Time-reversal acoustics and ultrasound-assisted convection-enhanced drug delivery to the brain.

Time-reversal acoustics is an effective way of focusing ultrasound deep inside heterogeneous media such as biological tissues. Convection-enhanced delivery is a method of delivering drugs into the brain by infusing them directly into the brain interstitium. These two technologies are combined in a focusing system that uses a "smart needle" to simultaneously infuse fluid into the brain and provide the necessary feedback for focusing ultrasound using time-reversal acoustics. The effects of time-reversal acoustics-focused ultrasound on the spatial distribution of infused low- and high-molecular weight tracer molecules are examined in live, anesthetized rats. Results show that exposing the rat brain to focused ultrasound significantly increases the penetration of infused compounds into the brain. The addition of stabilized microbubbles enhances the effect of ultrasound exposure.

Segmental increases in force application during colonoscope insertion: quantitative analysis using force monitoring technology.

BACKGROUND: Colonoscopy is a frequently performed procedure that requires extensive training and a high skill level. OBJECTIVE: Quantification of forces applied to the external portion of the colonoscope insertion tube during the insertion phase of colonoscopy. DESIGN: Observational cohort study of 7 expert and 9 trainee endoscopists for analysis of colonic segment force application in 49 patients. Forces were measured by using the colonoscopy force monitor, which is a wireless, handheld device that attaches to the insertion tube of the colonoscope. SETTING: Academic gastroenterology training programs. PATIENTS: Patients undergoing routine screening or diagnostic colonoscopy with complete segment force recordings. MAIN OUTCOME MEASUREMENTS: Axial and radial force and examination time. RESULTS: Both axial and radial force increased significantly as the colonoscope was advanced from the rectum to the cecum. Analysis of variance demonstrated highly significant operator-independent differences between segments of the colon (zones) in all axial and radial forces except average torque. Expert and trainee endoscopists differed only in the magnitude of counterclockwise force, average push/pull force rate used, and examination time. LIMITATIONS: Small study, observational design, effect of prototype device on insertion tube manipulation. CONCLUSION: Axial and radial forces used to advance the colonoscope increase through the segments of the colon and are operator independent.

Acoustic Radiation Force: A Review of Four Mechanisms for Biomedical Applications.

Radiation force is a universal phenomenon in any wave motion where the wave energy produces a static or transient force on the propagation medium. The theory of acoustic radiation force (ARF) dates back to the early 19th century. In recent years, there has been an increasing interest in the biomedical applications of ARF. Following a brief history of ARF, this article describes a concise theory of ARF under four physical mechanisms of radiation force generation in tissue-like media. These mechanisms are primarily based on the dissipation of acoustic energy of propagating waves, the reflection of the incident wave, gradients of the compressional wave speeds, and the spatial variations of energy density in standing acoustic waves. Examples describing some of the practical applications of ARF under each mechanism are presented. This article concludes with a discussion on selected ideas for potential future applications of ARF in biomedicine.

Characterization of forces applied by endoscopists during colonoscopy by using a wireless colonoscopy force monitor.

BACKGROUND: To perform a colonoscopy, the endoscopist maneuvers the colonoscope through a series of loops by applying force to the insertion tube. Colonoscopy insertion techniques are operator dependent but have never been comprehensively quantified. OBJECTIVE: To determine whether the Colonoscopy Force Monitor (CFM), a device that continually measures force applied to the insertion tube, can identify different force application patterns among experienced endoscopists. DESIGN: Observational study of 6 experienced endoscopists performing routine diagnostic and therapeutic colonoscopy in 30 patients. SETTING: Outpatient ambulatory endoscopy center. PATIENTS: Adult male and female patients between 30 and 75 years of age undergoing routine colonoscopy. INTERVENTIONS: CFM monitoring of force applied to the colonoscope insertion tube during colonoscopy. MAIN OUTCOME MEASUREMENTS: Maximum and mean linear and torque force, time derivative of force, combined linear and torque vector force, and total manipulation time. RESULTS: The CFM demonstrates differences among endoscopists for maximum and average push/pull and mean torque forces, time derivatives of force, combined push/torque force vector, and total manipulation time. Endoscopists could be grouped by force application patterns. LIMITATIONS: Only experienced endoscopists using conscious sedation in the patients were studied. Sample size was 30 patients. CONCLUSIONS: This study demonstrates that CFM allows continuous force monitoring, characterization, and display of similarities and differences in endoscopic technique. CFM has the potential to facilitate training by enabling trainees to assess, compare, and quantify their techniques and progress.

Evaluation of ultrasound velocity to assess the hydration status of wrestlers.

The objective of this study was to evaluate the utility of ultrasound velocity (UV) to detect changes in the hydration status of wrestlers after undergoing acute dehydration and a 2-hour rehydration period. Forty-seven NCAA wrestlers (mean+/-SEM); age 19.1+/-0.2 years, height 1.73+/-0.1 m, body mass (BM) 79.4+/-2.4 kg were tested in euhydrated, dehydrated, and a 2-hours rehydrated conditions. Hydration status was quantified by measuring changes in plasma osmolarity (Posm), urine osmolarity (Uosm), urine specific gravity (Usg), and BM. Ultrasound velocity was measured at 1 MHz using 1.5-microsecond duration tone burst in the soleus muscle. Significant changes (p<0.001) in UV during periods of dehydration (BM change=-3.6+/-0.14%) (UV=+2.18 m.s) and rehydration (BM change=+2.8+/-0.12%) (UV=-2.89 m.s) were found. Significant main effects (p<0.001) were also found for Usg, Uosm, and Posm during dehydration. The change in Posm from the 1 to 2-hour rehydration time period significantly correlated to the change in UV during the same time period (r=0.27, p<0.001). This study demonstrates that changes in UV correspond to the changes of Posm, Usg, Uosm, and BM during acute dehydration and rehydration in collegiate wrestlers. The use of ultrasound measures may have potential application as an alternative field-based method to assess the hydration status of collegiate wrestlers although future research is warranted.

Differentiation of benign and malignant breast lesions by mechanical imaging.

Mechanical imaging yields tissue elasticity map and provides quantitative characterization of a detected pathology. The changes in the surface stress patterns as a function of applied load provide information about the elastic composition and geometry of the underlying tissue structures. The objective of this study is the clinical evaluation of breast mechanical imager for breast lesion characterization and differentiation between benign and malignant lesions. The breast mechanical imager includes a probe with pressure sensor array, an electronic unit providing data acquisition from the pressure sensors and communication with a touch-screen laptop computer. We have developed an examination procedure and algorithms to provide assessment of breast lesion features such as hardness related parameters, mobility, and shape. A statistical Bayesian classifier was constructed to distinguish between benign and malignant lesions by utilizing all the listed features as the input. Clinical results for 179 cases, collected at four different clinical sites, have demonstrated that the breast mechanical imager provides a reliable image formation of breast tissue abnormalities and calculation of lesion features. Malignant breast lesions (histologically confirmed) demonstrated increased hardness and strain hardening as well as decreased mobility and longer boundary length in comparison with benign lesions. Statistical analysis of differentiation capability for 147 benign and 32 malignant lesions revealed an average sensitivity of 91.4% and specificity of 86.8% with a standard deviation of +/-6.1%. The area under the receiver operating characteristic curve characterizing benign and malignant lesion discrimination is 86.1% with the confidence interval ranging from 80.3 to 90.9%, with a significance level of P = 0.0001 (area = 50%). The multisite clinical study demonstrated the capability of mechanical imaging for characterization and differentiation of benign and malignant breast lesions. We hypothesize that the breast mechanical imager has the potential to be used as a cost effective device for cancer diagnostics that could reduce the benign biopsy rate, serve as an adjunct to mammography and to be utilized as a screening device for breast cancer detection.

Stirring and mixing of liquids using acoustic radiation force.

The possibility of using acoustic radiation force in standing waves for stirring and mixing small volumes of liquids is theoretically analyzed. The principle of stirring considered in this paper is based on moving the microparticles suspended in a standing acoustic wave by changing the frequency so that one standing wave mode is replaced by the other, with differently positioned minima of potential energy. The period-average transient dynamics of solid microparticles and gas microbubbles is considered, and simple analytical solutions are obtained for the case of standing waves of variable amplitude. It is shown that bubbles can be moved from one equilibrium position to another two to three orders of magnitude faster than solid particles. For example, radiation force in a standing acoustic wave field may induce movement of microbubbles with a speed of the order of a few m/s at a frequency of 1 MHz and ultrasound pressure amplitude of 100 kPa, whereas the speed of rigid particles does not exceed 1 cms under the same conditions. The stirring effect can be additionally enhanced due to the fact that the bubbles that are larger and smaller than the resonant bubbles move in opposite directions. Possible applications of the analyzed stirring mechanism, such as in microarrays, are discussed.

Wideband nonlinear time reversal seismo-acoustic method for landmine detection.

Acoustic and seismic waves provide a method to localize compliant mines by vibrating the top plate and a thin soil layer above the mine. This vibration is mostly linear, but also includes a small nonlinear deviation. The main goal of this paper is to introduce a method of processing that uses phase-inversion to observe nonlinear effects in a wide frequency band. The method extracts a nonlinear part of surface velocity from two similar broadcast signals of opposite sign by summing and cancelling the linear components and leaving the nonlinear components. This phase-inversion method is combined with time reversal focusing to provide increased seismic vibration and enhance the nonlinear effect. The experiments used six loudspeakers in a wood box placed over sand in which inert landmines were buried. The nonlinear surface velocity of the sand with a mine compared to the sand without a mine was greater as compared to a linear technique.

Prostate mechanical imaging: 3-D image composition and feature calculations.

We have developed a method and a device entitled prostate mechanical imager (PMI) for the real-time imaging of prostate using a transrectal probe equipped with a pressure sensor array and position tracking sensor. PMI operation is based on measurement of the stress pattern on the rectal wall when the probe is pressed against the prostate. Temporal and spatial changes in the stress pattern provide information on the elastic structure of the gland and allow two-dimensional (2-D) and three-dimensional (3-D) reconstruction of prostate anatomy and assessment of prostate mechanical properties. The data acquired allow the calculation of prostate features such as size, shape, nodularity, consistency/hardness, and mobility. The PMI prototype has been validated in laboratory experiments on prostate phantoms and in a clinical study. The results obtained on model systems and in vivo images from patients prove that PMI has potential to become a diagnostic tool that could largely supplant DRE through its higher sensitivity, quantitative record storage, ease-of-use and inherent low cost.

Model-based imaging.

The concept of model-based imaging provides a possibility of integration of both structural and functional information obtained by imaging and nonimaging sources of diagnostically relevant information. Merging information of different origin and nature in a simulated computer patient-specific three-dimensional (3-D) model is important for multimodal imaging approaches to medical diagnostics. The work of F. L. Lizzi on life-like imaging done nearly 20 years ago was the first successful attempt of patient-specific 3-D computer modeling using conventional ultrasonography data. He demonstrated the applications of such 3-D models, which incorporated acoustic, optical and thermal properties of imaged tissue, in physiologic studies, in planning and monitoring ultrasonic hyperthermia and ablation. However, numerous obstacles hinder the wide use of the model-based imaging concept. Using the example of model-based imaging of prostate, the advantages and limitation on the applicability of the concept are discussed. Attempts of implementing the model-based imaging concept in the mechanical imaging technology--imaging with the use of measurements of stress pattern on the surface of tissue--are described. It is shown that composing a patient-specific 3-D model requires well-defined and carefully validated algorithms for translating features of the object assessed by an imaging modality into the quantitative anatomic and histopathologic parameters.

Ultrasound velocity in human muscle in vivo: perspective for edema studies.

The present study examines the association of the changes in ultrasound velocity measured at 1 MHz using 1.5 micros duration tone burst in the human soleus muscle in vivo with several pathologies including patients with chronic renal failure (CRF) and disorders of the cardiovascular system. Total 127 subjects were investigated, with approximately equal number of male and female subjects uniformly distributed by age, from 15 to 70 years old. Since molecular composition of the tissue is thought to have greater effect on the bulk ultrasound velocity, potential contribution of both water and fat, two main variable components of a muscle, were taken into account. Observed negative correlation of ultrasound velocity with the body mass index was considered a result of an elevated fat content. Based on the obtained data, presence of leg edemas results in a measurably lower ultrasound velocity in the soleus muscle. Unless patients had visibly detected leg edema, no difference between healthy individuals, patients with chronic heart failure, or CRF was found. Despite relatively high individual variations in velocity, ranging from 1530 to 1615 m/s, a statistically significant gender correlated difference between average values of the velocity was observed. No dependence of velocity on subject age was detected. An indirect confirmation of the muscle fluid homeostasis was revealed in patients with CRF undergoing hemodialysis procedure. After hemodialysis, a significantly smaller increase (0.3% in average) of ultrasound velocity in the soleus muscle was observed than otherwise could be expected if a uniform relative loss of total body fluids was assumed (1-1.3%). In general, the study findings set a premise for using ultrasound velocity as a potential quantitative parameter for edema assessment.

Ultrasonic assessment of tissue hydration status.

Tissue water content is an important diagnostic parameter that can be used for estimation of water loss in muscles such as common dehydration during high endurance exercises. It could be also applied for evaluation of the increased fluids content in the tissue caused by the variety of pathological conditions or edemas. Ultrasonic method for tissue water content monitoring is based on the premise that the speed of a bulk or compression sound wave is determined mainly by the molecular content of the tissue. Most soft tissues, including muscles that consist of about 70-80% water, exhibit shift of the ultrasound velocity associated with the change in their water content. In the present paper, we tested the feasibility of assessing changes in tissue water content by measurements of ultrasound velocity in ex vivo animal muscle tissues. An increase in the ultrasound velocity correlated with the volumetric water loss in the tissue was observed when other tissue components (proteins, fat) remained constant. Possibility to assess muscle dehydration with 1% accuracy was confirmed in model dehydration experiments, where ultrasound velocity slope of about 3 m/s per 1% of water loss was revealed at measurement error less than 2 m/s. Hence, the ultrasonic approach can provide basis for a convenient, lightweight system in sports medicine for monitoring total body hydration during long-term endurance exercise in hot conditions, as well as for edemas monitoring and other medical applications.

Use of multiple acoustic wave modes for assessment of long bones: model study.

Multiple acoustic wave mode method has been proposed as a new modality in axial bone QUS. The new method is based on measurement of ultrasound velocity at different ratio of wavelength to the bone thickness, and taking into account both bulk and guided waves. It allows assessment of changes in both the material properties related to porosity and mineralization as well as the cortical thickness influenced by resorption from inner layers, which are equally important in diagnostics of osteoporosis and other bone osteopenia. Developed method was validated in model studies using a dual-frequency (100 and 500 kHz) ultrasound device. Three types of bone phantoms for long bones were developed and tested: (1) tubular specimens from polymer materials to model combined changes of material stiffness and cortical wall thickness; (2) layered specimens to model porosity in compact bone progressing from endosteum towards periosteum; (3) animal bone specimens with both cortical and trabecular components. Observed changes of the ultrasound velocity of guided waves at 100 kHz followed gradual changes in the thickness of the intact cortical layer. On the other hand, the bulk velocity at 500 kHz remained nearly constant at the different cortical layer thickness but was affected by the material stiffness. Similar trends were observed in phantoms and in fragments of animal bones.

Multi-frequency axial transmission bone ultrasonometer.

The last decade has seen a surge in the development of axial transmission QUS (Quantitative UltraSound) technologies for the assessment of long bones using various modes of acoustic waves. The condition of cortical bones and the development of osteoporosis are determined by numerous mechanical, micro-structural, and geometrical or macro-structural bone properties like hardness, porosity and cortical thickness. Such complex manifestations of osteoporosis require the evaluation of multiple parameters with different sensitivities to the various properties of bone that are affected by the disease. This objective may be achieved by using a multi-frequency ultrasonic examination The ratio of the acoustic wavelength to the cortical thickness can be changed by varying the frequency of the ultrasonic pulse propagating through the long bone that results in the change in composition of the induced wave comprised of a set of numerous modes of guided, longitudinal, and surface acoustic waves. The multi-frequency axial transmission QUS method developed at Artann Laboratories (Trenton, NJ) is implemented in the Bone Ultrasonic Scanner (BUSS). In the current version of the BUSS, a train of ultrasonic pulses with 60, 100, 400, 800, and 1200 kHz frequencies is used. The developed technology was tested on a variety of bone phantoms simulating normal, osteopenic, and osteoporotic bones. The results of this study confirm the feasibility of the multi-frequency approach for the assessment of the processes leading to osteoporosis.

Muscle as a molecular machine for protecting joints and bones by absorbing mechanical impacts.

We hypothesize that dissipation of mechanical energy of external impact to absorb mechanical shock is a fundamental function of skeletal muscle in addition to its primary function to convert chemical energy into mechanical energy. In physical systems, the common mechanism for absorbing mechanical shock is achieved with the use of both elastic and viscous elements and we hypothesize that the viscosity of the skeletal muscle is a variable parameter which can be voluntarily controlled by changing the tension of the contracting muscle. We further hypothesize that an ability of muscle to absorb shock has been an important factor in biological evolution, allowing the life to move from the ocean to land, from hydrodynamic to aerodynamic environment with dramatically different loading conditions for musculoskeletal system. The ability of muscle to redistribute the energy of mechanical shock in time and space and unload skeletal joints is of key importance in physical activities. We developed a mathematical model explaining the absorption of mechanical shock energy due to the increased viscosity of contracting skeletal muscles. The developed model, based on the classical theory of sliding filaments, demonstrates that the increased muscle viscosity is a result of the time delay (or phase shift) between the mechanical impact and the attachment/detachment of myosin heads to binding sites on the actin filaments. The increase in the contracted muscle's viscosity is time dependent. Since the forward and backward rate constants for binding the myosin heads to the actin filaments are on the order of 100s(-1), the viscosity of the contracted muscle starts to significantly increase with an impact time greater than 0.01s. The impact time is one of the key parameters in generating destructive stress in the colliding objects. In order to successfully dampen a short high power impact, muscles must first slow it down to engage the molecular mechanism of muscle viscosity. Muscle carries out two functions, acting first as a nonlinear spring to slow down impact and second as a viscous damper to absorb the impact. Exploring the ability of muscle to absorb mechanical shock may shed light to many problems of medical biomechanics and sports medicine. Currently there are no clinical devices for real-time quantitative assessment of viscoelastic properties of contracting muscles in vivo. Such assessment may be important for diagnosis and monitoring of treatment of various muscle disorders such as muscle dystrophy, motor neuron diseases, inflammatory and metabolic myopathies and many more.

Osteoporosis detection in postmenopausal women using axial transmission multi-frequency bone ultrasonometer: clinical findings.

The objective of this study was to evaluate if the Bone UltraSonic Scanner (BUSS) can detect osteoporosis in postmenopausal women. BUSS is an axial transmission multi-frequency ultrasonometer for acquisition of wave propagation profiles along the proximal anterior tibia. We derived 10 diagnostically significant BUSS parameters that were then compared with the DXA spine T-score, which was used in this study as the "gold standard" for the assessment of osteoporosis (T-score<-2.5). BUSS wave parameters were studied in 331 postmenopausal women examined by 9 trained operators at 3 clinical sites with use of 3 devices. The efficiency of each BUSS parameter in osteoporosis detection was assessed using a receiver operating characteristic curve analysis. Area under the curve (AUC) for each of 10 parameters ranged from 58.1% to 70.2%. Using these parameters a linear classifier was derived which provided at its output 83.0% AUC, 87.7% sensitivity and 63.2% specificity to DXA-identified osteoporosis. The results of this study confirm BUSS's capability to detect osteoporosis in postmenopausal women.

Acoustic waves in medical imaging and diagnostics.

Up until about two decades ago acoustic imaging and ultrasound imaging were synonymous. The term ultrasonography, or its abbreviated version sonography, meant an imaging modality based on the use of ultrasonic compressional bulk waves. Beginning in the 1990s, there started to emerge numerous acoustic imaging modalities based on the use of a different mode of acoustic wave: shear waves. Imaging with these waves was shown to provide very useful and very different information about the biological tissue being examined. We discuss the physical basis for the differences between these two basic modes of acoustic waves used in medical imaging and analyze the advantages associated with shear acoustic imaging. A comprehensive analysis of the range of acoustic wavelengths, velocities and frequencies that have been used in different imaging applications is presented. We discuss the potential for future shear wave imaging applications.

Comparative examination of human proximal tibiae in vitro by ultrasonic guided waves and pQCT.

The velocity of ultrasonic guided waves in long bones is dependent upon two determinants of bone strength: the cortical thickness and the material properties. In this study, six human proximal tibiae in vitro were examined to test the efficacy of an ultrasonic method based on guided waves. Peripheral quantitative computed tomography (pQCT) was used as the comparative reference modality. The guided wave velocity (c(F)) was derived from two-dimensional (2-D) spatial-temporal waveform profiles formed by multiple ultrasonic signals acquired along the bones at 100 kHz frequency and passed wavelet processing. The ultrasonic profiles from the examined bones were ranged according to pQCT measurements of cortical thickness (CTh), and cortical bone mineral density (CBMD). Strong correlations between c(F) and CTh (r(S) = 0.83, p < 0.0001) and CBMD (r(S) = 0.88, p < 0.0001) resulted. The study confirmed a potential for guided waves to assess atrophic changes of the proximal tibia.

AN OVERVIEW OF ELASTOGRAPHY - AN EMERGING BRANCH OF MEDICAL IMAGING.

From times immemorial manual palpation served as a source of information on the state of soft tissues and allowed detection of various diseases accompanied by changes in tissue elasticity. During the last two decades, the ancient art of palpation gained new life due to numerous emerging elasticity imaging (EI) methods. Areas of applications of EI in medical diagnostics and treatment monitoring are steadily expanding. Elasticity imaging methods are emerging as commercial applications, a true testament to the progress and importance of the field.In this paper we present a brief history and theoretical basis of EI, describe various techniques of EI and, analyze their advantages and limitations, and overview main clinical applications. We present a classification of elasticity measurement and imaging techniques based on the methods used for generating a stress in the tissue (external mechanical force, internal ultrasound radiation force, or an internal endogenous force), and measurement of the tissue response. The measurement method can be performed using differing physical principles including magnetic resonance imaging (MRI), ultrasound imaging, X-ray imaging, optical and acoustic signals.Until recently, EI was largely a research method used by a few select institutions having the special equipment needed to perform the studies. Since 2005 however, increasing numbers of mainstream manufacturers have added EI to their ultrasound systems so that today the majority of manufacturers offer some sort of Elastography or tissue stiffness imaging on their clinical systems. Now it is safe to say that some sort of elasticity imaging may be performed on virtually all types of focal and diffuse disease. Most of the new applications are still in the early stages of research, but a few are becoming common applications in clinical practice.

Time-reversal Techniques in Ultrasound-assisted Convection-enhanced Drug Delivery to the Brain: Technology Development and In Vivo Evaluation.

We describe a drug delivery method that combines Time-Reversal Acoustics (TRA) with Convection-Enhanced Delivery (CED) to improve the delivery of therapeutics to the interstitium of the brain. The Ultrasound-assisted CED approach (UCED) circumvents the blood-brain barrier by infusing compounds through a cannula that is inserted into the brain while simultaneously delivering ultrasound to improve the penetration of pharmaceuticals. CED without ultrasound-assistance has been used to treat a variety of neural disorders, including glioblastoma multiforme, a malignancy that presents a very poor prognosis for patients. We describe a novel system that is used to infuse fluids into the brain parenchyma while simultaneously exposing the tissue to safe levels of 1-MHz, low intensity, ultrasound energy. The system includes a combined infusion needle-hydrophone, a 10-channel ultralow-output impedance amplifier, a broad-band ultrasound resonator, and MatLab®-based TRA control and user-interface. TRA allows easy coupling of ultrasound therapy through the skull without complex phase-correction and array design. The smart targeting UCED system has been tested in vivo and results show it provides 1.5-mm spatial resolution for UCED and improves tracer distribution in the brain over CED alone.