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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

Biomedical applications of radiation force of ultrasound: historical roots and physical basis.

Radiation force is a universal phenomenon in any wave motion, electromagnetic or acoustic. Although acoustic and electromagnetic waves are both characterized by time variation of basic quantities, they are also both capable of exerting a steady force called radiation force. In 1902, Lord Rayleigh published his classic work on the radiation force of sound, introducing the concept of acoustic radiation pressure, and some years later, further fundamental contributions to the radiation force phenomenon were made by L. Brillouin and P. Langevin. Many of the studies discussing radiation force published before 1990 were related to techniques for measuring acoustic power of therapeutic devices; also, radiation force was one of the factors considered in the search for noncavitational, nonthermal mechanisms of ultrasonic bioeffects. A major surge in various biomedical applications of acoustic radiation force started in the 1990s and continues today. Numerous new applications emerged including manipulation of cells in suspension, increasing the sensitivity of biosensors and immunochemical tests, assessing viscoelastic properties of fluids and biological tissues, elasticity imaging, monitoring ablation of lesions during ablation therapy, targeted drug and gene delivery, molecular imaging and acoustical tweezers. We briefly present in this review the major milestones in the history of radiation force and its biomedical applications. In discussing the physical basis of radiation force and its applications, we present basic equations describing the relationship of radiation stress with parameters of acoustical fields and with the induced motion in the biological media. Momentum and force associated with a plane-traveling wave, equations for nonlinear and nonsteady-state acoustic streams, radiation stress tensor for solids and biological tissues and radiation force acting on particles and microbubbles are considered.

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.

Vaginal tactile imaging.

Changes in the elasticity of the vaginal walls, connective support tissues, and muscles are thought to be significant factors in the development of pelvic organ prolapse, a highly prevalent condition affecting at least 50% of women in the United States during their lifetimes. It creates two predominant concerns specific to the biomechanical properties of pelvic support tissues: how does tissue elasticity affect the development of pelvic organ prolapse and how can functional elasticity be maintained through reconstructive surgery. We designed a prototype of vaginal tactile imager (VTI) for visualization and assessment of elastic properties of pelvic floor tissues. In this paper, we analyze applicability of tactile imaging for evaluation of reconstructive surgery results and characterization of normal and pelvic organ prolapse conditions. A pilot clinical study with 13 patients demonstrated that VTI allows imaging of vaginal walls with increased rigidity due to implanted mesh grafts following reconstructive pelvic surgery and VTI has the potential for prolapse characterization and detection.

Time-reversal acoustic focusing system as a virtual random phased array.

This paper compares the performance of two different systems for dynamic focusing of ultrasonic waves: conventional 2-D phased arrays (PA) and a focusing system based on the principles of time-reversed acoustics (TRA). Focused ultrasound fields obtained in the experiments with the TRA focusing system (TRA FS), which employs a liquid-filled reverberator with 4 piezotransducers attached to its wall, are compared with the focused fields obtained by mathematical simulation of PAs comprised from several tens to several hundreds of elements distributed randomly on the array surface. The experimental and simulated focusing systems had the same aperture and operated at a frequency centered about 600 kHz. Experimental results demonstrated that the TRA FS with a small number of channels can produce complex focused patterns and can steer them with efficiency comparable to that of a PA with hundreds of elements. It is shown that the TRA FS can be realized using an extremely simple means, such as a reverberator made of a water-filled plastic bottle with just a few piezotransducers attached to its walls.

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.

Diversity of biomedical applications of acoustic radiation force.

This manuscript is a summary of the paper presented at the ICU'2009 on biomedical applications of acoustic radiation force with emphasis on emerging applications in microfluidics, biotechnology, biosensors and assessment of the skeletal system. In this brief overview of current and projected applications of radiation force, no detailed description of the experiments illustrating particular applications are given as this would result in a far different and longer paper. Various mechanisms of acoustic radiation force generations and their biomedical applications are considered. These mechanisms include: (a) change in the density of energy of the propagating wave due to absorption and scattering; (b) spatial variations of energy density in standing acoustic waves; (c) reflection from inclusions, walls or other interfaces; and (d) spatial variations in propagation velocity. The widest area of biomedical applications of radiation force is related to medical diagnostics, to assessing viscoelastic properties of biological tissues and fluids, and specifically to elasticity imaging. Another actively explored area is related to manipulation of biological cells and particles in standing ultrasonic wave fields. There are several poorly explored areas of potential biomedical applications of ultrasound radiation force. A promising area of biomedical application of ultrasound radiation force is stirring and mixing of microvolumes of liquids in microfluidics and in various biotechnological application where diffusion rate is the main factor limiting the efficiency of the process of interest. A new technique, called "swept frequency method", based on the use of radiation force in the standing acoustic wave for microstirring of liquids is described. The potential applications of the ultrasound radiation force for assessment of skeletal system, where conventional bone ultrasonometry are inapplicable are considered.

Time reversal acoustic focusing with a catheter balloon.

The ability to deliver configurable myocardial lesions was noted as a critical factor to the success of atrial fibrillation (AF) treatment. This article considers the implementation of time reversal acoustics (TRA) principles for ultrasound focusing using an AF cardiac catheter developed for pulmonary vein isolation. Experiments conducted with a single transmitting channel demonstrated that a catheter balloon could be used as an acoustic reverberator to enable focusing and steering of ultrasound short pulses in the TRA mode. The spatial effectiveness of the TRA focusing was improved using a catheter balloon of irregular, asymmetric shape and using a binary mode of ultrasound radiation. The experiments demonstrated the ability of steering the focal point over several millimeters without degradation of the focusing quality. An ability of the TRA mode to produce suitable therapeutic application focusing of long continuous ultrasonic signals was characterized in a theoretical model. (E-mail: yegorasha@yahoo.com).

Mechanical imaging in medical applications.

Mechanical Imaging (MI), a.k.a. tactile imaging or stress imaging, is a branch of Elasticity Imaging, a medical diagnostic technique based on the visualization of tissue internal structures in terms of their elasticity modulus. During the last decade, numerous methods and devices have been developed implementing MI technology in various medical applications, such as the visualization and evaluation of prostate conditions, breast cancer screening, the differentiation of benign and malignant lesions, and the characterization of vaginal wall elasticity. This paper presents an overview of MI technology and its applications, strengths and limitations. Results of laboratory and clinical studies clearly indicate that Mechanical Imaging devices have the potential to be used as a cost effective means for cancer screening as well as diagnostics of various diseases accompanied by changes of mechanical properties of soft tissues.

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.