Patrick Sutcliffe

A sensitive TLRH targeted imaging technique for ultrasonic molecular imaging

The primary goals of ultrasound molecular imaging are the detection and imaging of ultrasound contrast agents (microbubbles), which are bound to specific vascular surface receptors. Imaging methods that can sensitively and selectively detect and distinguish bound microbubbles from freely circulating microbubbles (free microbubbles) and surrounding tissue are critically important for the practical application of ultrasound contrast molecular imaging. Microbubbles excited by low-frequency acoustic pulses emit wide-band echoes with a bandwidth extending beyond 20 MHz; we refer to this technique as transmission at a low frequency and reception at a high frequency (TLRH). Using this wideband, transient echo, we have developed and implemented a targeted imaging technique incorporating a multifrequency colinear array and the Siemens Antares imaging system. The multifrequency colinear array integrates a center 5.4-MHz array, used to receive echoes and produce radiation force, and 2 outer 1.5-MHz arrays used to transmit low-frequency incident pulses. The targeted imaging technique makes use of an acoustic radiation force subsequence to enhance accumulation and a TLRH imaging subsequence to detect bound microbubbles. The radiofrequency (RF) data obtained from the TLRH imaging subsequence are processed to separate echo signatures between tissue, free microbubbles, and bound microbubbles. By imaging biotin-coated microbubbles targeted to avidin-coated cellulose tubes, we demonstrate that the proposed method has a high contrast-to-tissue ratio (up to 34 dB) and a high sensitivity to bound microbubbles (with the ratio of echoes from bound microbubbles versus free microbubbles extending up to 23 dB). The effects of the imaging pulse acoustic pressure, the radiation force subsequence, and the use of various slow-time filters on the targeted imaging quality are studied. The TLRH targeted imaging method is demonstrated in this study to provide sensitive and selective detection of bound microbubbles for ultrasound molecularly targeted imaging.

Spatial and Temporal-Controlled Tissue Heating on a Modified Clinical Ultrasound Scanner for Generating Mild Hyperthermia in Tumors

A new system is presented for generating controlled tissue heating with a clinical ultrasound scanner, and initial in vitro and in vivo results are presented that demonstrate both transient and sustained heating in the mild-hyperthermia range of 37°C-42°C. The system consists of a Siemens Antares ultrasound scanner, a custom dual-frequency three-row transducer array and an external temperature feedback control system. The transducer has two outer rows that operate at 1.5 MHz for tissue heating and a center row that operates at 5 MHz for B-mode imaging to guide the therapy. We compare the field maps obtained using a hydrophone against calculations of the ultrasound beam based on monochromatic and linear assumptions. Using the finite-difference time-domain (FDTD) method, we compare predicted time-dependent thermal profiles to measured profiles for soy tofu as a tissue-mimicking phantom. In vitro results show differential heating of 6°C for chicken breast and tofu. In vivo tests of the system were performed on three mice bearing Met-1 tumors, which is a model of aggressive, metastatic, and highly vascular breast cancer. In superficially implanted tumors, we demonstrate controlled heating to 42°C. We show that the system is able to maintain the temperature to within 0.1°C of the desired temperature both in vitro and in vivo.

Noninvasive thermometry assisted by a dual-function ultrasound transducer for mild hyperthermia

Mild hyperthermia is increasingly important for the activation of temperature-sensitive drug delivery vehicles. Noninvasive ultrasound thermometry based on a 2-D speckle tracking algorithm was examined in this study. Here, a commercial ultrasound scanner, a customized co-linear array transducer, and a controlling PC system were used to generate mild hyperthermia. Because the co-linear array transducer is capable of both therapy and imaging at widely separated frequencies, RF image frames were acquired during therapeutic insonation and then exported for off-line analysis. For in vivo studies in a mouse model, before temperature estimation, motion correction was applied between a reference RF frame and subsequent RF frames. Both in vitro and in vivo experiments were examined; in the in vitro and in vivo studies, the average temperature error had a standard deviation of 0.7°C and 0.8°C, respectively. The application of motion correction improved the accuracy of temperature estimation, where the error range was -1.9 to 4.5°C without correction compared with -1.1 to 1.0°C following correction. This study demonstrates the feasibility of combining therapy and monitoring using a commercial system. In the future, real-time temperature estimation will be incorporated into this system.

A sensitive ultrasonic imaging method for targeted contrast microbubble detection

We have recently developed a targeted imaging technique for selective and sensitive ultrasound molecular imaging by taking advantage of wideband transient high frequency acoustic emission from ultrasound contrast agents. The imaging modality makes use of a novel multi-frequency co-linear array (two outer 1.4MHz and one center 5.3MHz arrays) transducer integrated with the Siemens AntaresSystem. The imaging sequence includes a B-mode imaging pulse sequence in which a short pulse is transmitted with the outer low frequency arrays and received with the inner high frequency array (TLRH: transmit at low frequency and receive at high frequency), followed by a long radiation force pulse to induce immediate bubble adhesion using the center array, and a second B-mode imaging pulse sequence. The RF data obtained from the second B-mode pulse sequence are averaged and then subtracted from the first B-mode sequence. The imaging technique was tested in a targeted imaging phantom, where lipid-shelled biotin microbubbles flow within an avidin coated-cellulose. Results showed that tissue signals were suppressed up to 33 dB and a targeted bubble contrast-to-free bubble signal ratio of up to 23 dB was obtained from the composite sequence imaging.

Simulation and phantom validation of mild hyperthermia produced by a dual function ultrasound linear array

The prediction of the acoustic and temperature profiles is important for parameter optimization as a part of treatment planning for mild hyperthermia. A 3D acoustic field algorithm and a finite-difference time-domain (FDTD) method were combined in this study to calculate a 3D temperature profile in a tissue-mimicking phantom insonified by a dual function ultrasound linear array. In vitro validation was accomplished by using a fluorescent dye encapsulated in thermally-sensitive liposomes and an optical imaging system. For the single-beam insonation mode, the 39°C contour (by simulation) and dye-release area (in vitro) were 7.0 by 4.5 mm and 7.6 by 6.7 mm in the elevation and lateral directions, respectively. For the scanned-beam insonation mode, the 39°C contour and dye-release area were 12.0 by 11.4 mm and 12.2 by 11.6 mm in the elevation and lateral directions, respectively. The scanned-beam insonation mode showed a similar spatial extent of heating between simulation and in vitro experiments.

11A-3 A Novel Sensitive Targeted Imaging Technique for Ultrasonic Molecular Imaging

We have recently developed a targeted imaging technique for selective and sensitive ultrasound molecular imaging by taking advantage of wideband transient high frequency acoustic emission from ultrasound contrast agents. The imaging modality makes use of a novel multi-frequency co-linear array (two outer 1.4 MHz and one center 5.3 MHz arrays) transducer integrated with the Siemens Antares System. The imaging sequence includes a B-mode imaging pulse sequence in which a short pulse is transmitted with the outer low frequency arrays and received with the inner high frequency array (TLRH: transmit at low frequency and receive at high frequency), followed by a long radiation force pulse to induce immediate bubble adhesion using the center array, and a second B-mode imaging pulse sequence. The RF data obtained from the second B-mode pulse sequence are averaged and then subtracted from the first B-mode sequence. The imaging technique was tested in a targeted imaging phantom, where lipid-shelled biotin microbubbles flow within an avidin coated-cellulose. Results showed that tissue signals were suppressed up to 33 dB and a targeted bubble contrast-to-free bubble signal ratio of up to 23 dB was obtained from the composite sequence imaging.

Adaptive ultrasonic imaging using SONOLINE Elegra/sup TM/

Data acquisition, time delay estimation and correction for adaptive imaging are implemented on the SONOLINE Elegra/sup TM/ system using the system CPU, the Crescendo(TM) processor, and the existing front-end electronics, with no hardware modifications. With the current implementation, phase aberration correction takes about 2 seconds from activation to completion. The effects of compensating the transmit beam are studied using the waveform similarity factor and single transmit imaging. On a scattering phantom plus a 1-D aberration layer with an rms time fluctuation of 40 ns and correlation length of 5 mm, the waveform similarity factor of randomly scattered waveforms improved from 0.362 to 0.477 by iteration. Correspondingly, the -20 dB lateral resolution improved from 1.62 mm to 0.77 mm, and the image contrast improved by 8.5 dB (the speckle region is 6 dB brighter while the echo-free region is 2.5 dB darker). Experiments with a 2-D aberration layer and with a special phase aberration phantom showed less image improvements. Preliminary body scan trials with adaptive imaging showed improved image contrast and details in some cases but the results are mixed and influenced by such factors as isoplanatic patch size and complex scattering structures.

A fast ultrasound molecular imaging method and its 3D visualization in vivo

Using targeted microbubbles (MBs), ultrasound molecular imaging can be used to selectively and specifically visualize upregulated vascular receptors. In order to acquire bound MB echoes, a delay of ~7-15 minutes is commonly required for the clearance of freely circulating MBs. Here, we test whether echoes from MBs can be distinguished from the surrounding tissue, based on the transmission of pulses at low (1.5 MHz) and reception at high (5.5 MHz) frequencies (TLRH), without the requirement for destructive pulses. Pulses with a peak negative pressure of 230 kPa were transmitted (10 fps) and a 7th order IIR pulse-to-pulse filter was applied to the TLRH radiofrequency (RF) data to distinguish the signature of bound MBs from that of flowing MBs. 3D images of the accumulation of intravenously-administrated integrin-targeted MBs in a Met-1 mouse tumor model were acquired. An in vitro study demonstrated that the T2R15 contrast imaging technique has a ~2-fold resolution improvement over 2MHz contrast pulse sequencing (CPS) imaging. By applying the 7th order IIR filter to the TLRH RF data acquired at 2 minutes, echoes from flowing MBs in the surrounding tissue region were suppressed by 26±2 dB, while the signal intensity within the tumor was suppressed by 4±1 dB. The targeted images correctly represented the distribution of bound MBs. After the filter, the signal intensity resulting from cyclic RGD bearing MBs was 25±2 dB higher than that after the injection of non-targeted MBs.

Scanned-beam assisted mild tumor heating using a dual-functional ultrasound linear array

A commercial ultrasound scanner, a customized co-linear array ultrasound transducer and a real-time temperature feedback controller have been combined to generate controlled mild hyperthermia. Previous studies have shown that single beam-based image-guided local drug delivery can improve the treatment of small tumors. In this study, a scanned-beam based insonation mode was developed to achieve uniform therapy over a larger region. A color-region of interest (ROI) was used to define the scanned area, while periodic B-mode imaging was used to visualize the tumor. In this study, a thermal strain algorithm was also examined for temperature estimation and this algorithm will be applied for temperature control in the future.