive in vivo. For each experimental method, a computational scheme is accordingly proposed to calculate mechanical properties of soft biological tissues. Harmonic motion imaging (HMI) is a new technique that performs radio frequency (RF) signal tracking to estimate the localized oscillatory motion resulting from a radiation force produced by focused ultrasound. A mechanical model and computational scheme based on the superposition principle are developed in this paper to estimate the Young's modulus of a tissue mimicking phantom and bovine liver in vitro tissue from the harmonic displacement measured by HMI. The simulation results are verified by two groups of measurement data, and good agreement is shown in each comparison. Furthermore, an inverse function is observed to correlate the elastic modulus of uniform phantoms with amplitude of displacement measured in HMI. The computational scheme is also implemented to estimate 3D elastic modulus of bovine liver in vitro.

Deep Bleeder Acoustic Coagulation (DBAC)-part II: in vivo testing of a research prototype system.

BACKGROUND: Deep Bleeder Acoustic Coagulation (DBAC) is an ultrasound image-guided high-intensity focused ultrasound (HIFU) method proposed to automatically detect and localize (D&L) and treat deep, bleeding, combat wounds in the limbs of soldiers. A prototype DBAC system consisting of an applicator and control unit was developed for testing on animals. To enhance control, and thus safety, of the ultimate human DBAC autonomous product system, a thermal coagulation strategy that minimized cavitation, boiling, and non-linear behaviors was used. MATERIAL AND METHODS: The in vivo DBAC applicator design had four therapy tiles (Tx) and two 3D (volume) imaging probes (Ix) and was configured to be compatible with a porcine limb bleeder model developed in this research. The DBAC applicator was evaluated under quantitative test conditions (e.g., bleeder depths, flow rates, treatment time limits, and dose exposure time limits) in an in vivo study (final exam) comprising 12 bleeder treatments in three swine. To quantify blood flow rates, the "bleeder" targets were intact arterial branches, i.e., the superficial femoral artery (SFA) and a deep femoral artery (DFA). D&L identified, characterized, and targeted bleeders. The therapy sequence selected Tx arrays and determined the acoustic power and Tx beam steering, focus, and scan patterns. The user interface commands consisted of two buttons: "Start D&L" and "Start Therapy." Targeting accuracy was assessed by necropsy and histologic exams and efficacy (vessel coagulative occlusion) by angiography and histology. RESULTS: The D&L process (Part I article, J Ther Ultrasound, 2015 (this issue)) executed fully in all cases in under 5 min and targeting evaluation showed 11 of 12 thermal lesions centered on the correct vessel subsection, with minimal damage to adjacent structures. The automated therapy sequence also executed properly, with select manual steps. Because the dose exposure time limit (t dose ≤ 30 s) was associated with nonefficacious treatment, 60-s dosing and dual-dosing was also pursued. Thrombogenic evidence (blood clotting) and collagen denaturation (vessel shrinkage) were found in necropsy and histologically in all targeted SFAs. Acute SFA reductions in blood flow (20-30 %) were achieved in one subject, and one partial and one complete vessel occlusion were confirmed angiographically. The complete occlusion case was achieved with a dual dose (90 s total exposure) with focal intensity ≈500 W/cm(2) (spatial average, temporal average). CONCLUSIONS: While not meeting all in vivo objectives, the overall performance of the DBAC applicator was positive. In particular, D&L automation workflow was verified during each of the tests, with processing times well under specified (10 min) limits, and all bleeder branches were detected and localized. Further, gross necropsy and tissue examination confirmed that the HIFU thermal lesions were coincident with the target vessel locations in over 90 % of the multi-array dosing treatments. The SFA/DFA bleeder models selected, and the protocols used, were the most suitable practical model options for the given DBAC anatomical and bleeder requirements. The animal models were imperfect in some challenging aspects, including requiring tissue-mimicking material (TMM) standoffs to achieve deep target depths, thereby introducing device-tissue motion, with resultant imaging artifacts. The model "bleeders" involved intact vessels, which are subject to less efficient heating and coagulation cascade behaviors than true puncture injuries.

Deep bleeder acoustic coagulation (DBAC)-Part I: development and in vitro testing of a research prototype cuff system.

BACKGROUND: Bleeding from limb injuries is a leading cause of death on the battlefield, with deep wounds being least accessible. High-intensity focused ultrasound (HIFU) has been shown capable of coagulation of bleeding (cautery). This paper describes the development and refereed in vitro evaluation of an ultrasound (US) research prototype deep bleeder acoustic coagulation (DBAC) cuff system for evaluating the potential of DBAC in the battlefield. The device had to meet quantitative performance metrics on automated operation, therapeutic heating, bleeder detection, targeting accuracy, operational time limits, and cuff weight over a range of limb sizes and bleeder depths. These metrics drove innovative approaches in image segmentation, bleeder detection, therapy transducers, beam targeting, and dose monitoring. A companion (Part II) paper discusses the in vivo performance testing of an animal-specific DBAC system. MATERIALS AND METHODS: The cuff system employed 3D US imaging probes ("Ix") for detection and localization (D&L) and targeting, with the bleeders being identified by automated spectral Doppler analysis of flow waveforms. Unique high-element-count therapeutic arrays ("Tx") were developed, with the final cuff prototype having 21 Tx's and 6 Ix's. Spatial registration of Ix's and Tx's was done with a combination of image-registration, acoustic time-of-flight measurement, and tracking of the cuff shape via a fiber optic sensor. Acoustic radiation force impulse (ARFI) imaging or thermal strain imaging (TSI) at low-power doses were used to track the HIFU foci in closed-loop targeting. Recurrent neural network (RNN) acoustic thermometry guided closed-loop dosing. The cuff was tested on three phantom "limb" sizes: diameters = 25, 15, and 7.5 cm, with bleeder depths from 3.75 to 12.5 cm. "Integrated Phantoms" (IntP) were used for assessing D&L, closed-loop targeting, and closed-loop dosing. IntPs had surrogate arteries and bleeders, with blood-mimicking fluids moved by a pulsatile pump, and thermocouples (TCs) on the bleeders. Acoustic dosing was developed and tested using "HIFU Phantoms" having precisely located TCs, with end-of-dose target ∆T = 33-58 °C, and skin temperature ∆T ≤ 20 °C, being required. RESULTS: Most DBAC cuff performance requirements were met, including cuff weight, power delivery, targeting accuracy, skin temperature limit, and autonomous operation. The automated D&L completed in 9 of 15 tests (65 %), detecting the smallest (0.6 mm) bleeders, but it had difficulty with the lowest flow (3 cm/sec) bleeders, and in localizing bleeders in the smallest (7.5 cm) phantoms. D&L did not complete within the 9-min limit (results ranged 10-21 min). Closed-loop targeting converged in 20 of 31 tests (71 %), and closed-loop dosing power shut-off at preset ∆Ts was operational. SUMMARY AND CONCLUSION: The main performance objectives of the prototype DBAC cuff were met, however the designs required a number of challenging new technology developments. The novel Tx arrays exhibited high power with significant beam steering and focusing flexibility, while their integrated electronics enabled the required compact, lightweight configurability and simplified driving controls and cable/connector architecture. The compounded 3D imaging, combined with sophisticated software algorithms, enabled automated D&L and initial targeting and closed-loop targeting feedback via TSI. The development of RNN acoustic thermometry made possible feedback-controlled dosing. The lightweight architecture required significant design and fabrication effort to meet mechanical functionalities. Although not all target specifications were met, future engineering solutions addressing these performance deficiencies are proposed. Lastly, the program required very complex limb test phantoms and, while very challenging to develop, they performed well.

Harmonic Motion Imaging (HMI) for Tumor Imaging and Treatment Monitoring.

Palpation is an established screening procedure for the detection of several superficial cancers including breast, thyroid, prostate, and liver tumors through both self and clinical examinations. This is because solid masses typically have distinct stiffnesses compared to the surrounding normal tissue. In this paper, the application of Harmonic Motion Imaging (HMI) for tumor detection based on its stiffness as well as its relevance in thermal treatment is reviewed. HMI uses a focused ultrasound (FUS) beam to generate an oscillatory acoustic radiation force for an internal, non-contact palpation to internally estimate relative tissue hardness. HMI studies have dealt with the measurement of the tissue dynamic motion in response to an oscillatory acoustic force at the same frequency, and have been shown feasible in simulations, phantoms, ex vivo human and bovine tissues as well as animals in vivo. Using an FUS beam, HMI can also be used in an ideal integration setting with thermal ablation using high-intensity focused ultrasound (HIFU), which also leads to an alteration in the tumor stiffness. In this paper, a short review of HMI is provided that encompasses the findings in all the aforementioned areas. The findings presented herein demonstrate that the HMI displacement can accurately depict the underlying tissue stiffness, and the HMI image of the relative stiffness could accurately detect and characterize the tumor or thermal lesion based on its distinct properties. HMI may thus constitute a non-ionizing, cost-efficient and reliable complementary method for noninvasive tumor detection, localization, diagnosis and treatment monitoring.

Performance assessment of HIFU lesion detection by harmonic motion imaging for focused ultrasound (HMIFU): a 3-D finite-element-based framework with experimental validation.

Harmonic motion imaging for focused ultrasound (HMIFU) is a novel high-intensity focused ultrasound (HIFU) therapy monitoring method with feasibilities demonstrated in vitro, ex vivo and in vivo. Its principle is based on amplitude-modulated (AM) - harmonic motion imaging (HMI), an oscillatory radiation force used for imaging the tissue mechanical response during thermal ablation. In this study, a theoretical framework of HMIFU is presented, comprising a customized nonlinear wave propagation model, a finite-element (FE) analysis module and an image-formation model. The objective of this study is to develop such a framework to (1) assess the fundamental performance of HMIFU in detecting HIFU lesions based on the change in tissue apparent elasticity, i.e., the increasing Young's modulus, and the HIFU lesion size with respect to the HIFU exposure time and (2) validate the simulation findings ex vivo. The same HMI and HMIFU parameters as in the experimental studies were used, i.e., 4.5-MHz HIFU frequency and 25 Hz AM frequency. For a lesion-to-background Young's modulus ratio of 3, 6 and 9, the FE and estimated HMI displacement ratios were equal to 1.83, 3.69 and 5.39 and 1.65, 3.19 and 4.59, respectively. In experiments, the HMI displacement followed a similar increasing trend of 1.19, 1.28 and 1.78 at 10-s, 20-s and 30-s HIFU exposure, respectively. In addition, moderate agreement in lesion size growth was found in both simulations (16.2, 73.1 and 334.7 mm(2)) and experiments (26.2, 94.2 and 206.2 mm(2)). Therefore, the feasibility of HMIFU for HIFU lesion detection based on the underlying tissue elasticity changes was verified through the developed theoretical framework, i.e., validation of the fundamental performance of the HMIFU system for lesion detection, localization and quantification, was demonstrated both theoretically and ex vivo.

In vivo feasibility of real-time monitoring of focused ultrasound surgery (FUS) using harmonic motion imaging (HMI).

In this study, the Harmonic Motion Imaging for Focused Ultrasound (HMIFU) technique is applied to monitor changes in mechanical properties of tissues during thermal therapy in a transgenic breast cancer mouse model in vivo. An HMIFU system, composed of a 4.5-MHz focused ultrasound (FUS) and a 3.3-MHz phased-array imaging transducer, was mechanically moved to image and ablate the entire tumor. The FUS transducer was driven by an amplitude-modulated (AM) signal at 15 Hz. The acoustic intensity ( I(spta)) was equal to 1050 W/cm(2) at the focus. A digital low-pass filter was used to filter out the spectrum of the FUS beam and its harmonics prior to displacement estimation. The resulting axial displacement was estimated using 1-D cross-correlation on the acquired RF signals. Results from two mice with eight lesions formed in each mouse (16 lesions total) showed that the average peak-to-peak displacement amplitude before and after lesion formation was respectively equal to 17.34 +/- 1.34 microm and 10.98 +/- 1.82 microm ( p << 0.001). Cell death was also confirmed by hematoxylin and eosin histology. HMI displacement can be used to monitor the relative tissue stiffness changes in real time during heating so that the treatment procedure can be performed in a time-efficient manner. The HMIFU system may, therefore, constitute a cost-efficient and reliable alternative for real-time monitoring of thermal ablation.

Simulation study of amplitude-modulated (AM) harmonic motion imaging (HMI) for stiffness contrast quantification with experimental validation.

The objective of this study is to show that Harmonic Motion Imaging (HMI) can be used as a reliable tumor-mapping technique based on the tumor's distinct stiffness at the early onset of disease. HMI is a radiation-force-based imaging method that generates a localized vibration deep inside the tissue to estimate the relative tissue stiffness based on the resulting displacement amplitude. In this paper, a finite-element model (FEM) study is presented, followed by an experimental validation in tissue-mimicking polyacrylamide gels and excised human breast tumors ex vivo. This study compares the resulting tissue motion in simulations and experiments at four different gel stiffnesses and three distinct spherical inclusion diameters. The elastic moduli of the gels were separately measured using mechanical testing. Identical transducer parameters were used in both the FEM and experimental studies, i.e., a 4.5-MHz single-element focused ultrasound (FUS) and a 7.5-MHz diagnostic (pulse-echo) transducer. In the simulation, an acoustic pressure field was used as the input stimulus to generate a localized vibration inside the target. Radiofrequency (rf) signals were then simulated using a 2D convolution model. A one-dimensional cross-correlation technique was performed on the simulated and experimental rf signals to estimate the axial displacement resulting from the harmonic radiation force. In order to measure the reliability of the displacement profiles in estimating the tissue stiffness distribution, the contrast-transfer efficiency (CTE) was calculated. For tumor mapping ex vivo, a harmonic radiation force was applied using a 2D raster-scan technique. The 2D HMI images of the breast tumor ex vivo could detect a malignant tumor (20 x 10 mm2) surrounded by glandular and fat tissues. The FEM and experimental results from both gels and breast tumors ex vivo demonstrated that HMI was capable of detecting and mapping the tumor or stiff inclusion with various diameters or stiffnesses. HMI may thus constitute a promising technique in tumor detection (>3 mm in diameter) and mapping based on its distinct stiffness.

An all-ultrasound-based system for real-time monitoring and sonication of temperature change and ablation.

Previously, we introduced a new harmonic motion imaging (HMI) technique for simultaneous monitoring and generation of ultrasound therapy treatment using a single element focused-ultrasound and one pulse-echo transducer. The new HMI technique uses an amplitude-modulated beam (instead of using two beams) that has a stable focal zone for the applied harmonic radiation force. The harmonic radiation force was generated by a 4.68 MHz focused transducer and a 7.5 MHz pulse-echo transducer was used to acquire RF echoes. The RF echoes were recorded and used to estimate tissue displacements during sonication. The new HMI technique has been shown to provide tissue displacement information during ultrasound therapy. In this paper, a study on the temperature dependence of the new HMI method is presented. The sonication time used applied was approximately equal to 80 seconds at maximum acoustic intensity of 658 W/cm2 at the focus. The experiments were performed on bovine tissues in vitro. The results show that the temperature elevation at the focal zone during sonication rises rapidly until it reaches a temperature higher than 50 degrees C, which produces tissue damage. The new HMI technique provides temperature-related tissue displacement changes using the same transducer, which makes it simple for monitoring temperature rise and lesions formation during high intensity focused ultrasound (HIFU) treatment.

Single-element focused ultrasound transducer method for harmonic motion imaging.

The harmonic motion imaging (HMI) technique for simultaneous monitoring and generation of ultrasound therapy using two separate focused ultrasound transducer elements was previously demonstrated. In this study, a new HMI technique is described that images tissue displacement induced by a harmonic radiation force using a single focused-ultrasound element. A wave propagation simulation model first indicated that, unlike in the two-beam configuration, the amplitude-modulated beam produced a stable focal zone for the applied harmonic radiation force. The AM beam thus offered the unique advantage of sustaining the application of the spatially-invariant radiation force. Experiments were performed on gelatin phantoms and ex vivo tissues. The radiation force was generated by a 4.68 MHz focused ultrasound (FUS) transducer using a 50 Hz amplitude-modulated wave. A 7.5 MHz pulse-echo transducer was used to acquire rf echoes during the application of the harmonic radiation force. Consecutive rf echoes were acquired with a pulse repetition frequency (PRF) of 6.5 kHz and 1D cross-correlation was performed to estimate the resulting axial tissue displacement. The HMI technique was shown capable of estimating stiffness-dependent displacement amplitudes. Finally, taking advantage of the real-time capability of the HMI technique, temperature-dependent measurements enabled monitoring ofHIFU sonication in ex vivo tissues. The new HMI method may thus enable a highly-localized force and stiffness-dependent measurements as well as real-time and low-cost HIFU monitoring.