James F. Greenleaf

Sonoporation: Mechanical DNA Delivery by Ultrasonic Cavitation

Development of nonviral gene transfer methods would be a valuable addition to the gene-therapy armamentarium, particularly for localized targeting of specific tissue volumes. Ultrasound can produce a variety of nonthermal bioeffects via acoustic cavitation including DNA delivery. Cavitation bubbles may induce cell death or transient membrane permeabilization (sonoporation) on a single cell level, as well as microvascular hemorrhage and disruption of tissue structure. Application of sonoporation for gene delivery to cells requires control of cavitation activity. Many studies have been performed using in vitro exposure systems, for which cavitation is virtually ubiquitous. In vivo, cavitation initiation and control is more difficult, but can be enhanced by cavitation nucleation agents, such as an ultrasound contrast agent. Sonoporation and ultrasonically enhanced gene delivery has been reported for a wide range of conditions including low frequency sonication (kilohertz frequencies), lithotripter shockwaves, HIFU, and evendiagnostic ultrasound (megahertz frequencies). In vitro, a variety of cell lines has been successfully transfected, with concomitant cell killing. In vivo, initial applications have been to cancer gene therapy, for which cell killing can be a useful simultaneous treatment, and to cardiovascular disease. The use of ultrasound for nonviral gene delivery has been demonstrated for a robust array of in vitro and mammalian systems, which provides a fundamental basis and strong promise for development of new gene therapy methods for clinical medicine.

Complex-valued stiffness reconstruction for magnetic resonance elastography by algebraic inversion of the differential equation.

Noninvasive quantitation of the mechanical properties of tissue could improve early detection of pathology. Previously a method for detecting displacement from propagating shear waves using a phase‐contrast MRI technique was developed. In this work it is demonstrated how a collection of data representing the full vector displacement field could be used to potentially estimate the full complex stiffness tensor. An algebraic inversion approach useful for piece‐wise homogeneous materials is described in detail for the general isotropic case, which is then specialized to incompressible materials as a model for tissue. Results of the inversion approach are presented for simulated and experimental phantom data that show the technique can be used to obtain shear wave‐speed and attenuation in regions where there is sufficient signal‐to‐noise ratio in the displacement and its second spatial derivatives. The sensitivity to noise is higher in the attenuation estimates than the shear wave‐speed estimates. Magn Reson Med 45:299–310, 2001.

Use of gray value distribution of run lengths for texture analysis

Abstract Most of the texture measures based on run lengths use only the lengths of the runs and their distribution. We propose to use the gray value distribution of the runs to define two new features, viz., low gray level run emphasis ( LGRE ) and high gray level run emphasis ( HGRE ).

Ultrasonic nondiffracting transducer for medical imaging

The nondiffracting J/sub 0/ Bessel beam is evaluated, and its application to medical imaging is suggested. Computer simulations and experimental results for a ten-ring annular Bessel shaded transducer are described. Both continuous-wave (CW) and pulse-wave (PW) excitations are shown and compared to conventional Gaussian beams. The nondiffracting beam has about 1.27-nm radius main lobe with a 20-cm depth of field compared to the Gaussian transducer of the same size with a 1.27-mm radius main lobe at a focus of 12 cm and 2*4-cm depth of field. The side lobes of the nondiffracting beam are the same as the J/sub 0/ Bessel function. The effects of heterogeneity due to tissue on the nondiffracting beam and on the focused Gaussian beam are also reported.<<ETX>>

Experimental verification of nondiffracting X waves

The propagation of acoustic waves in isotropic/homogeneous media and electromagnetic waves in free space is governed by the isotropic/homogeneous (or free space) scalar wave equation. A zeroth-order acoustic X wave (axially symmetric) was experimentally produced with an acoustic annular array transducer. The generalized expression includes a term for the frequency response of the system and parameters for varying depth of field versus beam width of the resulting family of beams. Excellent agreement between theoretical predictions and experiment was obtained. An X wave of finite aperture driven with realizable (causal, finite energy) pulses is found to travel with a large depth of field (nondiffracting length).<<ETX>>

Ultrasound Echo Envelope Analysis Using a Homodyned K Distribution Signal Model

The statistics of ultrasound echo envelope signals can be used to characterize scattering media. The Rayleigh distribution and its generalized forms, the K and Rice distributions, have been previously used to model the echo signal. A more generalized statistical model, the homodyned K distribution, combines the K and Rice distribution features to better account for the statistics of the echo signal. We show that this model can give two parameters that are useful for media characterization: k, the ratio of coherent to diffuse signals, and, beta, which characterizes the clustering of scatters in the medium.

Pulse-echo imaging using a nondiffracting beam transducer

Conventional ultrasonic transducers generate beams that diffract as they travel. This phenomenon causes images produced in B-mode to be degraded in the far-field of the transducers. Focused transducers are used to improve image quality. Unfortunately, focused transducers have short depth of field. Although multiple pulse transmissions focused at several depths are used to increase the effective depth of field, imaging frame rate is reduced dramatically leading to blurred images of moving objects such as the heart. We present a family of transducers that produce nondiffracting beams of large depth of field. Therefore, uniformly high resolution throughout the imaging area can be obtained without sacrificing the imaging frame rate. In addition, the nondiffracting property of these beams makes the correction for beam diffraction negligible in tissue characterization. This paper reports the results of computer simulations as well as in vitro and in vivo pulse-echo imaging experiments with a nondiffracting transducer. Images are compared to those obtained by conventional focused Gaussian shaded beam transducers and a commercial ACUSON 128 B-scanner. The new transducer has much longer depth of field with higher sidelobes than conventional transducers of the same aperture. Sidelobes can be reduced using the new transducer to transmit and the dynamically focused transducer to receive.

Speckle analysis using signal to noise ratios based on fractional order moments

The SNR (signal-to-noise ratio) of the echo envelope image is a monotonically-increasing function of scatterer number density. Various SNRs, like amplitude SNR and intensity SNR, can be used to quantify the scatterer density. The problem of using a SNR based on higher order moments like the intensity SNR is that they require large sample sizes to obtain estimates with high confidence (the variance of the estimate becomes large for higher moments). In this paper, we consider SNRs based on fractional order moments (moments of order less than 1), and obtain mathematical analyses of their properties using the K distribution, which has been shown to be a good model for the density function of backscatter echo envelope signal. Statistics of SNRs based on fractional moment are derived and appear to be more robust and useful than the amplitude and intensity SNRs previously studied. The SNRs based on fractional order moments have greater dynamic range and the sample size requirements are smaller than those for integral order moment SNRs, like amplitude SNR or intensity SNR. Thus, SNRs based on fractional order moments could be used to better quantify the variations in scatterer density which can be used for tissue classification problems.

Comparison of stress field forming methods for vibro-acoustography

Vibro-acoustography is a method that produces images of the acoustic response of a material to a localized harmonic motion generated by ultrasound radiation force. The low-frequency, oscillatory radiation force (e.g., 10 kHz) is produced by amplitude modulating a single ultrasound beam, or by interfering two beams of slightly different frequencies. Proper beam forming for the stress field of the probing ultrasound is very important because it determines the resolution of the imaging system. Three beam-forming geometries are studied: amplitude modulation, confocal, and x-focal. The amplitude of radiation force on a unit point target is calculated from the ultrasound energy density averaged over a short period of time. The profiles of radiation stress amplitude oil the focal plane and on the beam axis are derived. The theory is validated by experiments using a small sphere as a point target. A laser vibrometer is used to measure the velocity of the sphere, which is proportional to the radiation stress exerted on the target as the transducer is scanned over the focal plane or along the beam axis. The measured velocity profiles match the theory. The theory and experimental technique may be useful in future transducer design for vibro-acoustography.

Evaluation of a nondiffracting transducer for tissue characterization

The authors describe a method for estimating backscatter coefficients of excised human liver samples and the RMI413A tissue equivalent phantom, using the J/sub 0/ Bessel nondiffracting transducer. A formula for the calculation of backscatter coefficients that requires only two one-dimensional integrations in addition to one-dimensional Fourier transforms is presented. This equation in combination with backscatter from a J/sub 0/ Bessel nondiffracting beam results in the ability to calculate backscatter coefficients in real time. In addition, estimations of the backscatter coefficients are more distance-independent because of the nonspreading nature of the J/sub 0/ Bessel nondiffracting beam. The present results compare well to those obtained by the conventional focused Gaussian beam transducer.<<ETX>>