Georg Schmitz

Tissue-characterization of the prostate using radio frequency ultrasonic signals

In this paper, we will present a complete method and system for the detection of prostatic carcinoma, providing color-coded images of the estimated probability of malignancy by processing radio-frequency ultrasonic echo signals. For this, a hardware setup based on a conventional diagnostic sonograph was realized. The image-processing software works on ultrasound images automatically segmented into regions of about 3/spl times/3.5 mm. System-dependent effects, as well as tissue attenuation, were measured and compensated for. Tissue-characterisation parameters, which have been used successfully by other authors, were calculated for each segment. To demonstrate the methods of selection of relevant parameters and comparison of different classifiers, a first clinical study using data of 33 patients with local prostatic carcinoma was performed. For these patients, location and extent of the carcinoma were known from histological findings after radical prostatectomy. Classifiers investigated during the study were: the linear and quadratic Bayes classifier, a nearest neighbor classifier, and several classifiers based on Kohonen-maps. The best classifier was used to calculate color-coded result images. Applying a threshold of 50% to the estimated probability of malignancy, produced the encouraging results of 82 and 88% for sensitivity and specificity, respectively.

Bubble dynamics involved in ultrasonic imaging.

In clinical ultrasound, blood cells cannot be differentiated from surrounding tissue, due to the low acoustic impedance difference between blood cells and their surroundings. Resonant gas bubbles introduced in the bloodstream are ideal markers, if rapid dissolution can be prevented. Ultrasound contrast agents consist of microscopically small bubbles encapsulated by an elastic shell. These microbubbles oscillate upon ultrasound insonification. Microbubbles with thin lipid shells have demonstrated highly nonlinear behavior. To enhance diagnostic ultrasound imaging techniques and to explore therapeutic applications, these medical microbubbles have been modeled. Several detection techniques have been proposed to improve the detectability of the microbubbles. A new generation of contrast agents, with special targeting ligands attached to the shells, may assist the imaging of nonphysical properties of target tissue. Owing to microbubble-based contrast agents, ultrasound is becoming an even more important technique in clinical diagnostics.

Bursting Bubbles and Bilayers

This paper discusses various interactions between ultrasound, phospholipid monolayer-coated gas bubbles, phospholipid bilayer vesicles, and cells. The paper begins with a review of microbubble physics models, developed to describe microbubble dynamic behavior in the presence of ultrasound, and follows this with a discussion of how such models can be used to predict inertial cavitation profiles. Predicted sensitivities of inertial cavitation to changes in the values of membrane properties, including surface tension, surface dilatational viscosity, and area expansion modulus, indicate that area expansion modulus exerts the greatest relative influence on inertial cavitation. Accordingly, the theoretical dependence of area expansion modulus on chemical composition - in particular, poly (ethylene glyclol) (PEG) - is reviewed, and predictions of inertial cavitation for different PEG molecular weights and compositions are compared with experiment. Noteworthy is the predicted dependence, or lack thereof, of inertial cavitation on PEG molecular weight and mole fraction. Specifically, inertial cavitation is predicted to be independent of PEG molecular weight and mole fraction in the so-called mushroom regime. In the “brush” regime, however, inertial cavitation is predicted to increase with PEG mole fraction but to decrease (to the inverse 3/5 power) with PEG molecular weight. While excellent agreement between experiment and theory can be achieved, it is shown that the calculated inertial cavitation profiles depend strongly on the criterion used to predict inertial cavitation. This is followed by a discussion of nesting microbubbles inside the aqueous core of microcapsules and how this significantly increases the inertial cavitation threshold. Nesting thus offers a means for avoiding unwanted inertial cavitation and cell death during imaging and other applications such as sonoporation. A review of putative sonoporation mechanisms is then presented, including those involving microbubbles to deliver cargo into a cell, and those - not necessarily involving microubbles - to release cargo from a phospholipid vesicle (or reverse sonoporation). It is shown that the rate of (reverse) sonoporation from liposomes correlates with phospholipid bilayer phase behavior, liquid-disordered phases giving appreciably faster release than liquid-ordered phases. Moreover, liquid-disordered phases exhibit evidence of two release mechanisms, which are described well mathematically by enhanced diffusion (possibly via dilation of membrane phospholipids) and irreversible membrane disruption, whereas liquid-ordered phases are described by a single mechanism, which has yet to be positively identified. The ability to tune release kinetics with bilayer composition makes reverse sonoporation of phospholipid vesicles a promising methodology for controlled drug delivery. Moreover, nesting of microbubbles inside vesicles constitutes a truly “theranostic” vehicle, one that can be used for both long-lasting, safe imaging and for controlled drug delivery.

Targeted Ultrasound Imaging of Cancer: An Emerging Technology on its Way to Clinics

Ultrasound is one of the workhorses in clinical cancer diagnosis. In particular, it is routinely used to characterize lesions in liver, urogenital tract, head and neck and soft tissues. During the last years image quality steadily improved, which, among others, can be attributed to the development of harmonic image analysis. Microbubbles were introduced as intravascular contrast agents and can be detected with superb sensitivity and specificity using contrast specific imaging modes. By aid of these unspecific contrast agents tissues can be characterised regarding their vascularity. Antibodies, peptides and other targeting moieties were bound to microbubbles to target sites of angiogenesis and inflammation intending to get more disease-specific information. Indeed, many preclinical studies proved the high potential of targeted ultrasound imaging to better characterize tumors and to more sensitively monitor therapy response. Recently, first targeted microbubbles had been developed that meet the pharmacological demands of a clinical contrast agent. This review articles gives an overview on the history and current status of targeted ultrasound imaging of cancer. Different imaging concepts and contrast agent designs are introduced ranging from the use of experimental nanodroplets to agents undergoing clinical evaluation. Although it is clear that targeted ultrasound imaging works reliably, its broad acceptance is hindered by the user dependency of ultrasound imaging in general. Automated 3D-scanning techniques-like being used for breast diagnosis - and novel 3D transducers will help to make this fascinating method clinical reality.

Multispectral photoacoustic coded excitation imaging using unipolar orthogonal Golay codes.

We present a method to speed up the acquisition of multispectral photoacoustic data sets by using unipolar orthogonal Golay codes as excitation sequences for the irradiation system. Multispectral photoacoustic coded excitation (MS-PACE) allows acquiring photoacoustic data sets for two irradiation wavelengths simultaneously and separating them afterwards, thus improving the SNR or speeding up the measurement. We derive an analytical estimation of the SNR improvement using MS-PACE compared to time equivalent averaging. We demonstrate the feasibility of the method by successfully imaging a phantom composed of two dyes using unipolar orthogonal Golay codes as excitation sequence for two high power laser diodes operating at two different wavelengths. The experimental results show very good agreement with the theoretical predictions.

Fast pulse-echo ultrasound imaging employing compressive sensing

In fast pulse-echo diagnostic ultrasound imaging the acquisition time for a single image is crucial. This time depends significantly on the number of sequentially emitted sound waves. For fewer wave emissions the inverse scattering problem is increasingly ill-posed. In this contribution we establish and investigate a solution based on compressive sensing (CS). This approach accounts for the lack of measurement data by assuming sparsity of the material parameters in an arbitrary basis. Using measurements obtained from a wire and a multi-tissue phantom, we evaluate the performance of our CS solution in comparison to synthetic aperture focussing, delay-and-sum (DAS) beamforming and filtered backpropagation (FBP). Emitting only a single plane wave, the CS approach yields the best results for the sparse wire phantom in terms of sidelobe reduction and lateral -6 dB-widths. For the non-sparse multi-tissue phantom, we observe equivalent results for CS, DAS, and FBP when a single plane wave is emitted and a discrete cosine basis is employed as sparsifying transform.

Tissue characterization of the prostate using Kohonen-maps

Although transrectal ultrasound is one of the most important tools in the diagnosis and early detection of prostatic cancer, the sensitivity and specificity of the standard sonographic methods are still insufficient. We describe a method which provides the clinician with additional information in the form of color-coded tissue characterization images based on the learning vector quantization (LVQ) algorithm proposed by Kohonen

Experimental evaluation of photoacoustic coded excitation using unipolar golay codes

Q-switched Nd:YAG lasers are commonly used as light sources for photoacoustic imaging. However, laser diodes are attractive as an alternative to Nd:YAG lasers because they are less expensive and more compact. Although laser diodes deliver about three orders of magnitude less light pulse energy than Nd:YAG lasers (tens of microjoules compared with tens of millijoules), their pulse repetition frequency (PRF) is four to five orders of magnitude higher (up to 1 MHz compared with tens of hertz); this enables the use of averaging to improve SNR without compromising the image acquisition rate. In photoacoustic imaging, the PRF is limited by the maximum acoustic time-of-flight. This limit can be overcome by using coded excitation schemes in which the coding eliminates ambiguities between echoes induced by subsequent pulses. To evaluate the benefits of photoacoustic coded excitation (PACE), the performance of unipolar Golay codes is investigated analytically and validated experimentally. PACE imaging of a copper slab using laser diodes at a PRF of 1 MHz and a modified clinical ultrasound scanner is successfully demonstrated. Considering laser safety regulations and taking into account a comparison between a laser diode system and Nd:YAG systems with respect to SNR, we conclude that PACE is feasible for small animal imaging.

Advanced characterization and refinement of poly N-butyl cyanoacrylate microbubbles for ultrasound imaging.

We aimed to develop and characterize poly n-butylcyanoacrylate (PBCA) microbubbles (MBs) with a narrow size distribution. MBs were synthesized by established emulsion polymerization techniques, size-isolated by centrifugation and functionalized for molecular imaging by coating their surface with streptavidin. The physical and acoustic properties of the parent solution, different-size isolated populations and functionalized MBs were measured and compared. As expected from negative zeta potentials at pH 7, cryo scanning electron microscopy showed no aggregates. In phantoms MBs were destructible at high mechanical indices and showed a frequency-dependent attenuation and backscattering. The MBs were stable in solution for more than 14 weeks and could be lyophilized without major damage. However, for injection, small needle diameters and high injection rates are shown to be critical because both lead to MB destruction. In summary, when being handled correctly, size-isolated PBCA MBs are promising candidates for preclinical functional and molecular ultrasound imaging.

Compressed Sensing for Fast Image Acquisition in Pulse-Echo Ultrasound

We propose a concept for fast image acquisition in diagnostic ultrasound imaging using compressed sensing (CS). Our concept is based on the formulation of an inverse scattering problem (ISP) to recover deviations in compressibility in a specified region from measurements of the scattered sound. For its derivation, we utilize the Born approximation and assume the emission of a single broadband plane sound wave. We employ CS to regularize this ill-posed ISP, assuming the existence of a sparse representation of the deviations in compressibility in a suitable basis or tight frame. We validate our concept experimentally and compare the recovered images to those generated by synthetic aperture (SA; 128 wave emissions), filtered backpropagation (FBP; single plane wave emission), and delay-and-sum (DAS; single plane wave emission) algorithms. For a sparse wire phantom, our concept outperformed SA, FBP and DAS in terms of sidelobe reduction and lateral -6 dB-widths. Axial -6 dB-widths were comparable. Using wave atoms or curvelets for sparse representation, our concept recovered a commercial multi-tissue phantom with fewer image artifacts and smaller lateral -6 dB-widths than FBP and DAS. Moreover, the achieved contrast was comparable to SA.