In focused ultrasound surgery (FUS), an ultrasound source radiates pressure waves into the patient’s body to achieve a desired therapeutic effect. FUS has already gained regulatory approval in the U.S. for treating uterine fibroids and pain palliation for bone metastases; other applications – including prostate cancer, liver cancer, and neurosurgery – remain active topics for clinical trials and research. Because applications of FUS often involve high intensity levels, insufficient knowledge of the acoustic field in the patient could lead to damage of healthy tissue away from the targeted treatment site. In this sense, high-intensity ultrasound treatments could cause collateral effects much like radiotherapy treatments that use ionizing radiation. In radiotherapy, treatment planning is critical for delivery of an effective and safe treatment: Typically, CT or MRI is used to form a virtual patient and the treatment is planned by computer-aided design. Simulations are used to plan the geometric, radiological, and dosimetric aspects of the therapy using radiation transport simulations. Analogous to a radiation beam, ultrasound therapy uses an acoustic beam as a 3D “scalpel” to treat tumors or other tissues. Accordingly, there is motivation to establish standard procedures for FUS treatment planning that parallel those in radiotherapy [1, 2]. However, such efforts toward treatment planning first require very precise knowledge of the source transducer in order to accurately predict the acoustic beam structure inside the patient.
Fig. 1 Acoustic holography to characterize an ultrasound source, with schematic illustration of the corresponding ultrasound field. A measured hologram in a plane can be used to reconstruct the entire wave field anywhere in 3D space.
Toward this end, it is instructive to recognize that ultrasound comprises pressure waves and thus possesses several basic features of wave physics that can be used in practice. One such feature is the potential to reproduce a 3D wave field from a 2D distribution of the wave amplitude and phase. This principle was made famous in optics by Dennis Gabor (Nobel Prize, 1971), who invented holography . A similar approach is possible in acoustics [4 – 8] and is illustrated in Fig. 1 for a therapeutic ultrasound source. To measure an acoustic hologram, a hydrophone (i.e., a microphone used underwater) can be scanned across a plane in front of the transducer. Because these measurements in 2D capture the whole field, this measured hologram can be used to reconstruct the surface vibrations of the source transducer. In turn, once the vibrations of the source are known, the corresponding acoustic field can be computed in water or tissue or any other medium with known properties.
Besides ultrasound surgery, holography techniques can be applied to characterize ultrasound transducers used for other therapeutic and diagnostic ultrasound-based applications. In this work we have used it for the first time to characterize a shock wave lithotripter source. Shock wave lithotripters radiate high intensity pulses that are focused on a kidney stone. High pressure, short rise time, and path-dependent nonlinearity make characterization in water and extrapolation to tissue difficult.
The electromagnetic lithotripter characterized in this effort is a commercial model (Dornier Compact S, Dornier MedTech GmbH, Wessling, Germany) with a 6.5 mm focal width. A broadband hydrophone (a fiber optic probe hydrophone, model FOPH 2000, RP Acoustics; Leutenbach, Germany) was used to sequentially measure the field over a set of points in a plane in front of the source. Following the previously developed transient holography approach, the recorded pressure field was numerically back-propagated to the source surface (Fig. 2). The method provides an accurate boundary condition from which the field in tissue can be simulated.
Fig. 2 Characterization of an electro-magnetic shock wave lithotripter. Top: A photo of the lithotripter head. Bottom: Holographically reconstructed peak-to-peak pressure along the transducer face.
In addition, we use acoustic holography to characterize imaging probes, which generate short, transient pulses of ultrasound (Fig. 3). Accurate 3D field representations have been confirmed .
Fig. 3 Characterization of a diagnostic imaging probe. Top: A photo of the HDI C5-2 probe, which was excited at a frequency of 2.3 MHz. Middle: Holographically reconstructed pattern of vibration velocities along the probe surface. Bottom: Corresponding phase distribution.
We believe that our research efforts on acoustic holography will make it possible in the near future for manufacturers to sell each medical ultrasound transducer with a “source hologram” as a part of its calibration. This practice will enable calculation of the 3D ultrasound and temperature fields produced by each source in situ, from which the “dose” delivered to a patient can be inferred with better accuracy than is currently achievable.
1. White PJ, Andre B, McDannold N, Clement GT. A pre-treatment planning strategy for high-intensity focused ultrasound (HIFU) treatments. Proceedings 2008 IEEE International Ultrasonics Symposium, 2056-2058 (2008).
2. Pulkkinen A, Hynynen K. Computational aspects in high intensity ultrasonic surgery planning. Comput. Med. Imaging Graph. 34(1), 69-78 (2010).
3. Gabor D. A new microscopic principle. Nature 161, 777-778 (1948).
4. Maynard JD, Williams EG, and Lee Y. Nearfield acoustic holography: I. Theory of generalized holography and the development of NAH. J. Acoust. Soc. Am. 78, 1395-1413 (1985).
5. Schafer ME, Lewin PA. Transducer characterization using the angular spectrum method. J. Acoust. Soc. Am. 85(5), 2202-2214 (1989).
6. Sapozhnikov O, Pishchalnikov Y, Morozov A. Reconstruction of the normal velocity distribution on the surface of an ultrasonic transducer from the acoustic pressure measured on a reference surface. Acoustical Physics 49(3), 354–360 (2003).
7. Sapozhnikov OA, Ponomarev AE, Smagin MA. Transient acoustic holography for reconstructing the particle velocity of the surface of an acoustic transducer. Acoustical Physics 52(3), 324–330 (2006).
8. Kreider W, Yuldashev PV, Sapozhnikov OA, Farr N, Partanen A, Bailey MR, Khokhlova VA. Characterization of a multi-element clinical HIFU system using acoustic holography and nonlinear modeling. IEEE Transactions on Ultrasonics, Ferroelectrics, and Frequency Control 60(8), 1683-1698 (2013).
9. Kreider W, Maxwell AD, Yuldashev PV, Cunitz BW, Dunmire B, Sapozhnikov OA, Khokhlova VA. Holography and numerical projection methods for characterizing the three-dimensional acoustic fields of arrays in continuous-wave and transient regimes. J. Acoust. Soc. Am. 134(5), Pt 2, 4153 (2013).
Oleg A. Sapozhnikov1,2, Sergey A. Tsysar1, Wayne Kreider2, Guangyan Li3,
Vera A. Khokhlova1,2, and Michael R. Bailey2,4
1Physics Faculty, Moscow State University, Leninskie Gory, Moscow 119991, Russia
2Center for Industrial and Medical Ultrasound, Applied Physics Laboratory, University of Washington, 1013 NE 40th Street, Seattle WA 98105, USA
3Department of Anatomy and Cell Biology, Indiana University School of Medicine, 635 Barnhill Dr. MS 5055 Indianapolis, IN 462025120
4Department of Urology, University of Washington Medical Center, 1959 NE Pacific Street, Box 356510, Seattle, WA 98195, USA
The cervix, which is the opening into the uterus, is a remarkable organ. It is the only structure in the entire body that has diametrically opposed functions. The normal cervix stays stiff and closed throughout most of pregnancy while the baby develops and then completely softens and opens at just the right time so the full-grown baby can be born normally, through the vagina. This process of softening and opening involves remodeling, or breaking down, of the cervix’s collagen structure together with an increase in water, or hydration, of the cervix. When the process happens too soon, babies can be born prematurely, which can cause serious lifelong disability and even death. When it happens too late, mothers may need a cesarean delivery. [1,2]
Amazingly, even after 100 years of research, nobody understands how this happens. Specifically, it is unclear how the cervix knows when to soften, or what molecular signals initiate and control this process. As a result, obstetrical providers today evaluate cervical softness in exactly the same way as they did in the 1800s: they feel the cervix with their fingers and classify it as ‘soft’, ‘medium’ or ‘firm’. And, unsurprisingly, despite significant research effort, the preterm birth rate remains unacceptably high and more than 95% of preterm births are intractable to any available therapies.
The cervix is like a cylinder with a canal in the middle that goes up into the uterus. This is where the sperm travels to fertilize the egg, which then nests in the uterus. Cervical collagen is roughly arranged in 3 layers. There is a thin layer on the inner part that where collagen is mostly aligned along the cervical canal, and similarly a thin layer that runs along the outside of the cervix. Between these layers, in the middle of the cervix is a thicker layer of collagen that is circumferential, aligned like a belt around the canal. Researchers theorize that the inner and outer layers stabilize the cervix from tearing off as it shortens and dilates for childbirth, while the middle circumferential layer is most important for the strength and stiffness of the cervix to prevent it from opening prematurely, but nobody is certain. This information is critical to understanding the process of normal, and abnormal, cervical remodeling, and that is why recently there is growing interest in developing technology that can non-invasively and thoroughly assess the collagen in the cervix and measure its softness and hydration status. The most promising approaches use regular clinical ultrasound systems that have special processing strategies to evaluate these tissue properties.
One approach to assessing tissue softness uses ultrasound pressure to induce a shear wave, which moves outward like rings in water after a stone is dropped. The speed of the shear wave provides a measurement of tissue stiffness because these waves travel slower in softer tissue. This method is used clinically in simple tissues without layers of collagen, such as the liver for staging fibrosis. Cervical tissue is very complex because of the collagen layers, but, after many years of research, we finally have adapted this method for the cervix. The first thing we did was compare shear wave speeds in hysterectomy specimens (surgically removed uterus and cervix) between two groups of women. The first group was given a medicine that softens the cervix in preparation for induction of labor, a process called “ripening”. The second group was not treated. We found that the shear wave speeds were slower in the women who had the medicine, indicating that our method could detect the cervices that had been softened with the medicine. We also found that the cervix was even more complex than we’d thought, that shear wave speeds are different in different parts of the cervix. Fortunately, we learned we could easily control for that by measuring the same place on every woman’s cervix. We confirmed that our measurements were accurate by performing second harmonic generation microscopy on the cervix samples in which we measured shear wave speeds. This is a sophisticated way of looking at the tiny collagen structure of a tissue. It told us that indeed, when the collagen structure was more organized, the shear wave speeds were faster, indicating stiffer tissue, and when the collagen started breaking down, the shear wave speeds were slower, indicating softer tissue.
The next step was to see if our methods worked outside of the laboratory. So we studied pregnant women who were undergoing cervical ripening in preparation for induction of labor. We took measurements from each woman before they got the ripening medicine, and then afterwards. We found that the shear wave speeds were slower after the cervix had been ripened, indicating the tissue had softened. This told us that we could obtain useful information about the cervix in pregnant women.
We also evaluated attenuation, which is loss of ultrasound signal as the wave propagates, because attenuation should increase as tissue hydration increases. This is a very complicated measurement, but we found that if we carefully control the angle of the ultrasound beams relative to the underlying cervical structure, attenuation estimates are sensitive to the difference between ripened and unripened tissue in hysterectomy specimens. This suggests the potential for an additional parameter to quantify and monitor the status of the cervix during pregnancy, and we are currently analyzing attenuation in the pregnant women before and after they received the ripening medicine.
This technology is exciting because it could change clinical practice. On a very basic level, obstetrical providers would be able to talk in objective terms about a woman’s cervix instead of the subject “soft, medium, or firm” designation they currently use, which would improve provider communication and thus patient care. More importantly, it could provide a means to thoroughly study normal and abnormal cervical remodeling, and associate structural changes in the cervix with molecular changes, which is the only way to discover new interventions for preterm birth.
1. Feltovich H, Hall TJ, and Berghella V. Beyond cervical length: Emerging technologies for assessing the pregnant cervix. Am J Obst & Gyn, 207(5): 345-354, 2012.
2. Feltovich, H and Hall TJ. Quantitative Imaging of the Cervix: Setting the Bar. Ultrasound Obstet Gynecol. 42(2): 121-128, 2013.
3. Carlson LC, Feltovich H, Palmeri ML, Dahl JJ, Del Rio AM, Hall TJ, Estimation of shear wave speed in the human uterine cervix. Ultrasound Obstet Gynecol. 43( 4): 452–458, 2014.
4. Carlson LC, Romero ST, Palmeri ML, Munoz del Rio A, Esplin SM, Rotemberg VM, Hall TJ, Feltovich H. Changes in shear wave speed pre and post induction of labor: A feasibility study. Ultrasound Obstet Gynecol.published online ahead of print Sep.2014.
Unlocking the Mystery of the Cervix
Timothy J Hall, Helen Feltovich, Lindsey C. Carlson, Quinton W. Guerrero, Ivan M. Rosado-Mendez
University of Wisconsin, Madison, WI (firstname.lastname@example.org)
Stone disease in the children is becoming more commonplace. Over the past 25 years the incidence has increased approximately 6-10% annually and is now 50 per 100,000 adolescents 1. The diagnosis of kidney stones in children, as in adults, relies primarily on diagnostic imaging. In adults, the most common imaging study performed in the United States for the initial diagnosis of kidney stones is a computed tomography (CT) scan, due to its superior sensitivity and specificity. This is not preferred for children as CT utilizes ionizing radiation and children have an increased sensitivity to radiation effects. In addition, stone formers often have recurrent stone episodes over their lifetime, which is especially relevant to younger stone formers. The repeated exposures of a CT scan could lead to an increased risks of secondary cancers2. As a result, ultrasound is often performed in children instead because there is no radiation associated with its use1. Ultrasound, however, is less sensitive and specific compared with CT, and is known to overestimate kidney stone size3-5, which is one of the primary determinants of how stones are managed.
We have identified a new technique to improve the accuracy of US stone sizing. Traditionally, a kidney stone will show up as a bright, or hyperechoic, object on US, and radiologists measure the longest linear dimension of the bright area to represent the stone size. We believe that the dark, or hypoechoic, acoustic shadow that appears behind a kidney stone provides additional information for predicting stone size. The resolution of the stone is affected by the distortion of the waves traveling through the intervening tissues; the resolution of the shadow is only affected by the local stone obstruction.
We screened 660 stone diagnoses over an 11 year period (2004 – 2014) at Seattle Children’s Hospital, a tertiary care referral center serving the greater Pacific Northwest. Over the study period, there were 37 patients presenting with an initial diagnosis of a kidney stone, and who had both a US and CT within three months of each other. Two reviewers retrospectively measured both the stone size and the shadow width from the ultrasound image. We compared the results to the stone size measured from the CT scan. A total of 48 stones were included in the study with an average size based on CT imaging of 7.85 mm. The shadow width was present in 88% of the cases, and, on average, was more accurate than measuring the stone itself. Measuring the stone width on ultrasound tended to overestimate the size of the stone by 1.2 ± 2.5 mm (reviewer 1) and 2.0 ± 1.7 mm (reviewer 2), while measuring the shadow width on ultrasound underestimated the size of the stone by -0.6 ± 2.5 mm (reviewer 1) and overestimated the stone size by 0.3 ± 1.2 mm (reviewer 2). In both cases, the shadow was a better predictor of stone size and, for reviewer 2, there was less variability in the data. Stone sizes based on CT are typically considered within 1 mm, with low variability.
Our technique is simple and can be easily adopted by pediatricians, radiologists, and urologists. It improves the accuracy of US and gives physicians more confidence that the reported size is more representative of the true stone size, without having to expose children to the radiation of a CT scan. This also allows the physician to make more accurate decisions about when to perform a surgery for a large stone or continue to observe a small stone that may pass on its own. The findings from this study may also potentially be applicable to stones in adult patients. We believe that with continued advancements in US, we can reduce the number of CT scans for both adults and children. The results in part highlight one of the drawbacks of ultrasound, which is user dependence; two users can have very different results. It is anticipated that future work on automated stone and shadow sizing can reduce this along with standardizing the method in which the shadow measurement is taken.
1. Tasian G and Copelovitch L. Evaluation and Management of Kidney Stones in Children. J Urol. 2014: Epub ahead of print
2. Pearce MS, Salotti JA, Little MP, et al. Radiation exposure from CT scans in childhood and subsequent risk of leukaemia and brain tumours: a retrospective cohort study. Lancet 2012; 380: 499-505.
3. Ray AA, Ghiculete D, Pace KT, Honey RJD. Limitations to ultrasound in the detection and measurement of urinary tract calculi. Urology 2010; 76(2):295-300.
4. Fowler KAB, Locken JA, Duchesne JH, Williamson MR. US for detecting renal calculi with nonehnanced CT as a reference standard. Radiology 2002; 222(1):109-113.
5. Dunmire B, Lee FC, Hsi RS, Cunitz BW, Paun M, Bailey MR, Sorensen MD, Harper JD. Tools to improve the accuracy of kidney stone sizing with ultrasound. Aug 2014; [Epub ahead of print].
Franklin C. Lee1 – email@example.com
Jonathan D. Harper 1 – firstname.lastname@example.org
Thomas S. Lendvay1, 2 – Thomas.email@example.com
Ziyue Liu3 – firstname.lastname@example.org
Barbrina Dunmire 4 – email@example.com
Manjiri Dighe 5 – firstname.lastname@example.org
Michael Bailey – email@example.com
Mathew D. Sorensen1, 6 – firstname.lastname@example.org
University of Washington
1 Department of Urology, Box 356510
5 Department of Radiology, Box 357115
1959 NE Pacific St, Seattle, WA 98195
2 Seattle Children’s Hospital
Urology, Developmental Pediatrics
4800 Sand Point WA NE, Seattle, WA 98105
3 Indiana University
Department of Biostatistics
410 W. Tenth St, Suite 3000, Indianapolis, IN 46202
4 University of Washington
Applied Physics Lab – Center for Industrial and Medical Ultrasound2
1013 NE 40th St, Seattle, WA 98105
6 Department of Veteran Affairs Medical Center
Division of Urology
1660 South Columbian Way, Seattle, WA 98108
Traumatic brain injuries from blast exposure have been called the “signature injury” of military conflicts in Iraq and Afghanistan. This is largely due to our enemies’ unprecedented reliance on explosive weaponry such as improvised explosive devices (IED) (Figure 1). Estimates indicate that approximately 19.5% of deployed military personnel have suffered traumatic brain injuries since 2001 (Rand Report, Invisible Wounds of War, 2008). With more than 2 million service members deployed to Iraq and Afghanistan, this means that over 400,000 American Veterans are currently living with the chronic effects of blast exposure.
Figure 1 caption: An armored military vehicle lies on its side after surviving a buried IED blast on April 15, 2007. The vehicle was hit by a deeply buried improvised explosive device while conducting operations just south of the Shiek Hamed village in Iraq. Photograph courtesy of the U.S. Army: http://www.army.mil/article/9708/general-lee-rides-again/
When a blast wave from a high-intensity explosive impacts the head, a wave of intense heat and pressure moves through the skull and brain. Delicate neural tissues are stretched and compressed, potentially leading to cell damage, cell death, hemorrhaging, and inflammation. All regions of the brain are at risk of damage, and the auditory system is no exception. In recent years, increasing numbers of young Veterans with blast exposure have sought help from VA audiologists for hearing-related problems such as poor speech understanding. However, standard tests of hearing sensitivity often show no signs of hearing loss. This this combination of factors often suggests damage to areas in the brain dealing with auditory signals. The efforts of hearing health professionals to help these Veterans are hampered by a lack of information regarding the effects of blast exposure on auditory function. The purpose of this presentation is to present some early results of a study currently underway at the National Center for Rehabilitative Auditory Research (NCRAR) investigating the long term consequences of blast exposure on hearing. Discovering the types of auditory problems caused by blast exposure is a crucial step toward developing effective rehabilitation options for this population.
Study participants include Veterans who experienced high-intensity blast waves within the past twelve years. The majority of participants have experienced multiple blast episodes, with the most severe events occurring approximately eight years prior to enrolling in the study. Another group of participants of similar age and gender but with no blast exposure are also included to serve as comparisons to the blast-exposed group (controls). On questionnaires assessing hearing ability in different contexts, blast-exposed Veterans described having more difficulties in many listening situations compared control participants. Common challenging situations reported by blast-exposed Veterans involve understanding speech in background noise, understanding when multiple people are talking simultaneously, and recalling multiple spoken instructions. Further, blast-exposed Veterans are more likely to rate the overall quality of sounds such as music and voices more poorly than control participants, and often report that listening requires greater effort. Different tests of listening abilities found many areas of difficulty which probably help explain self-reports. First, blast-exposed Veterans often have poorer ability to distinguish timing cues than control participants. Hence, sounds may seem blurry or smeared over time. Second, the ability to process sounds presented to both ears is often poorer in blast-exposed Veterans. Normally, listeners are able to utilize small differences in the timing and level of sound arriving at the two ears to improve listening performance, especially in noisy listening environments. This ability is often degraded in blast-exposed Veterans. Third, blast-exposed Veterans are poorer at distinguishing changes in the pitch of sounds compared to control participants, even when the pitch change is large. Lastly, blast-exposed Veterans often have greater difficulty ignoring distracting information in order to focus on listening. This leads to problems such as trouble conversing with others when the television is on or when conversing at restaurants or parties. Our study results show that these listening difficulties are often great enough to impact daily life, causing blast-exposed Veterans to avoid social situations that they once enjoyed.
Figure 2 caption: Average EEG responses from blast-exposed and control participant groups in response to a large change in tone pitch. The horizontal axis shows time since the pitch changed (which occurred at time 0 on this axis). The vertical axis shows the magnitude of the neural response of the brain. Notice that the peak of activity in the control group (blue star labeled ‘P300’)is considerably larger and occurs earlier in time compared to the blast-exposed group (red star labeled ‘P300’).
Self-assessment and behavioral performance measures are supported by numerous direct measures of auditory processing. Using a type of electroencephalography (EEG), we non-invasively measure the response of the brain to sound by assessing the timing and size of neural activity associated with sound perception and processing. These tests reveal that the brains of blast-exposed Veterans require more time to analyze sound and respond less actively to changes in sounds. For example, the average EEG responses of blast-exposed and control participants are shown in Figure 2. These waveforms reflect neural detection of a large change in the pitch of tones presented to participants. Notice that the peak marked ‘P300’ is larger and occurs earlier in time in control participants compared to blast-exposed Veterans. Similar effects are seen in response to more complex sounds, such as when participants are asked to identify target words among non-target filler words. Overall, these EEG results suggest degraded sound processing in the brains of blast-exposed Veterans compared to control participants.
In summary, our results strongly suggest that blast exposure can cause chronic problems in multiple areas of the brain where sound is processed. Blast exposure has the potential to damage auditory areas of the brain as well as cognitive regions, both of which likely contribute to hearing difficulties. Thus, though Veterans may have normal hearing sensitivity, blast exposure may cause problems processing complex sounds. These difficulties may persist for many years after blast exposure.
Melissa Papesh – Melissa.Papesh@va.gov
Frederick Gallun – Frederick.Gallun@va.gov
Robert Folmer – Robert.Folmer@va.gov
Michele Hutter – Michele.Hutter@va.gov
Heather Belding – Heather.Belding@va.gov
- Samantha Lewis – Michele.Lewis3@va.gov
National Center for Rehabilitative Auditory Research
Portland VA Medical Center
3710 SW US Veterans Hospital Road
Portland, OR 97239
Marjorie Leek – Marjorie.Leek@va.gov
Loma Linda VA Medical Center
11201 Benton St
Loma Linda, CA 92354
Popular version of paper “4pPP3. Effects of blast exposure on central auditory processing”
Presented Thursday afternoon, October 30, 2014
168th ASA Meeting, Indianapolis
The clinical evaluation of solid tumors typically includes needle biopsies, which can provide diagnostic (benign vs. cancer) and molecular information (targetable mutations, drug resistance, etc). This procedure has several diagnostic limitations, most notably, the potential to miss the mutations only millimeters away. In response to these limitations, the concept of “liquid biopsy” has emerged in recent years: the detection of nucleic acid cancer biomarkers, such as tumor-derived microRNAs (miRNAs) and circulating tumor DNA (ctDNA). These biomarkers have shown high diagnostic value and could guide the selection of appropriate targeted therapies. However, the abundance of these biomarker classes in the circulation is often too low to be detectable even with the most sensitive techniques because of their low levels of release from the tumor.
How can we make tumor cells release these biomarkers into the blood? The most straightforward way would be to puncture the cell membrane so that its content is released. One technology that allows for just that is high intensity focused ultrasound (HIFU). HIFU uses powerful, controlled ultrasound waves that are focused inside human body to ablate the targeted tissue at the focus without affecting the surrounding organs. Alternatively, if HIFU waves are sent in short, infrequent but powerful bursts, they cause mechanical disruption of tissue at the focus without any thermal effects. The disruption is achieved by small gas bubbles in tissue that appear, grow and collapse in response to the ultrasound wave– a phenomenon known as cavitation. Depending on the pulsing protocol employed, the outcome can range from small holes in cell membranes and capillaries to complete liquefaction of a small region of tumor. Using this technology, we seek to release biomarkers from tumor cells into the circulation in the effort to detect them using a blood test and avoiding biopsy.
Figure caption: Experimental setup and the basic concept of “ultrasound-aided liquid biopsy”. Pulsed high intensity focused ultrasound (HIFU) waves create, grow and collapse bubbles in tissue, which leads to puncturing of cell membranes and capillary walls. Cancer-derived microRNAs are thus released from the cells into the circulation and can be detected in a blood sample.
To test this approach, we applied pulsed HIFU exposures to prostate cancer tumors implanted under the skin of laboratory rats, as illustrated in the image above. For image guidance and targeting we used conventional ultrasound imaging. Blood samples were collected immediately before and at periodic intervals after HIFU treatment and were tested for the presence of microRNAs that are associated with rat prostate cancer. The levels of these miRNAs were elevated up to 12-fold within minutes after the ultrasound procedure, and then declined over the course of several hours. The effects on tissue were evaluated in the resected tumors, and we found only micron-sized areas of hemorrhage scattered through otherwise intact tissue, suggesting damage to small capillaries. These data provided the proof of principle for the approach that we termed “ultrasound-aided liquid biopsy”. We are now working on identifying other classes of clinically valuable biomarkers, most notably tumor-derived DNA, that could be amplified using this methodology.
Tatiana Khokhlova – email@example.com
George Schade – firstname.lastname@example.org
Yak-Nam Wang – email@example.com
Joo Ha Hwang – firstname.lastname@example.org
University of Washington
1013 NE 40th St
Seattle, WA 98105
John Chevillet – email@example.com
Institute for Systems Biology
401 Terry Ave N
Seattle, WA 98109
Maria Giraldez – firstname.lastname@example.org
Muneesh Tewari – email@example.com
University of Michigan
109 Zina Pitcher Place 4029
Ann Arbor, MI 48109
Popular version of paper 4pBA1
Presented Thursday afternoon, October 30, 2014, at 1:30 pm
168th ASA Meeting, Indianapolis
From listening to music to seeing an ultrasound of a baby in the womb, sounds are all around us and are an integral part of our daily life. Many of the sounds we want to hear – such as speaking with a friend at a restaurant – but other sounds (such as conversations at nearby tables) we want to block. This unwanted sound is referred to as noise, and for many years people have worked to make different types of passive devices (that is, does not require any power to operate) to reduce the noise level we hear, such as earplugs or sound absorbing panels.
These types of devices achieve their sound absorbing properties from the materials they are made of, which is traditionally a spongy material made from soft rubbers or fabrics. While effective at absorbing sound, these materials absorb sound equally from every direction, and the acoustic properties of such a material are referred to as isotropic. For applications where the source you are interested in (musicians on stage, friend seated across from you at dinner, etc.) is in one direction, and the source of the noise comes from another direction, these traditional sound absorbers will not discriminate between what you want to hear and what you don’t. Another limitation with traditional sound absorbers is the fact that these sound absorbing materials are visually opaque and cannot be used for transparent applications (which is why most indoor musical performance spaces or recording studios do not have windows).
Unfortunately, many of these qualities of sound absorbers are limited by the physical nature of the materials themselves. However, in recent years a new class of materials has been developed for acoustical applications referred to as acoustic metamaterials. Acoustic metamaterials use the acoustic motion of its carefully designed small-scale structure to create a composite material with extreme acoustic properties. These extreme properties are the focus of current research, and are being used to develop novel applications like acoustic cloaking and lenses with super-resolution (beyond the resolution which can be achieved with an ordinary lens). In these applications currently being investigated, acoustic metamaterials have typically been modeled using ideal materials with no losses (and therefore no absorption of sound), with the presence of losses seen as a hindrance to the design. In air, these losses arise from the friction of the air oscillating through the sound absorber. For sound absorber applications, however, accounting for these losses are necessary to absorb the acoustic energy.
Recently, there has been interest in using the losses within an acoustic metamaterial to make better sound absorbers using resonant structures. These resonant structures, like the ringing of a bell, are excited at a single frequency (tone), and only work over a very limited frequency range in the vicinity of that tone. An alternative approach is the use of sonic crystals, which are a periodic distribution of small, hard rods in air. Sonic crystals by themselves act like an ordinary sound absorber, but can be arranged and designed to create structures with extraordinary acoustic properties.
In this work, the use of densely packed sonic crystals was examined to demonstrate its applicability as a sound absorber. Sonic crystal samples were designed, modeled and then fabricated using a 3D printer to be acoustically tested. By varying the size and how densely packed the sonic crystals were, acoustic experimental measurements were made and compared with predicted values. Layered arrangements were designed and fabricated, which demonstrated different sound absorbing properties in different directions and are illustrated in Fig. 1.
Fig. 1 An acoustic metamaterial sound absorber made of alternating layers (shaded in gray) with each layer consisting of circular rods (black circles) that (a) absorbs sound in one direction, but (b) lets most of the sound through in the other direction. (c) A photo of a test sample (yellow) fabricated using a commercially available 3D printer.
While only a proof of concept, this work shows that acoustic metamaterials (in this case made from sonic crystals) can be used to create sound absorbers that are not isotropic (letting sound through in one direction while absorbing it in another). At the same time, the sonic crystals can be arranged to allow some visual transparency through the arrangement of rods, and can be fabricated using commercially available techniques such as a 3D printer. More details about the modeling, design and testing of this acoustic metamaterial absorber can be found in our paper, which is available at http://arxiv.org/abs/1405.7200
Matthew D. Guild* – firstname.lastname@example.org
Victor M. García-Chocano – email@example.com
Wave Phenomena Group
Dept. of Electronics Engineering,
Universitat Politècnica de València
Camino de vera s/n, E-46022 Valencia, Spain
Weiwei Kan – firstname.lastname@example.org
Department of Physics,
Key Laboratory of Modern Acoustics, MOE, Institute of Acoustics
Nanjing University, Nanjing 210093, People’s Republic of China
José Sánchez-Dehesa – email@example.com
Wave Phenomena Group
Dept. of Electronics Engineering,
Universitat Politècnica de València
Camino de vera s/n, E-46022 Valencia, Spain
* Current address: Acoustics Division, U.S. Naval Research Laboratory, Washington DC 20375, USA
Popular version of paper 1aNS2
Presented Monday morning, October 27, 2014
168th ASA Meeting, Indianapolis