- Email: [email protected]
A pilot study of endoluminal US for stool liquefaction
NEW METHODS: Experimental Endoscopy
A pilot study of endoluminal US for stool liquefaction Lyndon V. Hernandez, MD, MPH,1 George Triadafilopoulos, MD,2 Joseph Kost, PhD,3 Robert A. Ganz, MD,4 Shane Fleshman,5 Dominic Klyve, PhD,6 Martin Ton,7 George Lewis, PhD5 Franklin, Wisconsin; Palo Alto, California, USA; Beer-Sheva, Israel; Minneapolis, Minnesota; Trumbull, Connecticut; Ellensburg; Washington; Ithaca, New York, USA
Background: There is a need to cleanse patients who are poorly prepared for colonoscopy safely and efficiently during the procedure to minimize rescheduling. US is already being used in catheter-based intravascular thrombolysis, and time-reversal acoustic (TRA) has been explored in assisting drug delivery to the brain. Objective: To explore the efficacy and safety of a miniaturized endoluminal US device in stool dissolution as a means to salvage poor bowel preparation. Design: Proof of concept experimental study. Settings: Animal laboratory. Interventions: Low-frequency US and TRAs. Main Outcome Measurements: Feasibility, efficacy, and safety of US to liquefy stools ex vivo. Results: Depending on parameters, such as pulse rate, acoustic intensity, and duration, increases in liquefaction speeds by a factor of 50 and 100 times were obtained. There was a significant difference in weight change between the 20-kHz–treated sample compared with controls (P % .0001). There was no difference in sloughing of mucosa and mechanical injury among the US, water spray, and control groups. Limitations: Animal model. Conclusion: Endoluminal US can liquefy stools at acoustic exposure levels that do not damage ex vivo colonic mucosa. Endoluminal US should be able to dissolve stools more rapidly than water spray alone, thereby optimizing colonoscopic evaluation in vivo.
A good-quality bowel preparation at colonoscopy improves polyp detection rates1,2 and reduces the procedure duration.3 Poor colon cleansing increases the cost of colonoscopy by up to 22%,4 and using water spray and suction during a colonoscopy is too time-consuming when faced with a poorly prepared colon.
Our aim was to evaluate the efficacy and safety of endoluminal US to dissolve stool as a means to salvage poor bowel preparation or to serve as an adjunct to a partial bowel preparation. We also looked into the feasibility of using time-reversal acoustics (TRAs) to efficiently deliver US in the colon.
Abbreviations: PVDF, polyvinylidene fluoride; TRA, time-reversal acoustic.
Current affiliations: Medical College of Wisconsin, GI Associates, LLC, Milwaukee, Wisconsin (1), Stanford University, Palo Alto, California (2), Ben-Gurion University, Beer-Sheva, Israel (3), Minnesota Gastroenterology, Minneapolis, Minnesota (4), ZetrOz, LLC, Trumbull, Connecticut (5), Central Washington University, Ellensburg, Washington (6), Cornell University, Ithaca, New York (7).
DISCLOSURE: The following authors disclosed financial relationships relevant to this publication: S. Fleshman: Biomedical Engineer for Advanced Health Products for ZetrOz, LLC; George Lewis: Chief Scientific Officer, Inventor, and Co-founder for ZetrOz, LLC. All other authors disclosed no financial relationships relevant to this publication. Copyright ª 2014 by the American Society for Gastrointestinal Endoscopy 0016-5107/$36.00 http://dx.doi.org/10.1016/j.gie.2013.11.012 Received August 19, 2013. Accepted November 6, 2013.
508 GASTROINTESTINAL ENDOSCOPY Volume 79, No. 3 : 2014
Presented at Digestive Disease Week, May 20, 2013; and Acoustical Society of America Meeting in 2013, December 2-6, 2013 (Proc Meet Acoust 2013;19). Reprint requests: Lyndon V. Hernandez, MD, MPH, Medical College of Wisconsin, GI Associates, LLC, 3111 W. Rawson Ave, Suite 240, Franklin, WI 53132.
www.giejournal.org
Hernandez et al
Endoluminal US for stool liquefaction
METHODS Take-home Message
Bench studies We placed 20 mL of solid stools in saline solution. A US transducer (Sonics & Materials, Newtown, CT), operating at 20 kHz, was immersed at 40% duty cycle for up to 1 minute at an intensity of 3.2 W/cm2.
Low-frequency US can liquefy solid stools more rapidly than water spray alone. A low-cost, disposable material such as polyvinylidene fluoride can efficiently focus US energy in the colon.
Figure 1. US liquefaction experiment showing transducer within (A) and on (B) porcine colon.
Stool samples were categorized as type 4 as defined on the Bristol stool scale.5 After recording initial mass, we placed the samples into water and then either exposed the sample to US or left untreated for control. After
exposure, we aspirated water and debris, recorded the weight of remaining stool, and calculated the percent weight change of stool. We then carried out an ex vivo safety study on freshly harvested porcine colon, divided into 3 groups: US treated with water spray (n Z 3), water spray alone (n Z 3), or control (n Z 3). For the sonicated group, a colon segment was mounted onto a glass dish containing saline solution with the transducer at a height of 2.5 cm. A sonicator (ETL Testing Laboratories, Cortland, NY) operated at z80 kHz and produced z173 kPa (25.1 psi or 1.71 atm) for a 30-minute period, which is a far harsher acoustic pressure than that to which living tissue is exposed. Water spray was applied at a rate of 300 mL/min of water, which is about 3 times the flow rate of a standard colonoscope’s water spray.6 Histologic analysis of the tissues was performed by a pathologist who was unaware of the treatment delivered. Figure 1A and B illustrate a typical sonication experiment on a colon segment. For demonstration purposes, our initial nonworking prototype consisted of a miniaturized 30-element 235-kHz array (Fig. 2) mounted as a cap on the tip of a colonoscope (GIF-160 Olympus, Lake Success, NY).
www.giejournal.org
Volume 79, No. 3 : 2014 GASTROINTESTINAL ENDOSCOPY 509
Figure 2. First-generation US consisting of a 30-element, 235-kHz array mounted as a cap on the tip of a colonoscope.
Endoluminal US for stool liquefaction
Hernandez et al
Figure 3. TRA focusing in porcine model. A, Disposable PVDF on a colonoscope tip that detects US coming from the extracorporeal transducer and reflects it into the lumen. B, TRA electronic system consisting of National Instruments (NI) PXIe-1082 chassis, NI PXIe-8133 embedded controller, and custom amplification boards (Ithaca, NY). C, A 32-channel array transducer placed extracorporeally on swine hind limb.
Animal studies A second-generation US was developed consisting of a TRA extracorporeal 32-channel array that was electrically focused to flexible polyvinylidene fluoride (PVDF) detectors (Figs. 3A and B) on a colonoscope. The PVDF serves as a beacon to reflect US energy into the colon lumen. The 32-channel array was placed on the hind limb of a euthanized 35-kg domestic swine with a neoprene wrap (Fig. 3C), and the TRA colonoscope was inserted into the colon. Our Institutional Animal Care and Use Committee reviewed and approved our study.
low-frequency sonification (Fig. 4B). There was no detectable change in consistency after 10 minutes of exposure to water in the control group. Ultrasonic liquefaction also enhanced the ability to visualize mucosal detail (Fig. 4C-E). Higher frequencies (O1000 kHz) did not affect stool viscosity.
Exposure of ex vivo colonic mucosa to water spray and sonication
Solid stool samples in saline solution (Fig. 4A) turned into a fully dispersed liquid sludge within seconds of
Parametric exposure times and intensities were then explored for effectiveness of US on liquefying solid porcine stool. Figure 5 compares the time course of multiple transducers and their dichotomous efficacy when compared with water spray (control). Controls and 231-kHz samples actually swelled and increased in weight, whereas 85 kHz at 50 kPa (7.25 PSI or .493 atm) exposure to US increased liquefaction by greater than 50 times. Depending on parameters such as pulse rate, acoustic intensity, and duration, an increase in liquefaction speed by a factor of 50 and 100 times compared with control was obtained. Thus, the percent reduction in mass of the 85-kHz–sonicated stool from pre- to post-treatment was greater than 50 times that of the percent reduction in mass of the controls and 231 kHz. On the other hand, there was a significant
510 GASTROINTESTINAL ENDOSCOPY Volume 79, No. 3 : 2014
www.giejournal.org
Statistical analysis We calculated P values by running a series of 2-tailed, 1-sample t tests against the null hypothesis that the weight change induced by a given transducer is equal to the change induced by sonication using the lowest available frequency (20 kHz).
RESULTS In vitro liquefaction
Hernandez et al
Endoluminal US for stool liquefaction
Figure 4. Solid stool (A) in saline solution that is decanted in liquefied state (B) after ultrasonic treatment. Representative images demonstrating the enhanced ability to detect a colon polyp in a phantom colon model, after solid stool (C) was mostly cleared after ultrasonic liquefaction (D) and suction (E).
differences between water spray and US-treated tissues (Fig. 6).
TRA in an animal model The 3-dimensional resolution of the targeted US beam was 1.5 mm for 1-MHz arrays and 10.5 mm for 191-kHz arrays; this is the point at which the acoustic pressure is 3 decibels (or about 1.5 times) of the original strength. The focusing resolution of the ultrasonic field (Fig. 7) yielded a signal-to-noise ratio of 7, demonstrating accurate US focusing.
DISCUSSION
difference in weight change between the 20-kHz–treated sample compared with controls (P % .0001), 231 kHz (P % .0001), and 85 kHz (P % .0001). Histologic examination showed preservation of normal mucosa without
An estimated 25% of colonoscopic examinations7 lead to suboptimal bowel preparation and incomplete mucosal evaluation. Fourteen million screening colonoscopies are performed yearly in the United States8; thus, a substantial number of patients undergo substandard examinations using current methods of preprocedure and intraprocedure cleansing. The future of colonoscopy remains to be
www.giejournal.org
Volume 79, No. 3 : 2014 GASTROINTESTINAL ENDOSCOPY 511
Figure 5. Stool dissolution plot of stool liquefaction after various sonication frequencies (5 trials per transducer).
Endoluminal US for stool liquefaction
Hernandez et al
Figure 6. No damage or discoloration was seen in sonicated samples before (A) and after (B) US. Representative high-power microscopic images of porcine colon (H&E) showing no appreciable difference in sloughing of mucosa and mechanical injury other than expected autolysis (after US [C] and control [D]).
determined, but a time-efficient manner of delivering care will become a priority in an era of bundled, value-based payments. When low-frequency US energy passes through tissue, acoustic pressure waves impart a direct force needed for liquefaction. Microscopic bubbles, activated by acoustic cavitation in liquid medium, are the agents that deliver mechanical energy. In vascular tissues, fibrin lattice, which
anchors red blood cells together, undergo spatial disarrangement when exposed to US pressure waves, leading to enhanced thrombolysis. This concept forms the framework for sonothrombolysis in cerebral ischemia9 and myocardial infarction.10 The colon presents unique challenges for accurate focusing of ultrasonic waves because of heterogeneities of sound velocity in biologic tissues, air, and fluid and reflective boundaries that distort a US field. TRA is a simple technique based on the reversibility of acoustic propagation wherein a time-reversed version of an incident pressure field naturally refocuses on its source. Remarkably, numerous reflections from internal structures, which greatly limit conventional US, actually enhance focusing in the TRA system. Although TRA has been extensively investigated by many groups,11-14 the application of TRA to the GI tract can be considered innovative. Limitations in our preliminary study will need to be addressed in the future. First, bulky, solid stools are ideal for our method, but disaggregating soft stools that are adherent to the wall of the colon present an obvious challenge. One advantage of TRA is that a series of disposable PVDF can be wrapped along the entire length of the colonoscope. After the colonoscope is advanced, sonicating the colon will have cleared most adherent fecal material by the time the endoscopist is withdrawing from the cecum. Another advantage of this method is eliminating the risk of injury to the colon as compared with the first generation’s use of an unwieldy transducer on the tip of the colonoscope. These developments set the stage for innovative use of TRA to construct focal volumes of arbitrary shape that will
512 GASTROINTESTINAL ENDOSCOPY Volume 79, No. 3 : 2014
www.giejournal.org
Figure 7. Acoustic pressure graph showing focusing resolution at 191 kHz and 1 MHz.
Hernandez et al
Endoluminal US for stool liquefaction
extracorporeal transducers. However, design modifications will be required to address various stochastic challenges in a poorly prepared colon in vivo. ACKNOWLEDGMENTS We thank Professor Robert Langer of Cambridge, Massachusetts, for initiating our collaboration. We also thank Jacque Dresen for preparation of this manuscript. REFERENCES
match the unique intestinal dimensions of each patient. Aside from treating fecal impaction, TRA will be useful in other indications, such as clearing of blood clots15 in acute GI bleeding and dissolution of impacted food in the esophagus or gastric bezoars where a controlled acoustic ablation is needed to prevent intestinal wall injury. The creation of focal spots of desired shapes is made possible by superimposing time-reversed impulse responses at several points within the volume where US will be focused (Fig. 8). Recording a set of impulse responses along the insertion path of the colonoscope will provide a library of signals, enabling creation of a desired 3-dimensional shape. Using elastographic processing can also further improve contrast during colonoscopy to provide rapid feedback to the endoscopist where colon polyps are located, particularly those difficult to detect visually. We conclude that low-frequency sonication can generate sufficient acoustic mechanical agitation to liquefy stool samples and should lead to stool dissolution more rapidly than water spray alone at exposure levels that do not damage ex vivo colon. TRA is a simple method that enables the use of a disposable, low-cost material on a colonoscope, serving as a beacon to reflect US from reusable
1. Chiu HM, Lin JT, Wang HP, et al. The impact of colon preparation timing on colonoscopic detection of colorectal neoplasmsda prospective endoscopist-blinded randomized trial. Am J Gastroenterol 2006;101:2719-25. 2. Froehlich F, Wietlisbach V, Gonvers JJ, et al. Impact of colonic cleansing on quality and diagnostic yield of colonoscopy: the European Panel of Appropriateness of Gastrointestinal Endoscopy European multicenter study. Gastrointest Endosc 2005;61:378-84. 3. Kössi J, Kontula I, Laato M. Sodium phosphate is superior to polyethylene glycol in bowel cleansing and shortens the time it takes to visualize colon mucosa. Scand J Gastroenterol 2003;38:1187-90. 4. Rex DK, Imperiale TF, Latinovich DR, et al. Impact of bowel preparation on efficiency and cost of colonoscopy. Am J Gastroenterol 2002;97: 1696-700. 5. Lewis SJ, Heaton KW. Stool form scale as a useful guide to intestinal transit time. Scand J Gastroenterol 1997;32:920-4. 6. Moshkowitz M, Hirsch Y, Carmel I, et al. A novel device for rapid cleaning of poorly prepared colons. Endoscopy 2010;42:834-6. 7. Lebwohl B, Kastrinos F, Glick M, et al. The impact of suboptimal bowel preparation on adenoma miss rates and the factors associated with early repeat colonoscopy. Gastrointest Endosc 2011;73:1207-14. 8. Seeff LC, Manninen DL, Dong FB, et al. Is there endoscopic capacity to provide colorectal cancer screening to the unscreened population in the United States? Gastroenterology 2004;127:1661-9. 9. Ricci S, Dinia L, Del Sette M, et al. Sonothrombolysis for acute ischaemic stroke. Cochrane Database Syst Rev 2012, June 13;6: CDOO8348. 10. Slikkerveer J, Kleijn SA, Appelman Y, et al. Ultrasound enhanced prehospital thrombolysis using microbubbles infusion in patients with acute ST elevation myocardial infarction: pilot of the Sonolysis study. Ultrasound Med Biol 2012;38:247-52. 11. Lewis GK Jr, Guarino S, Gandhi G, et al. Time-reversal techniques in ultrasound-assisted convection-enhanced drug delivery to the brain: technology development and in vivo evaluation. Proc Meet Acoust 2011;11:20005-31. 12. Sarvazyan AP, Fillinger L, Gavrilov LR. A comparative study of systems used for dynamic focusing of ultrasound. Acoust Phys 2009;55: 630-7. 13. Sarvazyan A, Fillinger L, Gavrilov L. Time-reversal acoustic focusing system as a virtual random phased array. IEEE Trans Ultrason Ferroelectr Freq Control 2010;57:812-7. 14. Sutin A, Sarvazyan A. Advantages of time reversal acoustic focusing system in biomedical applications. J Acoust Soc Am 2005;118:1941. 15. Barlinn K, Alexandrov AV. Sonothrombolysis in ischemic stroke. Curr Treat Options Neurol 2013;15:91-103.
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Volume 79, No. 3 : 2014 GASTROINTESTINAL ENDOSCOPY 513
Figure 8. Illustration of multiple TRA points in the colon to allow various US intensities and frequencies that may be focused independently according to individual colonic shape. TRA, time-reversal acoustic.
A pilot study of endoluminal US for stool liquefaction Lyndon V. Hernandez, MD, MPH,1 George Triadafilopoulos, MD,2 Joseph Kost, PhD,3 Robert A. Ganz, MD,4 Shane Fleshman,5 Dominic Klyve, PhD,6 Martin Ton,7 George Lewis, PhD5 Franklin, Wisconsin; Palo Alto, California, USA; Beer-Sheva, Israel; Minneapolis, Minnesota; Trumbull, Connecticut; Ellensburg; Washington; Ithaca, New York, USA
Background: There is a need to cleanse patients who are poorly prepared for colonoscopy safely and efficiently during the procedure to minimize rescheduling. US is already being used in catheter-based intravascular thrombolysis, and time-reversal acoustic (TRA) has been explored in assisting drug delivery to the brain. Objective: To explore the efficacy and safety of a miniaturized endoluminal US device in stool dissolution as a means to salvage poor bowel preparation. Design: Proof of concept experimental study. Settings: Animal laboratory. Interventions: Low-frequency US and TRAs. Main Outcome Measurements: Feasibility, efficacy, and safety of US to liquefy stools ex vivo. Results: Depending on parameters, such as pulse rate, acoustic intensity, and duration, increases in liquefaction speeds by a factor of 50 and 100 times were obtained. There was a significant difference in weight change between the 20-kHz–treated sample compared with controls (P % .0001). There was no difference in sloughing of mucosa and mechanical injury among the US, water spray, and control groups. Limitations: Animal model. Conclusion: Endoluminal US can liquefy stools at acoustic exposure levels that do not damage ex vivo colonic mucosa. Endoluminal US should be able to dissolve stools more rapidly than water spray alone, thereby optimizing colonoscopic evaluation in vivo.
A good-quality bowel preparation at colonoscopy improves polyp detection rates1,2 and reduces the procedure duration.3 Poor colon cleansing increases the cost of colonoscopy by up to 22%,4 and using water spray and suction during a colonoscopy is too time-consuming when faced with a poorly prepared colon.
Our aim was to evaluate the efficacy and safety of endoluminal US to dissolve stool as a means to salvage poor bowel preparation or to serve as an adjunct to a partial bowel preparation. We also looked into the feasibility of using time-reversal acoustics (TRAs) to efficiently deliver US in the colon.
Abbreviations: PVDF, polyvinylidene fluoride; TRA, time-reversal acoustic.
Current affiliations: Medical College of Wisconsin, GI Associates, LLC, Milwaukee, Wisconsin (1), Stanford University, Palo Alto, California (2), Ben-Gurion University, Beer-Sheva, Israel (3), Minnesota Gastroenterology, Minneapolis, Minnesota (4), ZetrOz, LLC, Trumbull, Connecticut (5), Central Washington University, Ellensburg, Washington (6), Cornell University, Ithaca, New York (7).
DISCLOSURE: The following authors disclosed financial relationships relevant to this publication: S. Fleshman: Biomedical Engineer for Advanced Health Products for ZetrOz, LLC; George Lewis: Chief Scientific Officer, Inventor, and Co-founder for ZetrOz, LLC. All other authors disclosed no financial relationships relevant to this publication. Copyright ª 2014 by the American Society for Gastrointestinal Endoscopy 0016-5107/$36.00 http://dx.doi.org/10.1016/j.gie.2013.11.012 Received August 19, 2013. Accepted November 6, 2013.
508 GASTROINTESTINAL ENDOSCOPY Volume 79, No. 3 : 2014
Presented at Digestive Disease Week, May 20, 2013; and Acoustical Society of America Meeting in 2013, December 2-6, 2013 (Proc Meet Acoust 2013;19). Reprint requests: Lyndon V. Hernandez, MD, MPH, Medical College of Wisconsin, GI Associates, LLC, 3111 W. Rawson Ave, Suite 240, Franklin, WI 53132.
www.giejournal.org
Hernandez et al
Endoluminal US for stool liquefaction
METHODS Take-home Message
Bench studies We placed 20 mL of solid stools in saline solution. A US transducer (Sonics & Materials, Newtown, CT), operating at 20 kHz, was immersed at 40% duty cycle for up to 1 minute at an intensity of 3.2 W/cm2.
Low-frequency US can liquefy solid stools more rapidly than water spray alone. A low-cost, disposable material such as polyvinylidene fluoride can efficiently focus US energy in the colon.
Figure 1. US liquefaction experiment showing transducer within (A) and on (B) porcine colon.
Stool samples were categorized as type 4 as defined on the Bristol stool scale.5 After recording initial mass, we placed the samples into water and then either exposed the sample to US or left untreated for control. After
exposure, we aspirated water and debris, recorded the weight of remaining stool, and calculated the percent weight change of stool. We then carried out an ex vivo safety study on freshly harvested porcine colon, divided into 3 groups: US treated with water spray (n Z 3), water spray alone (n Z 3), or control (n Z 3). For the sonicated group, a colon segment was mounted onto a glass dish containing saline solution with the transducer at a height of 2.5 cm. A sonicator (ETL Testing Laboratories, Cortland, NY) operated at z80 kHz and produced z173 kPa (25.1 psi or 1.71 atm) for a 30-minute period, which is a far harsher acoustic pressure than that to which living tissue is exposed. Water spray was applied at a rate of 300 mL/min of water, which is about 3 times the flow rate of a standard colonoscope’s water spray.6 Histologic analysis of the tissues was performed by a pathologist who was unaware of the treatment delivered. Figure 1A and B illustrate a typical sonication experiment on a colon segment. For demonstration purposes, our initial nonworking prototype consisted of a miniaturized 30-element 235-kHz array (Fig. 2) mounted as a cap on the tip of a colonoscope (GIF-160 Olympus, Lake Success, NY).
www.giejournal.org
Volume 79, No. 3 : 2014 GASTROINTESTINAL ENDOSCOPY 509
Figure 2. First-generation US consisting of a 30-element, 235-kHz array mounted as a cap on the tip of a colonoscope.
Endoluminal US for stool liquefaction
Hernandez et al
Figure 3. TRA focusing in porcine model. A, Disposable PVDF on a colonoscope tip that detects US coming from the extracorporeal transducer and reflects it into the lumen. B, TRA electronic system consisting of National Instruments (NI) PXIe-1082 chassis, NI PXIe-8133 embedded controller, and custom amplification boards (Ithaca, NY). C, A 32-channel array transducer placed extracorporeally on swine hind limb.
Animal studies A second-generation US was developed consisting of a TRA extracorporeal 32-channel array that was electrically focused to flexible polyvinylidene fluoride (PVDF) detectors (Figs. 3A and B) on a colonoscope. The PVDF serves as a beacon to reflect US energy into the colon lumen. The 32-channel array was placed on the hind limb of a euthanized 35-kg domestic swine with a neoprene wrap (Fig. 3C), and the TRA colonoscope was inserted into the colon. Our Institutional Animal Care and Use Committee reviewed and approved our study.
low-frequency sonification (Fig. 4B). There was no detectable change in consistency after 10 minutes of exposure to water in the control group. Ultrasonic liquefaction also enhanced the ability to visualize mucosal detail (Fig. 4C-E). Higher frequencies (O1000 kHz) did not affect stool viscosity.
Exposure of ex vivo colonic mucosa to water spray and sonication
Solid stool samples in saline solution (Fig. 4A) turned into a fully dispersed liquid sludge within seconds of
Parametric exposure times and intensities were then explored for effectiveness of US on liquefying solid porcine stool. Figure 5 compares the time course of multiple transducers and their dichotomous efficacy when compared with water spray (control). Controls and 231-kHz samples actually swelled and increased in weight, whereas 85 kHz at 50 kPa (7.25 PSI or .493 atm) exposure to US increased liquefaction by greater than 50 times. Depending on parameters such as pulse rate, acoustic intensity, and duration, an increase in liquefaction speed by a factor of 50 and 100 times compared with control was obtained. Thus, the percent reduction in mass of the 85-kHz–sonicated stool from pre- to post-treatment was greater than 50 times that of the percent reduction in mass of the controls and 231 kHz. On the other hand, there was a significant
510 GASTROINTESTINAL ENDOSCOPY Volume 79, No. 3 : 2014
www.giejournal.org
Statistical analysis We calculated P values by running a series of 2-tailed, 1-sample t tests against the null hypothesis that the weight change induced by a given transducer is equal to the change induced by sonication using the lowest available frequency (20 kHz).
RESULTS In vitro liquefaction
Hernandez et al
Endoluminal US for stool liquefaction
Figure 4. Solid stool (A) in saline solution that is decanted in liquefied state (B) after ultrasonic treatment. Representative images demonstrating the enhanced ability to detect a colon polyp in a phantom colon model, after solid stool (C) was mostly cleared after ultrasonic liquefaction (D) and suction (E).
differences between water spray and US-treated tissues (Fig. 6).
TRA in an animal model The 3-dimensional resolution of the targeted US beam was 1.5 mm for 1-MHz arrays and 10.5 mm for 191-kHz arrays; this is the point at which the acoustic pressure is 3 decibels (or about 1.5 times) of the original strength. The focusing resolution of the ultrasonic field (Fig. 7) yielded a signal-to-noise ratio of 7, demonstrating accurate US focusing.
DISCUSSION
difference in weight change between the 20-kHz–treated sample compared with controls (P % .0001), 231 kHz (P % .0001), and 85 kHz (P % .0001). Histologic examination showed preservation of normal mucosa without
An estimated 25% of colonoscopic examinations7 lead to suboptimal bowel preparation and incomplete mucosal evaluation. Fourteen million screening colonoscopies are performed yearly in the United States8; thus, a substantial number of patients undergo substandard examinations using current methods of preprocedure and intraprocedure cleansing. The future of colonoscopy remains to be
www.giejournal.org
Volume 79, No. 3 : 2014 GASTROINTESTINAL ENDOSCOPY 511
Figure 5. Stool dissolution plot of stool liquefaction after various sonication frequencies (5 trials per transducer).
Endoluminal US for stool liquefaction
Hernandez et al
Figure 6. No damage or discoloration was seen in sonicated samples before (A) and after (B) US. Representative high-power microscopic images of porcine colon (H&E) showing no appreciable difference in sloughing of mucosa and mechanical injury other than expected autolysis (after US [C] and control [D]).
determined, but a time-efficient manner of delivering care will become a priority in an era of bundled, value-based payments. When low-frequency US energy passes through tissue, acoustic pressure waves impart a direct force needed for liquefaction. Microscopic bubbles, activated by acoustic cavitation in liquid medium, are the agents that deliver mechanical energy. In vascular tissues, fibrin lattice, which
anchors red blood cells together, undergo spatial disarrangement when exposed to US pressure waves, leading to enhanced thrombolysis. This concept forms the framework for sonothrombolysis in cerebral ischemia9 and myocardial infarction.10 The colon presents unique challenges for accurate focusing of ultrasonic waves because of heterogeneities of sound velocity in biologic tissues, air, and fluid and reflective boundaries that distort a US field. TRA is a simple technique based on the reversibility of acoustic propagation wherein a time-reversed version of an incident pressure field naturally refocuses on its source. Remarkably, numerous reflections from internal structures, which greatly limit conventional US, actually enhance focusing in the TRA system. Although TRA has been extensively investigated by many groups,11-14 the application of TRA to the GI tract can be considered innovative. Limitations in our preliminary study will need to be addressed in the future. First, bulky, solid stools are ideal for our method, but disaggregating soft stools that are adherent to the wall of the colon present an obvious challenge. One advantage of TRA is that a series of disposable PVDF can be wrapped along the entire length of the colonoscope. After the colonoscope is advanced, sonicating the colon will have cleared most adherent fecal material by the time the endoscopist is withdrawing from the cecum. Another advantage of this method is eliminating the risk of injury to the colon as compared with the first generation’s use of an unwieldy transducer on the tip of the colonoscope. These developments set the stage for innovative use of TRA to construct focal volumes of arbitrary shape that will
512 GASTROINTESTINAL ENDOSCOPY Volume 79, No. 3 : 2014
www.giejournal.org
Figure 7. Acoustic pressure graph showing focusing resolution at 191 kHz and 1 MHz.
Hernandez et al
Endoluminal US for stool liquefaction
extracorporeal transducers. However, design modifications will be required to address various stochastic challenges in a poorly prepared colon in vivo. ACKNOWLEDGMENTS We thank Professor Robert Langer of Cambridge, Massachusetts, for initiating our collaboration. We also thank Jacque Dresen for preparation of this manuscript. REFERENCES
match the unique intestinal dimensions of each patient. Aside from treating fecal impaction, TRA will be useful in other indications, such as clearing of blood clots15 in acute GI bleeding and dissolution of impacted food in the esophagus or gastric bezoars where a controlled acoustic ablation is needed to prevent intestinal wall injury. The creation of focal spots of desired shapes is made possible by superimposing time-reversed impulse responses at several points within the volume where US will be focused (Fig. 8). Recording a set of impulse responses along the insertion path of the colonoscope will provide a library of signals, enabling creation of a desired 3-dimensional shape. Using elastographic processing can also further improve contrast during colonoscopy to provide rapid feedback to the endoscopist where colon polyps are located, particularly those difficult to detect visually. We conclude that low-frequency sonication can generate sufficient acoustic mechanical agitation to liquefy stool samples and should lead to stool dissolution more rapidly than water spray alone at exposure levels that do not damage ex vivo colon. TRA is a simple method that enables the use of a disposable, low-cost material on a colonoscope, serving as a beacon to reflect US from reusable
1. Chiu HM, Lin JT, Wang HP, et al. The impact of colon preparation timing on colonoscopic detection of colorectal neoplasmsda prospective endoscopist-blinded randomized trial. Am J Gastroenterol 2006;101:2719-25. 2. Froehlich F, Wietlisbach V, Gonvers JJ, et al. Impact of colonic cleansing on quality and diagnostic yield of colonoscopy: the European Panel of Appropriateness of Gastrointestinal Endoscopy European multicenter study. Gastrointest Endosc 2005;61:378-84. 3. Kössi J, Kontula I, Laato M. Sodium phosphate is superior to polyethylene glycol in bowel cleansing and shortens the time it takes to visualize colon mucosa. Scand J Gastroenterol 2003;38:1187-90. 4. Rex DK, Imperiale TF, Latinovich DR, et al. Impact of bowel preparation on efficiency and cost of colonoscopy. Am J Gastroenterol 2002;97: 1696-700. 5. Lewis SJ, Heaton KW. Stool form scale as a useful guide to intestinal transit time. Scand J Gastroenterol 1997;32:920-4. 6. Moshkowitz M, Hirsch Y, Carmel I, et al. A novel device for rapid cleaning of poorly prepared colons. Endoscopy 2010;42:834-6. 7. Lebwohl B, Kastrinos F, Glick M, et al. The impact of suboptimal bowel preparation on adenoma miss rates and the factors associated with early repeat colonoscopy. Gastrointest Endosc 2011;73:1207-14. 8. Seeff LC, Manninen DL, Dong FB, et al. Is there endoscopic capacity to provide colorectal cancer screening to the unscreened population in the United States? Gastroenterology 2004;127:1661-9. 9. Ricci S, Dinia L, Del Sette M, et al. Sonothrombolysis for acute ischaemic stroke. Cochrane Database Syst Rev 2012, June 13;6: CDOO8348. 10. Slikkerveer J, Kleijn SA, Appelman Y, et al. Ultrasound enhanced prehospital thrombolysis using microbubbles infusion in patients with acute ST elevation myocardial infarction: pilot of the Sonolysis study. Ultrasound Med Biol 2012;38:247-52. 11. Lewis GK Jr, Guarino S, Gandhi G, et al. Time-reversal techniques in ultrasound-assisted convection-enhanced drug delivery to the brain: technology development and in vivo evaluation. Proc Meet Acoust 2011;11:20005-31. 12. Sarvazyan AP, Fillinger L, Gavrilov LR. A comparative study of systems used for dynamic focusing of ultrasound. Acoust Phys 2009;55: 630-7. 13. Sarvazyan A, Fillinger L, Gavrilov L. Time-reversal acoustic focusing system as a virtual random phased array. IEEE Trans Ultrason Ferroelectr Freq Control 2010;57:812-7. 14. Sutin A, Sarvazyan A. Advantages of time reversal acoustic focusing system in biomedical applications. J Acoust Soc Am 2005;118:1941. 15. Barlinn K, Alexandrov AV. Sonothrombolysis in ischemic stroke. Curr Treat Options Neurol 2013;15:91-103.
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Figure 8. Illustration of multiple TRA points in the colon to allow various US intensities and frequencies that may be focused independently according to individual colonic shape. TRA, time-reversal acoustic.