This article reviews acoustic microfiuidics: the use of acoustic fields, principally ultrasonics, for application in microfiuidics. Although acoustics is a classical field, its promising, and indeed perplexing, capabilities in powerfully manipulating both fluids and particles within those fluids on the microscale to nanoscale has revived interest in it. The bewildering state of the literature and ample jargon from decades of research is reorganized and presented in the context of models derived from first principles. This hopefully will make the area accessible for researchers with experience in materials science, fluid mechanics, or dynamics. The abundance of interesting phenomena arising from nonlinear interactions in ultrasound that easily appear at these small scales is considered, especially in surface acoustic wave devices that are simple to fabricate with planar lithography techniques common in microfluidics, along with the many applications in microfluidics and nanofluidics that appear through the literature.

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Microscale acoustofluidics: Microfluidics driven via acoustics and ultrasonics

Therapeutic ultrasound is an emerging field with many medical applications. High intensity focused ultrasound (HIFU) provides the ability to localize the deposition of acoustic energy within the body, which can cause tissue necrosis and hemostasis. Similarly, shock waves from a lithotripter penetrate the body to comminute kidney stones, and transcutaneous ultrasound enhances the transport of chemotherapy agents. New medical applications have required advances in transducer design and advances in numerical and experimental studies of the interaction of sound with biological tissues and fluids. The primary physical mechanism in HIFU is the conversion of acoustic energy into heat, which is often enhanced by nonlinear acoustic propagation and nonlinear scattering from bubbles. Other mechanical effects from ultrasound appear to stimulate an immune response, and bubble dynamics play an important role in lithotripsy and ultrasound-enhanced drug delivery. A dramatic shift to understand and exploit these nonlinear and mechanical mechanisms has occurred over the last few years. Specific challenges remain, such as treatment protocol planning and real-time treatment monitoring. An improved understanding of the physical mechanisms is essential to meet these challenges and to further advance therapeutic ultrasound.

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Physical mechanisms of the therapeutic effect of ultrasound (a review)

Double-blind, prospective, placebo-controlled clinical trials demonstrate that healing times of fresh fractures of the radius and tibia are reduced by up to 40% with the use of low-intensity ultrasound.

Animal studies indicate that low-intensity ultrasound exposure results in stronger and stiffer callus formation and in acceleration of the endochondral ossification process.

Extensive clinical evidence demonstrates that ultrasound represents a safe, noninvasive method of accelerating the healing of fresh fractures of the tibia, the distal aspect of the radius, the scaphoid, and the metatarsals.

Clinical studies indicate that ultrasound reduces the confounding effect of smoking and patient age on the fracture-healing process.

Ultrasound requires a brief, twenty-minute, daily at-home treatment regimen and has no known contraindications.

The effectiveness of low-intensity ultrasound has also been demonstrated in the clinical treatment of delayed unions and nonunions.

Fracture-healing is a complex biological process that involves the spatial and temporal orchestration of numerous cell types, hundreds if not thousands of genes, and the intricate organization of an extracellular matrix, all working toward restoring the bone's mechanical strength and rapid return to full function. It has often been argued that nature has optimized this process and thus it would be difficult to interventionally accelerate or augment fracture-healing. How can science conceivably improve upon 600 million years of vertebrate evolution? Nevertheless, it is just this goal that has inspired an intense effort among basic-science and clinical investigators from a vast array of biotechnology and bioengineering disciplines at academic as well as industrial laboratories, to seek a means of accelerating the healing of fractured bones. In this article, the basic-science and clinical evaluation of the use of low-intensity ultrasound is reviewed and the case is made that nature's process of fracture-healing, while elegant, can be accelerated with respect to achieving the ability to support clinically relevant loads.

The …

The use of low-intensity ultrasound to accelerate the healing of fractures.

The propagation of ultrasonic waves is nonlinear. Phenomena associated with the propagation of diagnostic ultrasound pulses cannot be predicted using linear assumptions alone. These include a progressive distortion in waveform, the generation of frequency harmonics and acoustic shocks, excess deposition of energy and acoustic saturation. These effects occur most strongly when ultrasound propagates within liquids with comparatively low acoustic attenuation, such as water, amniotic fluid or urine. Within soft tissues, similar effects occur, although they are limited by absorption and scattering. Nonlinear effects are of considerable importance during acoustic measurements, especially when these are used to predict in situ exposure. Harmonic generation may be used to create images. These offer improvements over conventional B-mode images in spatial resolution and, more significantly, in the suppression of acoustic clutter and side-lobe artifacts. B/A has promise as a parameter for tissue characterisation, but methods for imaging B/A have shown limited success.

Nonlinear acoustics in diagnostic ultrasound.

Ultrasonic pulse echo imaging in inhomogeneous media suffers from significant lateral and contrast resolution losses due to the defocusing effects of the inhomogeneities. The losses in lateral and contrast resolution are associated with increases in the width of the mainbeam and increases in sidelobe levels, respectively. These two forms of resolution loss represent significant hurdles to improving the clinical utility of biomedical ultrasonic imaging. A number of research efforts are currently under way to investigate the defocusing effects of tissue and to consider corrective measures. All of these efforts assume linear propagation, and base the image-formation process on the reception of the transmitted pulse. A novel pulse echo imaging scheme in which the image is formed using the finite amplitude distortion components of the received pulse is considered here. Alternatively, this could be described as image formation using the nonlinearly-generated higher harmonics. In homogeneous beam propagations, it has been established that the sidelobes of nonlinearly-generated higher harmonics are much lower than their linear counterparts. Computations considered here suggest that this relationship also holds for the case of propagations through abdominal wall and breast wall tissue. These computations also suggest that the lateral resolution limits imposed by abdominal wall and breast wall tissue are slightly smaller for nonlinearly-generated second harmonics than for their linear counterparts. The resulting potential of these higher harmonics to improve image resolution is investigated.

Finite amplitude distortion-based inhomogeneous pulse echo ultrasonic imaging

Axisymmetric flow equations for a viscous incompressible fluid are transformed into the vorticity transport and Poisson’s equations They are numerically solved via a finite difference method imposing appropriate initial and boundary conditions A model source of 1‐cm radius and 5‐cm focal length with Gaussian amplitude distribution radiates 5‐MHz ultrasound beams in water Numerical examples are shown for buildup of acoustic streaming along and across the acoustic axis Evidently, hydrodynamic nonlinearity has an essential effect on the streaming generation in comparison with a linear flow case; the nonlinearity reduces the streaming velocity in the focal and prefocal region, whereas it tends to accelerate the flow in the postfocal region

Acoustic streaming induced in focused Gaussian beams

Due to the inherent nonlinearity of the medium, finite amplitude ultrasound interacts with itself and generates some secondary waves in the sound beam. The parametric loudspeaker, making use of this phenomenon, has a sharp directivity and might be applied to a speech transmission system under the limited environment.



In this paper, a numerical analysis method available for high sound pressure levels, where the nonlinear interactions of ultrasound become greatly active, can be used successfully to theoretically design the parametric loudspeaker. It is reported that the numerical computations agree well with the experiments by a circular aperture projector of radius 21 cm and carrier frequency 27 kHz.



To develop the parametric loudspeaker for practical uses, the problems on harmonic distortions and the physiological effect on human being must be solved. Based on the theoretical prediction, the reasonable solutions for such problems are considered in accordance with appropriate primary wave modulations.

Parametric loudspeaker—characteristics of acoustic field and suitable modulation of carrier ultrasound

Theoretical analysis and some experiments are performed on nonlinearly generated harmonic components in bounded sound beams emitted from a rectangular aperture source The Khokhlov–Zabolotskaya–Kuznetsov equation, which takes account of nonlinearity, dissipation, and diffraction effects in the beams, is numerically solved by means of the alternating direction implicit difference method Using a planar source of size 24×44 cm, axial sound pressures and beam patterns of the first three harmonics are measured in air for initially sinusoidal ultrasounds of 25‐ and 30‐kHz frequency, and are compared with the theory They are in relatively good agreement Deformation of the source face from circular to rectangular shape results in the unclear appearance of pressure peaks and dips with propagation Within the framework of these studies, the harmonic pressure levels in the far field are almost the same as from a circular aperture source with equal face area and equal initial pressure, independent of the source le

Harmonic generation in finite amplitude sound beams from a rectangular aperture source

Nonlinear propagation of sound waves generated by a directive ultrasound source in air is discussed theoretically and experimentally. The circular source of 21 cm in radius consists of 1410 small PZT bimorph transducers, whose resonance frequency is 28 kHz. For a single‐frequency wave excitation, sound pressures of the fundamental, second, and third harmonics are measured and are compared with the numerical results using a method of Aanonsen et al. [J. Acoust. Soc. Am. 75, 749–768 (1984)]. Extending their initial condition to the case of a two‐frequency wave excitation, propagation curves and beam patterns of the difference frequency sound are obtained and compared with the measured data. All observations quantitatively agree very well with the numerical calculation. Nonlinear attenuation of spectral components by increasing the source pressure is clearly confirmed.Nonlinear propagation of sound waves generated by a directive ultrasound source in air is discussed theoretically and experimentally. The circular source of 21 cm in radius consists of 1410 small PZT bimorph transducers, whose resonance frequency is 28 kHz. For a single‐frequency wave excitation, sound pressures of the fundamental, second, and third harmonics are measured and are compared with the numerical results using a method of Aanonsen et al. [J. Acoust. Soc. Am. 75, 749–768 (1984)]. Extending their initial condition to the case of a two‐frequency wave excitation, propagation curves and beam patterns of the difference frequency sound are obtained and compared with the measured data. All observations quantitatively agree very well with the numerical calculation. Nonlinear attenuation of spectral components by increasing the source pressure is clearly confirmed.

Nonlinearly generated spectral components in the nearfield of a directive sound source

Eckart‐type acoustic streaming induced in confined sound beams from a piston source is examined in water theoretically and experimentally. Axisymmetric flow equations with a spatially distributed driving force in the beams are based on the continuity equation and the Navier–Stokes equation in a viscous, incompressible fluid. They are solved numerically by the stream‐function vorticity method [T. Kamakura et al., J. Acoust. Soc. Am. 97, 2740–2746 (1995)]. Experiments are conducted using a 5‐MHz planar transducer with a 9.5‐mm radius aperture. All measurements of the streaming velocities are carried out by a laser Doppler velocimeter and are compared with the numerical computations including the enhancement of the force due to finite‐amplitude sound distortion. These measurements agree well with the theoretical prediction. It is noted that diffraction of sound beams plays an important role in the generation of streaming, particularly in the early stage. Consistency between experiments and computations suggests that both acoustic and hydrodynamic nonlinearities should be taken into account in the present observation system.

Yoshiro Kumamoto

Papers

Acoustic streaming induced in focused Gaussian beams

Parametric loudspeaker—characteristics of acoustic field and suitable modulation of carrier ultrasound

Harmonic generation in finite amplitude sound beams from a rectangular aperture source

Nonlinearly generated spectral components in the nearfield of a directive sound source

Time evolution of acoustic streaming from a planar ultrasound source