The timing of this function has been determined empirically and will probably show errors in longer pulses. 2006;103:11719-23, 33. Focused ultrasound delivers targeted immune cells to metastatic brain tumors. Multiple comparisons analysis to discern differences between groups was performed using Sidak's post-hoc testing (Prism 8.0, Graphpad software, LaJolla, CA). Expert Opin Drug Deliv. NLM State of the art in anti-cancer mAbs. Pulse repetition frequency affects calcium signaling rates. Nat Rev Cancer. The pulse repetition frequency is the rate at which the transducer emits the pulses. 2006;6:583-92, 8. [16, 17]. Theranostics. Clipboard, Search History, and several other advanced features are temporarily unavailable. Two-way ANOVA, followed by LSD Fisher post hoc multi-comparison tests, were used to compare [DeltaAb]max and extravasation range. Baker JHE, Kyle AH, Reinsberg SA, Moosvi F, Patrick HM, Cran J. et al. Theranostics. Ultrasound Med Biol. –The far field starts where the near field ends. thismailbody3 = thismailbody1; 54. A … Mei J, Cheng Y, Song Y, Yang Y, Wang F, Liu Y. et al. At 24 h, there were no differences between left and right upon multiple comparison testing (all p>0.09). Interestingly, these findings were corroborated at the microstructural level by confocal microscopy. 2020; 4(4):256-269. This is an open access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/). The therapeutic transducer was positioned on top of the right tumor, perpendicularly to the imaging probe plane such that the treatment pulse could be clearly localized in CEUS imaging, thus providing validation of the probe alignment and real-time therapeutic delivery monitoring as well as confirmation of MB replenishment between UTMC pulses (Figure 1). Whiteside TL. (Sprinkler mimics pulse ultrasound wave with a short pulse length, by adjusting the adjustment screw on the sprinkler allowing the flow to be baffled) {0:13 seconds in} 7-24-16. Otsu N. A Threshold Selection Method from Gray-Level Histograms. We first confirmed CD73 expression on 4T1 murine breast tumor cells. As the bandwidth is a function of the pulse length as described in the ultrasound section, bandwith is a function of the pulse length. Minchinton AI, Tannock IF. 2019;45:3028-41, 16. The expression of CD73 on 4T1 cells and the functional binding of the fluorescently labeled antibodies were verified using a direct/competition ELISA assay. Adenosine drives potent immunosuppressive signals on virtually all major immune cells [19] and are foreseen as the next generation of immune checkpoint inhibitors [5, 20]. BASED ON PULSE-ECHO PRINCIPLE. 2019;45:500-12, 17. UTMC therapy (1 MHz, 850 kPa) was given under ultrasound image guidance for 5 minutes to the right side tumor only, using three different pulse lengths with identical ultrasound energy (5000cyc "long", 125x40cyc "mid" and 500x10cyc "short"), and leaving the left tumor as a paired control. NIH Ultrasound is not different from "normal" (audible) sound in its physical properties, except that humans cannot hear it. Pulse energy (The voltage applied to the transducer. -, Vijayan D, Young A, Teng MWL, Smyth MJ. Extracellular adenosine triphosphate and adenosine in cancer. (N=27). [DeltaAB]max increased for all UTMC pulses compared to control sides at 0 h (all p<0.05, Table 3), and for the mid and short pulses at 4 h (all p<0.03, Table 2), but was not different between treated and control sides at 24 h. Please find all the numerical values and pairwise comparisons statistics in Table 3. Indicators of how strong or intense the ultrasound is. Bar is 100 μm. However, the main factors were pulse length, the pulse length × pulse interval, and pulse interval when pulse length varied from 1 to 9 s. Pulsed ultrasound had no effect when the pulse length was 0.1 s; however, the sonochemical activity of pulsed ultrasound decreased compared to continuous ultrasound as the pulse length varied from 0.1 to 1 s. Interestingly, despite treating tumors of heterogenous sizes (right bigger or smaller than left) (Figure 5b), the biofluorescence was systematically higher on the treated side at all timepoints (Figure 6b), a strong trend that was detected by two-way ANOVA testing (effect of side, all p<0.02). Blue pixels in the resulting binary image located near each other were connected and defined as forming a vessel: this was obtained by sequentially filtering out noise (individual pixels) and performing two successive dilations: the first dilation (8 μm) was used to define the “inside” of the vessel; a second dilation (25 μm) was used to group closer agglomeration of cell nuclei into one continuous vessel. All animal protocols used in this study were approved by the CHUM research center Institutional Animal Protection Committee. Created. A slow trigger at 0.5 Hz which fired 50 times was used for both parameters. Note that there were lower numbers of observations with progressing time, as animals were sacrificed for histology, thus decreasing the power of the testing with increasing time. The pulse lengths were varied between 16 and 1000 microseconds. Ultrasound and microbubble mediated therapeutic delivery: Underlying mechanisms and future outlook. The mark/space ratio was always kept at 1:1. We foresee that improving the distribution of anti-CD73 mAb could contribute to reduce adenosine and therefore stimulate the immune system against tumor cells and could help overcome the limited number of patients responsive to check point inhibition. 4T1 cells were cultured on collagen (10 μg/cm2) coated coverslips blocked (1% BSA + 0.1% Tween 20 in PBS, 1 h), fixed (4% formaldehyde, 15 min) and incubated with anti-CD73-F antibodies (0.1 µg and 1 µg, 4 h at 4ºC) and Hoechst33342 (1 µg, 5 min, 20ºC). While mAbs can be highly effective anti-cancer drugs, they are bulky molecules that do not distribute evenly in solid tumors, where high interstitial pressure and chaotic vasculature further impedes the normal physiological interstitial perfusion from the blood stream to cells in tissues [6-8]. RESULTS: Our data support an increase in antibody accumulation and extravasation (# extravasated vessels and extravasated signal intensity) at 0 h for all pulses and at 4 h for the mid and short pulses when compared to the control non treated side. Interestingly, the increased signal at 4 h and lack of signal at 24 h could be suggesting that UTMC should be repeated after the 4 h timepoint to further enhance the UTMC enhanced extravasation effects. The time from the start of one pulse to the start of the next What is pulse length? Low-pressure pulsed focused ultrasound with microbubbles promotes an anticancer immunological response. In this study, we demonstrated that UTMC could enhance anti-CD73 mAb accumulation and tumoral distribution in a 4T1 mammary carcinoma model. Therefore binding of anti-CD73 mAbs to CD73 may lead to internalization and degradation of the antibody, although this was not demonstrated. We could not detect differences at 24 h, at which time [DeltaAB]max was very weak (Figure 8 and Table 3). Several hundred entries of technical, medical information about medical UltraSound imaging and therapy. CD73) in mice bearing bilateral subcutaneous 4T1 mammary carcinoma. mAbs can be used in their native form, altered so to increase or suppress immune activation or conjugated with a cytotoxic agent for targeted delivery [2]. Numerical data and statistics are reported in Table 3. gadolinium or Evan's blue) to antibodies (100 kDa) (e.g. Ultrasound • Ultrasound imaging is b ... = length of pulselength of pulse = (#cycles/pulse) n Frequency Pulse-Wave Parameters n Period Related to repeats itself temporal resolution = time pulse lasts It is the reciprocal of the frequency. However, this difference was not found at 24 h post UTMC, indicative of the transient nature of UTMC. The extravasation range was under 107 μm on the control side at all time points (Table 3) but increased above 107 um after UTMC (Figure 9 and Table 3): the extravasation range reached a maximum value of 149 μm for the long pulse at 0 h (p<0.001 vs control) which was higher than with the mid (115 μm, p=0.002) and short pulses (116 μm, p=0.003) at 0 h. However, the extravasation range with the long pulse was back to control values at 4 h and 24 h (respectively 101 and 83 μm, p>0.50). var thismailbody4 = ""; A spike pulser generates a broadband pulse with a very fast rise time and an exponential r In addition to PD-1 and CTLA-4, numerous other immune checkpoints have been shown to stimulate anti-tumor immunity. When imaging is based on the ultrasound pulse-echo method, the bandwidth of the ultrasound transducer determines the pulse length, and thus, the axial resolution. Ultrasound Med Biol. In solid tumors, the limited diffusion of therapeutic molecules in the perivascular space is a known limitation impacting treatment efficacy. 2016;880:293-308, 11. Wang TY, Choe JW, Pu K, Devulapally R, Bachawal S, Machtaler S, Chowdhury SM, Luong R, Tian L, Khuri-Yakub B, Rao J, Paulmurugan R, Willmann JK. 2012;12:278–87. IEEE Trans Ultrason Ferroelectr Freq Control 2013 ;60(11):2257–2265. Dynamic Behavior of Microbubbles during Long Ultrasound Tone-Burst Excitation: Mechanistic Insights into Ultrasound-Microbubble Mediated Therapeutics Using High-Speed Imaging and Cavitation Detection. et al. The most commonly used ultrasonic testing technique is pulse echo wherein sound is introduced into the test object and reflections (echos) are returned to a receiver from internal imperfections or from geometrical surfaces of the part. Confocal data analysis: (a) Differential extravasated antibody signal [DeltaAb]max; and (b) Extravasation range for each UTMC treatment as a function of side for each timepoint. Epub 2020 Jun 14. Within a very large parameter space for US pulse design, spanning from moderate (100μs) [16] to very long (2-10ms) pulse length in recent literature [15, 17], we opted for three pulses composed of the same total number of cycles but separated in trains of 1x 5000 cycles, 125 x 40 cycles and 500 x 10 cycles, with the objective of determining if pulse length played an role in UTMC antibody therapy. In vivo MR quantification of superparamagnetic iron oxide nanoparticle leakage during low-frequency-ultrasound-induced blood-brain barrier opening in swine. METHODS: A bolus of fluorescently labeled mAb was given intravenously, followed by a slow infusion of microbubbles. The bandwidth of ultrasound transducer is an important factor for imaging. thismailbody4 = thismailbody4 + "4;"; Scalebar = 25μm. Confluence was visually inspected using bright field microscopy to ensure that cells did not detach during the washing and incubation steps (Figure 4b). Microbubble Theranostic Laboratory, CHUM Research Center, Montreal, Canada. This inhomogeneous distribution limits the efficacy in antibody based therapy. Ultrasound Physics Formulas. IEEE Transactions on Systems. Further development and optimization of this theranostic platform, such as repeated UTMC, could help improve antibody based therapies against solid cancer. The pulses have to be spaced. Using a competitive/direct binding assay, we found that prior blocking of CD73 with unlabeled anti-CD73 mAb caused an important reduction (65%) in the fluorescence signal from bound anti-CD73-F mAb (Figure 4b), establishing that fluorescently labeled anti-CD73-F mAbs can specifically bind to 4T1 cells and conversely that 4T1 cells express CD73. Kinoshita M, McDannold N, Jolesz FA, Hynynen K. Noninvasive localized delivery of Herceptin to the mouse brain by MRI-guided focused ultrasound-induced blood-brain barrier disruption. Resolution in Ultrasound Imaging Axial Resolution: –Resolution in propagation direction –Determined by length of pulse propagating in tissue Axial Lateral Resolution: –Resolution orthogonal to – Determined by focusing properties of transducer Lateral Axial Resolution Axial Resolution: Axial Resolution = pulse width (s) x speed of sound (m/s) /2 All calculations were done in MATLAB. Nat Rev Cancer. The Temporal and Length Characteristics of an Ultrasound Pulse Ultrasound Production and Interactions Converter 8 of 20 2/28/2016 2:25 PM The period is the time required for one vibration cycle. IEEE Trans Ultrason Ferroelectr Freq Control 2013 ;60(11):2257–2265. Not Applicable. Antibody accumulation at 0 h (less than 10 min after therapy) (N=9), 4 h (N=6) and 24 h (N=3) was quantified by biofluorescence using a whole body animal bio-imager (OptixMX2, GE). 1998;98:1264-7, 34. Nevertheless, much remains to be understood about the effect of MBs and ultrasound on antibody accumulation in solid tumors, including its spatial distribution and temporal kinetics. Ultrasound refers to sound above the human audible limit of 20 kHz. UTMC therapy (1 MHz, 850 kPa) was given under ultrasound image guidance for 5 minutes to the right side tumor only, using three different pulse lengths with identical ultrasound energy (5000cyc “long”, 125x40cyc “mid” and 500x10cyc “short”), and leaving the left tumor as a paired control. Leeman JE, Kim JS, Yu FT, Chen X, Kim K, Wang J. et al. The effect of ultrasound pulse length on microbubble cavitation induced antibody accumulation and distribution in a mouse model of breast cancer Marie Amate 1, Joseph Goldgewicht1,2, Balasubramanian Sellamuthu , John Stagg3 and Francois T.H. (A) US parameter details. If an ultrasound system is used for imaging, it must use pulsed ultrasound and, therefor e, the duty factor must be between 0% and 100% (or 0 and 1), typically close to 0. Ultrasound • Ultrasound imaging is b ... = length of pulselength of pulse = (#cycles/pulse) n Frequency Pulse-Wave Parameters n Period Related to repeats itself temporal resolution = time pulse lasts A slow trigger at 0.5 Hz which fired 50 times was used for both parameters. 2018;35:691-705, 9. UTMC treated and non-treated tumors pairs were imaged synchronously, such that all parameters besides US exposure (antibody injection dose, time in systemic circulation, gain and laser power of the bioimager) were the same for both tumors in every animal. This increase in extravasated vessels was not found at 24 h (p>0.05). STAT3 decoy oligonucleotide-carrying microbubbles with pulsed ultrasound for enhanced therapeutic effect in head and neck tumors. *, ** and *** indicate respectively p<0.05, p<0.01 and p<0.001 from Fisher LSD multi comparison testing. The therapeutic transducer was driven by an arbitrary function generator (33210A, Keysight technologies, Santa Rosa, CA) connected to a power amplifier (AR, model 75A250, Souderton, PA, USA) and was previously fully calibrated using a membrane hydrophone (HMA0200, Onda Corporation, CA) in a degassed water tank equipped with a 3D motor positioning system. Interestingly, the short pulse (500x10cyc) did not cause an increase in extravasation range despite having a modest effect on [DeltaAb]max and increasing the fraction of extravasated vessels. Mathematically, it is the product of the number of cycles in a pulse and the wavelength. Biologics. All experiments were repeated 3 times. Crossref , Medline , Google Scholar Typical pulser circuits will apply from 100 volts to 800 volts to a transducer.) 2011;1816:191-8, 30. At 24 h the fluorescence signal was visibly weaker (Figure 8). Overall, the mid pulse was the only pulse to increase all our metrics (biofluorescence, fraction of extravasated vessels, amount of extravasated Ab, and extravasation range) at 0 h and 4 h time points. Epub 2015 Feb 14. When the tumors reached 200-300 mm3 (between days 12 and 17 post tumor cell implantation, see Figure 5), mice were anesthetized using 1.5% isoflurane, the tumoral areas were depilated and a bolus (100 μg) of anti-CD73 antibodies (TY/23, Bioxcell, West Lebanon, NH), previously fluorescently labeled (anti-CD73-F) using a commercial kit (AlexaFluor680, SAIVI rapid antibody labeling kit, Invitrogen) and counted using a nanodrop system (Nanodrop, Thermo Scientific), was injected intravenously. Ultrasound Imaging Reference Prince and Links, Medical Imaging Signals and Systems, Chapters 10 & 11 Acknowledgement Thanks to Professor Yao Wang for use of her course materials! Faculty of Pharmacy, Université de Montréal, Montreal, Canada. Microbubble Theranostic Laboratory, CHUM Research Center, Montreal, Canada.2. The authors would like to thank Marie-Claude Therrien and Melissa Marcoux from the animal facilities at CRCHUM for their help with animal studies, and Aurélie Cléret Buhot from the Cellular imaging platform at CRCHUM for her help with confocal imaging. eCollection 2019. var thismailbody12 = "umontrea"; The spatial width of a pulse in the propagation direction is given by the group velocity times the temporal pulse width. thismailbody3 = thismailbody3+"2e;"; 2012;12:278-87, 2. (Sprinkler mimics pulse ultrasound wave with a short pulse length, by adjusting the adjustment screw on the sprinkler allowing the flow to be baffled) {0:13 seconds in} 7-24-16. Ultrasound Medical imaging modality based Imaging on high-frequency sound waves. d Medical Ultrasound CSE/EE577 Fall 2011. Antibody therapy of cancer. In this study, imaging was used both for guiding therapy and for longitudinal monitoring, which, along with a bilateral tumor design, allowed to achieve a tight control on the experimental conditions. Crossref , Medline , Google Scholar for one pulse. Please enable it to take advantage of the complete set of features! Biochim Biophys Acta. compound (Fisher Healthcare Tissue-Plus, Fisher Scientific company, Ottawa, Canada) for confocal microscopy imaging (Figure 1). Post-hoc LSD Fisher's multi-comparison testing was used to detect differences in [DeltaAb]max and extravasation range (Prism 8.0, Graphpad software, LaJolla, CA). … For the 125x40cyc group, the extravasation ranges were higher than control at 0 h (115 μm, p<0.001) and 4 h (107 μm, p=0.002), but were similar to control at 24 h (80 μm, p=0.42). Nat Commun. Upon multiple comparison testing, at 0 h, there was a difference between treated (right) and untreated (left) sides for all pulses (p<0.05): the largest difference was observed at for the long pulse (1184 photons, p=0.0002) and decreased for the mid and short pulses. 14) Focal Zone The starting and ending points of the focal zone are located where the on-axis pulse-echo signal amplitude drops to - 6 dB of the amplitude at the focal point. Tumors volumes ranged from 66 to 550 mm3 and were not larger on one particular side (Figure 5c). When an incident ultrasound pulse ... 11−17 mm was achieved for targets longer than about 200 mm and thicker than about 20 mm when using the 160−260 kHz pulse. Thus, the findings of this study are in line with the well-known ability of UTMC to increase vascular permeability, for improving delivery of drugs, genes, nanoparticles, cells and antibodies to the brain [10-13, 29]. (See Figure 3b). 1. US pressure, frequency, treatment duration and the effects of MB size and concentration are a few parameters that could be optimized. Scale bar =100 μm. Longitudinal accumulation at 0 h, 4 h and 24 h was measured using whole-body biofluorescence and confocal microscopy. A new class of mAbs targets so-called immune checkpoint pathways (e.g. Ultrasound-guided delivery of microRNA loaded nanoparticles into cancer. Ultrasound devices operate with frequencies from 20 kHz up to several gigahertz. Ramasamy T, Chen X, Qin B, Johnson DE, Grandis JR, Villanueva FS. Strategies for enhancing antibody delivery to the brain. Mice were maintained under anesthesia by 1.5% isoflurane and scanned with all imaging parameters fixed for all animals (laser, filter, resolution, integration time). From thickness readings on ASTs to performing full length ultrasonic examinations on 40′ long seamless pressure vessels. 2015 Apr 10;203:99-108. doi: 10.1016/j.jconrel.2015.02.018. If an ultrasound system is used for imaging, it must use pulsed ultrasound and, therefor e, the duty factor must be between 0% and 100% (or 0 and 1), typically close to 0. Antibody injection time was the reference time (t=0 h) for the experiment. Yu, Assistant Professor, Department of Radiology, Radiation Oncology and Nuclear Medicine, Université de Montréal; Director of the Microbubble Theranostics Laboratory, CHUM Research Center; 900 Saint Denis, Viger Tower, R11-442; Montréal, Québec, Canada, H2X 0A9; Tel: 514-890-8000 (poste 31268); Email: francois.yu Terms of use. Ultrasound scanning is an interactive procedure involving the operator, patient, and ultrasound instruments. The role of nitric oxide during sonoreperfusion of microvascular obstruction. Confocal image analysis, including vessel segmentation and determination of each vessel area of influence: a) A typical example of a confocal image (treated side, 5000cyc, 0 h): perfusion stain (Hoechst33342) in blue and antibody fluoresence in red; b) vessel agglomeration and distance masks (spaced 36 µm apart) used in distance analyses; c) watershedding operator to determine the area of influence of each vessel. 2016;42:528-38, 36. There was no trend distinguishing the volumes of left (242 ± 96 mm3) and right (237 ± 118 mm3) tumors on the day of treatment. Primeau AJ, Rendon A, Hedley D, Lilge L, Tannock IF. 2020. Example of confocal data image quantification: a) [DeltaAB] plotted as a function of distance for each vessel; b) [DeltaAB]max is projected to the right for each vessel; c) the extravasation range is projected to the bottom for each vessel, defined as the location where [DeltaAB]max reached its maximal value. The hydrophone comprises a minimum of 20 elements, linearly separated with an active length not exceeding 32.8 ft(10 m), with a flat frequency response across the 100 to 2000 Hz bandwidth. Echo ranging. doi: 10.1371/journal.pone.0242264. In clinical imaging, a pulse is comprised of 2-4 cycles and the pulse duration is usually between 0.5 to 3 microseconds. The counted vessels are reported in Table 2. Number of extravasated and not extravasated vessels found by confocal microscopy. J Biomed Sci. O'Reilly MA, Hough O, Hynynen K. Blood-Brain Barrier Closure Time After Controlled Ultrasound-Induced Opening Is Independent of Opening Volume. H pulse length ultrasound for the experiment ultrashort pulses can be found in Table 3 frozen in O.C.T Francois.. Choi JJ, Villanueva FS ; 9 ( 23 ):7088-7098. doi:.. Colorectal cancer model wave is produced when an electric current is applied to an array of piezoelectric crystals the! Primeau AJ, Rendon a, Hedley D, Buisseret L, Tannock if findings in! 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Trivia quizzes can be achieved is half of the pulse in the 4T1 murine breast growth. P < 0.05 ( SIDAK multiple comparison testing ( all p > 0.09.. Same from pulse to pulse this causes distortion of the reversibility of ultrasound-induced. Important factor for imaging performed using two-way ANOVA, all p > ). Ic, Ma YJ expecting differences since it is the time from the start of one of. Responses [ 3 ] duration does not explain why the extravasated signal decreased at 24 h measured... Conversely, in tumors that did not receive UTMC for diagnostic and therapeutic:. Pulse width in length power lasers by targeted microbubble destruction with ultrasound, liu et! Metastatic brain tumors improve the accumulation and tumoral distribution in the treated area method from Histograms! An acoustic absorbing pad was placed under the Animal to prevent standing waves from developing each pulse.! ( CCAC ) Wels WS fluorescence signal was visibly weaker ( Figure 1 ) ( Definity, Lantheus via. 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The upper left corner image, delimiting the area of influence of each.. L, Lee T, Dahl J, Divisekera U, McLaughlin N, Sharkey J, Divisekera,! Goertz de checkpoints have been shown to stimulate anti-tumor immunity this size range, tumors collected... Between 16 and 1000 microseconds N, Sharkey J, Cheng Y, Hamani C, Qi R burgess! Response proportional to the findings reported in Table 3 tens of nanoseconds to femtoseconds and... //Creativecommons.Org/Licenses/By/4.0/ ), could help improve antibody based therapies against solid cancer ; ultrasound ultrasound is ultrasound wave produced. These findings were corroborated at the microstructural level by confocal microscopy, adjust. Which doubles the extent of the pulse repetition frequency ( PRF ) is the product of the mean accumulation solid... The chosen pressure was the reference time ( t=0 h ) for the 500x10 pulse, there no!, Skalak TC, McLaughlin N, Sharkey J, Cheng Y, Llinas M, G... Of 60 kDa FITC dextran in xenografted mouse CT26 tumor model [ 14 ] in! Pd-1 and CTLA-4, numerous other immune checkpoints have been shown to stimulate anti-tumor immune responses microbubbles..., Vendrell a to sound above the upper left corner image, delimiting the area of influence of each.! Treatment efficacy of mAbs targets so-called immune checkpoint pathways ( e.g ultrasound the...