@article{annayev_minhaj_adelegan_yamaner_dayton_oralkan_2024, title={Design and Fabrication of 1-D CMUT Arrays for Dual-Mode Dual-Frequency Acoustic Angiography Applications}, volume={71}, ISSN={["1525-8955"]}, url={https://doi.org/10.1109/TUFFC.2023.3342011}, DOI={10.1109/TUFFC.2023.3342011}, abstractNote={When microbubble contrast agents are excited at low frequencies (less than 5 MHz), they resonate and produce higher-order harmonics due to their nonlinear behavior. We propose a novel scheme with a capacitive micromachined ultrasonic transducer (CMUT) array to receive high-frequency microbubble harmonics in collapse mode and to transmit a low-frequency high-pressure pulse by releasing the CMUT plate from collapse and pull it back to collapse again in the same transmit-receive cycle. By patterning and etching the substrate to create glass spacers in the device cavity we can reliably operate the CMUT in collapse mode and receive high-frequency signals. Previously, we demonstrated a single-element CMUT with spacers operating in the described fashion. In this article, we present the design and fabrication of a dual-mode, dual-frequency 1-D CMUT array with 256 elements. We present two different insulating glass spacer designs in rectangular cells for the collapse mode. For the device with torus-shaped spacers, the 3 dB receive bandwidth is from 8 to 17 MHz, and the transmitted maximum peak-to-peak pressure from 32 elements at 4 mm focal depth was 2.12 MPa with a 1.21 MPa peak negative pressure, which corresponds to a mechanical index (MI) of 0.58 at 4.3 MHz. For the device with line-shaped spacers, the 3-dB receive bandwidth at 150 V dc bias extends from 10.9 to 19.2 MHz. By increasing the bias voltage to 180 V, the 3 dB bandwidth shifts, and extends from 11.7 to 20.4 MHz. The transmitting maximum peak-to-peak pressure with 32 elements at 4 mm was 2.06 MPa with a peak negative pressure of 1.19 MPa, which corresponds to an MI of 0.62 at 3.7 MHz.}, number={1}, journal={IEEE TRANSACTIONS ON ULTRASONICS FERROELECTRICS AND FREQUENCY CONTROL}, author={Annayev, Muhammetgeldi and Minhaj, Tamzid Ibn and Adelegan, Oluwafemi J. and Yamaner, Feysel Yalcin and Dayton, Paul A. and Oralkan, Omer}, year={2024}, month={Jan}, pages={191–201} }
 @article{mccall_chavignon_couture_dayton_pinton_2024, title={Element Position Calibration for Matrix Array Transducers with Multiple Disjoint Piezoelectric Panels}, ISSN={["1096-0910"]}, DOI={10.1177/01617346241227900}, abstractNote={Two-dimensional ultrasound transducers enable the acquisition of fully volumetric data that have been demonstrated to provide greater diagnostic information in the clinical setting and are a critical tool for emerging ultrasound methods, such as super-resolution and functional imaging. This technology, however, is not without its limitations. Due to increased fabrication complexity, some matrix probes with disjoint piezoelectric panels may require initial calibration. In this manuscript, two methods for calibrating the element positions of the Vermon 1024-channel 8 MHz matrix transducer are detailed. This calibration is a necessary step for acquiring high resolution B-mode images while minimizing transducer-based image degradation. This calibration is also necessary for eliminating vessel-doubling artifacts in super-resolution images and increasing the overall signal-to-noise ratio (SNR) of the image. Here, we show that the shape of the point spread function (PSF) can be significantly improved and PSF-doubling artifacts can be reduced by up to 10 dB via this simple calibration procedure.}, journal={ULTRASONIC IMAGING}, author={McCall, Jacob R. and Chavignon, Arthur and Couture, Olivier and Dayton, Paul A. and Pinton, Gianmarco F.}, year={2024}, month={Feb} }
 @article{mccall_jones_santibanez_latham_zou_dayton_pinton_2024, title={The development of a 1.25 MHz 1024-channel sparse array for human transcranial imaging: <i>in vitro</i> characterization}, volume={35}, ISSN={["1361-6501"]}, DOI={10.1088/1361-6501/ad117f}, abstractNote={Ultrasound imaging is overwhelmingly used as 2D modality even though 3D imaging capabilities have existed for decades. Recent generational shifts toward super-resolution ultrasound imaging and functional ultrasound imaging, especially in the brain, have generated renewed and sustained interest in acquiring truly volumetric, 4D data. However, volumetric imaging approaches are currently limited to small animals, due in part to the difficulty of imaging transcranially in humans and due to a lack of imaging arrays designed for this purpose. Clinical translation of these recent techniques as well as conventional diagnostic B-mode imaging may thus benefit from array designs that capitalize on large channel count imaging systems. We have designed and developed a 1024-channel sparse array with a 65 mm circular aperture and a 1–2 MHz bandwidth. This unique transducer achieves an aperture that is far larger than conventional matrix probes using a sparse arrangement of elements ordered in a density-tapered spiral design. This design has significantly decreased grating lobes compared to a matrix array probe. The large aperture of this probe also enables acquisition over a large field of view with a significant depth of more than 100 mm. Simulations, acoustic characterization, and in vitro tests demonstrate that this transducer achieves a high focal gain that enables ultrasonic visualization beneath the human skull and at large depths due to its low F-number capabilities. Furthermore, we show that this transducer is capable of high point target contrast and high soft tissue contrast, with contrast-to-noise ratios up to 1.9 when imaging transcranially through a 3 mm thick section of human skull. Because of the large surface area of this probe, it can capture over 3 coherence lengths in each dimension and is, therefore, able to able to ‘average out’ the aberration over a large surface area. This transducer is poised to have a significant clinical impact in transcranial human imaging.}, number={3}, journal={MEASUREMENT SCIENCE AND TECHNOLOGY}, author={McCall, J. R. and Jones, R. M. and Santibanez, F. and Latham, K. and Zou, J. and Dayton, P. A. and Pinton, G. F.}, year={2024}, month={Mar} }
 @article{zhang_wu_kim_welch_cornett_stocker_nogueira_kim_owens_dayton_et al._2023, title={A Model of High-Speed Endovascular Sonothrombolysis with Vortex Ultrasound-Induced Shear Stress to Treat Cerebral Venous Sinus Thrombosis}, volume={6}, ISSN={["2639-5274"]}, DOI={10.34133/research.0048}, abstractNote={This research aims to demonstrate a novel vortex ultrasound enabled endovascular thrombolysis method designed for treating cerebral venous sinus thrombosis (CVST). This is a topic of substantial importance since current treatment modalities for CVST still fail in as many as 20% to 40% of the cases, and the incidence of CVST has increased since the outbreak of the coronavirus disease 2019 pandemic. Compared with conventional anticoagulant or thrombolytic drugs, sonothrombolysis has the potential to remarkably shorten the required treatment time owing to the direct clot targeting with acoustic waves. However, previously reported strategies for sonothrombolysis have not demonstrated clinically meaningful outcomes (e.g., recanalization within 30 min) in treating large, completely occluded veins or arteries. Here, we demonstrated a new vortex ultrasound technique for endovascular sonothrombolysis utilizing wave-matter interaction-induced shear stress to enhance the lytic rate substantially. Our in vitro experiment showed that the lytic rate was increased by at least 64.3% compared with the nonvortex endovascular ultrasound treatment. A 3.1-g, 7.5-cm-long, completely occluded in vitro 3-dimensional model of acute CVST was fully recanalized within 8 min with a record-high lytic rate of 237.5 mg/min for acute bovine clot in vitro. Furthermore, we confirmed that the vortex ultrasound causes no vessel wall damage over ex vivo canine veins. This vortex ultrasound thrombolysis technique potentially presents a new life-saving tool for severe CVST cases that cannot be efficaciously treated using existing therapies.}, journal={RESEARCH}, author={Zhang, Bohua and Wu, Huaiyu and Kim, Howuk and Welch, Phoebe J. and Cornett, Ashley and Stocker, Greyson and Nogueira, Raul G. and Kim, Jinwook and Owens, Gabe and Dayton, Paul A. and et al.}, year={2023}, month={Jan}, pages={1–13} }
 @article{le_hoang_azarang_lance_natoli_gatrell_blogg_dayton_tillmans_lindholm_et al._2023, title={An open-source framework for synthetic post-dive Doppler ultrasound audio generation}, volume={18}, ISSN={["1932-6203"]}, DOI={10.1371/journal.pone.0284922}, abstractNote={Doppler ultrasound (DU) measurements are used to detect and evaluate venous gas emboli (VGE) formed after decompression. Automated methodologies for assessing VGE presence using signal processing have been developed on varying real-world datasets of limited size and without ground truth values preventing objective evaluation. We develop and report a method to generate synthetic post-dive data using DU signals collected in both precordium and subclavian vein with varying degrees of bubbling matching field-standard grading metrics. This method is adaptable, modifiable, and reproducible, allowing for researchers to tune the produced dataset for their desired purpose. We provide the baseline Doppler recordings and code required to generate synthetic data for researchers to reproduce our work and improve upon it. We also provide a set of pre-made synthetic post-dive DU data spanning six scenarios representing the Spencer and Kisman-Masurel (KM) grading scales as well as precordial and subclavian DU recordings. By providing a method for synthetic post-dive DU data generation, we aim to improve and accelerate the development of signal processing techniques for VGE analysis in Doppler ultrasound.}, number={4}, journal={PLOS ONE}, author={Le, David Q. and Hoang, Andrew H. and Azarang, Arian and Lance, Rachel M. and Natoli, Michael and Gatrell, Alan and Blogg, S. Lesley and Dayton, Paul A. and Tillmans, Frauke and Lindholm, Peter and et al.}, year={2023}, month={Apr} }
 @misc{bautista_kim_xu_jiang_dayton_2023, title={Current Status of Sub-micron Cavitation-Enhancing Agents for Sonothrombolysis}, volume={49}, ISSN={["1879-291X"]}, DOI={10.1016/j.ultrasmedbio.2023.01.018}, abstractNote={Thrombosis in cardiovascular disease is an urgent global issue, but treatment progress is limited by the risks of current antithrombotic approaches. The cavitation effect in ultrasound-mediated thrombolysis offers a promising mechanical alternative for clot lysis. Further addition of microbubble contrast agents introduces artificial cavitation nuclei that can enhance the mechanical disruption induced by ultrasound. Recent studies have proposed sub-micron particles as novel sonothrombolysis agents with increased spatial specificity, safety and stability for thrombus disruption. In this article, the applications of different sub-micron particles for sonothrombolysis are discussed. Also reviewed are in vitro and in vivo studies that apply these particles as cavitation agents and as adjuvants to thrombolytic drugs. Finally, perspectives on future developments in sub-micron agents for cavitation-enhanced sonothrombolysis are shared. Thrombosis in cardiovascular disease is an urgent global issue, but treatment progress is limited by the risks of current antithrombotic approaches. The cavitation effect in ultrasound-mediated thrombolysis offers a promising mechanical alternative for clot lysis. Further addition of microbubble contrast agents introduces artificial cavitation nuclei that can enhance the mechanical disruption induced by ultrasound. Recent studies have proposed sub-micron particles as novel sonothrombolysis agents with increased spatial specificity, safety and stability for thrombus disruption. In this article, the applications of different sub-micron particles for sonothrombolysis are discussed. Also reviewed are in vitro and in vivo studies that apply these particles as cavitation agents and as adjuvants to thrombolytic drugs. Finally, perspectives on future developments in sub-micron agents for cavitation-enhanced sonothrombolysis are shared.}, number={5}, journal={ULTRASOUND IN MEDICINE AND BIOLOGY}, author={Bautista, Kathlyne Jayne B. and Kim, Jinwook and Xu, Zhen and Jiang, Xiaoning and Dayton, Paul A.}, year={2023}, month={May}, pages={1049–1057} }
 @article{azarang_le_hoang_blogg_dayton_lance_natoli_gatrell_tillmans_moon_et al._2023, title={Deep Learning-Based Venous Gas Emboli Grade Classification in Doppler Ultrasound Audio Recordings}, volume={70}, ISSN={["1558-2531"]}, DOI={10.1109/TBME.2022.3217711}, abstractNote={Objective: Doppler ultrasound (DU) is used to detect venous gas emboli (VGE) post dive as a marker of decompression stress for diving physiology research as well as new decompression procedure validation to minimize decompression sickness risk. In this article, we propose the first deep learning model for VGE grading in DU audio recordings. Methods: A database of real-world data was assembled and labeled for the purpose of developing the algorithm, totaling 274 recordings comprising both subclavian and precordial measurements. Synthetic data was also generated by acquiring baseline DU signals from human volunteers and superimposing laboratory-acquired DU signals of bubbles flowing in a tissue mimicking material. A novel squeeze-and-excitation deep learning model was designed to effectively classify recordings on the 5-class Spencer scoring system used by trained human raters. Results: On the real-data test set, we show that synthetic data pretraining achieves average ordinal accuracy of 84.9% for precordial and 90.4% for subclavian DU which is a 24.6% and 26.2% increase over training with real-data and time-series augmentation only. The weighted kappa coefficients of agreement between the model and human ground truth were 0.74 and 0.69 for precordial and subclavian respectively, indicating substantial agreement similar to human inter-rater agreement for this type of data. Conclusion: The present work demonstrates the first application of deep-learning for DU VGE grading using a combination of synthetic and real-world data. Significance: The proposed method can contribute to accelerating DU analysis for decompression research.}, number={5}, journal={IEEE TRANSACTIONS ON BIOMEDICAL ENGINEERING}, author={Azarang, Arian and Le, David Q. and Hoang, Andrew H. and Blogg, S. Lesley and Dayton, Paul A. and Lance, Rachel M. and Natoli, Michael and Gatrell, Alan and Tillmans, Frauke and Moon, Richard E. and et al.}, year={2023}, month={May}, pages={1436–1446} }
 @article{durham_upadhyay_navarro-becerra_moon_borden_dayton_papadopoulou_2023, title={Effect of Anesthetic Carrier Gas on In Vivo Circulation Times of Intravenously Administered Phospholipid Oxygen Microbubbles in Rats}, volume={49}, ISSN={["1879-291X"]}, DOI={10.1016/j.ultrasmedbio.2023.04.016}, abstractNote={For the treatment of tumor hypoxia, microbubbles comprising oxygen as a majority component of the gas core with a stabilizing shell may be used to deliver and release oxygen locally at the tumor site through ultrasound destruction. Previous work has revealed differences in circulation half-life in vivo for perfluorocarbon-filled microbubbles, typically used as ultrasound imaging contrast agents, as a function of anesthetic carrier gas. These differences in circulation time in vivo were likely due to gas diffusion as a function of anesthetic carrier gas, among other variables. This work has motivated studies to evaluate the effect of anesthetic carrier gas on oxygen microbubble circulation dynamics.Circulation time for oxygen microbubbles was derived from ultrasound image intensity obtained during longitudinal kidney imaging. Studies were constructed for rats anesthetized on inhaled isoflurane with either pure oxygen or medical air as the anesthetic carrier gas.Results indicated that oxygen microbubbles were highly visible via contrast-specific imaging. Marked signal enhancement and duration differences were observed between animals breathing air and oxygen. Perhaps counterintuitively, oxygen microbubbles disappeared from circulation significantly faster when the animals were breathing pure oxygen compared with medical air. This may be explained by nitrogen counterdiffusion from blood into the bubble, effectively changing the gas composition of the core, as has been observed in perfluorocarbon core microbubbles.Our findings suggest that the apparent longevity and persistence of oxygen microbubbles in circulation may not be reflective of oxygen delivery when the animal is anesthetized breathing air.}, number={8}, journal={ULTRASOUND IN MEDICINE AND BIOLOGY}, author={Durham, Phillip G. and Upadhyay, Awaneesh and Navarro-Becerra, J. Angel and Moon, Richard E. and Borden, Mark A. and Dayton, Paul A. and Papadopoulou, Virginie}, year={2023}, month={Aug}, pages={1861–1866} }
 @article{moody_durham_dayton_brudno_2023, title={Loading Intracranial Drug-Eluting Reservoirs Across the Blood-Brain Barrier With Focused Ultrasound}, volume={49}, ISSN={["1879-291X"]}, DOI={10.1016/j.ultrasmedbio.2023.03.012}, abstractNote={Objective Efficient, sustained and long-term delivery of therapeutics to the brain remains an important challenge to treatment of diseases such as brain cancer, stroke and neurodegenerative disease. Focused ultrasound can assist movement of drugs into the brain, but frequent and long-term use has remained impractical. Single-use intracranial drug-eluting depots show promise but are limited for the treatment of chronic diseases as they cannot be refilled non-invasively. Refillable drug-eluting depots could serve as a long-term solution, but refilling is hindered by the blood–brain barrier (BBB), which prevents drug refills from accessing the brain. In this article, we describe how focused ultrasound enables non-invasive loading of intracranial drug depots in mice. Methods Female CD-1 mice (n = 6) were intracranially injected with click-reactive and fluorescent molecules that are capable of anchoring in the brain. After healing, animals were treated with high-intensity focused ultrasound and microbubbles to temporarily increase the permeability of the blood–brain barrier and deliver dibenzocyclooctyne (DBCO)–Cy7. The mice were perfused, and the brains were imaged via ex vivo fluorescence imaging. Results Fluorescence imaging indicated small molecule refills are captured by intracranial depots as long as 4 wk after administration and are retained for up to 4 wk based on fluorescence imaging. Efficient loading was dependent on both focused ultrasound and the presence of refillable depots in the brain as absence of either prevented intracranial loading. Conclusion The ability to target and retain small molecules at predetermined intracranial sites with pinpoint accuracy provides opportunities to continuously deliver drugs to the brain over weeks and months without excessive BBB opening and with minimal off-target side effects. Efficient, sustained and long-term delivery of therapeutics to the brain remains an important challenge to treatment of diseases such as brain cancer, stroke and neurodegenerative disease. Focused ultrasound can assist movement of drugs into the brain, but frequent and long-term use has remained impractical. Single-use intracranial drug-eluting depots show promise but are limited for the treatment of chronic diseases as they cannot be refilled non-invasively. Refillable drug-eluting depots could serve as a long-term solution, but refilling is hindered by the blood–brain barrier (BBB), which prevents drug refills from accessing the brain. In this article, we describe how focused ultrasound enables non-invasive loading of intracranial drug depots in mice. Female CD-1 mice (n = 6) were intracranially injected with click-reactive and fluorescent molecules that are capable of anchoring in the brain. After healing, animals were treated with high-intensity focused ultrasound and microbubbles to temporarily increase the permeability of the blood–brain barrier and deliver dibenzocyclooctyne (DBCO)–Cy7. The mice were perfused, and the brains were imaged via ex vivo fluorescence imaging. Fluorescence imaging indicated small molecule refills are captured by intracranial depots as long as 4 wk after administration and are retained for up to 4 wk based on fluorescence imaging. Efficient loading was dependent on both focused ultrasound and the presence of refillable depots in the brain as absence of either prevented intracranial loading. The ability to target and retain small molecules at predetermined intracranial sites with pinpoint accuracy provides opportunities to continuously deliver drugs to the brain over weeks and months without excessive BBB opening and with minimal off-target side effects.}, number={7}, journal={ULTRASOUND IN MEDICINE AND BIOLOGY}, author={Moody, Christopher T. and Durham, Phillip G. and Dayton, Paul A. and Brudno, Yevgeny}, year={2023}, month={Jul}, pages={1679–1685} }
 @article{mccall_santibanez_belgharbi_pinton_dayton_2023, title={Non-invasive transcranial volumetric ultrasound localization microscopy of the rat brain with continuous, high volume-rate acquisition}, volume={13}, ISSN={["1838-7640"]}, DOI={10.7150/thno.79189}, abstractNote={Rationale: Structure and function of the microvasculature provides critical information about disease state, can be used to identify local regions of pathology, and has been shown to be an indicator of response to therapy. Improved methods of assessing the microvasculature with non-invasive imaging modalities such as ultrasound will have an impact in biomedical theranostics. Ultrasound localization microscopy (ULM) is a new technology which allows processing of ultrasound data for visualization of microvasculature at a resolution better than allowed by acoustic diffraction with traditional ultrasound systems. Previous application of this modality in brain imaging has required the use of invasive procedures, such as a craniotomy, skull-thinning, or scalp removal, all of which are not feasible for the purpose of longitudinal studies. Methods: The impact of ultrasound localization microscopy is expanded using a 1024 channel matrix array ultrasonic transducer, four synchronized programmable ultrasound systems with customized high-performance hardware and software, and high-performance GPUs for processing. The potential of the imaging hardware and processing approaches are demonstrated in-vivo. Results: Our unique implementation allows asynchronous acquisition and data transfer for uninterrupted data collection at an ultra-high fixed frame rate. Using these methods, the vasculature was imaged using 100,000 volumes continuously at a volume acquisition rate of 500 volumes per second. With ULM, we achieved a resolution of 31 µm, which is a resolution improvement on conventional ultrasound imaging by nearly a factor of ten, in 3-D. This was accomplished while imaging through the intact skull with no scalp removal, which demonstrates the utility of this method for longitudinal studies. Conclusions: The results demonstrate new capabilities to rapidly image and analyze complex vascular networks in 3-D volume space for structural and functional imaging in disease assessment, targeted therapeutic delivery, monitoring response to therapy, and other theranostic applications.}, number={3}, journal={THERANOSTICS}, author={McCall, Jacob R. and Santibanez, Francisco and Belgharbi, Hatim and Pinton, Gianmarco F. and Dayton, Paul A.}, year={2023}, pages={1235–1246} }
 @article{papadopoulou_sidders_lu_velez_durham_bui_angeles-solano_dayton_rowe_2023, title={Overcoming biological barriers to improve treatment of a Staphylococcus aureus wound infection}, volume={30}, ISSN={["2451-9448"]}, DOI={10.1016/j.chembiol.2023.04.009}, abstractNote={<h2>Summary</h2> Chronic wounds frequently become infected with bacterial biofilms which respond poorly to antibiotic therapy. Aminoglycoside antibiotics are ineffective at treating deep-seated wound infections due to poor drug penetration, poor drug uptake into persister cells, and widespread antibiotic resistance. In this study, we combat the two major barriers to successful aminoglycoside treatment against a biofilm-infected wound: limited antibiotic uptake and limited biofilm penetration. To combat the limited antibiotic uptake, we employ palmitoleic acid, a host-produced monounsaturated fatty acid that perturbs the membrane of gram-positive pathogens and induces gentamicin uptake. This novel drug combination overcomes gentamicin tolerance and resistance in multiple gram-positive wound pathogens. To combat biofilm penetration, we examined the ability of sonobactericide, a non-invasive ultrasound-mediated-drug delivery technology to improve antibiotic efficacy using an <i>in vivo</i> biofilm model. This dual approach dramatically improved antibiotic efficacy against a methicillin-resistant <i>Staphylococcus aureus</i> (MRSA) wound infection in diabetic mice.}, number={5}, journal={CELL CHEMICAL BIOLOGY}, author={Papadopoulou, Virginie and Sidders, Ashelyn E. and Lu, Kuan-Yi and Velez, Amanda Z. and Durham, Phillip G. and Bui, Duyen T. and Angeles-Solano, Michelle and Dayton, Paul A. and Rowe, Sarah E.}, year={2023}, month={May}, pages={513-+} }
 @misc{papadopoulou_stride_borden_eisenbrey_dayton_2023, title={Radiotherapy Sensitization With Ultrasound-Stimulated Intravenously Injected Oxygen Microbubbles Can Have Contrary Effects Depending on the Study Model}, volume={49}, ISSN={["1879-291X"]}, DOI={10.1016/j.ultrasmedbio.2023.06.006}, abstractNote={We are writing to share our collective experience over the last few years working on radiosensitization strategies using intravenously administered, ultrasound-stimulated, oxygen microbubbles. There has been considerable pre-clinical success reported to date, including from our own groups, using oxygen microbubbles as a cancer theranostic agent to improve radiotherapy, sonodynamic therapy and brachytherapy treatments [ 1 Eisenbrey JR Shraim R Liu JB Li J Stanczak M Oeffinger B et al. Sensitization of hypoxic tumors to radiation therapy using ultrasound-sensitive oxygen microbubbles. Int J Radiat Oncol Biol Phys. 2018; 101: 88-96 Abstract Full Text Full Text PDF PubMed Scopus (68) Google Scholar , 2 Fix SM Papadopoulou V Velds H Kasoji SK Rivera JN Borden MA et al. Oxygen microbubbles improve radiotherapy tumor control in a rat fibrosarcoma model—a preliminary study. PLoS One. 2018; 13e0195667 Crossref Scopus (31) Google Scholar , 3 McEwan C Owen J Stride E Fowley C Nesbitt H Cochrane D et al. Oxygen carrying microbubbles for enhanced sonodynamic therapy of hypoxic tumours. J Control Release. 2015; 203: 51-56 Crossref PubMed Scopus (198) Google Scholar , 4 Peng S Song R Lin Q Zhang Y Yang Y Luo M et al. A robust oxygen microbubble radiosensitizer for iodine-125 brachytherapy. Adv Sci (Weinh). 2021; 82002567 Google Scholar ]. However, we have recently come across several unexpected findings that warrant further study and caution as these techniques move toward translation. As we work toward publishing these in the coming months, we believe that their implications are important to communicate quickly and we therefore outline key observations in this letter.}, number={9}, journal={ULTRASOUND IN MEDICINE AND BIOLOGY}, author={Papadopoulou, Virginie and Stride, Eleanor P. and Borden, Mark A. and Eisenbrey, John R. and Dayton, Paul A.}, year={2023}, month={Sep}, pages={2203–2204} }
 @article{walmer_ritter_sridharan_kasoji_altun_lee_olinger_wagner_radhakrishna_johnson_et al._2023, title={The Performance of Flash Replenishment Contrast-Enhanced Ultrasound for the Qualitative Assessment of Kidney Lesions in Patients with Chronic Kidney Disease}, volume={12}, ISSN={["2077-0383"]}, DOI={10.3390/jcm12206494}, abstractNote={We investigated the accuracy of CEUS for characterizing cystic and solid kidney lesions in patients with chronic kidney disease (CKD). Cystic lesions are assessed using Bosniak criteria for computed tomography (CT) and magnetic resonance imaging (MRI); however, in patients with moderate to severe kidney disease, CT and MRI contrast agents may be contraindicated. Contrast-enhanced ultrasound (CEUS) is a safe alternative for characterizing these lesions, but data on its performance among CKD patients are limited. We performed flash replenishment CEUS in 60 CKD patients (73 lesions). Final analysis included 53 patients (63 lesions). Four readers, blinded to true diagnosis, interpreted each lesion. Reader evaluations were compared to true lesion classifications. Performance metrics were calculated to assess malignant and benign diagnoses. Reader agreement was evaluated using Bowker’s symmetry test. Combined reader sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) for diagnosing malignant lesions were 71%, 75%, 45%, and 90%, respectively. Sensitivity (81%) and specificity (83%) were highest in CKD IV/V patients when grouped by CKD stage. Combined reader sensitivity, specificity, PPV, and NPV for diagnosing benign lesions were 70%, 86%, 91%, and 61%, respectively. Again, in CKD IV/V patients, sensitivity (81%), specificity (95%), and PPV (98%) were highest. Inter-reader diagnostic agreement varied from 72% to 90%. In CKD patients, CEUS is a potential low-risk option for screening kidney lesions. CEUS may be particularly beneficial for CKD IV/V patients, where kidney preservation techniques are highly relevant.}, number={20}, journal={JOURNAL OF CLINICAL MEDICINE}, author={Walmer, Rachel W. and Ritter, Victor S. and Sridharan, Anush and Kasoji, Sandeep K. and Altun, Ersan and Lee, Ellie and Olinger, Kristen and Wagner, Sean and Radhakrishna, Roshni and Johnson, Kennita A. and et al.}, year={2023}, month={Oct} }
 @article{moon_wu_zhang_kim_dayton_xu_jiang_2022, title={A Dual-Frequency Intravascular Ultrasound Transducer for Amplified Nanodroplet Vaporization Effects in Cavitation-Enhanced Sonothrombolysis}, ISSN={["1948-5719"]}, DOI={10.1109/IUS54386.2022.9958578}, abstractNote={Thromboembolism often leads to stroke, myocardial infarction, and other severe complications. There remains a need for new technologies for clinical thrombosis treatment. Sonothrombolysis mediated with cavitation-enhancing agents has shown promise in the treatment of thromboembolism in preclinical studies and clinical trials. Recent works have emphasized specifically efficient sonothrombolysis using phase-change nanodroplets, likely due to their generation of cavitation within the clot matrix. Yet, it has also been reported that nanodroplets might vaporize more effectively under high-frequency excitation and generate more cavitation with low-frequency excitation. Therefore, in this work, a dual-frequency (10 MHz/500 kHz) intravascular transducer intended for nanodroplet-specific sonothrombolysis was developed to improve clot mass reduction rate while retaining lower acoustic pressures than the typical nanodroplet vaporization threshold at sub-megahertz excitation (> 5 MPa). It results in a 34 % improvement of thrombolysis efficiency compared to a single low-frequency excitation.}, journal={2022 IEEE INTERNATIONAL ULTRASONICS SYMPOSIUM (IEEE IUS)}, author={Moon, Sunho and Wu, Huaiyu and Zhang, Bohua and Kim, Jinwook and Dayton, Paul A. and Xu, Zhen and Jiang, Xiaoning}, year={2022} }
 @article{sanders_biliroglu_newsome_adelegan_yamaner_dayton_oralkan_2022, title={A Handheld Imaging Probe for Acoustic Angiography With an Ultrawideband Capacitive Micromachined Ultrasonic Transducer (CMUT) Array}, volume={69}, ISSN={["1525-8955"]}, url={https://doi.org/10.1109/TUFFC.2022.3172566}, DOI={10.1109/TUFFC.2022.3172566}, abstractNote={This article presents an imaging probe with a 256-element ultrawideband (UWB) 1-D capacitive micromachined ultrasonic transducer (CMUT) array designed for acoustic angiography (AA). This array was fabricated on a borosilicate glass wafer with a reduced bottom electrode and an additional central plate mass to achieve the broad bandwidth. A custom 256-channel handheld probe was designed and implemented with integrated low-noise amplifiers and supporting power circuitry. This probe was used to characterize the UWB CMUT, which has a functional 3-dB frequency band from 3.5 to 23.5 MHz. A mechanical index (MI) of 0.33 was achieved at 3.5 MHz at a depth of 11 mm. These promising measurements are then combined to demonstrate AA. The use of alternate amplitude modulation (aAM) combined with a frequency analysis of the measured transmit signal demonstrates the suitability of the UWB CMUT for AA. This is achieved by measuring only a low level of unwanted high-frequency harmonics in both the transmit signal and the reconstructed image in the areas other than the contrast bubbles.}, number={7}, journal={IEEE TRANSACTIONS ON ULTRASONICS FERROELECTRICS AND FREQUENCY CONTROL}, publisher={Institute of Electrical and Electronics Engineers (IEEE)}, author={Sanders, Jean L. and Biliroglu, Ali Onder and Newsome, Isabel G. and Adelegan, Oluwafemi J. and Yamaner, Feysel Yalcin and Dayton, Paul A. and Oralkan, Omer}, year={2022}, month={Jul}, pages={2318–2330} }
 @article{kim_kasoji_durham_dayton_2022, title={Acoustic Hologram Lens Made of Nanoparticle-Epoxy Composite Molding for Directing Predefined Therapeutic Ultrasound Beams}, ISSN={["1948-5719"]}, DOI={10.1109/IUS54386.2022.9957379}, abstractNote={We present an acoustic hologram lens fabrication method for prototyping nondeformed hologram lenses with a tailored acoustic impedance. A pixelized hologram pattern is typically manufactured by photo-curing 3D printing methods, such as stereolithography (SLA) printing. However, SLA printing has major limitations for lens fabrication: vulnerability to deformation during photo-curing of a thin-plate shape lens structure and limited controllability of acoustic impedance. To overcome these limitations, we adopted a synthesized epoxy composite molding technique in this work. The used alumina nanoparticle (300 nm)-epoxy composite contains 22.5% alumina particles in volume. The characterized acoustic impedance of the composite was 4.68 MRayl whereas the conventional photopolymer exhibited 3.13 MRayl. We used these acoustic properties in lens modeling and acoustic hologram simulations. In simulations, the composite lens generated 145% pressure amplitude of the photopolymer lens due to improved acoustic impedance matching between a piezoelectric ceramic and water medium. We prototyped a composite lens through 1) 3D printing a lens cavity, 2) silicone rubber molding, and 3) epoxy composite lens molding. We observed no deformation of the prototyped composite lens whereas the photopolymer lens showed deformed edges. The beam mapping result using the composite lens showed 17% improved structural similarity with the designed pressure pattern compared to the photopolymer result. Due to the air bubbles trapped in a composite lens, the expected improvement of pressure amplitude over a photopolymer lens was not experimentally demonstrated. The additional degassing procedure will be included for future prototypes and pressure transmission will be evaluated.}, journal={2022 IEEE INTERNATIONAL ULTRASONICS SYMPOSIUM (IEEE IUS)}, author={Kim, Jinwook and Kasoji, Sandeep and Durham, Phillip G. and Dayton, Paul A.}, year={2022} }
 @article{kim_bautista_deruiter_goel_jiang_xu_dayton_2022, title={An Analysis of Sonothrombolysis and Cavitation for Retracted and Unretracted Clots Using Microbubbles Versus Low-Boiling-Point Nanodroplets}, volume={69}, ISSN={["1525-8955"]}, DOI={10.1109/TUFFC.2021.3137125}, abstractNote={The thrombolysis potential of low-boiling-point (−2 °C) perfluorocarbon phase-change nanodroplets (NDs) has previously been demonstrated on aged clots, and we hypothesized that this efficacy would extend to retracted clots. We tested this hypothesis by comparing sonothrombolysis of both unretracted and retracted clots using ND-mediated ultrasound (US+ND) and microbubble-mediated ultrasound (US+MB), respectively. Assessment data included clot mass reduction, cavitation detection, and cavitation cloud imaging in vitro. Acoustic parameters included a 7.9-MPa peak negative pressure and 180-cycle bursts with 5-Hz repetition (the corresponding duty cycle and time-averaged intensity of 0.09% and 1.87 W/cm2, respectively) based on prior studies. With these parameters, we observed a significantly reduced efficacy of US+MB in the retracted versus unretracted model (the averaged mass reduction rate from 1.83%/min to 0.54%/min). Unlike US+MB, US+ND exhibited less reduction of efficacy in the retracted model (from 2.15%/min to 1.04%/min on average). The cavitation detection results correlate with the sonothrombolysis efficacy results showing that both stable and inertial cavitation generated in a retracted clot by US+ND is higher than that by US+MB. We observed that ND-mediated cavitation shows a tendency to occur inside a clot, whereas MB-mediated cavitation occurs near the surface of a retracted clot, and this difference is more significant with retracted clots compared to unretracted clots. We conclude that ND-mediated sonothrombolysis outperforms MB-mediated therapy regardless of clot retraction, and this advantage of ND-mediated cavitation is emphasized for retracted clots. The primary mechanisms are hypothesized to be sustained cavitation level and cavitation clouds in the proximity of a retracted clot by US+ND.}, number={2}, journal={IEEE TRANSACTIONS ON ULTRASONICS FERROELECTRICS AND FREQUENCY CONTROL}, author={Kim, Jinwook and Bautista, Kathlyne Jayne B. and Deruiter, Ryan M. and Goel, Leela and Jiang, Xiaoning and Xu, Zhen and Dayton, Paul A.}, year={2022}, month={Feb}, pages={711–719} }
 @article{srivastava_sridharan_walmer_kasoji_burke_dayton_johnson_chang_2022, title={Association of Contrast-Enhanced Ultrasound-Derived Kidney Cortical Microvascular Perfusion with Kidney Function}, volume={3}, ISSN={["2641-7650"]}, DOI={10.34067/KID.0005452021}, abstractNote={Key Points Contrast-enhanced ultrasound is a noninvasive imaging modality that may noninvasively assess kidney cortical microvascular perfusion. Contrast-enhanced ultrasound–derived kidney cortical microvascular perfusion is associated with eGFR. Visual Abstract Background Individuals with chronic kidney disease (CKD) have decreased kidney cortical microvascular perfusion, which may lead to worsening kidney function over time, but methods to quantify kidney cortical microvascular perfusion are not feasible to incorporate into clinical practice. Contrast-enhanced ultrasound (CEUS) may quantify kidney cortical microvascular perfusion, which requires further investigation in individuals across the spectrum of kidney function. Methods We performed CEUS on a native kidney of 83 individuals across the spectrum of kidney function and calculated quantitative CEUS-derived kidney cortical microvascular perfusion biomarkers. Participants had a continuous infusion of the microbubble contrast agent (Definity) with a flash-replenishment sequence during their CEUS scan. Lower values of the microbubble velocity (β) and perfusion index (β×A) may represent lower kidney cortical microvascular perfusion. Multivariable linear regression models tested the associations of the microbubble velocity (β) and perfusion index (β×A) with estimated glomerular filtration rate (eGFR). Results Thirty-eight individuals with CKD (mean age±SD 65.2±12.6 years, median [IQR] eGFR 31.5 [18.9–41.5] ml/min per 1.73 m2), 37 individuals with end stage kidney disease (ESKD; age 54.8±12.3 years), and eight healthy volunteers (age 44.1±15.0 years, eGFR 117 [106–120] ml/min per 1.73 m2) underwent CEUS without side effects. Individuals with ESKD had the lowest microbubble velocity (β) and perfusion index (β×A) compared with individuals with CKD and healthy volunteers. The microbubble velocity (β) and perfusion index (β×A) had moderate positive correlations with eGFR (β: rs=0.44, P<0.001; β×A: rs=0.50, P<0.001). After multivariable adjustment, microbubble velocity (β) and perfusion index (β×A) remained significantly associated with eGFR (change in natural log transformed eGFR per 1 unit increase in natural log transformed biomarker: β, 0.38 [95%, CI 0.17 to 0.59]; β×A, 0.79 [95% CI, 0.45 to 1.13]). Conclusions CEUS-derived kidney cortical microvascular perfusion biomarkers are associated with eGFR. Future studies are needed to determine if CEUS-derived kidney cortical microvascular perfusion biomarkers have prognostic value.}, number={4}, journal={KIDNEY360}, author={Srivastava, Anand and Sridharan, Anush and Walmer, Rachel W. and Kasoji, Sandeep K. and Burke, Lauren M. B. and Dayton, Paul A. and Johnson, Kennita A. and Chang, Emily H.}, year={2022}, month={Apr}, pages={647–656} }
 @article{mccall_dayton_pinton_2022, title={Characterization of the Ultrasound Localization Microscopy Resolution Limit in the Presence of Image Degradation}, volume={69}, ISSN={["1525-8955"]}, DOI={10.1109/TUFFC.2021.3112074}, abstractNote={Ultrasound localization microscopy (ULM) has been able to overcome the diffraction limit of ultrasound imaging. The resolution limit of ULM has been previously modeled using the Cramér–Rao lower bound (CRLB). While this model has been validated in a homogeneous medium, it estimates a resolution limit, which has not yet been achieved in vivo. In this work, we investigated the effects of three sources of image degradation on the resolution limit of ULM. The Fullwave simulation tool was used to simulate acquisitions of transabdominal contrast-enhanced data at depth. The effects of reverberation clutter, trailing clutter, and phase aberration were studied. The resolution limit, in the presence of reverberation clutter alone, was empirically measured to be up to 39 times worse in the axial dimension and up to 2.1 times worse in the lateral dimension than the limit predicted by the CRLB. While reverberation clutter had an isotropic impact on the resolution, trailing clutter had a constant impact on both dimensions across all signal-to-trailing-clutter ratios (STCR). Phase aberration had a significant impact on the resolution limit over the studied analysis ranges. Phase aberration alone degraded the resolution limit up to 70 and 160 $\mu \text{m}$ in the lateral and axial dimensions, respectively. These results illustrate the importance of phase aberration correction and clutter filtering in ULM postprocessing. The analysis results were demonstrated through the simulation of the ULM process applied to a cross-tube model that was degraded by each of the three aforementioned sources of degradation.}, number={1}, journal={IEEE TRANSACTIONS ON ULTRASONICS FERROELECTRICS AND FREQUENCY CONTROL}, author={McCall, Jacob R. and Dayton, Paul A. and Pinton, Gianmarco F.}, year={2022}, month={Jan}, pages={124–134} }
 @article{czernuszewicz_aji_moore_montgomery_velasco_torres_anand_johnson_deal_zuki_et al._2022, title={Development of a Robotic Shear Wave Elastography System for Noninvasive Staging of Liver Disease in Murine Models}, ISSN={["2471-254X"]}, DOI={10.1002/hep4.1912}, abstractNote={Shear wave elastography (SWE) is an ultrasound‐based stiffness quantification technology that is used for noninvasive liver fibrosis assessment. However, despite widescale clinical adoption, SWE is largely unused by preclinical researchers and drug developers for studies of liver disease progression in small animal models due to significant experimental, technical, and reproducibility challenges. Therefore, the aim of this work was to develop a tool designed specifically for assessing liver stiffness and echogenicity in small animals to better enable longitudinal preclinical studies. A high‐frequency linear array transducer (12‐24 MHz) was integrated into a robotic small animal ultrasound system (Vega; SonoVol, Inc., Durham, NC) to perform liver stiffness and echogenicity measurements in three dimensions. The instrument was validated with tissue‐mimicking phantoms and a mouse model of nonalcoholic steatohepatitis. Female C57BL/6J mice (n = 40) were placed on choline‐deficient, L‐amino acid‐defined, high‐fat diet and imaged longitudinally for 15 weeks. A subset was sacrificed after each imaging timepoint (n = 5) for histological validation, and analyses of receiver operating characteristic (ROC) curves were performed. Results demonstrated that robotic measurements of echogenicity and stiffness were most strongly correlated with macrovesicular steatosis (R2 = 0.891) and fibrosis (R2 = 0.839), respectively. For diagnostic classification of fibrosis (Ishak score), areas under ROC (AUROCs) curves were 0.969 for ≥Ishak1, 0.984 for ≥Ishak2, 0.980 for ≥Ishak3, and 0.969 for ≥Ishak4. For classification of macrovesicular steatosis (S‐score), AUROCs were 1.00 for ≥S2 and 0.997 for ≥S3. Average scanning and analysis time was <5 minutes/liver. Conclusion: Robotic SWE in small animals is feasible and sensitive to small changes in liver disease state, facilitating in vivo staging of rodent liver disease with minimal sonographic expertise.}, journal={HEPATOLOGY COMMUNICATIONS}, author={Czernuszewicz, Tomasz J. and Aji, Adam M. and Moore, Christopher J. and Montgomery, Stephanie A. and Velasco, Brian and Torres, Gabriela and Anand, Keerthi S. and Johnson, Kennita A. and Deal, Allison M. and Zuki, Dzenan and et al.}, year={2022}, month={Feb} }
 @article{joiner_king_shrivastava_howard_cottrell_kashuba_dayton_benhabbour_2022, title={Effects of Injection Volume and Route of Administration on Dolutegravir In Situ Forming Implant Pharmacokinetics}, volume={14}, ISSN={["1999-4923"]}, DOI={10.3390/pharmaceutics14030615}, abstractNote={Due to the versatility of the in situ forming implant (ISFI) drug delivery system, it is crucial to understand the effects of formulation parameters for clinical translation. We utilized ultrasound imaging and pharmacokinetics (PK) in mice to understand the impact of administration route, injection volume, and drug loading on ISFI formation, degradation, and drug release in mice. Placebo ISFIs injected subcutaneously (SQ) with smaller volumes (40 μL) exhibited complete degradation within 30–45 days, compared to larger volumes (80 μL), which completely degraded within 45–60 days. However, all dolutegravir (DTG)-loaded ISFIs along the range of injection volumes tested (20–80 μL) were present at 90 days post-injection, suggesting that DTG can prolong ISFI degradation. Ultrasound imaging showed that intramuscular (IM) ISFIs flattened rapidly post administration compared to SQ, which coincides with the earlier Tmax for drug-loaded IM ISFIs. All mice exhibited DTG plasma concentrations above four times the protein-adjusted 90% inhibitory concentration (PA-IC90) throughout the entire 90 days of the study. ISFI release kinetics best fit to zero order or diffusion-controlled models. When total administered dose was held constant, there was no statistical difference in drug exposure regardless of the route of administration or number of injections.}, number={3}, journal={PHARMACEUTICS}, author={Joiner, Jordan B. and King, Jasmine L. and Shrivastava, Roopali and Howard, Sarah Anne and Cottrell, Mackenzie L. and Kashuba, Angela D. M. and Dayton, Paul A. and Benhabbour, Soumya Rahima}, year={2022}, month={Mar} }
 @misc{currens_dayton_buzzacott_papadopoulou_2022, title={Hyperbaric exposure in rodents with non- invasive imaging assessment of decompression bubbles: A scoping review protocol}, volume={17}, ISSN={["1932-6203"]}, DOI={10.1371/journal.pone.0274241}, abstractNote={Hyperbaric pressure experiments have provided researchers with valuable insights into the effects of pressure changes, using various species as subjects. Notably, extensive work has been done to observe rodents subjected to hyperbaric pressure, with differing imaging modalities used as an analytical tool. Decompression puts subjects at a greater risk for injury, which often justifies conducting such experiments using animal models. Therefore, it is important to provide a broad view of previously utilized methods for decompression research to describe imaging tools available for researchers to conduct rodent decompression experiments, to prevent duplicate experimentation, and to identify significant gaps in the literature for future researchers. Through a scoping review of published literature, we will provide an overview of decompression bubble information collected from rodent experiments using various non-invasive methods of ultrasound for decompression bubble assessment. This review will adhere to methods outlined by the Joanna Briggs Institute Manual for Evidence Synthesis and be reported according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses for Scoping Reviews (PRISMA-ScR). Literature will be obtained from the PubMed, Embase, and Scopus databases. Extracted sources will first be sorted to a list for inclusion based on title and abstract. Two independent researchers will then conduct full-text screening to further refine included papers to those relevant to the scope. The final review manuscript will cover methods, data, and findings for each included publication relevant to non-invasive in vivo bubble imaging.}, number={9}, journal={PLOS ONE}, author={Currens, Joshua and Dayton, Paul A. and Buzzacott, Peter and Papadopoulou, Virginie}, year={2022}, month={Sep} }
 @article{zhang_wu_kim_dayton_xu_jiang_2022, title={Integration of Forward-viewing and Side-viewing Ultrasound Transducers in an Intravascular Sonothrombolysis Catheter}, ISSN={["1948-5719"]}, DOI={10.1109/IUS54386.2022.9958224}, abstractNote={Thrombosis has emerged as one of the primary factors in mortality rates across the world. Conventional thrombolysis treatments for the rapid dissolution or extraction of massive thrombus, including fibrinolytic therapy and surgical thrombectomy, are time-consuming and may induce risks such as bleeding and vessel wall damage. Here we report a novel intravascular sonothrombolysis device with both forward-viewing and side-viewing elements. The developed FSV transducer prototype has a resonance frequency at 520 kHz and peak negative pressure (PNP) at 4.9 MPa (forward-viewing) and 3.2 MPa (side-viewing) under the driving voltage of 80 V pp. The combination of forward and side-viewing (FSV) ultrasound waves is expected to extend the treatment region and improve thrombolysis efficiency compared to a forward or side-viewing alone sonication.}, journal={2022 IEEE INTERNATIONAL ULTRASONICS SYMPOSIUM (IEEE IUS)}, author={Zhang, Bohua and Wu, Huaiyu and Kim, Jinwook and Dayton, Paul and Xu, Zhen and Jiang, Xiaoning}, year={2022} }
 @article{joiner_kren_durham_mcree_dayton_pylayeva-gupta_2022, title={LOW-INTENSITY FOCUSED ULTRASOUND PRODUCES IMMUNE RESPONSE IN PANCREATIC CANCER}, volume={48}, ISSN={["1879-291X"]}, DOI={10.1016/j.ultrasmedbio.2022.06.017}, abstractNote={Pancreatic adenocarcinoma is an aggressive malignancy with limited therapeutic treatments available and a 5-y survival less than 10%. Pancreatic cancers have been found to be immunogenically "cold" with a largely immunosuppressive tumor microenvironment. There is emerging evidence that focused ultrasound can induce changes in the tumor microenvironment and have a constructive impact on the effect of immunotherapy. However, the immune cells and timing involved in these effects remain unclear, which is essential to determining how to combine immunotherapy with ultrasound for treatment of pancreatic adenocarcinoma. We used low-intensity focused ultrasound and microbubbles (LoFU + MBs), which can mechanically disrupt cellular membranes and vascular endothelia, to treat subcutaneous pancreatic tumors in C57BL/6 mice. To evaluate the immune cell landscape and expression and/or localization of damage-associated molecular patterns (DAMPs) as a response to ultrasound, we performed flow cytometry and histology on tumors and draining lymph nodes 2 and 15 d post-treatment. We repeated this study on larger tumors and with multiple treatments to determine whether similar or greater effects could be achieved. Two days after treatment, draining lymph nodes exhibited a significant increase in activated antigen presenting cells, such as macrophages, as well as expansion of CD8+ T cells and CD4+ T cells. LoFU + MB treatment caused localized damage and facilitated the translocation of DAMP signals, as reflected by an increase in the cytoplasmic index for high-mobility-group box 1 (HMGB1) at 2 d. Tumors treated with LoFU + MBs exhibited a significant decrease in growth 15 d after treatment, indicating a tumor response that has the potential for additive effects. Our studies indicate that focused ultrasound treatments can cause tumoral damage and changes in macrophages and T cells 2 d post-treatment. The majority of these effects subsided after 15 d with only a single treatment, illustrating the need for additional treatment types and/or combination with immunotherapy. However, when larger tumors were treated, the effects seen at 2 d were diminished, even with an additional treatment. These results provide a working platform for further rational design of focused ultrasound and immunotherapy combinations in poorly immunogenic cancers.}, number={11}, journal={ULTRASOUND IN MEDICINE AND BIOLOGY}, author={Joiner, Jordan B. and Kren, Nancy P. and Durham, Phillip G. and McRee, Autumn J. and Dayton, Paul A. and Pylayeva-Gupta, Yuliya}, year={2022}, month={Nov}, pages={2344–2353} }
 @article{sendi_yazdimamaghani_hu_sultanpuram_wang_moody_mccabe_zhang_graboski_li_et al._2022, title={Nanoparticle Delivery of miR-122 Inhibits Colorectal Cancer Liver Metastasis}, volume={82}, ISSN={["1538-7445"]}, DOI={10.1158/0008-5472.CAN-21-2269}, abstractNote={Highly specific and efficient delivery of miRNA to hepatocytes using nanomedicine has therapeutic potential for the prevention and treatment of colorectal cancer liver metastasis. Liver metastasis is a leading cause of cancer morbidity and mortality. Thus, there has been strong interest in the development of therapeutics that can effectively prevent liver metastasis. One potential strategy is to utilize molecules that have broad effects on the liver microenvironment, such as miR-122, a liver-specific miRNA that is a key regulator of diverse hepatic functions. Here we report the development of a nanoformulation miR-122 as a therapeutic agent for preventing liver metastasis. We engineered a galactose-targeted lipid calcium phosphate (Gal-LCP) nanoformulation of miR-122. This nanotherapeutic elicited no significant toxicity and delivered miR-122 into hepatocytes with specificity and high efficiency. Across multiple colorectal cancer liver metastasis models, treatment with Gal-LCP miR-122 treatment effectively prevented colorectal cancer liver metastasis and prolonged survival. Mechanistic studies revealed that delivery of miR-122 was associated with downregulation of key genes involved in metastatic and cancer inflammation pathways, including several proinflammatory factors, matrix metalloproteinases, and other extracellular matrix degradation enzymes. Moreover, Gal-LCP miR-122 treatment was associated with an increased CD8+/CD4+ T-cell ratio and decreased immunosuppressive cell infiltration, which makes the liver more conducive to antitumor immune response. Collectively, this work presents a strategy to improve cancer prevention and treatment with nanomedicine-based delivery of miRNA. Significance: Highly specific and efficient delivery of miRNA to hepatocytes using nanomedicine has therapeutic potential for the prevention and treatment of colorectal cancer liver metastasis.}, number={1}, journal={CANCER RESEARCH}, author={Sendi, Hossein and Yazdimamaghani, Mostafa and Hu, Mengying and Sultanpuram, Nikhila and Wang, Jie and Moody, Amber S. and McCabe, Ellie and Zhang, Jiajie and Graboski, Amanda and Li, Liantao and et al.}, year={2022}, month={Jan}, pages={105–113} }
 @article{durham_kim_eltz_caskey_dayton_2022, title={POLYVINYL ALCOHOL CRYOGELS FOR ACOUSTIC CHARACTERIZATION OF PHASE-CHANGE CONTRAST AGENTS}, volume={48}, ISSN={["1879-291X"]}, DOI={10.1016/j.ultrasmedbio.2022.01.007}, abstractNote={Phase-change contrast agents (PCCAs) consisting of lipid-encapsulated low-boiling-point perfluorocarbons can be used in conjunction with ultrasound for diagnostic and therapeutic applications. One benefit of PCCAs is site-specific activation, whereby the liquid core is acoustically vaporized into a bubble detectable via ultrasound imaging. For further evaluation of PCCAs in a variety of applications, it is useful to disperse these nanodroplets into an acoustically compatible stationary matrix. However, many traditional phantom preparations require heating, which causes premature thermal activation of low-boiling-point PCCAs. Polyvinyl alcohol (PVA) cryogels do not require heat to set. Here we propose a simple method for the incorporation of the low-boiling-point PCCAs using octafluoropropane (OFP) and decafluorobutane (DFB) into PVA cryogels for a variety of acoustic characterization applications. We determined the utility of the phantoms by activating droplets with a focused transducer, visualizing the lesions with ultrasound imaging. At 1 MHz, droplet activation was consistently observed at 2.0 and 4.0 MPa for OFP and DFB, respectively.}, number={5}, journal={ULTRASOUND IN MEDICINE AND BIOLOGY}, author={Durham, Phillip G. and Kim, Jinwook and Eltz, Katherine M. and Caskey, Charles F. and Dayton, Paul A.}, year={2022}, month={May}, pages={954–960} }
 @article{belekov_bautista_annayev_adelegan_biliroglu_kierski_sanders_kemal_sennik_yamaner_et al._2022, title={Performance Assessment of Ultra-Wideband and Dual-Mode 1D CMUT Arrays for Acoustic Angiography}, ISSN={["1948-5719"]}, DOI={10.1109/IUS54386.2022.9958537}, abstractNote={In this work, we have demonstrated the imaging potential of 256-element ultra-wideband (UWB) and dual-mode CMUT 1D arrays for acoustic angiography through mechanical index measurements and in-vitro imaging experiments. We have designed a custom 256-channel imaging probe with integrated low-noise amplifiers and supporting power circuitry. To improve the elevational focusing, we mounted an acoustic lens on to the array. The acoustic characterization of the CMUT array was performed by a calibrated hydrophone, with which we measured sufficiently high mechanical indices (i.e., 0.79 MI for the UWB and 0.85 MI for the dual-mode array) at the focal spot at 15-mm depth. We conducted an imaging experiment with a tissue-mimicking phantom including a 0.2-mm-diameter cellulose tube, in which microbubbles and water flowed. We demonstrated a CTR of 62.12 ± 1.06 dB for the UWB array and a CTR of 59.69 ± 0.39 dB for the dual-mode array when microbubbles were flowing through the tube. These experiments presented a strong use case for the UWB and dual-mode CMUT arrays in acoustic angiography applications.}, journal={2022 IEEE INTERNATIONAL ULTRASONICS SYMPOSIUM (IEEE IUS)}, author={Belekov, Ermek and Bautista, Kathlyne J. and Annayev, Muhammetgeldi and Adelegan, Oluwafemi J. and Biliroglu, Ali O. and Kierski, Thomas M. and Sanders, Jean L. and Kemal, Remzi E. and Sennik, Erdem and Yamaner, Feysel Y. and et al.}, year={2022} }
 @misc{mccune_le_lindholm_nightingale_dayton_papadopoulou_2022, title={Perspective on ultrasound bioeffects and possible implications for continuous post-dive monitoring safety}, volume={52}, ISSN={["1833-3516"]}, DOI={10.28920/dhm52.2.136-148}, abstractNote={Ultrasound monitoring, both in the form of Doppler and 2D echocardiography, has been used post-dive to detect decompression bubbles circulating in the bloodstream. With large variability in both bubble time course and loads, it has been hypothesised that shorter periods between imaging, or even continuous imaging, could provide more accurate post-dive assessments. However, while considering applications of ultrasound imaging post-decompression, it may also be prudent to consider the possibility of ultrasound-induced bioeffects. Clinical ultrasound studies using microbubble contrast agents have shown bioeffect generation with acoustic powers much lower than those used in post-dive monitoring. However, to date no studies have specifically investigated potential bioeffect generation from continuous post-dive echocardiography. This review discusses what can be drawn from the current ultrasound and diving literature on the safety of bubble sonication and highlights areas where more studies are needed. An overview of the ultrasound-bubble mechanisms that lead to bioeffects and analyses of ultrasound contrast agent studies on bioeffect generation in the pulmonary and cardiovascular systems are provided to illustrate how bubbles under ultrasound can cause damage within the body. Along with clinical ultrasound studies, studies investigating the effects of decompression bubbles under ultrasound are analysed and open questions regarding continuous post-dive monitoring safety are discussed.}, number={2}, journal={DIVING AND HYPERBARIC MEDICINE}, author={McCune, Erica P. and Le, David Q. and Lindholm, Peter and Nightingale, Kathryn R. and Dayton, Paul A. and Papadopoulou, Virginie}, year={2022}, month={Jun}, pages={136–148} }
 @article{yang_cherin_yin_dayton_foster_demore_2022, title={Superharmonic Imaging with Plane Wave Beamforming Techniques}, ISSN={["1948-5719"]}, DOI={10.1109/IUS54386.2022.9957497}, abstractNote={Superharmonic imaging (SpHI) using dual-frequency (DF) transducers enables high-contrast microvasculature imaging while suppressing tissue clutter. It takes advantage of the high-frequency components within the nonlinear response of microbubble contrast agents when excited with a low-frequency pulse. SpHI has been demonstrated with array-based DF transducers with traditional line-by-line imaging schemes where the acquisition frame rate is limited by the number of image lines needed over the imaging field-of-view. In this work, we implement plane wave imaging approaches on programmable systems and investigate the image acquisition frame rate and image quality of SpHI in vitro and in vivo, using an integrated DF probe comprising a 21 MHz (high-frequency; 256 elements) array stacked on a 2 MHz (low-frequency; 32 elements) array. Micro-ultrasound imaging with high-frequency plane wave transmission at 25 steering angles and coherent compounding on receive was demonstrated in vivo, which showed good image contrast and resolution compared to traditional line-by-line imaging, while achieving an acquisition frame rate of 158 Hz. The 5-angle coherently compounded in vitro SpHI images showed ~4 dB improvement in tissue clutter suppression compared to images reconstructed from 0° steering. With 5-angle compounding, the acquisition frame rate in SpHI reached 588 Hz for a 30 mm imaging depth, moving SpHI towards 2D real-time imaging.}, journal={2022 IEEE INTERNATIONAL ULTRASONICS SYMPOSIUM (IEEE IUS)}, author={Yang, Jing and Cherin, Emmanuel and Yin, Jianhua and Dayton, Paul A. and Foster, F. Stuart and Demore, Christine E. M.}, year={2022} }
 @article{jones_caskey_dayton_oralkan_pinton_2022, title={Transcranial Neuromodulation Array With Imaging Aperture for Simultaneous Multifocus Stimulation in Nonhuman Primates}, volume={69}, ISSN={["1525-8955"]}, url={https://doi.org/10.1109/TUFFC.2021.3108448}, DOI={10.1109/TUFFC.2021.3108448}, abstractNote={Even simple behaviors arise from the simultaneous activation of multiple regions in the brain. Thus, the ability to simultaneously stimulate multiple regions within a brain circuit should allow for better modulation of function. However, performing simultaneous multifocus ultrasound neuromodulation introduces challenges to transducer design. Using 3-D Fullwave simulations, we have designed an ultrasound neuromodulation array for nonhuman primates that: 1) can simultaneously focus on multiple targets and 2) include an imaging aperture for additional functional imaging. This design is based on a spherical array, with 128 15-mm elements distributed in a spherical helix pattern. It is shown that clustering the elements tightly around the 65-mm imaging aperture located at the top of the array improves targeting at shallow depths, near the skull surface. Spherical arrays have good focusing capabilities through the skull at the center of the array, but focusing on off-center locations is more challenging due to the natural geometric configuration and the angle of incidence with the skull. In order to mitigate this, the 64 elements closest to the aperture were rotated toward and focusing on a shallow target, and the 64 elements farthest from the aperture were rotated toward and focusing on a deeper target. Data illustrated that this array produced focusing on the somatosensory cortex with a gain of 4.38 and to the thalamus with a gain of 3.82. To improve upon this, the array placement was optimized based on phase aberration simulations, allowing for the elements with the largest impact on the gain at each focal point to be found. This optimization resulted in an array design that can focus on the somatosensory cortex with a gain of 5.19 and the thalamus with a gain of 4.45. Simulations were also performed to evaluate the ability of the array to focus on 28 additional brain regions, showing that off-center target regions can be stimulated, but those closer to the skull will require corrective steps to deliver the same amount of energy to those locations. This simulation and design process can be adapted to an individual monkey or human skull morphologies and specific target locations within individuals by using orientable 3-D printing of the transducer case and by electronic phase aberration correction.}, number={1}, journal={IEEE TRANSACTIONS ON ULTRASONICS FERROELECTRICS AND FREQUENCY CONTROL}, publisher={Institute of Electrical and Electronics Engineers (IEEE)}, author={Jones, Rebecca M. and Caskey, Charles F. and Dayton, Paul A. and Oralkan, Omer and Pinton, Gianmarco F.}, year={2022}, month={Jan}, pages={261–272} }
 @article{rojas_joiner_velasco_bautista_aji_moore_beaumont_pylayeva-gupta_dayton_gessner_et al._2022, title={Validation of a combined ultrasound and bioluminescence imaging system with magnetic resonance imaging in orthotopic pancreatic murine tumors}, volume={12}, ISSN={["2045-2322"]}, DOI={10.1038/s41598-021-03684-z}, abstractNote={Preclinical mouse solid tumor models are widely used to evaluate efficacy of novel cancer therapeutics. Recent reports have highlighted the need for utilizing orthotopic implantation to represent clinical disease more accurately, however the deep tissue location of these tumors makes longitudinal assessment challenging without the use of imaging techniques. The purpose of this study was to evaluate the performance of a new multi-modality high-throughput in vivo imaging system that combines bioluminescence imaging (BLI) with robotic, hands-free ultrasound (US) for evaluating orthotopic mouse models. Long utilized in cancer research as independent modalities, we hypothesized that the combination of BLI and US would offer complementary advantages of detection sensitivity and quantification accuracy, while mitigating individual technological weaknesses. Bioluminescent pancreatic tumor cells were injected into the pancreas tail of C57BL/6 mice and imaged weekly with the combination system and magnetic resonance imaging (MRI) to serve as a gold standard. BLI photon flux was quantified to assess tumor activity and distribution, and US and MRI datasets were manually segmented for gross tumor volume. Robotic US and MRI demonstrated a strong agreement (R2 = 0.94) for tumor volume measurement. BLI showed a weak overall agreement with MRI (R2 = 0.21), however, it offered the greatest sensitivity to detecting the presence of tumors. We conclude that combining BLI with robotic US offers an efficient screening tool for orthotopic tumor models.}, number={1}, journal={SCIENTIFIC REPORTS}, author={Rojas, Juan D. and Joiner, Jordan B. and Velasco, Brian and Bautista, Kathlyne Jayne B. and Aji, Adam M. and Moore, Christopher J. and Beaumont, Nathan J. and Pylayeva-Gupta, Yuliya and Dayton, Paul A. and Gessner, Ryan C. and et al.}, year={2022}, month={Jan} }
 @article{kim_kim_wu_zhang_dayton_jiang_2021, title={A multi-pillar piezoelectric stack transducer for nanodroplet mediated intravascular sonothrombolysis}, volume={116}, ISSN={["1874-9968"]}, url={http://www.scopus.com/inward/record.url?eid=2-s2.0-85110135734&partnerID=MN8TOARS}, DOI={10.1016/j.ultras.2021.106520}, abstractNote={We aim to develop a nanodroplet (ND)-mediated intravascular ultrasound (US) transducer for deep vein thrombosis treatments. The US device, having an efficient forward directivity of the acoustic beam, is capable of expediting the clot dissolution rate by activating cavitation of NDs injected onto a thrombus. We designed and prototyped a multi-pillar piezoelectric stack (MPPS) transducer composed of four piezoelectric stacks. Each stack was made of five layers of PZT-4 plates, having a dimension of 0.85 × 0.85 × 0.2 mm3. The transducer was characterized by measuring the electrical impedance and acoustic pressure, compared to simulation results. Next, in-vitro tests were conducted in a blood flow mimicking system using the transducer equipped with an ND injecting tube. The miniaturized transducer, having an aperture size of 2.8 mm, provided a high mechanical index of 1.52 and a relatively wide focal zone of 3.4 mm at 80 Vpp, 0.96 MHz electric input. The mass-reduction rate of the proposed method (NDs + US) was assessed to be 4.1 and 4.6 mg/min with and without the flow model, respectively. The rate was higher than that (1.3-2.7 mg/min) of other intravascular ultrasound modalities using micron-sized bubble agents. The ND-mediated intravascular sonothrombolysis using MPPS transducers was demonstrated with an unprecedented lysis rate, which may offer a new clinical option for DVT treatments. The MPPS transducer generated a high acoustic pressure (~3.1 MPa) at a distance of approximately 2.2 wavelengths from the small aperture, providing synergistic efficacy with nanodroplets for thrombolysis without thrombolytic agents.}, journal={ULTRASONICS}, author={Kim, Howuk and Kim, Jinwook and Wu, Huaiyu and Zhang, Bohua and Dayton, Paul A. and Jiang, Xiaoning}, year={2021}, month={Sep} }
 @article{kim_kasoji_durham_dayton_2021, title={Acoustic holograms for directing arbitrary cavitation patterns}, volume={118}, ISSN={["1077-3118"]}, DOI={10.1063/5.0035298}, abstractNote={Cavitation is an important phenomenon in biomedical acoustics. It can produce both desired outcomes (i.e., local therapeutic effects in vivo) and undesired outcomes (i.e., tissue damage), and it is, thus, important to both understand and direct cavitation fields. Through the use of three-dimensional-printed acoustic lenses and cavitation-sensitive acoustic phantoms, we demonstrate the generation of arbitrary shape two-dimensional (2D) microbubble cavitation fields. In this study, we demonstrate shaping a 1 MHz acoustic beam as the character “7” on a target plane that contains a higher mechanical index than the cavitation threshold for encapsulated microbubbles in a gelatin phantom. The lens pattern is first designed by calculating the phase map of the desired field using an angular spectrum approach. After lens implementation, acoustic pulsing through the lens generated the target acoustic field in a phantom and produced a cavitation map following the intended 2D pattern. The cavitation pattern was similar (with the structural similarity of 0.476) to the acoustic pressure map of the excitation beam.}, number={5}, journal={APPLIED PHYSICS LETTERS}, author={Kim, Jinwook and Kasoji, Sandeep and Durham, Phillip G. and Dayton, Paul A.}, year={2021}, month={Feb} }
 @misc{durham_dayton_2021, title={Applications of sub-micron low-boiling point phase change contrast agents for ultrasound imaging and therapy}, volume={56}, ISSN={["1879-0399"]}, DOI={10.1016/j.cocis.2021.101498}, abstractNote={Phase change contrast agents (PCCAs) have been studied in the medical ultrasound field for nearly three decades. Their ability to convert from a liquid core droplet to an acoustically active microbubble has enhanced the possibilities of medical ultrasound, enabling new imaging approaches as well as therapeutic directions. However, traditional PCCAs are formulated with perfluorocarbons which are a liquid at standard temperature and pressure, requiring a high amount of energy to transition the encapsulated droplets to gas form, possibly resulting in undesired bioeffects. A new generation of low-boiling point PCCAs, which are formulated from gaseous perfluorocarbons in a metastable liquid state, seeks to overcome these limits. These super-heated liquid perfluorocarbon nanodroplets display longer circulation kinetics than microbubbles, their activation produces unique acoustic signatures, and their small particle size holds potential for extravascular applications. Low-boiling point nanodroplets can be phase-transitioned when activated with ultrasound at pressures and frequencies approved for diagnostic imaging. From the first publication almost 10 years ago, low-boiling point PCCA research has expanded rapidly, and recent advances in super-resolution imaging, drug delivery and neuromodulation made possible by these nanodroplets are just a few examples of this growing field of research. In this review, we discuss low-boiling point phase change contrast agents and their applications in ultrasound imaging and therapeutics.}, journal={CURRENT OPINION IN COLLOID & INTERFACE SCIENCE}, author={Durham, Phillip G. and Dayton, Paul A.}, year={2021}, month={Dec} }
 @article{yang_cherin_yin_newsome_kierski_pang_carnevale_dayton_foster_demore_2021, title={Characterization of an Array-Based Dual-Frequency Transducer for Superharmonic Contrast Imaging}, volume={68}, ISSN={["1525-8955"]}, DOI={10.1109/TUFFC.2021.3065952}, abstractNote={Superharmonic imaging with dual-frequency imaging systems uses conventional low-frequency ultrasound transducers on transmit, and high-frequency transducers on receive to detect higher order harmonic signals from microbubble contrast agents, enabling high-contrast imaging while suppressing clutter from background tissues. Current dual-frequency imaging systems for superharmonic imaging have been used for visualizing tumor microvasculature, with single-element transducers for each of the low- and high-frequency components. However, the useful field of view is limited by the fixed focus of single-element transducers, while image frame rates are limited by the mechanical translation of the transducers. In this article, we introduce an array-based dual-frequency transducer, with low-frequency and high-frequency arrays integrated within the probe head, to overcome the limitations of single-channel dual-frequency probes. The purpose of this study is to evaluate the line-by-line high-frequency imaging and superharmonic imaging capabilities of the array-based dual-frequency probe for acoustic angiography applications in vitro and in vivo. We report center frequencies of 1.86 MHz and 20.3 MHz with −6 dB bandwidths of 1.2 MHz (1.2–2.4 MHz) and 14.5 MHz (13.3–27.8 MHz) for the low- and high-frequency arrays, respectively. With the proposed beamforming schemes, excitation pressure was found to range from 336 to 458 kPa at its azimuthal foci. This was sufficient to induce nonlinear scattering from microbubble contrast agents. Specifically, in vitro contrast channel phantom imaging and in vivo xenograft mouse tumor imaging by this probe with superharmonic imaging showed contrast-to-tissue ratio improvements of 17.7 and 16.2 dB, respectively, compared to line-by-line micro-ultrasound B-mode imaging.}, number={7}, journal={IEEE TRANSACTIONS ON ULTRASONICS FERROELECTRICS AND FREQUENCY CONTROL}, author={Yang, Jing and Cherin, Emmanuel and Yin, Jianhua and Newsome, Isabel G. and Kierski, Thomas M. and Pang, Guofeng and Carnevale, Claudia A. and Dayton, Paul A. and Foster, F. Stuart and Demore, Christine E. M.}, year={2021}, month={Jul}, pages={2419–2431} }
 @article{annayev_adelegan_yamaner_dayton_oralkan_2021, title={Design and Fabrication of 1D CMUT Arrays for Dual-Mode Acoustic Angiography Applications - Preliminary Results}, ISSN={["1948-5719"]}, DOI={10.1109/IUS52206.2021.9593432}, abstractNote={When microbubble contrast agents are excited at low frequencies (less than 5 MHz), they resonate and produce higher order harmonics due to their non-linear behavior. We propose a novel scheme with a capacitive micromachined ultrasonic transducer (CMUT) array to receive high-frequency microbubble harmonics in collapse mode and to transmit a low-frequency high-pressure pulse by releasing the CMUT plate from collapse and pull it back to collapse again in the same transmit-receive cycle. By patterning and etching the substrate to create glass spacers in the device cavity we can operate the CMUT in collapse mode and receive high-frequency signals. Finite element model simulation results show that the fabricated devices can transmit at low frequency (< 5 MHz) and receive echoes at high frequency (> 15 MHz), which are verified by experimental results.}, journal={INTERNATIONAL ULTRASONICS SYMPOSIUM (IEEE IUS 2021)}, author={Annayev, Muhammetgeldi and Adelegan, Oluwafemi J. and Yamaner, F. Yalcin and Dayton, Paul A. and Oralkan, Omer}, year={2021} }
 @article{wu_goel_kim_zhang_kim_dayton_xu_jiang_2021, title={Dual-Frequency Intravascular Sonothrombolysis: An In Vitro Study}, volume={68}, ISSN={["1525-8955"]}, url={https://doi.org/10.1109/TUFFC.2021.3103409}, DOI={10.1109/TUFFC.2021.3103409}, abstractNote={Thrombo-occlusive disease is one of the leading causes of death worldwide. There has been active research on safe and effective thrombolysis in preclinical and clinical studies. Recently, the dual-frequency transcutaneous sonothrombolysis with contrast agents [microbubbles (MBs)] has been reported to be more efficient in trigging the acoustic cavitation, which leads to a higher lysis rate. Therefore, there is increasing interest in applying dual-frequency technique for more significant efficacy improvement in intravascular sonothrombolysis since a miniaturized intravascular ultrasound transducer typically has a limited power output to fully harness cavitation effects. In this work, we demonstrated this efficacy enhancement by developing a new broadband intravascular transducer and testing dual-frequency sonothromblysis in vitro. A broadband intravascular transducer with a center frequency of 750 kHz and a footprint size of 1.4 mm was designed, fabricated, and characterized. The measured −6-dB fractional bandwidth is 68.1%, and the peak negative pressure is 1.5 MPa under the driving voltage of 80 Vpp. By keeping one frequency component at 750 kHz, the second frequency component was selected from 450 to 650 kHz with an interval of 50 kHz. The in vitro sonothrombolysis tests were conducted with a flow model and the results indicated that the MB-mediated, dual-frequency (750+500 kHz) sonothrombolysis yields an 85% higher lysis rate compared with the single-frequency treatment, and the lysis rate of dual-frequency sonothrombolysis increases with the difference between the two frequency components. These findings suggest a dual-frequency excitation technique for more efficient intravascular sonothrombolysis than conventional single-frequency excitation}, number={12}, journal={IEEE TRANSACTIONS ON ULTRASONICS FERROELECTRICS AND FREQUENCY CONTROL}, publisher={Institute of Electrical and Electronics Engineers (IEEE)}, author={Wu, Huaiyu and Goel, Leela D. and Kim, Howuk and Zhang, Bohua and Kim, Jinwook and Dayton, Paul A. and Xu, Zhen and Jiang, Xiaoning}, year={2021}, month={Dec}, pages={3599–3607} }
 @article{le_papadopoulou_dayton_2021, title={EFFECT OF ACOUSTIC PARAMETERS AND MICROBUBBLE CONCENTRATION ON THE LIKELIHOOD OF ENCAPSULATED MICROBUBBLE COALESCENCE}, volume={47}, ISSN={["1879-291X"]}, DOI={10.1016/j.ultrasmedbio.2021.06.020}, abstractNote={Microbubble contrast agents are commonly used for therapeutic and diagnostic imaging applications. Under certain conditions, these contrast agents can coalesce on ultrasound application and form larger bubbles than the initial population. The formation of large microbubbles potentially influences therapeutic outcomes and imaging quality. We studied clinically relevant ultrasound parameters related to low-pressure therapy and contrast-enhanced ultrasound imaging to determine their effect on microbubble coalescence and subsequent changes in microbubble size distributions in vitro. Results indicate that therapeutic ultrasound at low frequencies, moderate pressures and high duty cycles are capable of forming bubbles greater than two times larger than the initial bubble distribution. Furthermore, acoustic parameters related to contrast-enhanced ultrasound imaging that are at higher frequency, low-pressure and low-duty cycle exhibit no statistically significant changes in bubble diameter, suggesting that standard contrast ultrasound imaging does not cause coalescence. Overall, this work suggests that the microbubble coalescence phenomenon can readily occur at acoustic parameters used in therapeutic ultrasound, generating bubbles much larger than those found in commercial contrast agents, although coalescence is unlikely to be significant in diagnostic contrast-enhanced ultrasound imaging. This observation warrants further expansion of parameter ranges and investigation of resulting effects.}, number={10}, journal={ULTRASOUND IN MEDICINE AND BIOLOGY}, author={Le, David Q. and Papadopoulou, Virginie and Dayton, Paul A.}, year={2021}, month={Oct}, pages={2980–2989} }
 @article{durham_sidders_beam_kedziora_dayton_conlon_papadopoulou_rowe_2021, title={Harnessing ultrasound-stimulated phase change contrast agents to improve antibiotic efficacy against methicillin-resistant Staphylococcus aureus biofilms}, volume={3}, ISSN={["2590-2075"]}, DOI={10.1016/j.bioflm.2021.100049}, abstractNote={Bacterial biofilms, often associated with chronic infections, respond poorly to antibiotic therapy and frequently require surgical intervention. Biofilms harbor persister cells, metabolically indolent cells, which are tolerant to most conventional antibiotics. In addition, the biofilm matrix can act as a physical barrier, impeding diffusion of antibiotics. Novel therapeutic approaches frequently improve biofilm killing, but usually fail to achieve eradication. Failure to eradicate the biofilm leads to chronic and relapsing infection, is associated with major financial healthcare costs and significant morbidity and mortality. We address this problem with a two-pronged strategy using 1) antibiotics that target persister cells and 2) ultrasound-stimulated phase-change contrast agents (US-PCCA), which improve antibiotic penetration. We previously demonstrated that rhamnolipids, produced by Pseudomonas aeruginosa, could induce aminoglycoside uptake in gram-positive organisms, leading to persister cell death. We have also shown that US-PCCA can transiently disrupt biological barriers to improve penetration of therapeutic macromolecules. We hypothesized that combining antibiotics which target persister cells with US-PCCA to improve drug penetration could improve treatment of methicillin resistant S. aureus (MRSA) biofilms. Aminoglycosides alone or in combination with US-PCCA displayed limited efficacy against MRSA biofilms. In contrast, the anti-persister combination of rhamnolipids and aminoglycosides combined with US-PCCA dramatically improved biofilm killing. This novel treatment strategy has the potential for rapid clinical translation as the PCCA formulation is a variant of FDA-approved ultrasound contrast agents that are already in clinical practice and the low-pressure ultrasound settings used in our study can be achieved with existing ultrasound hardware at pressures below the FDA set limits for diagnostic imaging.}, journal={BIOFILM}, author={Durham, Phillip G. and Sidders, Ashelyn E. and Beam, Jenna E. and Kedziora, Katarzyna M. and Dayton, Paul A. and Conlon, Brian P. and Papadopoulou, Virginie and Rowe, Sarah E.}, year={2021}, month={Dec} }
 @article{stocker_shi_ives_maxwell_dayton_jiang_xu_owens_2021, title={IN VIVO PORCINE AGED DEEP VEIN THROMBOSIS MODEL FOR TESTING ULTRASOUND-BASED THROMBOLYSIS TECHNIQUES}, volume={47}, ISSN={["1879-291X"]}, DOI={10.1016/j.ultrasmedbio.2021.08.017}, abstractNote={As blood clots age, many thrombolytic techniques become less effective. To fully evaluate these techniques for potential clinical use, a large animal aged-clot model is needed. Previous minimally invasive attempts to allow clots to age in an in vivo large animal model were unsuccessful because of the clot clearance associated with relatively high level of cardiac health of readily available research pigs. Prior models have thus subsequently used invasive surgical techniques with the associated morbidity, animal stress and cost. We propose a method for forming sub-acute venous blood clots in an in-vivo porcine model. The age of the clots can be controlled and varied. By using an intravenous scaffold to anchor the clot to the vessel wall during the aging process, we can show that sub-acute clots can consistently be formed with a minimally invasive, percutaneous approach. The clot formed in this study remained intact for at least 1 wk in all subjects. Therefore, we established a new minimally invasive, large animal aged-clot model for evaluation of thrombolytic techniques.}, number={12}, journal={ULTRASOUND IN MEDICINE AND BIOLOGY}, author={Stocker, Greyson E. and Shi, Jiaqi and Ives, Kimberly and Maxwell, Adam D. and Dayton, Paul A. and Jiang, Xiaoning and Xu, Zhen and Owens, Gabe E.}, year={2021}, month={Dec}, pages={3447–3457} }
 @misc{moody_dayton_zamboni_2021, title={Imaging methods to evaluate tumor microenvironment factors affecting nanoparticle drug delivery and antitumor response}, volume={4}, ISSN={["2578-532X"]}, DOI={10.20517/cdr.2020.94}, abstractNote={Standard small molecule and nanoparticulate chemotherapies are used for cancer treatment; however, their effectiveness remains highly variable. One reason for this variable response is hypothesized to be due to nonspecific drug distribution and heterogeneity of the tumor microenvironment, which affect tumor delivery of the agents. Nanoparticle drugs have many theoretical advantages, but due to variability in tumor microenvironment (TME) factors, the overall drug delivery to tumors and associated antitumor response are low. The nanotechnology field would greatly benefit from a thorough analysis of the TME factors that create these physiological barriers to tumor delivery and treatment in preclinical models and in patients. Thus, there is a need to develop methods that can be used to reveal the content of the TME, determine how these TME factors affect drug delivery, and modulate TME factors to increase the tumor delivery and efficacy of nanoparticles. In this review, we will discuss TME factors involved in drug delivery, and how biomedical imaging tools can be used to evaluate tumor barriers and predict drug delivery to tumors and antitumor response.}, number={2}, journal={CANCER DRUG RESISTANCE}, author={Moody, Amber S. and Dayton, Paul A. and Zamboni, William C.}, year={2021}, pages={382–413} }
 @article{newsome_kierski_pang_yin_yang_cherin_foster_carnevale_demore_dayton_2021, title={Implementation of a Novel 288-Element Dual-Frequency Array for Acoustic Angiography: In Vitro and In Vivo Characterization}, volume={68}, ISSN={["1525-8955"]}, DOI={10.1109/TUFFC.2021.3074025}, abstractNote={Acoustic angiography is a superharmonic contrast-enhanced ultrasound imaging method that produces high-resolution, 3-D maps of the microvasculature. Previous acoustic angiography studies have used twoelement, annular,mechanicallyactuated transducers(called “wobblers”) to image microvasculature in preclinical tumor models with high contrast-to-tissue ratio and resolution, but these earlywobbler transducerscould not achieve the depth and sensitivity required for clinical acoustic angiography. In this work, we present a system for performing acoustic angiography with a novel dual-frequency(DF) transducer—a coaxially stacked DF array (DFA). We evaluate the DFA system bothin vitro andin vivo and demonstrate improvements in sensitivity and imaging depth up to 13.1 dB and 10 mm, respectively, compared with previous wobbler probes.}, number={8}, journal={IEEE TRANSACTIONS ON ULTRASONICS FERROELECTRICS AND FREQUENCY CONTROL}, author={Newsome, Isabel G. and Kierski, Thomas M. and Pang, Guofeng and Yin, Jianhua and Yang, Jing and Cherin, Emmanuel and Foster, F. Stuart and Carnevale, Claudia A. and Demore, Christine E. M. and Dayton, Paul A.}, year={2021}, month={Aug}, pages={2657–2666} }
 @article{wu_kim_zhang_kim_dayton_xu_jiang_2021, title={Intravascular Dual-frequency Ultrasound Transducer Using a Stack Composite}, ISSN={["1948-5719"]}, url={http://www.scopus.com/inward/record.url?eid=2-s2.0-85122850530&partnerID=MN8TOARS}, DOI={10.1109/IUS52206.2021.9593424}, abstractNote={Intravascular sonothrombolysis has attracted much attention due to the safe and effective treatment potential compared to other conventional mechanical thrombectomy and high-dose medication. Meanwhile, multiple frequency sonothrombolysis is known to be more efficient to activate cavitation of micro or nano size contrast agents. Yet, the multiple frequency effects combined with an intravascular device have rarely been studied in the past due to technical limitations in transmitting acoustic pressure output with multiple frequencies from a single small aperture. Therefore, in this study, an intravascular ultrasound transducer with a composite structure is reported, which can operate with the dual-frequency condition for enhancing the cavitation effect of infused contrast agents. Compared with single frequency excitation, the in-vitro test results showed a 34% improvement in the lysis rate when the dual-frequency excitation was applied with the nanodroplets infusion.}, journal={INTERNATIONAL ULTRASONICS SYMPOSIUM (IEEE IUS 2021)}, author={Wu, Huaiyu and Kim, Howuk and Zhang, Bohua and Kim, Jinwook and Dayton, Paul and Xu, Zhen and Jiang, Xiaoning}, year={2021} }
 @article{zhang_wu_goel_kim_peng_kim_dayton_gao_jiang_2021, title={Magneto-sonothrombolysis with combination of magnetic microbubbles and nanodroplets}, volume={116}, ISSN={["1874-9968"]}, url={http://www.scopus.com/inward/record.url?eid=2-s2.0-85107639068&partnerID=MN8TOARS}, DOI={10.1016/j.ultras.2021.106487}, abstractNote={This paper reports a novel technique using the rotational magnetic field oscillation and low-intensity sub-megahertz ultrasound stimulation of magnetic microbubbles (MMBs) to promote the nanodroplets (NDs) phase transition and improve the permeation of NDs into the blood clot fibrin network to enhance the sonothrombolysis efficiency. In this study, the influence of different treatment methods with a combination of MMBs and NDs on the thrombolysis rate of both unretracted and retracted clots were investigated, including the stable and inertial cavitation, tPA effects, MMBs/NDs concentration ratio, sonication factors (input voltage, duty cycle) and rotational magnetic field factors (flux density, frequency). We demonstrated that tPA-mediated magneto-sonothrombolysis in combining NDs with MMBs could significantly enhance in vitro lysis of both unretracted clots (85 ± 8.3%) and retracted clots (57 ± 6.5%) in a flow model with 30 min treatment. The results showed that the combination of MMBs and NDs substantially improves in vitro lysis of blood clots with an unprecedented lysis rate.}, journal={ULTRASONICS}, author={Zhang, Bohua and Wu, Huaiyu and Goel, Leela and Kim, Howuk and Peng, Chang and Kim, Jinwook and Dayton, Paul A. and Gao, Yu and Jiang, Xiaoning}, year={2021}, month={Sep} }
 @article{goel_wu_zhang_kim_dayton_xu_jiang_2021, title={Nanodroplet-mediated catheter-directed sonothrombolysis of retracted blood clots}, volume={7}, ISSN={["2055-7434"]}, url={http://www.scopus.com/inward/record.url?eid=2-s2.0-85098869774&partnerID=MN8TOARS}, DOI={10.1038/s41378-020-00228-9}, abstractNote={Abstract One major challenge in current microbubble (MB) and tissue plasminogen activator (tPA)-mediated sonothrombolysis techniques is effectively treating retracted blood clots, owing to the high density and low porosity of retracted clots. Nanodroplets (NDs) have the potential to enhance retracted clot lysis owing to their small size and ability to penetrate into retracted clots to enhance drug delivery. For the first time, we demonstrate that a sub-megahertz, forward-viewing intravascular (FVI) transducer can be used for ND-mediated sonothrombolysis, in vitro. In this study, we determined the minimum peak negative pressure to induce cavitation with low-boiling point phase change nanodroplets and clot lysis. We then compared nanodroplet mediated sonothrombolysis to MB and tPA mediate techniques. The clot lysis as a percent mass decrease in retracted clots was 9 ± 8%, 9 ± 5%, 16 ± 5%, 14 ± 9%, 17 ± 9%, 30 ± 8%, and 40 ± 9% for the control group, tPA alone, tPA + US, MB + US, MB + tPA + US, ND + US, and ND + tPA + US groups, respectively. In retracted blood clots, combined ND- and tPA-mediated sonothrombolysis was able to significantly enhance retracted clot lysis compared with traditional MB and tPA-mediated sonothrombolysis techniques. Combined nanodroplet with tPA-mediated sonothrombolysis may provide a feasible strategy for safely treating retracted clots.}, number={1}, journal={MICROSYSTEMS & NANOENGINEERING}, author={Goel, Leela and Wu, Huaiyu and Zhang, Bohua and Kim, Jinwook and Dayton, Paul A. and Xu, Zhen and Jiang, Xiaoning}, year={2021}, month={Jan} }
 @article{goel_wu_zhang_kim_dayton_xu_jiang_2021, title={SAFETY EVALUATION OF A FORWARD-VIEWING INTRAVASCULAR TRANSDUCER FOR SONOTHROMBOLYSIS: AN IN VITRO AND EX VIVO STUDY}, volume={47}, ISSN={["1879-291X"]}, url={http://www.scopus.com/inward/record.url?eid=2-s2.0-85113414436&partnerID=MN8TOARS}, DOI={10.1016/j.ultrasmedbio.2021.07.018}, abstractNote={Recent in vitro work has revealed that a forward-viewing intravascular (FVI) transducer has sonothrombolysis applications. However, the safety of this device has yet to be evaluated. In this study, we evaluated the safety of this device in terms of tissue heating, vessel damage and particle debris size during sonothrombolysis using microbubbles or nanodroplets with tissue plasminogen activator, in both retracted and unretracted blood clots. The in vitro and ex vivo sonothrombolysis tests using FVI transducers revealed a temperature rise of less than 1°C, no vessel damage as assessed by histology and no downstream clot particles >500 µm. These in vitro and ex vivo results indicate that the FVI transducer poses minimal risk for sonothrombolysis applications and should be further evaluated in animal models.}, number={11}, journal={ULTRASOUND IN MEDICINE AND BIOLOGY}, author={Goel, Leela and Wu, Huaiyu and Zhang, Bohua and Kim, Jinwook and Dayton, Paul A. and Xu, Zhen and Jiang, Xiaoning}, year={2021}, month={Nov}, pages={3231–3239} }
 @article{peng_zhang_wu_dayton_xu_jiang_2021, title={Ultrasound Imaging-Guided Microbubble-Mediated Catheter-Directed Sonothrombolysis: An In-Vitro Study}, ISSN={["2378-377X"]}, DOI={10.1109/NMDC50713.2021.9677506}, abstractNote={Summary form only given, as follows. The complete presentation was not made available for publication as part of the conference proceedings. Deep vein thrombosis (DVT) is the formation of a blood clot in a deep vein, usually in the lower leg or thigh. The most serious complication of DVT is pulmonary embolism, which happens when part of the blood clot breaks off and travels through the bloodstream to the lungs, suddenly blocking blood flow. While using clot dissolving drugs is the standard treatment for DVT, thrombolytic drugs illustrate low thrombolysis efficiency and risk of bleeding side effects. Catheter-directed thrombolysis that uses a catheter to guide medication or a medical device to the site of a blood clot to dissolve the blockage, has become one of the most widely available and effective treatments for DVT. In this study, we combine a catheter-delivered forward-looking ultrasound transducer with microbubbles for microbubble-mediated catheter-directed sonothrombolysis, in order to reduce treatment time and increase treatment efficacy. A 600 kHz stack ultrasound transducer is developed and integrated into one lumen of an 8 Fr two-lumen catheter. During the sonothrombolysis procedure, the catheter location relative to the thrombus within a blood vessel is monitoring using ultrasound imaging guidance; the catheter tip distance to the blood clot is continuously controlled via a micro linear actuator with a speed of 100 μm/min.}, journal={2021 IEEE 16TH NANOTECHNOLOGY MATERIALS AND DEVICES CONFERENCE (NMDC 2021)}, author={Peng, Chang and Zhang, Bohua and Wu, Huaiyu and Dayton, Paul and Xu, Zhen and Jiang, Xiaoning}, year={2021} }
 @article{kim_deruiter_goel_xu_jiang_dayton_2020, title={A COMPARISON OF SONOTHROMBOLYSIS IN AGED CLOTS BETWEEN LOWBOILING-POINT PHASE-CHANGE NANODROPLETS AND MICROBUBBLES OF THE SAME COMPOSITION}, volume={46}, ISSN={["1879-291X"]}, DOI={10.1016/j.ultrasmedbio.2020.07.008}, abstractNote={We present enhanced cavitation erosion of blood clots exposed to low-boiling-point (−2°C) perfluorocarbon phase-change nanodroplets and pulsed ultrasound, as well as microbubbles with the same formulation under the same conditions. Given prior success with microbubbles as a sonothrombolysis agent, we considered that perfluorocarbon phase-change nanodroplets could enhance clot disruption further beyond that achieved with microbubbles. It has been hypothesized that owing to their small size and ability to penetrate into a clot, nanodroplets could enhance cavitation inside a blood clot and increase sonothrombolysis efficacy. The thrombolytic effects of lipid-shell-decafluorobutane nanodroplets were evaluated and compared with those of microbubbles with the same formulation, in an aged bovine blood clot flow model. Seven different pulsing schemes, with an acoustic intensity (ISPTA) range of 0.021–34.8 W/cm2 were applied in three different therapy scenarios: ultrasound only, ultrasound with microbubbles and ultrasound with nanodroplets (n = 5). Data indicated that pulsing schemes with 0.35 W/cm2 and 5.22 W/cm2 produced a significant difference (p < 0.05) in nanodroplet sonothrombolysis performance compared with compositionally identical microbubbles. With these excitation conditions, nanodroplet-mediated treatment achieved a 140% average thrombolysis rate over the microbubble-mediated case. We observed distinctive internal erosion in the middle of bovine clot samples from nanodroplet-mediated ultrasound, whereas the microbubble-mediated case generated surface erosion. This erosion pattern was supported by ultrasound imaging during sonothrombolysis, which revealed that nanodroplets generated cavitation clouds throughout a clot, whereas microbubble cavitation formed larger cavitation clouds only outside a clot sample.}, number={11}, journal={ULTRASOUND IN MEDICINE AND BIOLOGY}, author={Kim, Jinwook and DeRuiter, Ryan M. and Goel, Leela and Xu, Zhen and Jiang, Xiaoning and Dayton, Paul A.}, year={2020}, month={Nov}, pages={3059–3068} }
 @article{goel_wu_kim_zhang_kim_dayton_xu_jiang_2020, title={EXAMINING THE INFLUENCE OF LOW-DOSE TISSUE PLASMINOGEN ACTIVATOR ON MICROBUBBLE-MEDIATED FORWARD-VIEWING INTRAVASCULAR SONOTHROMBOLYSIS}, volume={46}, ISSN={["1879-291X"]}, url={http://www.scopus.com/inward/record.url?eid=2-s2.0-85086524519&partnerID=MN8TOARS}, DOI={10.1016/j.ultrasmedbio.2020.03.012}, abstractNote={Previous work revealed that a forward-viewing intravascular (FVI) transducer can be used for microbubble (MB)-mediated sonothrombolysis and that the clot lysis was dependent on MB concentration. This study examined the effects of combining tissue plasminogen activator (tPA) with MB-mediated FVI sonothrombolysis. In vitro clot lysis and passive cavitation experiments were conducted to study the effect of low-dose tPA in FVI sonothrombolysis with varying MB concentrations. Enhanced FVI sonothrombolysis was observed in cases in which ultrasound (US) was combined with tPA or MBs compared with control, tPA alone or US alone. The lysis rate of US + tPA + MBs was improved by up to 130%, 31% and 8% for MB concentrations of 106, 107 and 108 MBs/mL, respectively, compared with MBs + US alone. Changes in stable and inertial cavitation doses were observed, corresponding to changes in clot lysis in MB-mediated FVI sonothrombolysis with and without tPA.}, number={7}, journal={ULTRASOUND IN MEDICINE AND BIOLOGY}, author={Goel, Leela and Wu, Huaiyu and Kim, Howuk and Zhang, Bohua and Kim, Jinwook and Dayton, Paul A. and Xu, Zhen and Jiang, Xiaoning}, year={2020}, month={Jul}, pages={1698–1706} }
 @misc{joiner_pylayeva-gupta_dayton_2020, title={Focused Ultrasound for Immunomodulation of the Tumor Microenvironment}, volume={205}, ISSN={["1550-6606"]}, DOI={10.4049/jimmunol.1901430}, abstractNote={Focused ultrasound (FUS) has recently emerged as a modulator of the tumor microenvironment, paving the way for FUS to become a safe yet formidable cancer treatment option. Several mechanisms have been proposed for the role of FUS in facilitating immune responses and overcoming drug delivery barriers. However, with the wide variety of FUS parameters used in diverse tumor types, it is challenging to pinpoint FUS specifications that may elicit the desired antitumor response. To clarify FUS bioeffects, we summarize four mechanisms of action, including thermal ablation, hyperthermia/thermal stress, mechanical perturbation, and histotripsy, each inducing unique vascular and immunological effects. Notable tumor responses to FUS include enhanced vascular permeability, increased T cell infiltration, and tumor growth suppression. In this review, we have categorized and reviewed recent methods of using therapeutic ultrasound to elicit an antitumor immune response with examples that reveal specific solutions and challenges in this new research area.}, number={9}, journal={JOURNAL OF IMMUNOLOGY}, author={Joiner, Jordan B. and Pylayeva-Gupta, Yuliya and Dayton, Paul A.}, year={2020}, month={Nov}, pages={2327–2341} }
 @article{singh_nyankima_anthony phipps_chaplin_dayton_caskey_2020, title={Improving the heating efficiency of high intensity focused ultrasound ablation through the use of phase change nanodroplets and multifocus sonication}, volume={65}, ISSN={["1361-6560"]}, DOI={10.1088/1361-6560/ab9559}, abstractNote={Thermal ablation by ultrasound is being explored as a local therapy for cancers of soft tissue, such as the liver or breast. One challenge for these treatments are off-target effects, including heating outside of the intended region or skin burns. Improvements in heating efficiency can mitigate these undesired outcomes, and here, we describe methods for using phase-shift nanodroplets (PSNDs) with multi-focus sonications to enhance volumetric ablation and ablation efficiency at constant powers while increasing the pre-focal temperature by less than 6 ∘C. Multi-focus ablation with 4 foci performed the best and achieved a mean ablation volume of 120.2 ± 22.4 mm3 and ablation efficiency of 0.04 mm3 J−1 versus an ablation volume of 61.2 ± 21.16 mm3 and ablation efficiency of 0.02 mm3 J−1 in single focus case. The combined use of PSNDs with multi-focal ultrasound presented here is a new approach to increasing ablation efficiency while reducing off-target effects and could be generally applied in various focused ultrasound thermal ablation treatments.}, number={20}, journal={PHYSICS IN MEDICINE AND BIOLOGY}, author={Singh, Aparna and Nyankima, A. Gloria and Anthony Phipps, M. and Chaplin, Vandiver and Dayton, Paul A. and Caskey, Charles}, year={2020}, month={Oct} }
 @article{kierski_dayton_2020, title={Perspectives on high resolution microvascular imaging with contrast ultrasound}, volume={116}, ISSN={["1077-3118"]}, DOI={10.1063/5.0012283}, abstractNote={Recent developments in contrast enhanced ultrasound have demonstrated a potential to visualize small blood vessels in vivo, unlike anything possible with traditional grayscale ultrasound. This Perspective article introduces microvascular imaging strategies and their underlying technology.}, number={21}, journal={APPLIED PHYSICS LETTERS}, author={Kierski, Thomas M. and Dayton, Paul A.}, year={2020}, month={May} }
 @article{espindola_deruiter_santibanez_dayton_pinton_2020, title={Quantitative sub-resolution blood velocity estimation using ultrasound localization microscopy ex-vivo and in-vivo}, volume={6}, ISSN={["2057-1976"]}, DOI={10.1088/2057-1976/ab7f26}, abstractNote={Super-resolution ultrasound imaging relies on the sub-wavelength localization of microbubble contrast agents. By tracking individual microbubbles, the velocity and flow within microvessels can be estimated. It has been shown that the average flow velocity, within a microvessel ranging from tens to hundreds of microns in diameter, can be measured. However, a 2D super-resolution image can only localize bubbles with sub-wavelength resolution in the imaging plane whereas the resolution in the elevation plane is limited by conventional beamwidth physics. Since ultrasound imaging integrates echoes over the elevation dimension, velocity estimates at a single location in the imaging plane include information throughout the imaging slice thickness. This slice thickness is typically a few orders or magnitude larger than the super-resolution limit. It is shown here that in order to estimate the velocity, a spatial integration over the elevation direction must be considered. This operation yields a multiplicative correction factor that compensates for the elevation integration. A correlation-based velocity estimation technique is then presented. Calibrated microtube phantom experiments are used to validate the proposed velocity estimation method and the proposed elevation integration correction factor. It is shown that velocity measurements are in excellent agreement with theoretical predictions within the considered range of flow rates (10 to 90 μl/min) in a microtube with a diameter of 200 μm. Then, the proposed technique is applied to two in-vivo mouse tail experiments imaged with a low frequency human clinical transducer (ATL L7-4) with human clinical concentrations of microbubbles. In the first experiment, a vein was visible with a diameter of 140 μm and a peak flow velocity of 0.8 mm s−1. In the second experiment, a vein was observed in the super-resolved image with a diameter of 120 μm and with maximum local velocity of ≈4.4 mm s−1. It is shown that the parabolic flow profiles within these micro-vessels are resolvable.}, number={3}, journal={BIOMEDICAL PHYSICS & ENGINEERING EXPRESS}, author={Espindola, David and DeRuiter, Ryan M. and Santibanez, Francisco and Dayton, Paul A. and Pinton, Gianmarco}, year={2020}, month={Apr} }
 @misc{christensen-jeffries_couture_dayton_eldar_hynynen_kiessling_o'reilly_pinton_schmitz_tang_et al._2020, title={SUPER-RESOLUTION ULTRASOUND IMAGING}, volume={46}, ISSN={["1879-291X"]}, DOI={10.1016/j.ultrasmedbio.2019.11.013}, abstractNote={The majority of exchanges of oxygen and nutrients are performed around vessels smaller than 100 μm, allowing cells to thrive everywhere in the body. Pathologies such as cancer, diabetes and arteriosclerosis can profoundly alter the microvasculature. Unfortunately, medical imaging modalities only provide indirect observation at this scale. Inspired by optical microscopy, ultrasound localization microscopy has bypassed the classic compromise between penetration and resolution in ultrasonic imaging. By localization of individual injected microbubbles and tracking of their displacement with a subwavelength resolution, vascular and velocity maps can be produced at the scale of the micrometer. Super-resolution ultrasound has also been performed through signal fluctuations with the same type of contrast agents, or through switching on and off nano-sized phase-change contrast agents. These techniques are now being applied pre-clinically and clinically for imaging of the microvasculature of the brain, kidney, skin, tumors and lymph nodes.}, number={4}, journal={ULTRASOUND IN MEDICINE AND BIOLOGY}, author={Christensen-Jeffries, Kirsten and Couture, Olivier and Dayton, Paul A. and Eldar, Yonina C. and Hynynen, Kullervo and Kiessling, Fabian and O'Reilly, Meaghan and Pinton, I. Gianmarco F. and Schmitz, Georg and Tang, Meng-Xing and et al.}, year={2020}, month={Apr}, pages={865–891} }
 @article{soulioti_espindola_dayton_pinton_2020, title={Super-Resolution Imaging Through the Human Skull}, volume={67}, ISSN={["1525-8955"]}, DOI={10.1109/TUFFC.2019.2937733}, abstractNote={High-resolution transcranial ultrasound imaging in humans has been a persistent challenge for ultrasound due to the imaging degradation effects from aberration and reverberation. These mechanisms depend strongly on skull morphology and have high variability across individuals. Here, we demonstrate the feasibility of human transcranial super-resolution imaging using a geometrical focusing approach to efficiently concentrate energy at the region of interest, and a phase correction focusing approach that takes the skull morphology into account. It is shown that using the proposed focused super-resolution method, we can image a 208-<inline-formula> <tex-math notation="LaTeX">$\mu \text{m}$ </tex-math></inline-formula> microtube behind a human skull phantom in both an out-of-plane and an in-plane configuration. Individual phase correction profiles for the temporal region of the human skull were calculated and subsequently applied to transmit–receive a custom focused super-resolution imaging sequence through a human skull phantom, targeting the 208-<inline-formula> <tex-math notation="LaTeX">$\mu \text{m}$ </tex-math></inline-formula> diameter microtube at 68.5 mm in depth and at 2.5 MHz. Microbubble contrast agents were diluted to a concentration of <inline-formula> <tex-math notation="LaTeX">$1.6\times 10^{6}$ </tex-math></inline-formula> bubbles/mL and perfused through the microtube. It is shown that by correcting for the skull aberration, the RF signal amplitude from the tube improved by a factor of 1.6 in the out-of-plane focused emission case. The lateral registration error of the tube’s position, which in the uncorrected case was 990 <inline-formula> <tex-math notation="LaTeX">$\mu \text{m}$ </tex-math></inline-formula>, was reduced to as low as 50 <inline-formula> <tex-math notation="LaTeX">$\mu \text{m}$ </tex-math></inline-formula> in the corrected case as measured in the B-mode images. Sensitivity in microbubble detection for the phase-corrected case increased by a factor of 1.48 in the out-of-plane imaging case, while, in the in-plane target case, it improved by a factor of 1.31 while achieving an axial registration correction from an initial 1885-<inline-formula> <tex-math notation="LaTeX">$\mu \text{m}$ </tex-math></inline-formula> error for the uncorrected emission, to a 284-<inline-formula> <tex-math notation="LaTeX">$\mu \text{m}$ </tex-math></inline-formula> error for the corrected counterpart. These findings suggest that super-resolution imaging may be used far more generally as a clinical imaging modality in the brain.}, number={1}, journal={IEEE TRANSACTIONS ON ULTRASONICS FERROELECTRICS AND FREQUENCY CONTROL}, author={Soulioti, Danai E. and Espindola, David and Dayton, Paul A. and Pinton, Gianmarco F.}, year={2020}, month={Jan}, pages={25–36} }
 @article{kierski_espindola_newsome_cherin_yin_foster_demore_pinton_dayton_2020, title={Superharmonic Ultrasound for Motion-Independent Localization Microscopy: Applications to Microvascular Imaging From Low to High Flow Rates}, volume={67}, ISSN={["1525-8955"]}, DOI={10.1109/TUFFC.2020.2965767}, abstractNote={Recent advances in high frame rate biomedical ultrasound have led to the development of ultrasound localization microscopy (ULM), a method of imaging microbubble (MB) contrast agents beyond the diffraction limit of conventional coherent imaging techniques. By localizing and tracking the positions of thousands of individual MBs, ultrahigh resolution vascular maps are generated which can be further analyzed to study disease. Isolating bubble echoes from tissue signal is a key requirement for super-resolution imaging which relies on the spatiotemporal separability and localization of the bubble signals. To date, this has been accomplished either during acquisition using contrast imaging sequences or post-beamforming by applying a spatiotemporal filter to the B-mode images. Superharmonic imaging (SHI) is another contrast imaging method that separates bubbles from tissue based on their strongly nonlinear acoustic properties. This approach is highly sensitive, and, unlike spatiotemporal filters, it does not require decorrelation of contrast agent signals. Since this superharmonic method does not rely on bubble velocity, it can detect completely stationary and moving bubbles alike. In this work, we apply SHI to ULM and demonstrate an average improvement in SNR of 10.3-dB in vitro when compared with the standard singular value decomposition filter approach and an increase in SNR at low flow ( $0.27~\mu \text{m}$ /frame) from 5 to 16.5 dB. Additionally, we apply this method to imaging a rodent kidney in vivo and measure vessels as small as $20~\mu \text{m}$ in diameter after motion correction.}, number={5}, journal={IEEE TRANSACTIONS ON ULTRASONICS FERROELECTRICS AND FREQUENCY CONTROL}, author={Kierski, Thomas M. and Espindola, David and Newsome, Isabel G. and Cherin, Emmanuel and Yin, Jianhua and Foster, F. Stuart and Demore, Christine E. M. and Pinton, Gianmarco F. and Dayton, Paul A.}, year={2020}, month={May}, pages={957–967} }
 @article{deruiter_markley_rojas_pinton_dayton_2020, title={Transient acoustic vaporization signatures unique to low boiling point phase change contrast agents enable super-resolution ultrasound imaging without spatiotemporal filtering}, volume={10}, ISSN={["2158-3226"]}, DOI={10.1063/5.0029207}, abstractNote={The unique activation signal of phase-change contrast agents (PCCAs or droplets) can be separated from the tissue signal and localized to generate super-resolution (SR) ultrasound (US) images. Lipid-shelled, perfluorocarbon PCCAs can be stochastically vaporized (activated) by a plane wave US transmission thereby enabling them to be used as separable targets for ultrasound localization microscopy. The unique signature of droplet vaporization imaging and the transient inherent nature of this signature increases signal contrast and therefore localization confidence, while the poor resolution of the low-frequency vaporization signal is overcome by the super-resolution result. Furthermore, our proposed PCCA SR technique does not require the use of user-dependent and flow-dependent spatio-temporal filtering via singular-value decomposition. Rather, matched filters selected by Fourier-domain analysis are able to identify and localize PCCA activations. Droplet SR was demonstrated in a crossed-microtube water phantom by localizing the activation signals of octafluoropropane nanodroplets (OFP, C3F8, −37 °C boiling point) to resolve 100 µm diameter fluorinated ethylene propylene tubes, which are ordinarily 35% smaller than the native diffraction-limited resolution of the imaging system utilized.}, number={10}, journal={AIP ADVANCES}, author={DeRuiter, R. M. and Markley, E. N. and Rojas, J. D. and Pinton, G. F. and Dayton, P. A.}, year={2020}, month={Oct} }
 @misc{newsome_dayton_2020, title={VISUALIZATION OF MICROVASCULAR ANGIOGENESIS USING DUAL-FREQUENCY CONTRAST-ENHANCED ACOUSTIC ANGIOGRAPHY: A REVIEW}, volume={46}, ISSN={["1879-291X"]}, DOI={10.1016/j.ultrasmedbio.2020.06.009}, abstractNote={Cancerous tumor growth is associated with the development of tortuous, chaotic microvasculature, and this aberrant microvascular morphology can act as a biomarker of malignant disease. Acoustic angiography is a contrast-enhanced ultrasound technique that relies on superharmonic imaging to form high-resolution 3-D maps of the microvasculature. To date, acoustic angiography has been performed with dual-element transducers that can achieve high contrast-to-tissue ratio and resolution in pre-clinical small animal models. In this review, we first describe the development of acoustic angiography, including the principle, transducer design, and optimization of superharmonic imaging techniques. We then detail several preclinical applications of this microvascular imaging method, as well as the current and future development of acoustic angiography as a pre-clinical and clinical diagnostic tool.}, number={10}, journal={ULTRASOUND IN MEDICINE AND BIOLOGY}, author={Newsome, Isabel G. and Dayton, Paul A.}, year={2020}, month={Oct}, pages={2625–2635} }
 @article{czernuszewicz_papadopoulou_rojas_rajamahendiran_perdomo_butler_harlacher_o'connell_zukic_dayton_et al._2019, title={A preclinical ultrasound platform for widefield 3D imaging of rodent tumors}, volume={79}, ISSN={["1538-7445"]}, DOI={10.1158/1538-7445.AM2019-1955}, abstractNote={Abstract}, number={13}, journal={CANCER RESEARCH}, author={Czernuszewicz, Tomasz and Papadopoulou, Virginie and Rojas, Juan D. and Rajamahendiran, Rajalekha and Perdomo, Jonathan and Butler, James and Harlacher, Max and O'Connell, Graeme and Zukic, Dzenan and Dayton, Paul A. and et al.}, year={2019}, month={Jul} }
 @article{newsome_kierski_dayton_2019, title={ASSESSMENT OF THE SUPERHARMONIC RESPONSE OF MICROBUBBLE CONTRAST AGENTS FOR ACOUSTIC ANGIOGRAPHY AS A FUNCTION OF MICROBUBBLE PARAMETERS}, volume={45}, ISSN={["1879-291X"]}, DOI={10.1016/j.ultrasmedbio.2019.04.027}, abstractNote={Acoustic angiography is a superharmonic contrast-enhanced ultrasound imaging technique that enables 3-D high-resolution microvascular visualization. This technique utilizes a dual-frequency imaging strategy, transmitting at a low frequency and receiving at a higher frequency, to detect high-frequency contrast agent signatures and separate them from tissue background. Prior studies have illustrated differences in microbubble scatter dependent on microbubble size and composition; however, most previously reported data have utilized a relatively narrow frequency bandwidth centered around the excitation frequency. To date, a comprehensive study of isolated microbubble superharmonic responses with a broadband dual-frequency system has not been performed. Here, the superharmonic signal production of 14 contrast agents with various gas cores, shell compositions, and bubble diameters at mechanical indices of 0.2 to 1.2 was evaluated using a transmit 4 MHz, receive 25 MHz configuration. Results indicate that perfluorocarbon cores or lipid shells with 18- or 20-carbon acyl chains produce more superharmonic signal than sulfur hexafluoride cores or lipid shells with 16-carbon acyl chains, respectively. As microbubble diameter increases from 1 to 4 µm, superharmonic generation decreases. In a comparison of two clinical agents, Definity and Optison, and one preclinical agent, Micromarker, Optison produced the least superharmonic signal. Overall, this work suggests that microbubbles around 1 μm in diameter with perfluorocarbon cores and longer-chained lipid shells perform best for superharmonic imaging at 4 MHz. Studies have found that microbubble superharmonic response follows trends different from those described in prior studies using a narrower frequency bandwidth centered around the excitation frequency. Future work will apply these results in vivo to optimize the sensitivity of acoustic angiography.}, number={9}, journal={ULTRASOUND IN MEDICINE AND BIOLOGY}, author={Newsome, Isabel G. and Kierski, Thomas M. and Dayton, Paul A.}, year={2019}, month={Sep}, pages={2515–2524} }
 @article{kim_kim_chang_huang_jiang_dayton_2019, title={Candle-Soot Carbon Nanoparticles in Photoacoustics Advantages and challenges for laser ultrasound transmitters}, volume={13}, ISSN={["1942-7808"]}, DOI={10.1109/MNANO.2019.2904773}, abstractNote={This article provides a review of candle-soot nanoparticle (CSNP) composite laser ultrasound transmitters (LUTs) and compares and contrasts this technology with other carbon-composite designs. Among many carbon-based composite LUTs, a CSNP composite has demonstrated its advantages of maximum energy conversion and fabrication simplicity for developing highly efficient ultrasound transmitters. We focus on the advantages and challenges of the CSNP-composite transmitter in the areas of nanostructure design, fabrication procedure, and promising applications.}, number={3}, journal={IEEE NANOTECHNOLOGY MAGAZINE}, author={Kim, Jinwook and Kim, Howuk and Chang, Wei-Yi and Huang, Wenbin and Jiang, Xiaoning and Dayton, Paul A.}, year={2019}, month={Jun}, pages={13–28} }
 @article{suo_govind_gu_dayton_jing_2019, title={Dynamic assessment of dual-frequency microbubble-mediated sonothrombolysis in vitro}, volume={125}, ISSN={["1089-7550"]}, DOI={10.1063/1.5083908}, abstractNote={Optimizing the use of high intensity focused ultrasound (HIFU) for recanalization of occluded blood vessels is an actively researched area. This yields an alternative therapy to the use of thrombolytic drugs in the treatment of ischemic stroke. HIFU treatment, used in conjunction with microbubbles (MBs) in the fluid stream, serves to augment the dissipation of the blood clot. In this study, using an in vitro approach, we implement a flow system to simulate the dynamic dispersion of blood clots using single-frequency focused ultrasound (SFFU) and dual-frequency focused ultrasound (DFFU). The effects of permutations of acoustic power and driving frequency (SFFU vs. DFFU) on the rate of disintegration and site-specific lytic action are quantified under the influence of fluid akin to that in a blood vessel, for specific microbubble concentrations. It is found that dual-frequency excitation in general produces a faster rate of clot dissipation in comparison to single-frequency excitation, and this observation is corroborated by cavitation signal detection. Our observations indicate that accelerated thrombolysis may be realized by the inertial cavitation threshold of DFFU being lower than that of SFFU. Furthermore, the thrombolytic effect with variance in microbubble concentration is studied for a fixed acoustic power. The efficacy of DFFU is not found to vary appreciably with an increase in microbubble concentration from 108 MBs/ml to 109 MBs/ml, possibly due to acoustic shadowing induced at increased concentrations.}, number={8}, journal={JOURNAL OF APPLIED PHYSICS}, author={Suo, Dingjie and Govind, Bala and Gu, Juanjuan and Dayton, Paul A. and Jing, Yun}, year={2019}, month={Feb} }
 @article{rojas_borden_dayton_2019, title={EFFECT OF HYDROSTATIC PRESSURE, BOUNDARY CONSTRAINTS AND VISCOSITY ON THE VAPORIZATION THRESHOLD OF LOW-BOILING-POINT PHASE-CHANGE CONTRAST AGENTS}, volume={45}, ISSN={["1879-291X"]}, DOI={10.1016/j.ultrasmedbio.2018.11.006}, abstractNote={The vaporization of low-boiling-point phase-change contrast agents (PCCAs) using ultrasound has been explored in vitro and in vivo. However, it has been reported that the pressure required for activation is higher in vivo, even after attenuation is accounted for. In this study, the effect of boundary constraints, hydrostatic pressure and viscosity on PCCA vaporization pressure threshold are evaluated to explore possible mechanisms for variations in in vivo vaporization behavior. Vaporization was measured in microtubes of varying inner diameter and a pressurized chamber under different hydrostatic pressures using a range of ultrasound pressures. Furthermore, the activation threshold was evaluated in the kidneys of rats. The results confirm that the vaporization threshold is higher in vivo and reveal an increasing activation threshold inversely proportional to constraining tube size and inversely proportional to surrounding viscosity in constrained environments. Counterintuitively, increased hydrostatic pressure had no significant effect experimentally on the PCCA vaporization threshold, although it was confirmed that this result was supported by homogeneous nucleation theory for liquid perfluorocarbon vaporization. These factors suggest that constraints caused by the surrounding tissue and capillary walls, as well as increased viscosity in vivo, contribute to the increased vaporization threshold compared with in vitro experiments, although more work is required to confirm all relevant factors.}, number={4}, journal={ULTRASOUND IN MEDICINE AND BIOLOGY}, author={Rojas, Juan D. and Borden, Mark A. and Dayton, Paul A.}, year={2019}, month={Apr}, pages={968–979} }
 @article{rojas_papadopoulou_czernuszewicz_rajamahendiran_chytil_chiang_chong_bautch_rathmell_aylward_et al._2019, title={Early treatment response detected in a murine clear cell renal cell carcinoma model in response to combination therapy with antiangiogenic and notch inhibition therapy using a non-invasive imaging tool}, volume={79}, ISSN={["1538-7445"]}, DOI={10.1158/1538-7445.AM2019-1958}, abstractNote={Abstract}, number={13}, journal={CANCER RESEARCH}, author={Rojas, Juan D. and Papadopoulou, Virginie and Czernuszewicz, Tomasz and Rajamahendiran, Rajalekha and Chytil, Anna and Chiang, Yun-Chen and Chong, Diana and Bautch, Victoria L. and Rathmell, Wendy K. and Aylward, Stephen and et al.}, year={2019}, month={Jul} }
 @article{nyankima_kasoji_cianciolo_dayton_chang_2019, title={Histological and blood chemistry examination of the rodent kidney after exposure to flash-replenishment ultrasound contrast imaging}, volume={98}, ISSN={["1874-9968"]}, DOI={10.1016/j.ultras.2019.05.003}, abstractNote={The purpose of this work is to investigate whether imaging sequences of flash-replenishment contrast enhanced ultrasound (CEUS) of the kidney result in chronic or acute bioeffects. Kidneys of female Fischer 344 rats were imaged using the flash-replenishment technique. Animals were separated into four groups (N = 31). Imaging was conducted with a 4C1 probe, driven by an Acuson Sequoia system with Definity microbubbles as the ultrasound contrast agent. During the flash phase of the imaging sequence, one kidney in each animal was exposed to either a mechanical index (MI) of 1.0 or 1.9. For each MI, half of the animals were sacrificed shortly after imaging (4 h) or after 2 weeks. A blinded veterinary nephropathologist reviewed the histopathology of both the imaged and control (non-imaged) kidney. Blood urea nitrogen (BUN) was measured for each animal prior to imaging and at the time of necropsy. Histopathology assessments in both the 1.0 and 1.9 MI groups revealed no signs of hemorrhage at either the 4-h or 2-week time point. BUN showed minor but statistically significant elevations in both the 1.0 and 1.9 MI groups, but no significant difference was present at the 2-week time point in the 1.0 MI group. All BUN levels (at both time points) remained in the normal range. In conclusion, CEUS with flash-replenishment imaging sequences did not result in kidney bioeffects observable with histology at early or late time points. Increases in BUN levels were observed after imaging, but were minimized when using a moderate MI (1.0).}, journal={ULTRASONICS}, author={Nyankima, A. Gloria and Kasoji, Sandeep and Cianciolo, Rachel and Dayton, Paul A. and Chang, Emily H.}, year={2019}, month={Sep}, pages={1–6} }
 @article{cherin_yin_forbrich_white_dayton_foster_demore_2019, title={IN VITRO SUPERHARMONIC CONTRAST IMAGING USING A HYBRID DUAL-FREQUENCY PROBE}, volume={45}, ISSN={["1879-291X"]}, DOI={10.1016/j.ultrasmedbio.2019.05.012}, abstractNote={Superharmonic imaging is an ultrasound contrast imaging technique that differentiates microbubble echoes from tissue through detection of higher-order bubble harmonics in a broad frequency range well above the excitation frequency. Application of superharmonic imaging in three dimensions allows specific visualization of the tissue microvasculature with high resolution and contrast, a technique referred to as acoustic angiography. Because of the need to transmit and receive across a bandwidth that spans up to the fifth harmonic of the fundamental and higher, this imaging approach requires imaging probes comprising dedicated transducers for transmit and receive. In this work, we report on a new dual-frequency probe including two 1.7-MHz rectangular transducers positioned one on each side of a 20-MHz 256-element array. Finite element modeling-based design, fabrication processes and assembly of the transducer are described, as is integration with a high-frequency ultrasound imaging platform. Dual-frequency single-plane-wave imaging was performed with a microbubble contrast agent in flow phantoms and compared with conventional high-frequency B-mode imaging, and resolution and contrast-to-tissue ratio were quantified. This work represents an intermediate but informative step toward the development of dual-frequency imaging probes based on array technology, specifically designed for clinical applications of acoustic angiography.}, number={9}, journal={ULTRASOUND IN MEDICINE AND BIOLOGY}, author={Cherin, Emmanuel and Yin, Jianhua and Forbrich, Alex and White, Christopher and Dayton, Paul A. and Foster, F. Stuart and Demore, Christine E. M.}, year={2019}, month={Sep}, pages={2525–2539} }
 @article{rojas_dayton_2019, title={IN VIVO MOLECULAR IMAGING USING LOW-BOILING-POINT PHASE-CHANGE CONTRAST AGENTS: A PROOF OF CONCEPT STUDY}, volume={45}, ISSN={["1879-291X"]}, DOI={10.1016/j.ultrasmedbio.2018.08.004}, abstractNote={Sub-micron phase-change contrast agents (PCCAs) have been proposed as a tool for ultrasound molecular imaging based on their potential to extravasate and target extravascular markers and also because of the potential to image these contrast agents with a high contrast-to-tissue ratio. We compare in vivo ultrasound molecular imaging with targeted low-boiling-point PCCAs and targeted microbubble contrast agents. Both agents were targeted to the intravascular (endothelial) integrin αvß3via a cyclic RGD peptide (cyclo-Arg-Gly-Asp-D-Tyr-Cys) mechanism and imaged in vivo in a rodent fibrosarcoma model, which exhibits angiogenic microvasculature. Signal intensity was measured using two different techniques, conventional contrast-specific imaging (amplitude/phase modulation) and a droplet vaporization imaging sequence, which detects the unique signature of vaporizing PCCAs. Data indicate that PCCA-specific imaging is more sensitive to small numbers of bound agents than conventional contrast imaging. However, data also revealed that contrast from targeted microbubbles was greater than that provided by PCCAs. Both control and targeted PCCAs were observed to be retained in tissue post-vaporization, which was expected for targeted agents but not expected for control agents. The exact mechanism underlying this observation remains unknown.}, number={1}, journal={ULTRASOUND IN MEDICINE AND BIOLOGY}, author={Rojas, Juan D. and Dayton, Paul A.}, year={2019}, month={Jan}, pages={177–191} }
 @article{panfilova_shelton_caresio_sloun_molinari_wijkstra_dayton_mischi_2019, title={ON THE RELATIONSHIP BETWEEN DYNAMIC CONTRAST-ENHANCED ULTRASOUND PARAMETERS AND THE UNDERLYING VASCULAR ARCHITECTURE EXTRACTED FROM ACOUSTIC ANGIOGRAPHY}, volume={45}, ISSN={["1879-291X"]}, url={https://europepmc.org/articles/PMC6352898}, DOI={10.1016/j.ultrasmedbio.2018.08.018}, abstractNote={Dynamic contrast-enhanced ultrasound (DCE-US) has been proposed as a powerful tool for cancer diagnosis by estimation of perfusion and dispersion parameters reflecting angiogenic vascular changes. This work was aimed at identifying which vascular features are reflected by the estimated perfusion and dispersion parameters through comparison with acoustic angiography (AA). AA is a high-resolution technique that allows quantification of vascular morphology. Three-dimensional AA and 2-D DCE-US bolus acquisitions were used to monitor the growth of fibrosarcoma tumors in nine rats. AA-derived vascular properties were analyzed along with DCE-US perfusion and dispersion to investigate the differences between tumor and control and their evolution in time. AA-derived microvascular density and DCE-US perfusion exhibited good agreement, confirmed by their spatial distributions. No vascular feature was correlated with dispersion. Yet, dispersion provided better cancer classification than perfusion. We therefore hypothesize that dispersion characterizes vessels that are smaller than those visible with AA.}, number={2}, journal={ULTRASOUND IN MEDICINE AND BIOLOGY}, author={Panfilova, Anastasiia and Shelton, Sarah E. and Caresio, Cristina and Sloun, Ruud J. G. and Molinari, Filippo and Wijkstra, Hessel and Dayton, Paul A. and Mischi, Massimo}, year={2019}, month={Feb}, pages={539–548} }
 @article{marvin_ding_white_orlova_wang_zywot_vickerman_harr_tarrant_dayton_et al._2019, title={On Command Drug Delivery via Cell-Conveyed Phototherapeutics}, volume={15}, ISSN={["1613-6829"]}, DOI={10.1002/smll.201901442}, abstractNote={Abstract}, number={37}, journal={SMALL}, author={Marvin, Christina M. and Ding, Song and White, Rachel E. and Orlova, Natalia and Wang, Qunzhao and Zywot, Emilia M. and Vickerman, Brianna M. and Harr, Lauren and Tarrant, Teresa K. and Dayton, Paul A. and et al.}, year={2019}, month={Sep} }
 @article{wahl_de_fernandez_lenarcic_xu_cockrell_cleary_johnson_schramm_rank_et al._2019, title={Precision mouse models with expanded tropism for human pathogens}, volume={37}, ISSN={["1546-1696"]}, DOI={10.1038/s41587-019-0225-9}, abstractNote={A major limitation of current humanized mouse models is that they primarily enable the analysis of human-specific pathogens that infect hematopoietic cells. However, most human pathogens target other cell types, including epithelial, endothelial and mesenchymal cells. Here, we show that implantation of human lung tissue, which contains up to 40 cell types, including nonhematopoietic cells, into immunodeficient mice (lung-only mice) resulted in the development of a highly vascularized lung implant. We demonstrate that emerging and clinically relevant human pathogens such as Middle East respiratory syndrome coronavirus, Zika virus, respiratory syncytial virus and cytomegalovirus replicate in vivo in these lung implants. When incorporated into bone marrow/liver/thymus humanized mice, lung implants are repopulated with autologous human hematopoietic cells. We show robust antigen-specific humoral and T-cell responses following cytomegalovirus infection that control virus replication. Lung-only mice and bone marrow/liver/thymus-lung humanized mice substantially increase the number of human pathogens that can be studied in vivo, facilitating the in vivo testing of therapeutics. Implantation of lung tissue into humanized mice enables in vivo study of the human immune response to pathogens.}, number={10}, journal={NATURE BIOTECHNOLOGY}, author={Wahl, Angela and De, Chandrav and Fernandez, Maria Abad and Lenarcic, Erik M. and Xu, Yinyan and Cockrell, Adam S. and Cleary, Rachel A. and Johnson, Claire E. and Schramm, Nathaniel J. and Rank, Laura M. and et al.}, year={2019}, month={Oct}, pages={1163-+} }
 @article{nyankima_kasoji_cianciolo_dayton_chang_2019, title={The biological response of rodent kidneys to low frequency, full volume diagnostic contrast-enhanced ultrasound imaging: Pilot data}, volume={25}, ISSN={["2352-3409"]}, DOI={10.1016/j.dib.2019.104170}, abstractNote={With the growth of contrast-enhanced ultrasound (CEUS) clinically, there are concerns about histologic bioeffects in regards to the implementation of high mechanical index (MI) imaging, such as the imaging sequence used for a specific CEUS technique known as flash-replenishment. The data presented are results from a pilot study, which explored flash-replenishment with high and moderate MI imaging sequences at time points of 24 hours and 2 weeks post imaging. This pilot study was followed by a larger study, which can be found in a journal article entitled “Histological and Blood Chemistry Examination of the Rodent Kidney After Exposure to Flash-Replenishment Ultrasound Contrast Imaging” Nyankima et al., 2019.}, journal={DATA IN BRIEF}, author={Nyankima, A. Gloria and Kasoji, Sandeep and Cianciolo, Rachel and Dayton, Paul A. and Chang, Emily H.}, year={2019}, month={Aug} }
 @article{rojas_rajamahendiran_czernuszewicz_velasco_perdomo_harlacher_o'connell_butler_damania_dayton_et al._2019, title={Tracking angiogenesis induced microvascular changes in a lymphoma model via a new high throughput non-invasive dual modality imaging platform}, volume={79}, ISSN={["1538-7445"]}, DOI={10.1158/1538-7445.AM2019-1935}, abstractNote={Abstract}, number={13}, journal={CANCER RESEARCH}, author={Rojas, Juan D. and Rajamahendiran, Rajalekha and Czernuszewicz, Tomasz J. and Velasco, Brian and Perdomo, Jonathan and Harlacher, Max and O'Connell, Graeme and Butler, James and Damania, Blossom and Dayton, Paul A. and et al.}, year={2019}, month={Jul} }
 @article{fix_koppolu_novell_hopkins_kierski_zaharoff_dayton_papadopoulou_2019, title={ULTRASOUND-STIMULATED PHASE-CHANGE CONTRAST AGENTS FOR TRANSEPITHELIAL DELIVERY OF MACROMOLECULES, TOWARD GASTROINTESTINAL DRUG DELIVERY}, volume={45}, ISSN={["1879-291X"]}, DOI={10.1016/j.ultrasmedbio.2019.02.004}, abstractNote={The gastrointestinal (GI) tract presents a notoriously difficult barrier for macromolecular drug delivery, especially for biologics. Herein, we demonstrate that ultrasound-stimulated phase change contrast agents (PCCAs) can transiently disrupt confluent colorectal adenocarcinoma monolayers and improve the transepithelial transport of a macromolecular model drug. With ultrasound treatment in the presence of PCCAs, we achieved a maximum of 44 ± 15% transepithelial delivery of 70-kDa fluorescein isothiocyanate-dextran, compared with negligible delivery through sham control monolayers. Among all tested rarefactional pressures (300–600 kPa), dextran delivery efficiency was consistently greatest at 300 kPa. To explore this unexpected finding, we quantified stable and inertial cavitation energy generated by various ultrasound exposure conditions. In general, lower pressures resulted in more persistent cavitation activity during the 30-s ultrasound exposures, which may explain the enhanced dextran delivery efficiency. Thus, a unique advantage of using low boiling point PCCAs for this application is that the same low-pressure pulses can be used to induce vaporization and provide maximal delivery.}, number={7}, journal={ULTRASOUND IN MEDICINE AND BIOLOGY}, author={Fix, Samantha M. and Koppolu, Bhanu P. and Novell, Anthony and Hopkins, Jared and Kierski, Thomas M. and Zaharoff, David A. and Dayton, Paul A. and Papadopoulou, Virginie}, year={2019}, month={Jul}, pages={1762–1776} }
 @article{benhabbour_kovarova_jones_copeland_shrivastava_swanson_sykes_ho_cottrell_sridharan_et al._2019, title={Ultra-long-acting tunable biodegradable and removable controlled release implants for drug delivery}, volume={10}, ISSN={["2041-1723"]}, DOI={10.1038/s41467-019-12141-5}, abstractNote={Abstract}, journal={NATURE COMMUNICATIONS}, author={Benhabbour, S. Rahima and Kovarova, Martina and Jones, Clinton and Copeland, Daijha J. and Shrivastava, Roopali and Swanson, Michael D. and Sykes, Craig and Ho, Phong T. and Cottrell, Mackenzie L. and Sridharan, Anush and et al.}, year={2019}, month={Sep} }
 @article{rojas_papadopoulou_czernuszewicz_rajamahendiran_chytil_chiang_chong_bautch_rathmell_aylward_et al._2019, title={Ultrasound Measurement of Vascular Density to Evaluate Response to Anti-Angiogenic Therapy in Renal Cell Carcinoma}, volume={66}, ISSN={["1558-2531"]}, DOI={10.1109/TBME.2018.2860932}, abstractNote={<italic>Background:</italic> Functional and molecular changes often precede gross anatomical changes, so early assessment of a tumor's functional and molecular response to therapy can help reduce a patient's exposure to the side effects of ineffective chemotherapeutics or other treatment strategies. <italic>Objective:</italic> Our intent was to test the hypothesis that an ultrasound microvascular imaging approach might provide indications of response to therapy prior to assessment of tumor size. <italic>Methods:</italic> Mice bearing clear-cell renal cell carcinoma xenograft tumors were treated with antiangiogenic and Notch inhibition therapies. An ultrasound measurement of microvascular density was used to serially track the tumor response to therapy. <italic>Results:</italic> Data indicated that ultrasound-derived microvascular density can indicate response to therapy a week prior to changes in tumor volume and is strongly correlated with physiological characteristics of the tumors as measured by histology (<inline-formula><tex-math notation="LaTeX">$\rho = {\text{0.75}}$</tex-math></inline-formula>). Furthermore, data demonstrated that ultrasound measurements of vascular density can determine response to therapy and classify between-treatment groups with high sensitivity and specificity. <italic>Conclusion/Significance:</italic> Results suggests that future applications utilizing ultrasound imaging to monitor tumor response to therapy may be able to provide earlier insight into tumor behavior from metrics of microvascular density rather than anatomical tumor size measurements.}, number={3}, journal={IEEE TRANSACTIONS ON BIOMEDICAL ENGINEERING}, author={Rojas, Juan D. and Papadopoulou, Virginie and Czernuszewicz, Tomasz J. and Rajamahendiran, Rajalekha M. and Chytil, Anna and Chiang, Yun-Chen and Chong, Diana C. and Bautch, Victoria L. and Rathmell, W. Kimryn and Aylward, Stephen and et al.}, year={2019}, month={Mar}, pages={873–880} }
 @article{mohanty_papadopoulou_newsome_shelton_dayton_muller_2019, title={Ultrasound multiple scattering with microbubbles can differentiate between tumor and healthy tissue in vivo}, volume={64}, ISSN={["1361-6560"]}, url={https://europepmc.org/articles/PMC6876296}, DOI={10.1088/1361-6560/ab1a44}, abstractNote={Most solid tumors are characterized by highly dense, isotropic vessel networks. Characterization of such features has shown promise for early cancer diagnosis. Ultrasound diffusion has been used to characterize the micro-architecture of complex media, such as bone and the lungs. In this work, we examine a non-invasive diffusion-based ultrasound technique to assess neo-vascularization. Because the diffusion constant reflects the density of scatterers in heterogeneous media, we hypothesize that by injecting microbubbles into the vasculature, ultrasound diffusivity can reflect vascular density (VD), thus differentiating the microvascular patterns between tumors and healthy tissue. The diffusion constant and its anisotropy are shown to be significantly different between fibrosarcoma tumors (n  =  16) and control tissue (n  =  18) in a rat animal model in vivo. The diffusion constant values for control and tumor were found to be 1.38  ±  0.51 mm2 µs−1 and 0.65  ±  0.27 mm2 µs−1, respectively. These results are corroborated with VD from acoustic angiography (AA) data, confirming increased vessel density in tumors compared to controls. The diffusion constant offers a promising way to quantitatively assess vascular networks when combined with contrast agents, which may allow early tumor detection and characterization.}, number={11}, journal={PHYSICS IN MEDICINE AND BIOLOGY}, author={Mohanty, Kaustav and Papadopoulou, Virginie and Newsome, Isabel G. and Shelton, Sarah and Dayton, Paul A. and Muller, Marie}, year={2019}, month={Jun} }
 @article{rojas_dayton_2019, title={VAPORIZATION DETECTIONIMAGING: A TECHNIQUE FOR IMAGING LOW-BOILING-POINTPHASE-CHANGE ONTRAST AGENTS WITH A HIGH DEPTH OF PENETRATION AND CONTRAST-TO-TISSUERATIO}, volume={45}, ISSN={["1879-291X"]}, DOI={10.1016/j.ultrasmedbio.2018.08.017}, abstractNote={Phase-change contrast agents (PCCAs) possess advantages over microbubble contrast agents, such as the ability to extravasate and circulate longer in the vasculature that could enhance the diagnostic capabilities of contrast-enhanced ultrasound. PCCAs typically have a liquid perfluorocarbon (PFC) core that can be vaporized into echogenic microbubbles. Vaporization of submicron agents filled with liquid PFCs at body temperature usually requires therapeutic pressures higher than typically used for diagnostic imaging, but low-boiling-point PCCAs using decafluorobutane or octafluoropropane can be vaporized using pressures in the diagnostic imaging regime. Low-boiling-point PCCAs produce a unique acoustic signature that can be separated from tissue and bubble signals to make images with high contrast-to-tissue ratios. In this work, we explore the effect of pulse length and concentration on the vaporization signal of PCCAs and a new technique to capture and use the signals to make high contrast-to-tissue ratio images in vivo. The results indicate that using a short pulse may be ideal for imaging because it does not interact with created bubbles but still produces strong signals for making images. Furthermore, it was found that capturing PCCA vaporization signals produced higher contrast-to-tissue ratio values and better depth of penetration than imaging the bubbles generated by droplet activation using conventional contrast imaging techniques. The resolution of the vaporization signal images is poor because of the low frequency of the signals, but their high sensitivity may be used for applications such as molecular imaging, where the detection of small numbers of contrast agents is important.}, number={1}, journal={ULTRASOUND IN MEDICINE AND BIOLOGY}, author={Rojas, Juan D. and Dayton, Paul A.}, year={2019}, month={Jan}, pages={192–207} }
 @article{li_kim_wang_kasoji_lindsey_dayton_jiang_2018, title={A Dual-Frequency Colinear Array for Acoustic Angiography in Prostate Cancer Evaluation}, volume={65}, ISSN={["1525-8955"]}, DOI={10.1109/TUFFC.2018.2872911}, abstractNote={Approximately 80% of men who reach 80 years of age will have some form of prostate cancer. The challenge remains to differentiate benign and malignant lesions. Based on recent research, acoustic angiography, a novel contrast-enhanced ultrasound imaging technique, can provide high-resolution visualization of tissue microvasculature and has demonstrated the ability to differentiate vascular characteristics between healthy and tumor tissue in preclinical studies. We hypothesize that transrectal acoustic angiography may enhance the assessment of prostate cancer. In this paper, we describe the development of a dual frequency, dual-layer colinear array transducer for transrectal acoustic angiography. The probe consists of 64 transmitting (TX) elements with a center frequency of 3 MHz and 128 receiving (RX) elements with a center frequency of 15 MHz. The dimensions of the array are 18 mm in azimuth and 9 mm in elevation. The pitch is  $280~\mu \text{m}$  for TX elements and 140  $\mu \text{m}$  for RX elements. Pulse-echo tests of TX/RX elements and aperture acoustic field measurements were conducted, and both results were compared with the simulation results. Real-time contrast imaging was performed using a Verasonics system and a tissue-mimicking phantom. Nonlinear acoustic responses from microbubble contrast agents at a depth of 35 mm were clearly observed. In vivo imaging in a rodent model demonstrated the ability to detect individual vessels underneath the skin. These results indicate the potential use of the array described herein for acoustic angiography imaging of prostate tumor and identification of regions of neovascularization for the guidance of prostate biopsies.}, number={12}, journal={IEEE TRANSACTIONS ON ULTRASONICS FERROELECTRICS AND FREQUENCY CONTROL}, author={Li, Sibo and Kim, Jinwook and Wang, Zhuochen and Kasoji, Sandeep and Lindsey, Brooks D. and Dayton, Paul A. and Jiang, Xiaoning}, year={2018}, month={Dec}, pages={2418–2428} }
 @article{espindola_lin_soulioti_dayton_pinton_2018, title={Adaptive Multifocus Beamforming for Contrast-Enhanced-Super-Resolution Ultrasound Imaging in Deep Tissue}, volume={65}, ISSN={["1525-8955"]}, DOI={10.1109/TUFFC.2018.2865903}, abstractNote={Contrast-enhanced-super-resolution ultrasound imaging, also referred to as ultrasound localization microscopy, can resolve vessels that are smaller than the diffraction limit and has recently been able to generate super-resolved vascular images of shallow in vivo structures in small animals. To fully translate this technology to the clinic, it is advantageous to be able to detect microbubbles at deeper locations in tissue while maintaining a short acquisition time. Current implementations of this imaging method rely on plane-wave imaging. This method has the advantage of maximizing the frame rate, which is important due to the large amount of frames required for super-resolution processing. However, the wide planar beam used to illuminate the field of view produces poor contrast and low sensitivity bubble detection. Here, we propose an “adaptive multifocus” sequence, a new ultrasound imaging sequence that combines the high frame rate feature of a plane wave with the increased bubble detection sensitivity of a focused beam. This sequence simultaneously sonicates two or more foci with a single emission, hence retaining a high frame rate, yet achieving improved sensitivity to microbubbles. In the limit of one target, the beam reduces to a conventional focused transmission; and for an infinite number of targets, it converges to plane-wave imaging. Numerical simulations, using the full-wave code, are performed to compare the point spread function of the proposed sequence to that generated by the plane-wave emission. Our numerical results predict an improvement of up to 15 dB in the signal-to-noise ratio. Ex vivo experiments of a tissue-embedded microtube phantom are used to generate super-resolved images and to compare the adaptive beamforming approach to plane-wave imaging. These experimental results show that the adaptive multifocus sequence successfully detects 744 microbubble events at 60 mm when they are undetectable by the plane-wave sequence under the same imaging conditions. At a shallower depth of 44 mm, the proposed adaptive multifocus method detects 6.9 times more bubbles than plane-wave imaging (1763 versus 257 bubble events).}, number={12}, journal={IEEE TRANSACTIONS ON ULTRASONICS FERROELECTRICS AND FREQUENCY CONTROL}, author={Espindola, David and Lin, Fanglue and Soulioti, Danai E. and Dayton, Paul A. and Pinton, Gianmarco F.}, year={2018}, month={Dec}, pages={2255–2263} }
 @article{chiarella_quimby_mehrab-mohseni_velasco_kasoji_davis_dayton_hathaway_pattenden_2018, title={Cavitation enhancement increases the efficiency and consistency of chromatin fragmentation from fixed cells for downstream quantitative applications}, volume={57}, DOI={10.1021/acs.biochem.8b00075}, abstractNote={One of the most sensitive, time-consuming, and variable steps of chromatin immunoprecipitation (ChIP) is chromatin sonication. Traditionally, this process can take hours to properly sonicate enough chromatin for multiple ChIP assays. Further, the length of sheared DNA is often inconsistent. In order to faithfully measure chemical and structural changes at the chromatin level, sonication needs to be reliable. Thus, chromatin fragmentation by sonication represents a significant bottleneck to downstream quantitative analysis. To improve the consistency and efficiency of chromatin sonication, we developed and tested a cavitation enhancing reagent based on sonically active nanodroplets. Here, we show that nanodroplets increase sonication efficiency by 16-fold and provide more consistent levels of chromatin fragmentation. Using the previously characterized chromatin in vivo assay (CiA) platform, we generated two distinct chromatin states in order to test nanodroplet-assisted sonication sensitivity in measuring post-translational chromatin marks. By comparing euchromatin to chemically induced heterochromatin at the same CiA:Oct4 locus, we quantitatively measure the capability of our new sonication technique to resolve differences in chromatin structure. We confirm that nanodroplet-assisted sonication results are indistinguishable from those of samples processed with traditional sonication in downstream applications. While the processing time for each sample was reduced from 38.4 to 2.3 min, DNA fragment distribution sizes were significantly more consistent with a coefficient of variation 2.7 times lower for samples sonicated in the presence of nanodroplets. In conclusion, sonication utilizing the nanodroplet cavitation enhancement reagent drastically reduces the amount of processing time and provides consistently fragmented chromatin of high quality for downstream applications.}, number={19}, journal={Biochemistry}, author={Chiarella, A. M. and Quimby, A. L. and Mehrab-Mohseni, M. and Velasco, B. and Kasoji, S. K. and Davis, I. J. and Dayton, P. A. and Hathaway, N. A. and Pattenden, S. G.}, year={2018}, pages={2756–2761} }
 @article{wu_fix_arena_chen_zheng_olumolade_papadopoulou_novell_dayton_konofagou_2018, title={Focused ultrasound-facilitated brain drug delivery using optimized nanodroplets: vaporization efficiency dictates large molecular delivery}, volume={63}, ISSN={["1361-6560"]}, DOI={10.1088/1361-6560/aaa30d}, abstractNote={Focused ultrasound with nanodroplets could facilitate localized drug delivery after vaporization with potentially improved in vivo stability, drug payload, and minimal interference outside of the focal zone compared with microbubbles. While the feasibility of blood–brain barrier (BBB) opening using nanodroplets has been previously reported, characterization of the associated delivery has not been achieved. It was hypothesized that the outcome of drug delivery was associated with the droplet’s sensitivity to acoustic energy, and can be modulated with the boiling point of the liquid core. Therefore, in this study, octafluoropropane (OFP) and decafluorobutane (DFB) nanodroplets were used both in vitro for assessing their relative vaporization efficiency with high-speed microscopy, and in vivo for delivering molecules with a size relevant to proteins (40 kDa dextran) to the murine brain. It was found that at low pressures (300–450 kPa), OFP droplets vaporized into a greater number of microbubbles compared to DFB droplets at higher pressures (750–900 kPa) in the in vitro study. In the in vivo study, successful delivery was achieved with OFP droplets at 300 kPa and 450 kPa without evidence of cavitation damage using ¼ dosage, compared to DFB droplets at 900 kPa where histology indicated tissue damage due to inertial cavitation. In conclusion, the vaporization efficiency of nanodroplets positively impacted the amount of molecules delivered to the brain. The OFP droplets due to the higher vaporization efficiency served as better acoustic agents to deliver large molecules efficiently to the brain compared with the DFB droplets.}, number={3}, journal={PHYSICS IN MEDICINE AND BIOLOGY}, author={Wu, Shih-Ying and Fix, Samantha M. and Arena, Christopher B. and Chen, Cherry C. and Zheng, Wenlan and Olumolade, Oluyemi O. and Papadopoulou, Virginie and Novell, Anthony and Dayton, Paul A. and Konofagou, Elisa E.}, year={2018}, month={Feb} }
 @article{papadopoulou_germonpre_cosgrove_eckersley_dayton_obeid_boutros_tang_theunissen_balestra_2018, title={Variability in circulating gas emboli after a same scuba diving exposure}, volume={118}, ISSN={["1439-6327"]}, DOI={10.1007/s00421-018-3854-7}, abstractNote={{"Label"=>"PURPOSE", "NlmCategory"=>"OBJECTIVE"} A reduction in ambient pressure or decompression from scuba diving can result in ultrasound-detectable venous gas emboli (VGE). These environmental exposures carry a risk of decompression sickness (DCS) which is mitigated by adherence to decompression schedules; however, bubbles are routinely observed for dives well within these limits and significant inter-personal variability in DCS risk exists. Here, we assess the variability and evolution of VGE for 2 h post-dive using echocardiography, following a standardized pool dive in calm warm conditions. {"Label"=>"METHODS", "NlmCategory"=>"METHODS"} 14 divers performed either one or two (with a 24 h interval) standardized scuba dives to 33 mfw (400 kPa) for 20 min of immersion time at NEMO 33 in Brussels, Belgium. Measurements were performed at 21, 56, 91 and 126 min post-dive: bubbles were counted for all 68 echocardiography recordings and the average over ten consecutive cardiac cycles taken as the bubble score. {"Label"=>"RESULTS", "NlmCategory"=>"RESULTS"} Significant inter-personal variability was demonstrated despite all divers following the same protocol in controlled pool conditions: in the detection or not of VGE, in the peak VGE score, as well as time to VGE peak. In addition, intra-personal differences in 2/3 of the consecutive day dives were seen (lower VGE counts or faster clearance). {"Label"=>"CONCLUSIONS", "NlmCategory"=>"CONCLUSIONS"} Since VGE evolution post-dive varies between people, more work is clearly needed to isolate contributing factors. In this respect, going toward a more continuous evaluation, or developing new means to detect decompression stress markers, may offer the ability to better assess dynamic correlations to other physiological parameters.}, number={6}, journal={EUROPEAN JOURNAL OF APPLIED PHYSIOLOGY}, author={Papadopoulou, V. and Germonpre, P. and Cosgrove, D. and Eckersley, R. J. and Dayton, P. A. and Obeid, G. and Boutros, A. and Tang, M. -X. and Theunissen, S. and Balestra, C.}, year={2018}, month={Jun}, pages={1255–1264} }
 @article{lin_shelton_espíndola_rojas_pinton_dayton_2017, title={3-D Ultrasound Localization Microscopy for Identifying Microvascular Morphology Features of Tumor Angiogenesis at a Resolution Beyond the Diffraction Limit of Conventional Ultrasound}, volume={7}, ISSN={1838-7640}, url={http://dx.doi.org/10.7150/thno.16899}, DOI={10.7150/thno.16899}, abstractNote={Angiogenesis has been known as a hallmark of solid tumor cancers for decades, yet ultrasound has been limited in its ability to detect the microvascular changes associated with malignancy. Here, we demonstrate the potential of 'ultrasound localization microscopy' applied volumetrically in combination with quantitative analysis of microvascular morphology, as an approach to overcome this limitation. This pilot study demonstrates our ability to image complex microvascular patterns associated with tumor angiogenesis in-vivo at a resolution of tens of microns - substantially better than the diffraction limit of traditional clinical ultrasound, yet using an 8 MHz clinical ultrasound probe. Furthermore, it is observed that data from healthy and tumor-bearing tissue exhibit significant differences in microvascular pattern and density. Results suggests that with continued development of these novel technologies, ultrasound has the potential to detect biomarkers of cancer based on the microvascular 'fingerprint' of malignant angiogenesis rather than through imaging of blood flow dynamics or the tumor mass itself.}, number={1}, journal={Theranostics}, publisher={Ivyspring International Publisher}, author={Lin, Fanglue and Shelton, Sarah E. and Espíndola, David and Rojas, Juan D. and Pinton, Gianmarco and Dayton, Paul A.}, year={2017}, pages={196–204} }
 @article{kasoji_chang_mullin_chong_rathmell_dayton_2017, title={A Pilot Clinical Study in Characterization of Malignant Renal-cell Carcinoma Subtype with Contrast-enhanced Ultrasound}, volume={39}, ISSN={["1096-0910"]}, DOI={10.1177/0161734616666383}, abstractNote={ Malignant renal cell carcinoma (RCC) is a diverse set of diseases, which are independently difficult to characterize using conventional MRI and CT protocols due to low temporal resolution to study perfusion characteristics. Because different disease subtypes have different prognoses and involve varying treatment regimens, the ability to determine RCC subtype non-invasively is a clinical need. Contrast-enhanced ultrasound (CEUS) has been assessed as a tool to characterize kidney lesions based on qualitative and quantitative assessment of perfusion patterns, and we hypothesize that this technique might help differentiate disease subtypes. Twelve patients with RCC confirmed pathologically were imaged using contrast-enhanced ultrasound. Time intensity curves were generated and analyzed quantitatively using 10 characteristic metrics. Results showed that peak intensity ( p = 0.001) and time-to-80% on wash-out ( p = 0.004) provided significant differences between clear cell, papillary, and chromophobe RCC subtypes. These results suggest that CEUS may be a feasible test for characterizing RCC subtypes. }, number={2}, journal={ULTRASONIC IMAGING}, author={Kasoji, Sandeep K. and Chang, Emily H. and Mullin, Lee B. and Chong, Wui K. and Rathmell, W. Kimryn and Dayton, Paul A.}, year={2017}, month={Mar}, pages={126–136} }
 @article{fix_novell_yun_dayton_arena_2017, title={An evaluation of the sonoporation potential of low-boiling point phase-change ultrasound contrast agents in vitro}, volume={5}, ISSN={["2050-5736"]}, DOI={10.1186/s40349-017-0085-z}, abstractNote={Phase-change ultrasound contrast agents (PCCAs) offer a solution to the inherent limitations associated with using microbubbles for sonoporation; they are characterized by prolonged circulation lifetimes, and their nanometer-scale sizes may allow for passive accumulation in solid tumors. As a first step towards the goal of extravascular cell permeabilization, we aim to characterize the sonoporation potential of a low-boiling point formulation of PCCAs in vitro.Parameters to induce acoustic droplet vaporization and subsequent microbubble cavitation were optimized in vitro using high-speed optical microscopy. Sonoporation of pancreatic cancer cells in suspension was then characterized at a range of pressures (125-600 kPa) and pulse lengths (5-50 cycles) using propidium iodide as an indicator molecule.We achieved sonoporation efficiencies ranging from 8 ± 1% to 36 ± 4% (percent of viable cells), as evidenced by flow cytometry. Increasing sonoporation efficiency trended with increasing pulse length and peak negative pressure.We conclude that PCCAs can be used to induce the sonoporation of cells in vitro, and our results warrant further investigation into the use of PCCAs as extravascular sonoporation agents in vivo.}, journal={JOURNAL OF THERAPEUTIC ULTRASOUND}, author={Fix, Samantha M. and Novell, Anthony and Yun, Yeoheung and Dayton, Paul A. and Arena, Christopher B.}, year={2017}, month={Jan}, pages={1–11} }
 @article{lindsey_shelton_foster_dayton_2017, title={Assessment of Molecular Acoustic Angiography for Combined Microvascular and Molecular Imaging in Preclinical Tumor Models}, volume={19}, ISSN={1536-1632 1860-2002}, url={http://dx.doi.org/10.1007/s11307-016-0991-4}, DOI={10.1007/s11307-016-0991-4}, abstractNote={The purposes of the present study is to evaluate a new ultrasound molecular imaging approach in its ability to image a preclinical tumor model and to investigate the capacity to visualize and quantify co-registered microvascular and molecular imaging volumes.Molecular imaging using the new technique was compared with a conventional ultrasound molecular imaging technique (multi-pulse imaging) by varying the injected microbubble dose and scanning each animal using both techniques. Each of the 14 animals was randomly assigned one of three doses; bolus dose was varied, and the animals were imaged for three consecutive days so that each animal received every dose. A microvascular scan was also acquired for each animal by administering an infusion of nontargeted microbubbles. These scans were paired with co-registered molecular images (VEGFR2-targeted microbubbles), the vessels were segmented, and the spatial relationships between vessels and VEGFR2 targeting locations were analyzed. In five animals, an additional scan was performed in which the animal received a bolus of microbubbles targeted to E- and P-selectins. Vessel tortuosity as a function of distance from VEGF and selectin targeting was analyzed in these animals.Although resulting differences in image intensity due to varying microbubble dose were not significant between the two lowest doses, superharmonic imaging had significantly higher contrast-to-tissue ratio (CTR) than multi-pulse imaging (mean across all doses 13.98 dB for molecular acoustic angiography vs. 0.53 dB for multi-pulse imaging; p = 4.9 × 10-10). Analysis of registered microvascular and molecular imaging volumes indicated that vessel tortuosity decreases with increasing distance from both VEGFR2- and selectin-targeting sites.Molecular acoustic angiography (superharmonic molecular imaging) exhibited a significant increase in CTR at all doses tested due to superior rejection of tissue artifact signals. Due to the high resolution of acoustic angiography molecular imaging, it is possible to analyze spatial relationships in aligned microvascular and molecular superharmonic imaging volumes. Future studies are required to separate the effects of biomarker expression and blood flow kinetics in comparing local tortuosity differences between different endothelial markers such as VEGFR2, E-selectin, and P-selectin.}, number={2}, journal={Molecular Imaging and Biology}, publisher={Springer Science and Business Media LLC}, author={Lindsey, Brooks D. and Shelton, Sarah E. and Foster, F. Stuart and Dayton, Paul A.}, year={2017}, pages={194–202} }
 @article{wang_martin_huang_dayton_jiang_2017, title={Contrast Enhanced Superharmonic Imaging for Acoustic Angiography Using Reduced Form-Factor Lateral Mode Transmitters for Intravascular and Intracavity Applications}, volume={64}, ISSN={["1525-8955"]}, DOI={10.1109/tuffc.2016.2619687}, abstractNote={Techniques to image the microvasculature may play an important role in imaging tumor-related angiogenesis and vasa vasorum associated with vulnerable atherosclerotic plaques. However, the microvasculature associated with these pathologies is difficult to detect using traditional B-mode ultrasound or even harmonic imaging due to small vessel size and poor differentiation from surrounding tissue. Acoustic angiography, a microvascular imaging technique that utilizes superharmonic imaging (detection of higher order harmonics of microbubble response), can yield a much higher contrast-to-tissue ratio than second harmonic imaging methods. In this paper, two dual-frequency transducers using lateral mode transmitters were developed for superharmonic detection and acoustic angiography imaging in intracavity applications. A single element dual-frequency intravascular ultrasound transducer was developed for concept validation, which achieved larger signal amplitude, better contrast-to-noise ratio (CNR), and pulselength compared to the previous work. A dual-frequency [Pb(Mg<sub>1/3</sub>Nb<sub>2/3</sub>)O<sub>3</sub>]–x[PbTiO<sub>3</sub>] array transducer was then developed for superharmonic imaging with dynamic focusing. The axial and lateral sizes of the microbubbles in a 200-<inline-formula> <tex-math notation="LaTeX">$\mu \text{m}$ </tex-math></inline-formula> tube were measured to be 269 and <inline-formula> <tex-math notation="LaTeX">$200~\mu \text{m}$ </tex-math></inline-formula>, respectively. The maximum CNR was calculated to be 22 dB. These results show that superharmonic imaging with a low frequency lateral mode transmitter is a feasible alternative to thickness mode transmitters when the final transducer size requirements dictate design choices.}, number={2}, journal={IEEE TRANSACTIONS ON ULTRASONICS FERROELECTRICS AND FREQUENCY CONTROL}, author={Wang, Zhuochen and Martin, K. Heath and Huang, Wenbin and Dayton, Paul A. and Jiang, Xiaoning}, year={2017}, month={Feb}, pages={311–319} }
 @article{lindsey_kim_dayton_jiang_2017, title={Dual-Frequency Piezoelectric Endoscopic Transducer for Imaging Vascular Invasion in Pancreatic Cancer}, volume={64}, ISSN={["1525-8955"]}, DOI={10.1109/tuffc.2017.2702010}, abstractNote={Cancers of the pancreas have the poorest prognosis among all cancers, as many tumors are not detected until surgery is no longer a viable option. Surgical viability is typically determined via endoscopic ultrasound imaging. However, many patients who may be eligible for resection are not offered surgery due to diagnostic challenges in determining vascular or lymphatic invasion. In this paper, we describe the development of a dual-frequency piezoelectric transducer for rotational endoscopic imaging designed to transmit at 4 MHz and receive at 20 MHz in order to image microbubble-specific superharmonic signals. Imaging performance is assessed in a tissue-mimicking phantom at depths from 1 cm [contrast-to-tissue ratio (CTR) = 21.6 dB] to 2.5 cm (CTR = 11.4 dB), in ex vivo porcine vessels, and in vivo in a rodent. The prototyped 1.1-mm aperture transducer demonstrates contrast-specific imaging of microbubbles in a 200- $\mu \text{m}$ -diameter tube through the wall of a 1-cm-diameter porcine artery, suggesting such a device may enable direct visualization of small vessels from within the lumen of larger vessels such as the portal vein or superior mesenteric vein.}, number={7}, journal={IEEE TRANSACTIONS ON ULTRASONICS FERROELECTRICS AND FREQUENCY CONTROL}, author={Lindsey, Brooks D. and Kim, Jinwook and Dayton, Paul A. and Jiang, Xiaoning}, year={2017}, month={Jul}, pages={1078–1086} }
 @article{li_duan_semenov_kim_2017, title={Electrical switching of antiferromagnets via strongly spin-orbit coupled materials}, volume={121}, ISSN={0021-8979 1089-7550}, url={http://dx.doi.org/10.1063/1.4974027}, DOI={10.1063/1.4974027}, abstractNote={Electrically controlled ultra-fast switching of an antiferromagnet (AFM) is shown to be realizable by interfacing it with a material of strong spin-orbit coupling. The proximity interaction between the sublattice magnetic moments of a layered AFM and the spin-polarized free electrons at the interface offers an efficient way to manipulate antiferromagnetic states. A quantitative analysis, using the combination with a topological insulator as an example, demonstrates highly reliable 90° and 180° rotations of AFM magnetic states under two different mechanisms of effective torque generation at the interface. The estimated switching speed and energy requirement are in the ps and aJ ranges, respectively, which are about two-three orders of magnitude better than the ferromagnetic counterparts. The observed differences in the magnetization dynamics may explain the disparate characteristic responses. Unlike the usual precessional/chiral motions in the ferromagnets, those of the AFMs can essentially be described as a damped oscillator with a more direct path. The impact of random thermal fluctuations is also examined.}, number={2}, journal={Journal of Applied Physics}, publisher={AIP Publishing}, author={Li, Xi-Lai and Duan, Xiaopeng and Semenov, Yuriy G. and Kim, Ki Wook}, year={2017}, month={Jan}, pages={023907} }
 @article{shelton_lindsey_dayton_lee_2017, title={First-in-Human Study of Acoustic Angiography in the Breast and Peripheral Vasculature}, volume={43}, ISSN={0301-5629}, url={http://dx.doi.org/10.1016/j.ultrasmedbio.2017.08.1881}, DOI={10.1016/j.ultrasmedbio.2017.08.1881}, abstractNote={Screening with mammography has been found to increase breast cancer survival rates by about 20%. However, the current system in which mammography is used to direct patients toward biopsy or surgical excision also results in relatively high rates of unnecessary biopsy, as 66.8% of biopsies are benign. A non-ionizing radiation imaging approach with increased specificity might reduce the rate of unnecessary biopsies. Quantifying the vascular characteristics within and surrounding lesions represents one potential target for assessing likelihood of malignancy via imaging. In this clinical note, we describe the translation of a contrast-enhanced ultrasound technique, acoustic angiography, to human imaging. We illustrate the feasibility of this technique with initial studies in imaging the hand, wrist and breast using Definity microbubble contrast agent and a mechanically steered prototype dual-frequency transducer in healthy volunteers. Finally, this approach was used to image pre-biopsy Breast Imaging Reporting and Data System (BI-RADS) 4 and 5 lesions <2 cm in depth in 11 patients. Results indicate that sensitivity and spatial resolution are sufficient to image vessels as small as 0.2 mm in diameter at depths of ~15 mm in the human breast. Challenges observed include motion artifacts, as well as limited depth of field and sensitivity, which could be improved by correction algorithms and improved transducer technologies.}, number={12}, journal={Ultrasound in Medicine & Biology}, publisher={Elsevier BV}, author={Shelton, Sarah E. and Lindsey, Brooks D. and Dayton, Paul A. and Lee, Yueh Z.}, year={2017}, month={Dec}, pages={2939–2946} }
 @article{lindsey_shelton_martin_ozgun_rojas_foster_dayton_2017, title={High Resolution Ultrasound Superharmonic Perfusion Imaging: In Vivo Feasibility and Quantification of Dynamic Contrast-Enhanced Acoustic Angiography}, volume={45}, ISSN={["1573-9686"]}, url={https://europepmc.org/articles/PMC5682933}, DOI={10.1007/s10439-016-1753-9}, abstractNote={Mapping blood perfusion quantitatively allows localization of abnormal physiology and can improve understanding of disease progression. Dynamic contrast-enhanced ultrasound is a low-cost, real-time technique for imaging perfusion dynamics with microbubble contrast agents. Previously, we have demonstrated another contrast agent-specific ultrasound imaging technique, acoustic angiography, which forms static anatomical images of the superharmonic signal produced by microbubbles. In this work, we seek to determine whether acoustic angiography can be utilized for high resolution perfusion imaging in vivo by examining the effect of acquisition rate on superharmonic imaging at low flow rates and demonstrating the feasibility of dynamic contrast-enhanced superharmonic perfusion imaging for the first time. Results in the chorioallantoic membrane model indicate that frame rate and frame averaging do not affect the measured diameter of individual vessels observed, but that frame rate does influence the detection of vessels near and below the resolution limit. The highest number of resolvable vessels was observed at an intermediate frame rate of 3 Hz using a mechanically-steered prototype transducer. We also demonstrate the feasibility of quantitatively mapping perfusion rate in 2D in a mouse model with spatial resolution of ~100 μm. This type of imaging could provide non-invasive, high resolution quantification of microvascular function at penetration depths of several centimeters.}, number={4}, journal={ANNALS OF BIOMEDICAL ENGINEERING}, author={Lindsey, Brooks D. and Shelton, Sarah E. and Martin, K. Heath and Ozgun, Kathryn A. and Rojas, Juan D. and Foster, F. Stuart and Dayton, Paul A.}, year={2017}, month={Apr}, pages={939–948} }
 @article{kim_lindsey_chang_dai_stavas_dayton_jiang_2017, title={Intravascular forward-looking ultrasound transducers for microbubble-mediated sonothrombolysis}, volume={7}, ISSN={["2045-2322"]}, DOI={10.1038/s41598-017-03492-4}, abstractNote={Abstract}, journal={SCIENTIFIC REPORTS}, author={Kim, Jinwook and Lindsey, Brooks D. and Chang, Wei-Yi and Dai, Xuming and Stavas, Joseph M. and Dayton, Paul A. and Jiang, Xiaoning}, year={2017}, month={Jun} }
 @article{lin_tsuruta_rojas_dayton_2017, title={OPTIMIZING SENSITIVITY OF ULTRASOUND CONTRAST-ENHANCED SUPER-RESOLUTION IMAGING BY TAILORING SIZE DISTRIBUTION OF MICROBUBBLE CONTRAST AGENT}, volume={43}, ISSN={["1879-291X"]}, DOI={10.1016/j.ultrasmedbio.2017.05.014}, abstractNote={Ultrasound contrast-enhanced super-resolution imaging has recently attracted attention because of its extraordinary ability to image vascular features much smaller than the ultrasound diffraction limit. This method requires sensitive detection of separable microbubble events despite a noisy tissue background to indicate the microvasculature, and any approach that could improve the sensitivity of the ultrasound system to individual microbubbles would be highly beneficial. In this study, we evaluated the effect of varying microbubble size on super-resolution imaging sensitivity. Microbubble preparations were size sorted into different mean diameters and then were imaged at equal concentrations. Commercially manufactured Definity and Optison were also imaged for comparison. Both in vitro experiments in phantom vessels and in vivo experiments imaging rat tumors revealed that the sensitivity of contrast-enhanced super-resolution imaging can be improved by using microbubbles with a larger diameter.}, number={10}, journal={ULTRASOUND IN MEDICINE AND BIOLOGY}, author={Lin, Fanglue and Tsuruta, James K. and Rojas, Juan D. and Dayton, Paul A.}, year={2017}, month={Oct}, pages={2488–2493} }
 @article{rojas_dayton_2017, title={Optimizing Acoustic Activation of Phase Change Contrast Agents With the Activation Pressure Matching Method: A Review}, volume={64}, ISSN={["1525-8955"]}, DOI={10.1109/tuffc.2016.2616304}, abstractNote={Submicrometer phase-change contrast agents (PCCAs) consist of a liquid perfluorocarbon (PFC) core that can be vaporized by ultrasound (acoustic droplet vaporization) to generate contrast with excellent spatial and temporal control. When these agents, commonly referred to as nanodroplets, are formulated with cores of low boiling-point PFCs such as decafluorobutane and octafluoropropane, they can be activated with low-mechanical-index (MI) imaging pulses for diagnostic applications. Since the utilization of minimum MI is often desirable to avoid unnecessary biological effects, enabling consistent activation of these agents in an acoustic field is a challenge because the energy that must be delivered to achieve the vaporization threshold increases with depth due to attenuation. A novel vaporization approach called activation pressure matching (APM) has been developed to deliver the same pressure throughout a field of view in order to produce uniform nanodroplet vaporization and to limit the amount of energy that is delivered. In this paper, we discuss the application of this method with a Verasonics V1 Research Ultrasound System to modulate the output pressure from an ATL L11-5 transducer. Vaporization-pulse spacing optimization can be used in addition to matching the activation pressure through depth, and we demonstrate the feasibility of this approach both in vivo and in vitro. The use of optimized vaporization parameters increases the amount of time a single bolus of nanodroplets can generate useful contrast and provides consistent image enhancement in vivo. Therefore, APM is a useful technique for maximizing the efficacy of PCCA while minimizing delivered acoustic energy.}, number={1}, journal={IEEE TRANSACTIONS ON ULTRASONICS FERROELECTRICS AND FREQUENCY CONTROL}, author={Rojas, Juan D. and Dayton, Paul A.}, year={2017}, month={Jan}, pages={264–272} }
 @article{tsuruta_schaub_rojas_streeter_klauber-demore_dayton_2017, title={Optimizing ultrasound molecular imaging of secreted frizzled related protein 2 expression in angiosarcoma}, volume={12}, ISSN={["1932-6203"]}, DOI={10.1371/journal.pone.0174281}, abstractNote={Secreted frizzled related protein 2 (SFRP2) is a tumor endothelial marker expressed in angiosarcoma. Previously, we showed ultrasound molecular imaging with SFRP2-targeted contrast increased average video pixel intensity (VI) of angiosarcoma vessels by 2.2 ± 0.6 VI versus streptavidin contrast. We hypothesized that redesigning our contrast agents would increase imaging performance. Improved molecular imaging reagents were created by combining NeutrAvidin™-functionalized microbubbles with biotinylated SFRP2 or IgY control antibodies. When angiosarcoma tumors in nude mice reached 8 mm, time-intensity, antibody loading, and microbubble dose experiments optimized molecular imaging. 10 minutes after injection, the control-subtracted time-intensity curve (TIC) for SFRP2-targeted contrast reached a maximum, after subtracting the contribution of free-flowing contrast. SFRP2 antibody-targeted VI was greater when contrast was formulated with 10-fold molar excess of maleimide-activated NeutrAvidin™ versus 3-fold (4.5 ± 0.18 vs. 0.32 ± 0.15, VI ± SEM, 5 x 106 dose, p < 0.001). Tumor vasculature returned greater average video pixel intensity using 5 x 107 versus 5 x 106 microbubbles (21.2 ± 2.5 vs. 4.5 ± 0.18, p = 0.0011). Specificity for tumor vasculature was confirmed by low VI for SFRP2-targeted, and control contrast in peri-tumoral vasculature (3.2 ± 0.52 vs. 1.6 ± 0.71, p = 0.92). After optimization, average video pixel intensity of tumor vasculature was 14.2 ± 3.0 VI units higher with SFRP2-targeted contrast versus IgY-targeted control (22.1 ± 2.5 vs. 7.9 ± 1.6, p < 0.001). After log decompression, 14.2 ΔVI was equal to ~70% higher signal, in arbitray acoustic units (AU), for SFRP2 versus IgY. This provided ~18- fold higher acoustic signal enhancement than provided previously by 2.2 ΔVI. Basing our targeted contrast on NeutrAvidin™-functionalized microbubbles, using IgY antibodies for our control contrast, and optimizing our imaging protocol significantly increased the SFRP2-specific signal returned from angiosarcoma vasculature, and may provide new opportunities for targeted molecular imaging.}, number={3}, journal={PLOS ONE}, author={Tsuruta, James K. and Schaub, Nicholas P. and Rojas, Juan D. and Streeter, Jason and Klauber-DeMore, Nancy and Dayton, Paul}, year={2017}, month={Mar} }
 @inproceedings{li_kim_wang_jiang_kasoji_lindsey_dayton_2016, title={A dual-frequency co-linear array for prostate acoustic angiography}, DOI={10.1109/ultsym.2016.7728718}, abstractNote={Approximately 80% of men who reach 80-years of age will have some form of prostate cancer. The challenge remains to differentiate indolent from aggressive disease. Based on recent research, acoustic angiography, a novel contrast enhanced ultrasound imaging technique, can provide high-resolution visualization of tissue microvasculature and has demonstrated the ability to differentiate vascular characteristics between healthy and tumor tissue. We hypothesize that transrectal acoustic angiography may enhance assessment of prostate cancer. In this paper, we describe the development of a dual layer co-linear array ultrasound transducer for transrectal acoustic angiography. The KLM model and Field II were used for the element design and acoustic field simulation, respectively. The probe consists of 64 transmit elements with a center frequency of 3 MHz and 128 receive elements with a center frequency of 15 MHz. The dimensions of the array are 18 mm in azimuth and 8 mm in elevation. The pitch is 280 μm for transmitting (TX) elements and 140 μm for receiving (RX) elements. Pulse-echo test of TX/RX elements were conducted and compared with the simulation results. Real-time contrast imaging was tested using a Verasonics system. Non-linear responses from microbubble contrast agents at a depth of 18 mm were clearly observed. The axial beam width (-6 dB) and CTR were calculated from the measured signals to be 400 μm and 20 dB, respectively. These results suggest that the prototype co-linear array is capable of performing dual-frequency superharmonic imaging of microbubbles for prostate cancer assessment.}, booktitle={2016 ieee international ultrasonics symposium (ius)}, author={Li, S. B. and Kim, J. and Wang, Z. C. and Jiang, X. N. and Kasoji, S. and Lindsey, B. and Dayton, P. A.}, year={2016} }
 @inproceedings{lindsey_dayton_kim_jiang_2016, title={A dual-frequency endoscopic transducer for imaging vascular invasion in pancreatic cancer}, DOI={10.1109/ultsym.2016.7728435}, abstractNote={Pancreatic adenocarcinoma is among the most deadly of cancers, with surgery being typically the only curative option. Tumor resectability is typically determined via endoscopic ultrasound imaging, however, many patients who may be eligible for resection are not offered surgery due to the difficulty in determining vascular or lymphatic invasion. Contrast-enhanced ultrasound imaging may address this problem. We describe the development of a single element dual-frequency transducer for rotational endoscopic imaging designed to operate at 4/20 MHz to image microbubble superharmonics. The ability of the developed transducer to image in a tissue mimicking phantom at depths from 1.0 cm (CTR = 21.6 dB) to 2.5 cm (CTR = 11.4 dB) is demonstrated. The completed 4-Fr transducer is also capable of imaging microbubbles in a 200 μm-diameter tube through the wall of a ~1 cm-diameter porcine artery, suggesting such a device may be suitable for direct visualization of small vessels from within the lumen of larger vessels such as the portal vein.}, booktitle={2016 ieee international ultrasonics symposium (ius)}, author={Lindsey, B. D. and Dayton, P. A. and Kim, J. and Jiang, X. N.}, year={2016} }
 @article{shelton_lindsey_gessner_lee_aylward_lee_cherin_foster_dayton_2016, title={Acoustic angiography: A new high frequency contrast ultrasound technique for biomedical imaging}, volume={9871}, ISSN={["1996-756X"]}, DOI={10.1117/12.2229179}, abstractNote={Acoustic Angiography is a new approach to high-resolution contrast enhanced ultrasound imaging enabled by ultra-broadband transducer designs. The high frequency imaging technique provides signal separation from tissue which does not produce significant harmonics in the same frequency range, as well as high resolution. This approach enables imaging of microvasculature in-vivo with high resolution and signal to noise, producing images that resemble x-ray angiography. Data shows that acoustic angiography can provide important information about the presence of disease based on vascular patterns, and may enable a new paradigm in medical imaging.}, journal={SENSING AND ANALYSIS TECHNOLOGIES FOR BIOMEDICAL AND COGNITIVE APPLICATIONS 2016}, author={Shelton, Sarah E. and Lindsey, Brooks D. and Gessner, Ryan and Lee, Yueh and Aylward, Stephen and Lee, Hyunggyun and Cherin, Emmanuel and Foster, F. Stuart and Dayton, Paul A.}, year={2016} }
 @article{lindsey_martin_jiang_dayton_2016, title={Adaptive windowing in contrast-enhanced intravascular ultrasound imaging}, volume={70}, ISSN={["1874-9968"]}, DOI={10.1016/j.ultras.2016.04.022}, abstractNote={Intravascular ultrasound (IVUS) is one of the most commonly-used interventional imaging techniques and has seen recent innovations which attempt to characterize the risk posed by atherosclerotic plaques. One such development is the use of microbubble contrast agents to image vasa vasorum, fine vessels which supply oxygen and nutrients to the walls of coronary arteries and typically have diameters less than 200μm. The degree of vasa vasorum neovascularization within plaques is positively correlated with plaque vulnerability. Having recently presented a prototype dual-frequency transducer for contrast agent-specific intravascular imaging, here we describe signal processing approaches based on minimum variance (MV) beamforming and the phase coherence factor (PCF) for improving the spatial resolution and contrast-to-tissue ratio (CTR) in IVUS imaging. These approaches are examined through simulations, phantom studies, ex vivo studies in porcine arteries, and in vivo studies in chicken embryos. In phantom studies, PCF processing improved CTR by a mean of 4.2dB, while combined MV and PCF processing improved spatial resolution by 41.7%. Improvements of 2.2dB in CTR and 37.2% in resolution were observed in vivo. Applying these processing strategies can enhance image quality in conventional B-mode IVUS or in contrast-enhanced IVUS, where signal-to-noise ratio is relatively low and resolution is at a premium.}, journal={ULTRASONICS}, author={Lindsey, Brooks D. and Martin, K. Heath and Jiang, Xiaoning and Dayton, Paul A.}, year={2016}, month={Aug}, pages={123–135} }
 @inproceedings{lindsey_dayton_jiang_2016, title={Adaptive windowing in mechanically-steered intravascular ultrasound imaging: Ex vivo and in vivo studies with contrast enhancement}, DOI={10.1109/ultsym.2016.7728433}, abstractNote={Intravascular ultrasound (IVUS) is utilized frequently in vascular diseases such as coronary artery disease and peripheral vascular disease. Many techniques-including but not limited to IVUS-seek to characterize plaques in coronary artery disease in order to determine which are likely to rupture. Biologists have recently identified the development of intra-plaque vasa vasorum, small vessels which supply the coronaries with oxygen and nutrients, as a potential indicator of plaque vulnerability. By imaging plaques with penetrating vasa vasorum, high resolution contrast-enhanced ultrasound imaging may allow identification of vulnerable plaques prior to rupture. Here we present processing techniques for improving spatial resolution and image contrast in mechanically steered ultrasound imaging based on minimum variance (MV) beamforming and the phase coherence factor (PCF). In tissue-mimicking phantom studies, PCF processing improved CTR by a mean of 4.2 dB, while combined MV and PCF processing improved spatial resolution by 41.7%. These processing strategies may improve image quality in both conventional B-mode IVUS and contrast-enhanced IVUS.}, booktitle={2016 ieee international ultrasonics symposium (ius)}, author={Lindsey, B. D. and Dayton, P. A. and Jiang, X. N.}, year={2016} }
 @article{li_ma_martin_yu_ma_dayton_jiang_shung_zhou_2016, title={An Integrated System for Superharmonic Contrast-Enhanced Ultrasound Imaging: Design and Intravascular Phantom Imaging Study}, volume={63}, ISSN={["1558-2531"]}, DOI={10.1109/tbme.2015.2506639}, abstractNote={Objective: Superharmonic contrast-enhanced ultrasound imaging, also called acoustic angiography, has previously been used for the imaging of microvasculature. This approach excites microbubble contrast agents near their resonance frequency and receives echoes at nonoverlapping superharmonic bandwidths. No integrated system currently exists could fully support this application. To fulfill this need, an integrated dual-channel transmit/receive system for superharmonic imaging was designed, built, and characterized experimentally. Method: The system was uniquely designed for superharmonic imaging and high-resolution B-mode imaging. A complete ultrasound system including a pulse generator, a data acquisition unit, and a signal processing unit were integrated into a single package. The system was controlled by a field-programmable gate array, on which multiple user-defined modes were implemented. A 6-, 35-MHz dual-frequency dual-element intravascular ultrasound transducer was designed and used for imaging. Result: The system successfully obtained high-resolution B-mode images of coronary artery ex vivo with 45-dB dynamic range. The system was capable of acquiring in vitro superharmonic images of a vasa vasorum mimicking phantom with 30-dB contrast. It could detect a contrast agent filled tissue mimicking tube of 200 μm diameter. Conclusion: For the first time, high-resolution B-mode images and superharmonic images were obtained in an intravascular phantom, made possible by the dedicated integrated system proposed. The system greatly reduced the cost and complexity of the superharmonic imaging intended for preclinical study. Significant: The system showed promise for high-contrast intravascular microvascular imaging, which may have significant importance in assessment of the vasa vasorum associated with atherosclerotic plaques.}, number={9}, journal={IEEE TRANSACTIONS ON BIOMEDICAL ENGINEERING}, author={Li, Yang and Ma, Jianguo and Martin, K. Heath and Yu, Mingyue and Ma, Teng and Dayton, Paul A. and Jiang, Xiaoning and Shung, K. Kirk and Zhou, Qifa}, year={2016}, month={Sep}, pages={1933–1943} }
 @article{seiler_campbell_nixon_tsuruta_dayton_jennings_redding_lustgarten_2016, title={FEASIBILITY AND SAFETY OF CONTRAST-ENHANCED ULTRASOUND IN THE DISTAL LIMB OF SIX HORSES}, volume={57}, ISSN={["1740-8261"]}, DOI={10.1111/vru.12333}, abstractNote={Vascular alterations play important roles in many orthopedic diseases such as osteoarthritis, tendonitis, and synovitis in both human and equine athletes. Understanding these alterations could enhance diagnosis, prognosis, and treatment. Contrast‐enhanced ultrasound (CEUS) could be a valuable method for evaluation of blood flow and perfusion of these processes in the equine distal limb, however no reports were found describing feasibility or safety of the technique. The goal of this prospective, experimental study was to describe the feasibility and safety of distal limb CEUS in a sample of six horses. For each horse, CEUS of the distal limb was performed after intravenous injections of 5 and 10 ml, as well as intra‐arterial injections of 0.5 and 1 ml contrast medium. Vital parameters were monitored and CEUS images were assessed qualitatively and quantitatively for degree of contrast enhancement. None of the horses had clinically significant changes in their vital parameters after contrast medium injection. One horse had a transient increase in respiratory rate, and several horses had mild increases of systolic blood pressure of short duration after intravenous, but not after intra‐arterial injections. Intra‐arterial injection was possible in all horses and resulted in significantly improved contrast enhancement both quantitatively (P = 0.027) and qualitatively (P = 0.019). Findings from this study indicated that CEUS is a feasible and safe diagnostic test for evaluation of the equine distal limb. Future studies are needed to assess the clinical utility of this test for horses with musculoskeletal diseases.}, number={3}, journal={VETERINARY RADIOLOGY & ULTRASOUND}, author={Seiler, Gabriela S. and Campbell, Nigel and Nixon, Britton and Tsuruta, James K. and Dayton, Paul A. and Jennings, Samuel and Redding, W. Rich and Lustgarten, Meghann}, year={2016}, pages={282–289} }
 @article{marshalek_sheeran_ingram_dayton_witte_matsunaga_2016, title={Intracellular delivery and ultrasonic activation of folate receptor-targeted phase-change contrast agents in breast cancer cells in vitro}, volume={243}, ISSN={["1873-4995"]}, DOI={10.1016/j.jconrel.2016.09.010}, abstractNote={Breast cancer is a diverse and complex disease that remains one of the leading causes of death among women. Novel, outside-of-the-box imaging and treatment methods are needed to supplement currently available technologies. In this study, we present evidence for the intracellular delivery and ultrasound-stimulated activation of folate receptor (FR)-targeted phase-change contrast agents (PCCAs) in MDA-MB-231 and MCF-7 breast cancer cells in vitro. PCCAs are lipid-coated, perfluorocarbon-filled particles formulated as nanoscale liquid droplets capable of vaporization into gaseous microbubbles for imaging or therapy. Cells were incubated with 1:1 decafluorobutane (DFB)/octafluoropropane (OFP) PCCAs for 1h, imaged via confocal microscopy, exposed to ultrasound (9MHz, MI=1.0 or 1.5), and imaged again after insonation. FR-targeted PCCAs were observed intracellularly in both cell lines, but uptake was significantly greater (p<0.001) in MDA-MB-231 cells (93.0% internalization at MI=1.0, 79.5% at MI=1.5) than MCF-7 cells (42.4% internalization at MI=1.0, 35.7% at MI=1.5). Folate incorporation increased the frequency of intracellular PCCA detection 45-fold for MDA-MB-231 cells and 7-fold for MCF-7 cells, relative to untargeted PCCAs. Intracellularly activated PCCAs ranged from 500nm to 6μm (IQR=800nm-1.5μm) with a mean diameter of 1.15±0.59 (SD) microns. The work presented herein demonstrates the feasibility of PCCA intracellular delivery and activation using breast cancer cells, illuminating a new platform toward intracellular imaging or therapeutic delivery with ultrasound.}, journal={JOURNAL OF CONTROLLED RELEASE}, author={Marshalek, Joseph P. and Sheeran, Paul S. and Ingram, Pier and Dayton, Paul A. and Witte, Russell S. and Matsunaga, Terry O.}, year={2016}, month={Dec}, pages={69–77} }
 @inproceedings{kim_chang_lindsey_dayton_dai_stavas_jiang_2016, title={Laser-generated-focused ultrasound transducers for microbubble-mediated, dual-excitation sonothrombolysis}, DOI={10.1109/ultsym.2016.7728473}, abstractNote={A laser-generated-focused ultrasound (LGFU) transducer generates high-pressure (up to 20 MPa), high-frequency (>10 MHz) shock waves with a tight focal spot. In this work, we aim to demonstrate the feasibility of using LGFU transducers for sonothrombolysis in vitro. A carbon black LGFU transducer was designed, fabricated and characterized. The prototyped LGFU was applied with in-vitro thrombolysis tests involving microbubble contrast agent (MCA). A conventional piezo ultrasound transducer was used as a secondary excitation source to enhance the cavitation effect by dual-frequency excitation. The in vitro test results showed that microbubble-mediated LGFU treatment can yield the lytic rate of approximately 2 mg/min, suggesting that LGFU transducers may be useful in precision high lytic rate sonothrombolysis.}, booktitle={2016 ieee international ultrasonics symposium (ius)}, author={Kim, J. and Chang, W. Y. and Lindsey, B. D. and Dayton, P. A. and Dai, X. M. and Stavas, J. M. and Jiang, X. N.}, year={2016} }
 @article{shelton_lindsey_tsuruta_foster_dayton_2016, title={MOLECULAR ACOUSTIC ANGIOGRAPHY: A NEW TECHNIQUE FOR HIGH-RESOLUTION SUPERHARMONIC ULTRASOUND MOLECULAR IMAGING}, volume={42}, ISSN={["1879-291X"]}, url={https://europepmc.org/articles/PMC5653972}, DOI={10.1016/j.ultrasmedbio.2015.10.015}, abstractNote={Ultrasound molecular imaging utilizes targeted microbubbles to bind to vascular targets such as integrins, selectins and other extracellular binding domains. After binding, these microbubbles are typically imaged using low pressures and multi-pulse imaging sequences. In this article, we present an alternative approach for molecular imaging using ultrasound that relies on superharmonic signals produced by microbubble contrast agents. Bound bubbles were insonified near resonance using a low frequency (4 MHz) element and superharmonic echoes were received at high frequencies (25-30 MHz). Although this approach was observed to produce declining image intensity during repeated imaging in both in vitro and in vivo experiments because of bubble destruction, the feasibility of superharmonic molecular imaging was demonstrated for transmit pressures, which are sufficiently high to induce shell disruption in bound microbubbles. This approach was validated using microbubbles targeted to the αvβ3 integrin in a rat fibrosarcoma model (n = 5) and combined with superharmonic images of free microbubbles to produce high-contrast, high-resolution 3-D volumes of both microvascular anatomy and molecular targeting. Image intensity over repeated scans and the effect of microbubble diameter were also assessed in vivo, indicating that larger microbubbles yield increased persistence in image intensity. Using ultrasound-based acoustic angiography images rather than conventional B-mode ultrasound to provide the underlying anatomic information facilitates anatomic localization of molecular markers. Quantitative analysis of relationships between microvasculature and targeting information indicated that most targeting occurred within 50 μm of a resolvable vessel (>100 μm diameter). The combined information provided by these scans may present new opportunities for analyzing relationships between microvascular anatomy and vascular targets, subject only to limitations of the current mechanically scanned system and microbubble persistence to repeated imaging at moderate mechanical indices.}, number={3}, journal={ULTRASOUND IN MEDICINE AND BIOLOGY}, author={Shelton, Sarah E. and Lindsey, Brooks D. and Tsuruta, James K. and Foster, F. Stuart and Dayton, Paul A.}, year={2016}, month={Mar}, pages={769–781} }
 @inproceedings{shelton_lindsey_dayton_foster_2016, title={Molecular acoustic angiography: Comparison of contrast-to-tissue ratio with multi-pulse techniques and imaging multiple targeted microbubbles}, url={http://dx.doi.org/10.1109/ultsym.2016.7728703}, DOI={10.1109/ultsym.2016.7728703}, abstractNote={Acoustic angiography is a high resolution (~100 μm) approach that utilizes the superharmonic signal produced by microbubbles, which we have recently extended for molecular imaging. These molecular images can also be overlaid onto images of microvascular anatomy in order to assess relationships between vascular morphology and targeting distribution. In this work we compare the contrast-to-tissue ratio (CTR) between superharmonic and multi-pulse molecular imaging and present images of microbubbles targeted to different biomarkers expressed by the vascular endothelial cells. Combing molecular and microvascular information about developing tumors could provide vital information for treatment planning, monitoring, and for ensuring clean margins in surgical resection.}, booktitle={2016 IEEE International Ultrasonics Symposium (IUS)}, publisher={IEEE}, author={Shelton, Sarah E. and Lindsey, Brooks D. and Dayton, Paul A. and Foster, F. Stuart}, year={2016}, month={Sep} }
 @article{porter_arena_sayyed_lof_high_xie_dayton_2016, title={Targeted Transthoracic Acoustic Activation of Systemically Administered Nanodroplets to Detect Myocardial Perfusion Abnormalities}, volume={9}, ISSN={["1942-0080"]}, DOI={10.1161/circimaging.115.003770}, abstractNote={
            Background—
            Liquid core nanodroplets containing condensed gaseous fluorocarbons can be vaporized at clinically relevant acoustic energies and have been hypothesized as an alternative ultrasound contrast agent instead of gas-core agents. The potential for targeted activation and imaging of these agents was tested with droplets formulated from liquid octafluoropropane (C3) and 1:1 mixtures of C3 with liquid decafluorobutane (C3C4).
          }, number={1}, journal={CIRCULATION-CARDIOVASCULAR IMAGING}, author={Porter, Thomas R. and Arena, Christopher and Sayyed, Samer and Lof, John and High, Robin R. and Xie, Feng and Dayton, Paul A.}, year={2016}, month={Jan} }
 @article{rao_shelton_dayton_2016, title={The "Fingerprint" of Cancer Extends Beyond Solid Tumor Boundaries: Assessment With a Novel Ultrasound Imaging Approach}, volume={63}, ISSN={["1558-2531"]}, url={https://europepmc.org/articles/PMC5070672}, DOI={10.1109/tbme.2015.2479590}, abstractNote={Goal: Abnormalities of microvascular morphology have been associated with tumor angiogenesis for more than a decade, and are believed to be intimately related to both tumor malignancy and response to treatment. However, the study of these vascular changes in-vivo has been challenged due to the lack of imaging approaches which can assess the microvasculature in 3-D volumes noninvasively. Here, we use contrast-enhanced “acoustic angiography” ultrasound imaging to observe and quantify heterogeneity in vascular morphology around solid tumors. Methods: Acoustic angiography, a recent advance in contrast-enhanced ultrasound imaging, generates high-resolution microvascular images unlike anything possible with standard ultrasound imaging techniques. Acoustic angiography images of a genetically engineered mouse breast cancer model were acquired to develop an image acquisition and processing routine that isolated radially expanding regions of a 3-D image from the tumor boundary to the edge of the imaging field for assessment of vascular morphology of tumor and surrounding vessels. Results: Quantitative analysis of vessel tortuosity for the tissue surrounding tumors 3 to 7 mm in diameter revealed that tortuosity decreased in a region 6 to 10 mm from the tumor boundary, but was still significantly elevated when compared to control vasculature. Conclusion: Our analysis of angiogenesis-induced changes in the vasculature outside the tumor margin reveals that the extent of abnormal tortuosity extends significantly beyond the primary tumor mass. Significance: Visualization of abnormal vascular tortuosity may make acoustic angiography an invaluable tool for early tumor detection based on quantifying the vascular footprint of small tumors and a sensitive method for understanding changes in the vascular microenvironment during tumor progression.}, number={5}, journal={IEEE TRANSACTIONS ON BIOMEDICAL ENGINEERING}, author={Rao, Sneha R. and Shelton, Sarah E. and Dayton, Paul A.}, year={2016}, month={May}, pages={1082–1086} }
 @inproceedings{shelton_dayton_aylward_foster_2016, title={The application of acoustic angiography to assess the progression of angiogenesis in a spontaneous mouse model of breast cancer}, url={http://dx.doi.org/10.1109/ultsym.2016.7728697}, DOI={10.1109/ultsym.2016.7728697}, abstractNote={Acoustic angiography is a method for contrast enhanced ultrasound imaging that provides sufficient contrast and resolution to visualize microvasculature non-invasively. A dual-frequency transducer is used to transmit at low frequency and receive high frequency (superharmonic) echoes originating from intravascular microbubbles. Analysis of these images in healthy and tumor-bearing mice revealed that tumors possess quantifiably different vascular structure than healthy control animals, through measurements of vascular density and 2 metrics of tortuosity. Furthermore, tortuosity is correlated to proximity to the tumor margin, and distal tissue surrounding tumor regions has an intermediate level of tortuosity between that of tumor and control tissue. Overall, these results indicate that acoustic angiography images can reveal microvasculature in sufficient detail for vascular morphology to be used as a biomarker for cancer imaging.}, booktitle={2016 IEEE International Ultrasonics Symposium (IUS)}, publisher={IEEE}, author={Shelton, Sarah E. and Dayton, Paul A. and Aylward, Stephen R. and Foster, F. Stuart}, year={2016}, month={Sep} }
 @article{novell_arena_oralkan_dayton_2016, title={Wideband acoustic activation and detection of droplet vaporization events using a capacitive micromachined ultrasonic transducer}, volume={139}, ISSN={["1520-8524"]}, DOI={10.1121/1.4953580}, abstractNote={An ongoing challenge exists in understanding and optimizing the acoustic droplet vaporization (ADV) process to enhance contrast agent effectiveness for biomedical applications. Acoustic signatures from vaporization events can be identified and differentiated from microbubble or tissue signals based on their frequency content. The present study exploited the wide bandwidth of a 128-element capacitive micromachined ultrasonic transducer (CMUT) array for activation (8 MHz) and real-time imaging (1 MHz) of ADV events from droplets circulating in a tube. Compared to a commercial piezoelectric probe, the CMUT array provides a substantial increase of the contrast-to-noise ratio.}, number={6}, journal={JOURNAL OF THE ACOUSTICAL SOCIETY OF AMERICA}, author={Novell, Anthony and Arena, Christopher B. and Oralkan, Omer and Dayton, Paul A.}, year={2016}, month={Jun}, pages={3193–3198} }
 @article{li_kim_wang_jiang_kasoji_lindsey_dayton_2015, title={A 3 MHz/18 MHz Dual-layer Co-Linear Array for Transrectal Acoustic Angiography}, ISSN={["1948-5719"]}, DOI={10.1109/ultsym.2015.0030}, abstractNote={In this paper, a novel dual layer co-linear array ultrasound transducer was developed for transrectal dual-frequency superharmonic imaging. The KLM model and Field II were used for the acoustic stack design and simulation of the acoustic field of the array, respectively. The newly designed and fabricated probe consists of 50 transmit elements with a center frequency of 3 MHz and 100 receive elements with a center frequency of 18 MHz. The dimensions of the array are 15 mm in azimuth and 9 mm in elevation. The pitch is 270 μm for the transmitting elements and 135 μm for the receiving element. Pulse-echo testing of TX/RX elements corresponded with the simulation results. Real-time contrast imaging was tested using a multi-channel imaging system. The non-linear responses from microbubble contrast agents flowing through a 200 μm cellulose tube at a distance of 30 mm from the probe were clearly observed and displayed in the image. The axial beam width and CNR were calculated to be 200 μm and 18 dB, respectively. These results suggest that the prototyped co-linear array is capable of performing dual-frequency superharmonic imaging of microbubbles (“acoustic angiography”) for prostate cancer assessment.}, journal={2015 IEEE INTERNATIONAL ULTRASONICS SYMPOSIUM (IUS)}, author={Li, Sibo and Kim, Jinwook and Wang, Zhuochen and Jiang, Xiaoning and Kasoji, Sunny and Lindsey, Brooks and Dayton, Paul A.}, year={2015} }
 @article{kasoji_pattenden_malc_jayakody_tsuruta_mieczkowski_janzen_dayton_2015, title={Cavitation Enhancing Nanodroplets Mediate Efficient DNA Fragmentation in a Bench Top Ultrasonic Water Bath}, volume={10}, ISSN={["1932-6203"]}, DOI={10.1371/journal.pone.0133014}, abstractNote={A perfluorocarbon nanodroplet formulation is shown to be an effective cavitation enhancement agent, enabling rapid and consistent fragmentation of genomic DNA in a standard ultrasonic water bath. This nanodroplet-enhanced method produces genomic DNA libraries and next-generation sequencing results indistinguishable from DNA samples fragmented in dedicated commercial acoustic sonication equipment, and with higher throughput. This technique thus enables widespread access to fast bench-top genomic DNA fragmentation.}, number={7}, journal={PLOS ONE}, author={Kasoji, Sandeep K. and Pattenden, Samantha G. and Malc, Ewa P. and Jayakody, Chatura N. and Tsuruta, James K. and Mieczkowski, Piotr A. and Janzen, William P. and Dayton, Paul A.}, year={2015}, month={Jul} }
 @article{arena_novell_sheeran_puett_moyer_dayton_2015, title={Dual-Frequency Acoustic Droplet Vaporization Detection for Medical Imaging}, volume={62}, ISSN={["1525-8955"]}, DOI={10.1109/tuffc.2014.006883}, abstractNote={Liquid-filled perfluorocarbon droplets emit a unique acoustic signature when vaporized into gas-filled microbubbles using ultrasound. Here, we conducted a pilot study in a tissue-mimicking flow phantom to explore the spatial aspects of droplet vaporization and investigate the effects of applied pressure and droplet concentration on image contrast and axial and lateral resolution. Control microbubble contrast agents were used for comparison. A confocal dual-frequency transducer was used to transmit at 8 MHz and passively receive at 1 MHz. Droplet signals were of significantly higher energy than microbubble signals. This resulted in improved signal separation and high contrast-to-tissue ratios (CTR). Specifically, with a peak negative pressure (PNP) of 450 kPa applied at the focus, the CTR of B-mode images was 18.3 dB for droplets and -0.4 for microbubbles. The lateral resolution was dictated by the size of the droplet activation area, with lower pressures resulting in smaller activation areas and improved lateral resolution (0.67 mm at 450 kPa). The axial resolution in droplet images was dictated by the size of the initial droplet and was independent of the properties of the transmit pulse (3.86 mm at 450 kPa). In post-processing, time-domain averaging (TDA) improved droplet and microbubble signal separation at high pressures (640 kPa and 700 kPa). Taken together, these results indicate that it is possible to generate high-sensitivity, high-contrast images of vaporization events. In the future, this has the potential to be applied in combination with dropletmediated therapy to track treatment outcomes or as a standalone diagnostic system to monitor the physical properties of the surrounding environment.}, number={9}, journal={IEEE TRANSACTIONS ON ULTRASONICS FERROELECTRICS AND FREQUENCY CONTROL}, author={Arena, Christopher B. and Novell, Anthony and Sheeran, Paul S. and Puett, Connor and Moyer, Linsey C. and Dayton, Paul A.}, year={2015}, month={Sep}, pages={1623–1633} }
 @article{kim_li_kasoji_dayton_jiang_2015, title={Dual-frequency Super Harmonic Imaging Piezoelectric Transducers for Transrectal Ultrasound}, volume={9438}, ISSN={["0277-786X"]}, DOI={10.1117/12.2084459}, abstractNote={In this paper, a 2/14 MHz dual-frequency single-element transducer and a 2/22 MHz sub-array (16/48-elements linear array) transducer were developed for contrast enhanced super-harmonic ultrasound imaging of prostate cancer with the low frequency ultrasound transducer as a transmitter for contrast agent (microbubble) excitation and the high frequency transducer as a receiver for detection of nonlinear responses from microbubbles. The 1-3 piezoelectric composite was used as active materials of the single-element transducers due to its low acoustic impedance and high coupling factor. A high dielectric constant PZT ceramic was used for the sub-array transducer due to its high dielectric property induced relatively low electrical impedance. The possible resonance modes of the active elements were estimated using finite element analysis (FEA). The pulse-echo response, peak-negative pressure and bubble response were tested, followed by in vitro contrast imaging tests using a graphite-gelatin tissue-mimicking phantom. The single-element dual frequency transducer (8 × 4 × 2 mm3) showed a -6 dB fractional bandwidth of 56.5% for the transmitter, and 41.8% for the receiver. A 2 MHz-transmitter (730 μm pitch and 6.5 mm elevation aperture) and a 22 MHz-receiver (240 μm pitch and 1.5 mm aperture) of the sub-array transducer exhibited -6 dB fractional bandwidth of 51.0% and 40.2%, respectively. The peak negative pressure at the far field was about -1.3 MPa with 200 Vpp, 1-cycle 2 MHz burst, which is high enough to excite microbubbles for nonlinear responses. The 7th harmonic responses from micro bubbles were successfully detected in the phantom imaging test showing a contrast-to-tissue ratio (CTR) of 16 dB.}, journal={HEALTH MONITORING OF STRUCTURAL AND BIOLOGICAL SYSTEMS 2015}, author={Kim, Jinwook and Li, Sibo and Kasoji, Sandeep and Dayton, Paul A. and Jiang, Xiaoning}, year={2015} }
 @article{lindsey_rojas_dayton_2015, title={ON THE RELATIONSHIP BETWEEN MICROBUBBLE FRAGMENTATION, DEFLATION AND BROADBAND SUPERHARMONIC SIGNAL PRODUCTION}, volume={41}, ISSN={["1879-291X"]}, DOI={10.1016/j.ultrasmedbio.2014.12.668}, abstractNote={Acoustic angiography imaging of microbubble contrast agents uses the superharmonic energy produced from excited microbubbles and enables high-contrast, high-resolution imaging. However, the exact mechanism by which broadband harmonic energy is produced is not fully understood. To elucidate the role of microbubble shell fragmentation in superharmonic signal production, simultaneous optical and acoustic measurements were performed on individual microbubbles at transmit frequencies from 1.75 to 3.75 MHz and pressures near the shell fragmentation threshold for microbubbles of varying diameter. High-amplitude, broadband superharmonic signals were produced with shell fragmentation, whereas weaker signals (approximately 25% of peak amplitude) were observed in the presence of shrinking bubbles. Furthermore, when populations of stationary microbubbles were imaged with a dual-frequency ultrasound imaging system, a sharper decline in image intensity with respect to frame number was observed for 1-μm bubbles than for 4-μm bubbles. Finally, in a study of two rodents, increasing frame rate from 4 to 7 Hz resulted in decreases in mean steady-state image intensity of 27% at 1000 kPa and 29% at 1300 kPa. Although the existence of superharmonic signals when bubbles shrink has the potential to prolong the imaging efficacy of microbubbles, parameters such as frame rate and peak pressure must be balanced with expected re-perfusion rate to maintain adequate contrast during in vivo imaging.}, number={6}, journal={ULTRASOUND IN MEDICINE AND BIOLOGY}, author={Lindsey, Brooks D. and Rojas, Juan D. and Dayton, Paul A.}, year={2015}, month={Jun}, pages={1711–1725} }
 @article{lindsey_shelton_dayton_2015, title={Optimization of Contrast-to-Tissue Ratio Through Pulse Windowing in Dual-Frequency “Acoustic Angiography” Imaging}, volume={41}, ISSN={0301-5629}, url={http://dx.doi.org/10.1016/j.ultrasmedbio.2015.02.011}, DOI={10.1016/j.ultrasmedbio.2015.02.011}, abstractNote={Early-stage tumors in many cancers are characterized by vascular remodeling, indicative of transformations in cell function. We have previously presented a high-resolution ultrasound imaging approach to detecting these changes that is based on microbubble contrast agents. In this technique, images are formed from only the higher harmonics of microbubble contrast agents, producing images of vasculature alone with 100- to 200-μm resolution. In this study, shaped transmit pulses were used to image the higher broadband harmonic echoes of microbubble contrast agents, and the effects of varying pulse window and phasing on microbubble and tissue harmonic echoes were evaluated using a dual-frequency transducer in vitro and in vivo. An increase in the contrast-to-tissue ratio of 6.8 ± 2.3 dB was observed in vitro using an inverted pulse with a cosine window relative to a non-inverted pulse with a rectangular window. The increase in mean image intensity resulting from contrast enhancement in vivo in five rodents was 13.9 ± 3.0 dB greater for an inverted cosine-windowed pulse and 17.8 ± 3.6 dB greater for a non-inverted Gaussian-windowed pulse relative to a non-inverted pulse with a rectangular window. Implications for pre-clinical and diagnostic imaging are discussed.}, number={7}, journal={Ultrasound in Medicine & Biology}, publisher={Elsevier BV}, author={Lindsey, Brooks D. and Shelton, Sarah E. and Dayton, Paul A.}, year={2015}, month={Jul}, pages={1884–1895} }
 @article{novell_arena_kasoji_dayton_2015, title={Optimization of multi-pulse sequences for nonlinear contrast agent imaging using a cMUT array}, volume={60}, ISSN={["1361-6560"]}, DOI={10.1088/0031-9155/60/8/3111}, abstractNote={Capacitive micromachined ultrasonic transducer (cMUT) technology provides advantages such as wide frequency bandwidth, which can be exploited for contrast agent imaging. Nevertheless, the efficiency of traditional multi-pulse imaging schemes, such as pulse inversion (PI), remains limited because of the intrinsic nonlinear character of cMUTs. Recently, a new contrast imaging sequence, called bias voltage modulation sequence (BVM), has been specifically developed for cMUTs to suppress their unwanted nonlinear behavior. In this study, we propose to optimize contrast agent detection by combining the BVM sequence with PI and/or chirp reversal (CR). An aqueous dispersion of lipid encapsulated microbubbles was exposed to several combinations of multi-pulse imaging sequences. Approaches were evaluated in vitro using 9 inter-connected elements of a cMUT linear array (excitation frequency of 4 MHz; peak negative pressure of 100 kPa). For sequences using chirp excitations, a specific compression filter was designed to compress and extract several nonlinear components from the received microbubble responses. A satisfactory cancellation of the nonlinear signal from the source is achieved when BVM is combined with PI and CR. In comparison with PI and CR imaging modes alone, using sequences incorporating BVM increases the contrast-to-tissue ratio by 10.0 dB and 4.6 dB, respectively. Furthermore, the combination of BVM with CR and PI results in a significant increase of the contrast-to-noise ratio (+29 dB). This enhancement is attributed to the use of chirps as excitation signals and the improved preservation of several nonlinear components contained within the contrast agent response.}, number={8}, journal={PHYSICS IN MEDICINE AND BIOLOGY}, author={Novell, Anthony and Arena, Christopher B. and Kasoji, Sandeep and Dayton, Paul A.}, year={2015}, month={Apr}, pages={3111–3127} }
 @article{kim_li_kasoji_dayton_jiang_2015, title={Phantom evaluation of stacked-type dual-frequency 1-3 composite transducers: A feasibility study on intracavitary acoustic angiography}, volume={63}, ISSN={["1874-9968"]}, DOI={10.1016/j.ultras.2015.06.009}, abstractNote={In this paper, we present phantom evaluation results of a stacked-type dual-frequency 1-3 piezoelectric composite transducer as a feasibility study for intracavitary acoustic angiography. Our previous design (6.5/30 MHz PMN-PT single crystal transducer) for intravascular contrast ultrasound imaging exhibited a contrast-to-tissue ratio (CTR) of 12 dB with a penetration depth of 2.5 mm. For improved penetration depth (>3 mm) and comparable contrast-to-tissue ratio (>12 dB), we evaluated a lower frequency 2/14 MHz PZT 1-3 composite transducer. Superharmonic imaging performance of this transducer and a detailed characterization of key parameters for acoustic angiography are presented. The 2/14 MHz arrangement demonstrated a -6 dB fractional bandwidth of 56.5% for the transmitter and 41.8% for the receiver, and produced sufficient peak-negative pressures (>1.5 MPa) at 2 MHz to induce a strong nonlinear harmonic response from microbubble contrast agents. In an in-vitro contrast ultrasound study using a tissue mimicking phantom and 200 μm cellulose microvessels, higher harmonic microbubble responses, from the 5th through the 7th harmonics, were detected with a signal-to-noise ratio of 16 dB. The microvessels were resolved in a two-dimensional image with a -6dB axial resolution of 615 μm (5.5 times the wavelength of 14 MHz waves) and a contrast-to-tissue ratio of 16 dB. This feasibility study, including detailed explanation of phantom evaluation and characterization procedures for key parameters, will be useful for the development of future dual-frequency array transducers for intracavitary acoustic angiography.}, journal={ULTRASONICS}, author={Kim, Jinwook and Li, Sibo and Kasoji, Sandeep and Dayton, Paul A. and Jiang, Xiaoning}, year={2015}, month={Dec}, pages={7–15} }
 @article{shelton_lee_lee_cherin_foster_aylward_dayton_2015, title={QUANTIFICATION OF MICROVASCULAR TORTUOSITY DURING TUMOR EVOLUTION USING ACOUSTIC ANGIOGRAPHY}, volume={41}, ISSN={["1879-291X"]}, url={https://europepmc.org/articles/PMC4778417}, DOI={10.1016/j.ultrasmedbio.2015.02.012}, abstractNote={The recent design of ultra-broadband, multifrequency ultrasound transducers has enabled high-sensitivity, high-resolution contrast imaging, with very efficient suppression of tissue background using a technique called acoustic angiography. Here we perform the first application of acoustic angiography to evolving tumors in mice predisposed to develop mammary carcinoma, with the intent of visualizing and quantifying angiogenesis progression associated with tumor growth. Metrics compared include vascular density and two measures of vessel tortuosity quantified from segmentations of vessels traversing and surrounding 24 tumors and abdominal vessels from control mice. Quantitative morphologic analysis of tumor vessels revealed significantly increased vascular tortuosity abnormalities associated with tumor growth, with the distance metric elevated approximately 14% and the sum of angles metric increased 60% in tumor vessels versus controls. Future applications of this imaging approach may provide clinicians with a new tool in tumor detection, differentiation or evaluation, though with limited depth of penetration using the current configuration.}, number={7}, journal={ULTRASOUND IN MEDICINE AND BIOLOGY}, author={Shelton, Sarah E. and Lee, Yueh Z. and Lee, Mike and Cherin, Emmanuel and Foster, F. Stuart and Aylward, Stephen R. and Dayton, Paul A.}, year={2015}, month={Jul}, pages={1896–1904} }
 @misc{fix_borden_dayton_2015, title={Therapeutic gas delivery via microbubbles and liposomes}, volume={209}, ISSN={["1873-4995"]}, DOI={10.1016/j.jconrel.2015.04.027}, abstractNote={Gaseous molecules including nitric oxide, hydrogen sulfide, carbon monoxide and oxygen mediate numerous cell signaling pathways and have important physiological roles. Several noble gasses have been shown to elicit biological responses. These bioactive gasses hold great therapeutic potential, however, their controlled delivery remains a significant challenge. Recently, researchers have begun using microbubbles and liposomes to encapsulate such gasses for parenteral delivery. The resultant particles are acoustically active, and ultrasound can be used to stimulate and/or image gas release in a targeted region. This review provides a summary of recent advances in therapeutic gas delivery using microbubbles and liposomes.}, journal={JOURNAL OF CONTROLLED RELEASE}, author={Fix, Samantha M. and Borden, Mark A. and Dayton, Paul A.}, year={2015}, month={Jul}, pages={139–149} }
 @article{lindsey_rojas_martin_shelton_dayton_2014, title={Acoustic Characterization of Contrast-to-issue Ratio and Axial Resolution for Dual-Frequency Contrast-Specific Acoustic Angiography Imaging}, volume={61}, ISSN={["1525-8955"]}, url={https://europepmc.org/articles/PMC8375273}, DOI={10.1109/tuffc.2014.006466}, abstractNote={Recently, dual-frequency transducers have enabled high-spatial-resolution and high-contrast imaging of vasculature with minimal tissue artifacts by transmitting at a low frequency and receiving broadband superharmonic echoes scattered by microbubble contrast agents. In this work, we examine the imaging parameters for optimizing contrast-totissue ratio (CTR) for dual-frequency imaging and the relationship with spatial resolution. Confocal piston transducers are used in a water bath setup to measure the SNR, CTR, and axial resolution for ultrasound imaging of nonlinear scattering of microbubble contrast agents when transmitting at a lower frequency (1.5 to 8 MHz) and receiving at a higher frequency (7.5 to 25 MHz). Parameters varied include the frequency and peak negative pressure of transmitted waves, center frequency of the receiving transducer, microbubble concentration, and microbubble size. CTR is maximized at the lowest transmission frequencies but would be acceptable for imaging in the 1.5 to 3.5 MHz range. At these frequencies, CTR is optimized when a receiving transducer with a center frequency of 10 MHz is used, with the maximum CTR of 25.5 dB occurring when transmitting at 1.5 MHz with a peak negative pressure of 1600 kPa and receiving with a center frequency of 10 MHz. Axial resolution is influenced more heavily by the receiving center frequency, with a weak decrease in measured pulse lengths associated with increasing transmit frequency. A microbubble population containing predominately 4-μm-diameter bubbles yielded the greatest CTR, followed by 1- and then 2-μm bubbles. Varying concentration showed little effect over the tested parameters. CTR dependence on transmit frequency and peak pressure were confirmed through in vivo imaging in two rodents. These findings may lead to improved imaging of vascular remodeling in superficial or luminal cancers such as those of the breast, prostate, and colon.}, number={10}, journal={IEEE TRANSACTIONS ON ULTRASONICS FERROELECTRICS AND FREQUENCY CONTROL}, author={Lindsey, Brooks D. and Rojas, Juan D. and Martin, K. Heath and Shelton, Sarah E. and Dayton, Paul A.}, year={2014}, month={Oct}, pages={1668–1687} }
 @article{wang_ma_jiang_martin_dayton_2014, title={An array transmitter for dual-frequency contrast enhanced intravascular ultrasound imaging}, ISSN={["1948-5719"]}, DOI={10.1109/ultsym.2014.0524}, abstractNote={Recent studies suggests that contrast ultrasound for molecular imaging or vasa vasorum (VV) assessment may be promising in identification of vulnerable plaques. However, conventional intravascular ultrasound (IVUS) transducers with frequency of 15 MHz - 60 MHz are not optimized for imaging with micro bubble contrast agents due to the ineffective micro bubble excitation at high frequencies and poor signal separation from tissue. This paper presents design and fabrication of a lateral mode transducer array with center frequency of 2 MHz for contrast enhanced IVUS (CE-IVUS) imaging, which can generate sufficient pressure to excite microbubbles more effectively and therefore could be used for dual-frequency microbubble superharmonic imaging, or `acoustic angiography'. Several commercial transducers with central frequency of 15 MHz, 20 MHz and 25 MHz were used as receivers to receive the contrast signal. In the contrast testing, the high frequency echo of the nonlinear response from microbubbles in a micro-tube with diameter of 0.2 mm was detected. The maximum contrast to noise ratio was 12.2 dB. The results show that superharmonic signals (over 9th harmonic) can be received; suggesting good resolution and signal separation in contrast enhanced IVUS imaging.}, journal={2014 IEEE INTERNATIONAL ULTRASONICS SYMPOSIUM (IUS)}, author={Wang, Zhuochen and Ma, Jianguo and Jiang, Xiaoning and Martin, Karl Heath and Dayton, Paul A.}, year={2014}, pages={2104–2107} }
 @misc{martin_lindsey_ma_lee_li_foster_jiang_dayton_2014, title={Dual-Frequency Piezoelectric Transducers for Contrast Enhanced Ultrasound Imaging}, volume={14}, ISSN={["1424-8220"]}, DOI={10.3390/s141120825}, abstractNote={For many years, ultrasound has provided clinicians with an affordable and effective imaging tool for applications ranging from cardiology to obstetrics. Development of microbubble contrast agents over the past several decades has enabled ultrasound to distinguish between blood flow and surrounding tissue. Current clinical practices using microbubble contrast agents rely heavily on user training to evaluate degree of localized perfusion. Advances in separating the signals produced from contrast agents versus surrounding tissue backscatter provide unique opportunities for specialized sensors designed to image microbubbles with higher signal to noise and resolution than previously possible. In this review article, we describe the background principles and recent developments of ultrasound transducer technology for receiving signals produced by contrast agents while rejecting signals arising from soft tissue. This approach relies on transmitting at a low-frequency and receiving microbubble harmonic signals at frequencies many times higher than the transmitted frequency. Design and fabrication of dual-frequency transducers and the extension of recent developments in transducer technology for dual-frequency harmonic imaging are discussed.}, number={11}, journal={SENSORS}, author={Martin, K. Heath and Lindsey, Brooks D. and Ma, Jianguo and Lee, Mike and Li, Sibo and Foster, F. Stuart and Jiang, Xiaoning and Dayton, Paul A.}, year={2014}, month={Nov}, pages={20825–20842} }
 @article{doinikov_bouakaz_sheeran_dayton_2014, title={Dynamics of volatile phase-change contrast agents: Theoretical model and experimental measurements}, ISSN={["1948-5719"]}, DOI={10.1109/ultsym.2014.0566}, abstractNote={Interest in perfluorocarbon (PFC) phase-change contrast agents (PCCAs) is motivated by the fact that they can be triggered to transition from the liquid state to the gas state by an externally applied acoustic pulse. This property opens up new approaches to ultrasound imaging and therapy. Insight into the physics of this process is vital for effective use of PCCAs and for anticipating bioeffects. Our paper reports on the development of a new theoretical model that describes the conversion of a PFC droplet into a vapor bubble and subsequent bubble evolution. The development of the model was specifically aimed at exploring the complex behavior which is demonstrated experimentally by volatile PFC droplets with low boiling points but has not been well-described theoretically so far. The model is validated by comparison with in vitro experimental data acquired by ultra-high-speed video microscopy for decafluorobutane (DFB) and octafluoropropane (OFP) microdroplets of different sizes.}, journal={2014 IEEE INTERNATIONAL ULTRASONICS SYMPOSIUM (IUS)}, author={Doinikov, Alexander A. and Bouakaz, Ayache and Sheeran, Paul S. and Dayton, Paul A.}, year={2014}, pages={2273–2276} }
 @article{novell_legros_gregoire_dayton_bouakaz_2014, title={Evaluation of bias voltage modulation sequence for nonlinear contrast agent imaging using a capacitive micromachined ultrasonic transducer array}, volume={59}, ISSN={["1361-6560"]}, DOI={10.1088/0031-9155/59/17/4879}, abstractNote={Many clinical diagnoses have now been improved thanks to the development of new techniques dedicated to contrast agent nonlinear imaging. Over the past few years, Capacitive Micromachined Ultrasonic Transducers (cMUTs) have emerged as a promising alternative to traditional piezoelectric transducers. One notable advantage of cMUTs is their wide frequency bandwidth. However, their use in nonlinear imaging approaches such as those used to detect contrast agents have been challenging due their intrinsic nonlinear character. We propose a new contrast imaging sequence, called bias voltage modulation (BVM), specifically developed for cMUTs to suppress their inherent nonlinear behavior. Theoretical and experimental results show that a complete cancellation of the nonlinear signal from the source can be reached when the BVM sequence is implemented. In-vitro validation of the sequence is performed using a cMUT probe connected to an open scanner and a flow phantom setup containing SonoVue microbubbles. Compared to the standard amplitude modulation imaging mode, a 6 dB increase of contrast-to-tissue ratio was achieved when the BVM sequence is applied. These results reveal that the problem of cMUT nonlinearity can be addressed, thus expanding the potential of this new transducer technology for nonlinear contrast agent detection and imaging.}, number={17}, journal={PHYSICS IN MEDICINE AND BIOLOGY}, author={Novell, Anthony and Legros, Mathieu and Gregoire, Jean-Marc and Dayton, Paul A. and Bouakaz, Ayache}, year={2014}, month={Sep}, pages={4879–4896} }
 @article{sheeran_rojas_puett_hjelmquist_arena_dayton_2014, title={In Vivo Quantification of Image Enhancement and Circulation Kinetics for Phase Change Perfluorocarbon Agents Using Custom Pulse Sequences}, ISSN={["1948-5719"]}, DOI={10.1109/ultsym.2014.0103}, abstractNote={Few investigations have been published demonstrating the in vivo contrast characteristics of phase-change perfluorocarbon droplets. In this study, we examine the properties of low boiling point nanoscale droplets compared to microbubbles with respect to image enhancement and circulation time. To accomplish this, we develop a custom pulse sequence to vaporize and image droplets using the Verasonics research platform. Results show that droplets can produce similar contrast compared to microbubbles, and can circulate for significantly longer than microbubbles, depending on formulation. Finally, this study demonstrates a novel concept in contrast-enhanced ultrasound: capture of droplet-generated contrast wash-out in the target organ.}, journal={2014 IEEE INTERNATIONAL ULTRASONICS SYMPOSIUM (IUS)}, author={Sheeran, Paul S. and Rojas, Juan D. and Puett, Connor and Hjelmquist, Jordan and Arena, Christopher B. and Dayton, Paul A.}, year={2014}, pages={417–420} }
 @article{lindsey_rojas_martin_shelton_dayton_2014, title={Optimization of Contrast-to-tissue Ratio and Role of Bubble Destruction in Dual-Frequency Contrast-Specific "Acoustic Angiography" Imaging}, ISSN={["1948-5719"]}, DOI={10.1109/ultsym.2014.0440}, abstractNote={Recently, dual-frequency transducers have enabled high-spatial resolution, high-contrast imaging of microvasculature by transmitting at a low frequency and receiving broadband superharmonic echoes from microbubble contrast agents at a higher frequency. In this work, we examine the imaging parameters for optimizing contrast-to-tissue ratio (CTR) for dual-frequency imaging and the relationship between bubble destruction and broadband harmonic signal production. CTR was assessed in vitro by acquiring scattered echoes by bubbles and beef muscle for transmit pressures up to 2 MPa, transmit frequencies from 1.5-8 MHz, and receive frequencies from 7.5 to 25 MHz. Optimum CTR (25.5 dB) was found to occur at the lowest transmit frequencies, though a broad peak exists within the 1.5-3.5 MHz range. At these frequencies, CTR is optimized when receiving at a center frequency of 10 - 15 MHz. A 4 μm-diameter microbubble population yielded ~5 dB higher CTR than a 1 μm population. Single bubble behavior was assessed with simultaneous acoustic and optical recordings. For n=250 single bubbles subjected to five consecutive single-cycle pulses (100-500 kPa), three primary categories of bubble behavior were observed optically: 1) no change in bubble diameter, 2) bubble shrinking (deflation), and 3) immediate bubble destruction (fragmentation). Matched acoustic data indicate that superharmonic signals having the broadest bandwidth and highest energy are associated with shell fragmentation. In the deflation case, a weaker superharmonic signal is produced with an amplitude approximately 25% of the signal in the shell fragmentation case. Similar regimes were observed in vivo, suggesting that bubble diameter, transmit frequency, peak negative pressure, and frame rate must be selected in light of the intended application, accounting for attenuation and local perfusion rate in the region of interest.}, journal={2014 IEEE INTERNATIONAL ULTRASONICS SYMPOSIUM (IUS)}, author={Lindsey, Brooks D. and Rojas, Juan D. and Martin, K. Heath and Shelton, Sarah E. and Dayton, Paul A.}, year={2014}, pages={1774–1777} }
 @article{sheeran_matsunaga_dayton_2014, title={Phase change events of volatile liquid perfluorocarbon contrast agents produce unique acoustic signatures}, volume={59}, ISSN={["1361-6560"]}, DOI={10.1088/0031-9155/59/2/379}, abstractNote={Phase-change contrast agents (PCCAs) provide a dynamic platform to approach problems in medical ultrasound (US). Upon US-mediated activation, the liquid core vaporizes and expands to produce a gas bubble ideal for US imaging and therapy. In this study, we demonstrate through high-speed video microscopy and US interrogation that PCCAs composed of highly volatile perfluorocarbons (PFCs) exhibit unique acoustic behavior that can be detected and differentiated from standard microbubble contrast agents. Experimental results show that when activated with short pulses PCCAs will over-expand and undergo unforced radial oscillation while settling to a final bubble diameter. The size-dependent oscillation phenomenon generates a unique acoustic signal that can be passively detected in both time and frequency domain using confocal piston transducers with an ‘activate high’ (8 MHz, 2 cycles), ‘listen low’ (1 MHz) scheme. Results show that the magnitude of the acoustic ‘signature’ increases as PFC boiling point decreases. By using a band-limited spectral processing technique, the droplet signals can be isolated from controls and used to build experimental relationships between concentration and vaporization pressure. The techniques shown here may be useful for physical studies as well as development of droplet-specific imaging techniques.}, number={2}, journal={PHYSICS IN MEDICINE AND BIOLOGY}, author={Sheeran, Paul S. and Matsunaga, Terry O. and Dayton, Paul A.}, year={2014}, month={Jan}, pages={379–401} }
 @article{puett_sheeran_rojas_dayton_2014, title={Pulse sequences for uniform perfluorocarbon droplet vaporization and ultrasound imaging}, volume={54}, ISSN={["1874-9968"]}, DOI={10.1016/j.ultras.2014.05.013}, abstractNote={Phase-change contrast agents (PCCAs) consist of liquid perfluorocarbon droplets that can be vaporized into gas-filled microbubbles by pulsed ultrasound waves at diagnostic pressures and frequencies. These activatable contrast agents provide benefits of longer circulating times and smaller sizes relative to conventional microbubble contrast agents. However, optimizing ultrasound-induced activation of these agents requires coordinated pulse sequences not found on current clinical systems, in order to both initiate droplet vaporization and image the resulting microbubble population. Specifically, the activation process must provide a spatially uniform distribution of microbubbles and needs to occur quickly enough to image the vaporized agents before they migrate out of the imaging field of view. The development and evaluation of protocols for PCCA-enhanced ultrasound imaging using a commercial array transducer are described. The developed pulse sequences consist of three states: (1) initial imaging at sub-activation pressures, (2) activating droplets within a selected region of interest, and (3) imaging the resulting microbubbles. Bubble clouds produced by the vaporization of decafluorobutane and octafluoropropane droplets were characterized as a function of focused pulse parameters and acoustic field location. Pulse sequences were designed to manipulate the geometries of discrete microbubble clouds using electronic steering, and cloud spacing was tailored to build a uniform vaporization field. The complete pulse sequence was demonstrated in the water bath and then in vivo in a rodent kidney. The resulting contrast provided a significant increase (>15 dB) in signal intensity.}, number={7}, journal={ULTRASONICS}, author={Puett, C. and Sheeran, P. S. and Rojas, J. D. and Dayton, P. A.}, year={2014}, month={Sep}, pages={2024–2033} }
 @article{arena_novell_sheeran_puett_phillips_dayton_2014, title={Ultrasound Imaging from Vaporization Signals Emitted by Phase Change Contrast Agents}, ISSN={["1948-5719"]}, DOI={10.1109/ultsym.2014.0441}, abstractNote={Phase change contrast agents (PCCAs) exhibit a unique acoustic signature during the transition from a liquid droplet to a gas microbubble. Here, we demonstrate that this event can be used to generate an ultrasound image, and that the signal can be separated from that of a conventional microbubble. This presents a new opportunity to monitor PCCA activation in both diagnostic and therapeutic applications. A confocal, dual-frequency transducer was used to transmit 2 cycle, Gaussian enveloped sinusoids at 8 MHz and passively receive at 1 MHz. PCCAs were continuously infused through a microcellulose tube (250 μm diameter). At low pressures, vaporization signals from PCCAs were of significantly higher energy than signals emitted from the equivalent microbubble formulation. Specifically, when a peak negative pressure (PNP) of 0.51 MPa was transmitted, the contrast-to-noise ratio (CNR) was 18.94 dB for PCCAs and 2.28 dB for control microbubbles. As the PNP was increased to 0.76 MPa, these values changed to 22.1 dB and 9.73 dB, respectively. Time-domain averaging (TDA) helped to increase the separation of PCCA and microbubble signals. After TDA, the CNR at 0.76 MPa was 23.79 dB for PCCAs and 1.72 dB for microbubbles. The lateral resolution of the system was pressure dependent. With increasing pressure, the apparent diameter of the tube increased from 0.74 mm at 0.51 MPa to 1.14 mm at 0.76 MPa. This is due to the fact that the focal zone capable of activating PCCAs expands with increasing pressure.}, journal={2014 IEEE INTERNATIONAL ULTRASONICS SYMPOSIUM (IUS)}, author={Arena, Christopher B. and Novell, Anthony and Sheeran, Paul S. and Puett, Connor and Phillips, Linsey C. and Dayton, Paul A.}, year={2014}, pages={1778–1781} }
 @article{doinikov_sheeran_bouakaz_dayton_2014, title={Vaporization dynamics of volatile perfluorocarbon droplets: A theoretical model and in vitro validation}, volume={41}, ISSN={["0094-2405"]}, DOI={10.1118/1.4894804}, abstractNote={Purpose:Perfluorocarbon (PFC) microdroplets, called phase‐change contrast agents (PCCAs), are a promising tool in ultrasound imaging and therapy. Interest in PCCAs is motivated by the fact that they can be triggered to transition from the liquid state to the gas state by an externally applied acoustic pulse. This property opens up new approaches to applications in ultrasound medicine. Insight into the physics of vaporization of PFC droplets is vital for effective use of PCCAs and for anticipating bioeffects. PCCAs composed of volatile PFCs (with low boiling point) exhibit complex dynamic behavior: after vaporization by a short acoustic pulse, a PFC droplet turns into a vapor bubble which undergoes overexpansion and damped radial oscillation until settling to a final diameter. This behavior has not been well described theoretically so far. The purpose of our study is to develop an improved theoretical model that describes the vaporization dynamics of volatile PFC droplets and to validate this model by comparison with in vitro experimental data.}, number={10}, journal={MEDICAL PHYSICS}, author={Doinikov, Alexander A. and Sheeran, Paul S. and Bouakaz, Ayache and Dayton, Paul A.}, year={2014}, month={Oct} }
 @article{dunleavey_xiao_thompson_kim_shields_shelton_irvin_brings_ollila_brekken_et al._2014, title={Vascular channels formed by subpopulations of PECAM1+ melanoma cells}, volume={5}, ISSN={2041-1723}, url={http://dx.doi.org/10.1038/ncomms6200}, DOI={10.1038/ncomms6200}, abstractNote={Targeting the vasculature remains a promising approach for treating solid tumours; however, the mechanisms of tumour neovascularization are diverse and complex. Here we uncover a new subpopulation of melanoma cells that express the vascular cell adhesion molecule PECAM1, but not VEGFR-2, and participate in a PECAM1-dependent form of vasculogenic mimicry (VM). Clonally derived PECAM1+ tumour cells coalesce to form PECAM1-dependent networks in vitro and they generate well-perfused, vascular endothelial growth factor (VEGF)-independent channels in mice. The neural crest specifier AP-2α is diminished in PECAM1+ melanoma cells and is a transcriptional repressor of PECAM1. Re-introduction of AP-2α into PECAM1+ tumour cells represses PECAM1 and abolishes tube-forming ability, whereas AP-2α knockdown in PECAM1− tumour cells upregulates PECAM1 expression and promotes tube formation. Thus, VM-competent subpopulations, rather than all cells within a tumour, may instigate VM, supplant host-derived endothelium, and form PECAM1-dependent conduits that are not diminished by neutralizing VEGF. Tumours acquire new vasculature through angiogenesis or through alternative pathways including the less understood vasculogenesis mimicry. Here the authors identify a vasculogenic mimicry-competent subpopulation of melanoma cells that expresses the vascular cell adhesion molecule PECAM1, but not VEGFR-2.}, number={1}, journal={Nature Communications}, publisher={Springer Science and Business Media LLC}, author={Dunleavey, James M. and Xiao, Lin and Thompson, Joshua and Kim, Mi Mi and Shields, Janiel M. and Shelton, Sarah E. and Irvin, David M. and Brings, Victoria E. and Ollila, David W. and Brekken, Rolf A. and et al.}, year={2014}, month={Oct} }
 @article{streeter_herrera-loeza_neel_yeh_dayton_2013, title={A Comparative Evaluation of Ultrasound Molecular Imaging, Perfusion Imaging, and Volume Measurements in Evaluating Response to Therapy in Patient-Derived Xenografts}, volume={12}, ISSN={["1533-0346"]}, DOI={10.7785/tcrt.2012.500321}, abstractNote={ Most pre-clinical therapy studies use the change in tumor volume as a measure for disease response. However, tumor size measurements alone may not reflect early changes in tumor physiology that occur as a response to treatment. Ultrasonic molecular imaging (USMI) and Dynamic Contrast Enhanced-Perfusion Imaging (DCE-PI) with ultrasound are two attractive alternatives to tumor volume measurements. Since these techniques can provide information prior to the appearance of gross phenotypic changes, it has been proposed that USMI and DCE-PI could be used to characterize response to treatment earlier than traditional methods. This study evaluated the ability of tumor volume measurements, DCE-PI, and USMI to characterize response to therapy in two different types of patient-derived xenografts (known responders and known non-responders). For both responders and non-responders, 7 animals received a dose of 30 mg/kg of MLN8237, an investigational aurora-A kinase inhibitor, for 14 days or a vehicle control. Volumetric USMI (target integrin: αvβ3) and DCE-PI were performed on day 0, day 2, day 7, and day 14 in the same animals. For USMI, day 2 was the earliest point at which there was a statistical difference between the untreated and treated populations in the responder cohort (Untreated: 1.20 ± 0.53 vs. Treated: 0.49 ± 0.40; p < 0.05). In contrast, statistically significant differences between the untreated and treated populations as detected using DCE-PI were not observed until day 14 (Untreated: 0.94 ± 0.23 vs. Treated: 1.31 ± 0.22; p < 0.05). Volume measurements alone suggested no statistical differences between treated and untreated populations at any read-point. Monitoring volumetric changes is the “gold standard” for evaluating treatment in preclinical studies, however, our data suggests that volumetric USMI and DCE-PI may be used to earlier classify and robustly characterize tumor response. }, number={4}, journal={TECHNOLOGY IN CANCER RESEARCH & TREATMENT}, author={Streeter, J. E. and Herrera-Loeza, S. G. and Neel, N. F. and Yeh, J. J. and Dayton, P. A.}, year={2013}, month={Aug}, pages={311–321} }
 @article{zhushma_lebedeva_sen_rubinstein_sheiko_dayton_2013, title={A system for acoustical and optical analysis of encapsulated microbubbles at ultrahigh hydrostatic pressures}, volume={84}, ISSN={["1089-7623"]}, DOI={10.1063/1.4803158}, abstractNote={Acoustics are commonly used for borehole (i.e., oil well) imaging applications, under conditions where temperature and pressure reach extremes beyond that of conventional medical ultrasonics. Recently, there has been an interest in the application of encapsulated microbubbles as borehole contrast agents for acoustic assessment of fluid composition and flow. Although such microbubbles are widely studied under physiological conditions for medical imaging applications, to date there is a paucity of information on the behavior of encapsulated gas-filled microbubbles at high pressures. One major limitation is that there is a lack of experimental systems to assess both optical and acoustic data of micrometer-sized particles data at these extremes. In this paper, we present the design and application of a high-pressure cell designed for acoustical and optical studies of microbubbles at hydrostatic pressures up to 27.5 MPa (271 atm).}, number={5}, journal={REVIEW OF SCIENTIFIC INSTRUMENTS}, author={Zhushma, Aleksandr and Lebedeva, Natalia and Sen, Pabitra and Rubinstein, Michael and Sheiko, Sergei S. and Dayton, Paul A.}, year={2013}, month={May} }
 @article{streeter_dayton_2013, title={An In Vivo Evaluation of the Effect of Repeated Administration and Clearance of Targeted Contrast Agents on Molecular Imaging Signal Enhancement}, volume={3}, ISSN={["1838-7640"]}, DOI={10.7150/thno.5341}, abstractNote={Competitive inhibition diminishes ligand adhesion as receptor sites become occupied with competing ligands. It is unknown if this effect occurs in ultrasound molecular imaging studies where endothelial binding sites become occupied with adherent bubbles or bubble fragments. The goal of this pilot study was to assess the effect that repeated administration and clearance of targeted agents has on successive adhesion. Two groups of animals were imaged with 3-D ultrasonic molecular imaging. Injections and imaging were performed on Group 1 at time 0 and 60 minutes. Group 2 received injections of microbubbles at 0, 15, 30, 45 and 60 minutes with imaging at 0 and 60 minutes. At 60 minutes, Group 1 targeting relative to baseline was not significantly different from Group 2 (1.06±0.27 vs. 1.08±0.34, p=0.93). Data suggest that multiple injections of targeted microbubbles do not block sufficient binding sites to bias molecular imaging data in serial studies.}, number={2}, journal={THERANOSTICS}, author={Streeter, Jason E. and Dayton, Paul A.}, year={2013}, pages={93–98} }
 @misc{martin_dayton_2013, title={Current status and prospects for microbubbles in ultrasound theranostics}, volume={5}, ISSN={["1939-0041"]}, DOI={10.1002/wnan.1219}, abstractNote={Abstract}, number={4}, journal={WILEY INTERDISCIPLINARY REVIEWS-NANOMEDICINE AND NANOBIOTECHNOLOGY}, author={Martin, K. Heath and Dayton, Paul A.}, year={2013}, pages={329–345} }
 @article{czernuszewicz_streeter_dayton_gallippi_2013, title={Experimental Validation of Displacement Underestimation in ARFI Ultrasound}, volume={35}, ISSN={["1096-0910"]}, DOI={10.1177/0161734613493262}, abstractNote={ Acoustic radiation force impulse (ARFI) imaging is an elastography technique that uses ultrasonic pulses to displace and track tissue motion. Previous modeling studies have shown that ARFI displacements are susceptible to underestimation due to lateral and elevational shearing that occurs within the tracking resolution cell. In this study, optical tracking was utilized to experimentally measure the displacement underestimation achieved by acoustic tracking using a clinical ultrasound system. Three optically translucent phantoms of varying stiffness were created, embedded with subwavelength diameter microspheres, and ARFI excitation pulses with F/1.5 or F/3 lateral focal configurations were transmitted from a standard linear array to induce phantom motion. Displacements were tracked using confocal optical and acoustic methods. As predicted by earlier finite element method studies, significant acoustic displacement underestimation was observed for both excitation focal configurations; the maximum underestimation error was 35% of the optically measured displacement for the F/1.5 excitation pulse in the softest phantom. Using higher F/#, less tightly focused beams in the lateral dimension improved accuracy of displacements by approximately 10 percentage points. This work experimentally demonstrates limitations of ARFI implemented on a clinical scanner using a standard linear array and sets up a framework for future displacement tracking validation studies. }, number={3}, journal={ULTRASONIC IMAGING}, author={Czernuszewicz, Tomasz J. and Streeter, Jason E. and Dayton, Paul A. and Gallippi, Caterina M.}, year={2013}, month={Jul}, pages={196–213} }
 @article{shih_bardin_martz_sheeran_dayton_lee_2013, title={Flow-focusing regimes for accelerated production of monodisperse drug-loadable microbubbles toward clinical-scale applications}, volume={13}, ISSN={["1473-0189"]}, DOI={10.1039/c3lc51016f}, abstractNote={Ultrasound imaging often calls for the injection of contrast agents, micron-sized bubbles which echo strongly in blood and help distinguish vascularized tissue. Such microbubbles are also being augmented for targeted drug delivery and gene therapy, by the addition of surface receptors and therapeutic payloads. Unfortunately, conventional production methods yield a polydisperse population, whose nonuniform resonance and drug-loading are less than ideal. An alternative technique, microfluidic flow-focusing, is able to produce highly monodisperse microbubbles with stabilizing lipid membranes and drug-carrying oil layers. However, the published 1 kHz production rate for these uniform drug bubbles is very low compared to conventional methods, and must be improved before clinical use can be practical. In this study, flow-focusing production of oil-layered lipid microbubbles was tested up to 300 kHz, with coalescence suppressed by high lipid concentrations or inclusion of Pluronic F68 surfactant in the lipid solution. The transition between geometry-controlled and dripping production regimes was analysed, and production scaling was found to be continuous, with a power trend of exponent ~5/12 similar to literature. Unlike prior studies with this trend, however, scaling curves here were found to be pressure-dependent, particularly at lower pressure-flow equilibria (e.g. <15 psi). Adjustments in oil flow rate were observed to have a similar effect, akin to a pressure change of 1-3 psi. This analysis and characterization of high-speed dual-layer bubble generation will enable more-predictive production control, at rates practical for in vivo or clinical use.}, number={24}, journal={LAB ON A CHIP}, author={Shih, Roger and Bardin, David and Martz, Thomas D. and Sheeran, Paul S. and Dayton, Paul A. and Lee, Abraham P.}, year={2013}, pages={4816–4826} }
 @article{borden_streeter_sirsi_dayton_2013, title={In Vivo Demonstration of Cancer Molecular Imaging with Ultrasound Radiation Force and Buried-Ligand Microbubbles}, volume={12}, ISSN={["1536-0121"]}, DOI={10.2310/7290.2013.00052}, abstractNote={In designing targeted contrast agent materials for imaging, the need to present a targeting ligand for recognition and binding by the target is counterbalanced by the need to minimize interactions with plasma components and to avoid recognition by the immune system. We have previously reported on a microbubble imaging probe for ultrasound molecular imaging that uses a buried-ligand surface architecture to minimize unwanted interactions and immunogenicity. Here we examine for the first time the utility of this approach for in vivo molecular imaging. In accordance with previous results, we showed a threefold increase in circulation persistence through the tumor of a fibrosarcoma model in comparison with controls. The buried-ligand microbubbles were then activated for targeted adhesion through the application of noninvasive ultrasound radiation forces applied specifically to the tumor region. Using a clinical ultrasound scanner, microbubbles were activated, imaged, and silenced. The results showed visually conspicuous images of tumor neovasculature and a twofold increase in ultrasound radiation force enhancement of acoustic contrast intensity for buried-ligand microbubbles, whereas no such increase was found for exposed-ligand microbubbles. We therefore conclude that the use of acoustically active buried-ligand microbubbles for ultrasound molecular imaging bridges the demand for low immunogenicity with the necessity of maintaining targeting efficacy and imaging conspicuity in vivo.}, number={6}, journal={MOLECULAR IMAGING}, author={Borden, Mark A. and Streeter, Jason E. and Sirsi, Shashank R. and Dayton, Paul A.}, year={2013}, month={Sep} }
 @article{abbaspourrad_duncanson_lebedeva_kim_zhushma_datta_dayton_sheiko_rubinstein_weitz_2013, title={Microfluidic Fabrication of Stable Gas-Filled Microcapsules for Acoustic Contrast Enhancement}, volume={29}, ISSN={["0743-7463"]}, DOI={10.1021/la402598p}, abstractNote={We introduce a facile approach for the production of gas-filled microcapsules designed to withstand high pressures. We exploit microfluidics to fabricate water-filled microcapsules that are then externally triggered to become gas-filled, thus making them more echogenic. In addition, the gas-filled microcapsules have a solid polymer shell making them resistant to pressure-induced buckling, which makes them more mechanically robust than traditional prestabilized microbubbles; this should increase the potential of their utility for acoustic imaging of porous media with high hydrostatic pressures such as oil reservoirs.}, number={40}, journal={LANGMUIR}, author={Abbaspourrad, Alireza and Duncanson, Wynter J. and Lebedeva, Natalia and Kim, Shin-Hyun and Zhushma, Aleksandr P. and Datta, Sujit S. and Dayton, Paul A. and Sheiko, Sergei S. and Rubinstein, Michael and Weitz, David A.}, year={2013}, month={Oct}, pages={12352–12357} }
 @article{mullin_phillips_dayton_2013, title={Nanoparticle Delivery Enhancement With Acoustically Activated Microbubbles}, volume={60}, ISSN={["1525-8955"]}, DOI={10.1109/tuffc.2013.2538}, abstractNote={The application of microbubbles and ultrasound to deliver nanoparticle carriers for drug and gene delivery is an area that has expanded greatly in recent years. Under ultrasound exposure, microbubbles can enhance nanoparticle delivery by increasing cellular and vascular permeability. In this review, the underlying mechanisms of enhanced nanoparticle delivery with ultrasound and microbubbles and various proposed delivery techniques are discussed. Additionally, types of nanoparticles currently being investigated in preclinical studies, as well as the general limitations and benefits of a microbubble- based approach to nanoparticle delivery, are reviewed.}, number={1}, journal={IEEE TRANSACTIONS ON ULTRASONICS FERROELECTRICS AND FREQUENCY CONTROL}, author={Mullin, Lee B. and Phillips, Linsey C. and Dayton, Paul A.}, year={2013}, month={Jan}, pages={65–77} }
 @article{bardin_kendall_dayton_lee_2013, title={Parallel generation of uniform fine droplets at hundreds of kilohertz in a flow-focusing module}, volume={7}, ISSN={["1932-1058"]}, DOI={10.1063/1.4811276}, abstractNote={Droplet-based microfluidic systems enable a variety of biomedical applications from point-of-care diagnostics with third world implications, to targeted therapeutics alongside medical ultrasound, to molecular screening and genetic testing. Though these systems maintain the key advantage of precise control of the size and composition of the droplet as compared to conventional methods of production, the low rates at which droplets are produced limits translation beyond the laboratory setting. As well, previous attempts to scale up shear-based microfluidic systems focused on increasing the volumetric throughput and formed large droplets, negating many practical applications of emulsions such as site-specific therapeutics. We present the operation of a parallel module with eight flow-focusing orifices in the dripping regime of droplet formation for the generation of uniform fine droplets at rates in the hundreds of kilohertz. Elevating the capillary number to access dripping, generation of monodisperse droplets of liquid perfluoropentane in the parallel module exceeded 3.69 × 105 droplets per second, or 1.33 × 109 droplets per hour, at a mean diameter of 9.8 μm. Our microfluidic method offers a novel means to amass uniform fine droplets in practical amounts, for instance, to satisfy clinical needs, with the potential for modification to form massive amounts of more complex droplets.}, number={3}, journal={BIOMICROFLUIDICS}, author={Bardin, David and Kendall, Michael R. and Dayton, Paul A. and Lee, Abraham P.}, year={2013}, month={May} }
 @article{sheeran_matsunaga_dayton_2013, title={Phase-transition thresholds and vaporization phenomena for ultrasound phase-change nanoemulsions assessed via high-speed optical microscopy}, volume={58}, ISSN={["1361-6560"]}, DOI={10.1088/0031-9155/58/13/4513}, abstractNote={Ultrasonically activated phase-change contrast agents (PCCAs) based on perfluorocarbon droplets have been proposed for a variety of therapeutic and diagnostic clinical applications. When generated at the nanoscale, droplets may be small enough to exit the vascular space and then be induced to vaporize with high spatial and temporal specificity by externally-applied ultrasound. The use of acoustical techniques for optimizing ultrasound parameters for given applications can be a significant challenge for nanoscale PCCAs due to the contributions of larger outlier droplets. Similarly, optical techniques can be a challenge due to the sub-micron size of nanodroplet agents and resolution limits of optical microscopy. In this study, an optical method for determining activation thresholds of nanoscale emulsions based on the in vitro distribution of bubbles resulting from vaporization of PCCAs after single, short (<10 cycles) ultrasound pulses is evaluated. Through ultra-high-speed microscopy it is shown that the bubbles produced early in the pulse from vaporized droplets are strongly affected by subsequent cycles of the vaporization pulse, and these effects increase with pulse length. Results show that decafluorobutane nanoemulsions with peak diameters on the order of 200 nm can be optimally vaporized with short pulses using pressures amenable to clinical diagnostic ultrasound machines.}, number={13}, journal={PHYSICS IN MEDICINE AND BIOLOGY}, author={Sheeran, Paul S. and Matsunaga, Terry O. and Dayton, Paul A.}, year={2013}, month={Jul}, pages={4513–4534} }
 @article{sheeran_streeter_mullin_matsunaga_dayton_2013, title={TOWARD ULTRASOUND MOLECULAR IMAGING WITH PHASE-CHANGE CONTRAST AGENTS: AN IN VITRO PROOF OF PRINCIPLE}, volume={39}, ISSN={["1879-291X"]}, DOI={10.1016/j.ultrasmedbio.2012.11.017}, abstractNote={Phase-change contrast agents (PCCAs), which normally consist of nanoscale or microscale droplets of liquid perfluorocarbons in an encapsulating shell, can be triggered to undergo a phase transition to the highly echogenic gaseous state upon the input of sufficient acoustic energy. As a result of the subsequent volumetric expansion, a number of unique applications have emerged that are not possible with traditional ultrasound microbubble contrast agents. Although many studies have explored the therapeutic aspects of the PCCA platform, few have examined the potential of PCCAs for molecular imaging purposes. In this study, we demonstrate a PCCA-based platform for molecular imaging using α(v)β(3)-targeted nanoscale PCCAs composed of low-boiling-point perfluorocarbons. In vitro, nanoscale PCCAs adhered to target cells, could be activated and imaged with a clinical ultrasound system and produced a six-fold increase in image contrast compared with non-targeted control PCCAs and a greater than fifty-fold increase over baseline. Data suggest that low-boiling-point nanoscale PCCAs could enable future ultrasound-based molecular imaging techniques in both the vascular and extravascular spaces.}, number={5}, journal={ULTRASOUND IN MEDICINE AND BIOLOGY}, author={Sheeran, Paul S. and Streeter, Jason E. and Mullin, Lee B. and Matsunaga, Terry O. and Dayton, Paul A.}, year={2013}, month={May}, pages={893–902} }
 @article{chen_sheeran_wu_olumolade_dayton_konofagou_2013, title={Targeted drug delivery with focused ultrasound-induced blood-brain barrier opening using acoustically-activated nanodroplets}, volume={172}, ISSN={["1873-4995"]}, DOI={10.1016/j.jconrel.2013.09.025}, abstractNote={Focused ultrasound (FUS) in the presence of systemically administered microbubbles has been shown to locally, transiently and reversibly increase the permeability of the blood-brain barrier (BBB), thus allowing targeted delivery of therapeutic agents in the brain for the treatment of central nervous system diseases. Currently, microbubbles are the only agents that have been used to facilitate the FUS-induced BBB opening. However, they are constrained within the intravascular space due to their micron-size diameters, limiting the delivery effect at or near the microvessels. In the present study, acoustically-activated nanodroplets were used as a new class of contrast agents to mediate FUS-induced BBB opening in order to study the feasibility of utilizing these nanoscale phase-shift particles for targeted drug delivery in the brain. Significant dextran delivery was achieved in the mouse hippocampus using nanodroplets at clinically relevant pressures. Passive cavitation detection was used in the attempt to establish a correlation between the amount of dextran delivered in the brain and the acoustic emission recorded during sonication. Conventional microbubbles with the same lipid shell composition and perfluorobutane core as the nanodroplets were also used to compare the efficiency of an FUS-induced dextran delivery. It was found that nanodroplets had a higher BBB opening pressure threshold but a lower stable cavitation threshold than microbubbles, suggesting that contrast agent-dependent acoustic emission monitoring was needed. A more homogeneous dextran delivery within the targeted hippocampus was achieved using nanodroplets without inducing inertial cavitation or compromising safety. Our results offered a new means of developing the FUS-induced BBB opening technology for potential extravascular targeted drug delivery in the brain, extending the potential drug delivery region beyond the cerebral vasculature.}, number={3}, journal={JOURNAL OF CONTROLLED RELEASE}, author={Chen, Cherry C. and Sheeran, Paul S. and Wu, Shih-Ying and Olumolade, Oluyemi O. and Dayton, Paul A. and Konofagou, Elisa E.}, year={2013}, month={Dec}, pages={795–804} }
 @article{gessner_streeter_kothadia_feingold_dayton_2012, title={AN IN VIVO VALIDATION OF THE APPLICATION OF ACOUSTIC RADIATION FORCE TO ENHANCE THE DIAGNOSTIC UTILITY OF MOLECULAR IMAGING USING 3-D ULTRASOUND}, volume={38}, ISSN={["1879-291X"]}, DOI={10.1016/j.ultrasmedbio.2011.12.005}, abstractNote={For more than a decade, the application of acoustic radiation force (ARF) has been proposed as a mechanism to increase ultrasonic molecular imaging (MI) sensitivity in vivo. Presented herein is the first noninvasive in vivo validation of ARF-enhanced MI with an unmodified clinical system. First, an in vitro optical-acoustical setup was used to optimize system parameters and ensure sufficient microbubble translation when exposed to ARF. 3-D ARF-enhanced MI was then performed on 7 rat fibrosarcoma tumors using microbubbles targeted to αvβ3 and nontargeted microbubbles. Low-amplitude (<25 kPa) 3-D ARF pulse sequences were tested and compared with passive targeting studies in the same animal. Our results demonstrate that a 78% increase in image intensity from targeted microbubbles can be achieved when using ARF relative to the passive targeting studies. Furthermore, ARF did not significantly increase image contrast when applied to nontargeted agents, suggesting that ARF did not increase nonspecific adhesion.}, number={4}, journal={ULTRASOUND IN MEDICINE AND BIOLOGY}, author={Gessner, Ryan C. and Streeter, Jason E. and Kothadia, Roshni and Feingold, Steven and Dayton, Paul A.}, year={2012}, month={Apr}, pages={651–660} }
 @article{sheeran_luois_mullin_matsunaga_dayton_2012, title={Design of ultrasonically-activatable nanoparticles using low boiling point perfluorocarbons}, volume={33}, ISSN={["1878-5905"]}, DOI={10.1016/j.biomaterials.2012.01.021}, abstractNote={Recently, an interest has developed in designing biomaterials for medical ultrasonics that can provide the acoustic activity of microbubbles, but with improved stability in vivo and a smaller size distribution for extravascular interrogation. One proposed alternative is the phase-change contrast agent. Phase-change contrast agents (PCCAs) consist of perfluorocarbons (PFCs) that are initially in liquid form, but can then be vaporized with acoustic energy. Crucial parameters for PCCAs include their sensitivity to acoustic energy, their size distribution, and their stability, and this manuscript provides insight into the custom design of PCCAs for balancing these parameters. Specifically, the relationship between size, thermal stability and sensitivity to ultrasound as a function of PFC boiling point and ambient temperature is illustrated. Emulsion stability and sensitivity can be 'tuned' by mixing PFCs in the gaseous state prior to condensation. Novel observations illustrate that stable droplets can be generated from PFCs with extremely low boiling points, such as octafluoropropane (b.p. -36.7 °C), which can be vaporized with acoustic parameters lower than previously observed. Results demonstrate the potential for low boiling point PFCs as a useful new class of compounds for activatable agents, which can be tailored to the desired application.}, number={11}, journal={BIOMATERIALS}, author={Sheeran, Paul S. and Luois, Samantha H. and Mullin, Lee B. and Matsunaga, Terry O. and Dayton, Paul A.}, year={2012}, month={Apr}, pages={3262–3269} }
 @article{gessner_aylward_dayton_2012, title={Mapping Microvasculature with Acoustic Angiography Yields Quantifiable Differences between Healthy and Tumor-bearing Tissue Volumes in a Rodent Model}, volume={264}, ISSN={["0033-8419"]}, DOI={10.1148/radiol.12112000}, abstractNote={PURPOSE
To determine if the morphologies of microvessels could be extracted from contrast material-enhanced acoustic angiographic ultrasonographic (US) images and used as a quantitative basis for distinguishing healthy from diseased tissue.


MATERIALS AND METHODS
All studies were institutional animal care and use committee approved. Three-dimensional contrast-enhanced acoustic angiographic images were acquired in both healthy (n = 7) and tumor-bearing (n = 10) rats. High-spatial-resolution and high signal-to-noise acquisition was enabled by using a prototype dual-frequency US transducer (transmit at 4 MHz, receive at 30 MHz). A segmentation algorithm was utilized to extract microvessel structure from image data, and the distance metric (DM) and the sum of angles metric (SOAM), designed to distinguish different types of tortuosity, were applied to image data. The vessel populations extracted from tumor-bearing tissue volumes were compared against vessels extracted from tissue volumes in the same anatomic location within healthy control animals by using the two-sided Student t test.


RESULTS
Metrics of microvascular tortuosity were significantly higher in the tumor population. The average DM of the tumor population (1.34 ± 0.40 [standard deviation]) was 23.76% higher than that of the control population (1.08 ± 0.08) (P < .0001), while the average SOAM (22.53 ± 7.82) was 50.73% higher than that of the control population (14.95 ± 4.83) (P < .0001). The DM and SOAM metrics for the control and tumor populations were significantly different when all vessels were pooled between the two animal populations. In addition, each animal in the tumor population had significantly different DM and SOAM metrics relative to the control population (P < .05 for all; P value ranges for DM, 3.89 × 10(-)(7) to 5.63 × 10(-)(3); and those for SOAM, 2.42 × 10(-)(12) to 1.57 × 10(-)(3)).


CONCLUSION
Vascular network quantification by using high-spatial-resolution acoustic angiographic images is feasible. Data suggest that the angiogenic processes associated with tumor development in the models studied result in higher instances of vessel tortuosity near the tumor site.}, number={3}, journal={RADIOLOGY}, author={Gessner, Ryan C. and Aylward, Stephen R. and Dayton, Paul A.}, year={2012}, month={Sep}, pages={733–740} }
 @article{martz_bardin_sheeran_lee_dayton_2012, title={Microfluidic Generation of Acoustically Active Nanodroplets}, volume={8}, ISSN={["1613-6810"]}, DOI={10.1002/smll.201102418}, abstractNote={A microfluidic approach for the generation of perfluorocarbon nanodroplets as the primary emulsion with diameters as small as 300-400 nm is described. The system uses a pressure-controlled delivery of all reagents and increased viscosity in the continuous phase to drive the device into an advanced tip-streaming regime, which results in generation of droplets in the sub-micrometer range. Such nanodroplets may be appropriate for emerging biomedical applications.}, number={12}, journal={SMALL}, author={Martz, Thomas D. and Bardin, David and Sheeran, Paul S. and Lee, Abraham P. and Dayton, Paul A.}, year={2012}, month={Jun}, pages={1876–1879} }
 @misc{sheeran_dayton_2012, title={Phase-change contrast agents for imaging and therapy}, volume={18}, DOI={10.2174/138161212800099883}, abstractNote={Phase-change contrast agents (PCCAs) for ultrasound-based applications have resulted in novel ways of approaching diagnostic and therapeutic techniques beyond what is possible with microbubble contrast agents and liquid emulsions. When subjected to sufficient pressures delivered by an ultrasound transducer, stabilized droplets undergo a phase-transition to the gaseous state and a volumetric expansion occurs. This phenomenon, termed acoustic droplet vaporization, has been proposed as a means to address a number of in vivo applications at the microscale and nanoscale. In this review, the history of PCCAs, physical mechanisms involved, and proposed applications are discussed with a summary of studies demonstrated in vivo. Factors that influence the design of PCCAs are discussed, as well as the need for future studies to characterize potential bioeffects for administration in humans and optimization of ultrasound parameters.}, number={15}, journal={Current Pharmaceutical Design}, author={Sheeran, P. S. and Dayton, P. A.}, year={2012}, pages={2152–2165} }
 @article{kwan_kaya_borden_dayton_2012, title={Theranostic Oxygen Delivery Using Ultrasound and Microbubbles}, volume={2}, ISSN={["1838-7640"]}, DOI={10.7150/thno.4410}, abstractNote={Means to overcome tumor hypoxia have been the subject of clinical investigations since the 1960's; however these studies have yet to find a treatment which is widely accepted. It has been known for nearly a century that hypoxic cells are more resistant to radiotherapy than aerobic cells, and tumor hypoxia is a major factor leading to the resistance of tumors to radiation treatment as well as several cytotoxic agents. In this manuscript, the application of ultrasound combined with oxygen-carrier microbubbles is demonstrated as a method to locally increase dissolved oxygen. Microbubbles can also be imaged by ultrasound, thus providing the opportunity for image-guided oxygen delivery. Simulations of gas diffusion and microbubble gas exchange show that small amounts (down to 5 vol%) of a low-solubility osmotic gas can substantially increase microbubble persistence and therefore production rates and stability of oxygen-carrier microbubbles. Simulations also indicate that the lipid shell can be engineered with long-chain lipids to increase oxygen payload during in vivo transit. Experimental results demonstrate that the application of ultrasound to destroy the microbubbles significantly enhances the local oxygen release. We propose this technology as an application for ultrasound image-guided release of oxygen directly to hypoxic tissue, such as tumor sites to enhance radiotherapy.}, number={12}, journal={THERANOSTICS}, author={Kwan, James J. and Kaya, Mehmet and Borden, Mark A. and Dayton, Paul A.}, year={2012}, pages={1174–1184} }
 @article{gessner_kothadia_feingold_dayton_2011, title={3-D MICROVESSEL-MIMICKING ULTRASOUND PHANTOMS PRODUCED WITH A SCANNING MOTION SYSTEM}, volume={37}, ISSN={["1879-291X"]}, DOI={10.1016/j.ultrasmedbio.2010.12.013}, abstractNote={Ultrasound techniques are currently being developed that can assess the vascularization of tissue as a marker for therapeutic response. Some of these ultrasound imaging techniques seek to extract quantitative features about vessel networks, whereas high-frequency imaging also allows individual vessels to be resolved. The development of these new techniques, and subsequent imaging analysis strategies, necessitates an understanding of their sensitivities to vessel and vessel network structural abnormalities. Constructing in-vitro flow phantoms for this purpose can be prohibitively challenging, because simulating precise flow environments with nontrivial structures is often impossible using conventional methods of construction for flow phantoms. Presented in this manuscript is a method to create predefined structures with <10 μm precision using a three-axis motion system. The application of this technique is demonstrated for the creation of individual vessel and vessel networks, which can easily be made to simulate the development of structural abnormalities typical of diseased vasculature in vivo. In addition, beyond facilitating the creation of phantoms that would otherwise be very challenging to construct, the method presented herein enables one to precisely simulate very slow blood flow and respiration artifacts, and to measure imaging resolution. (E-mail: [email protected])}, number={5}, journal={ULTRASOUND IN MEDICINE AND BIOLOGY}, author={Gessner, Ryan C. and Kothadia, Roshni and Feingold, Steven and Dayton, Paul A.}, year={2011}, month={May}, pages={827–833} }
 @article{sheeran_wong_luois_mcfarland_ross_feingold_matsunaga_dayton_2011, title={DECAFLUOROBUTANE AS A PHASE-CHANGE CONTRAST AGENT FOR LOW-ENERGY EXTRAVASCULAR ULTRASONIC IMAGING}, volume={37}, ISSN={["1879-291X"]}, DOI={10.1016/j.ultrasmedbio.2011.05.021}, abstractNote={Currently available microbubbles used for ultrasound imaging and therapeutics are limited to intravascular space due to their size distribution in the micron range. Phase-change contrast agents (PCCAs) have been proposed as a means to overcome this limitation, since droplets formed in the hundred nanometer size range might be able to extravasate through leaky microvasculature, after which they could be activated to form larger highly echogenic microbubbles. Existing PCCAs in the sub-micron size range require substantial acoustic energy to be vaporized, increasing the likelihood of unwanted bioeffects. Thus, there exists a need for PCCAs with reduced acoustic activation energies for use in imaging studies. In this article, it is shown that decafluorobutane, which is normally a gas at room temperature, can be incorporated into metastable liquid sub-micron droplets with appropriate encapsulation methods. The resulting droplets are activatable with substantially less energy than other favored PCCA compounds. Decafluorobutane nanodroplets may present a new means to safely extend ultrasound imaging beyond the vascular space.}, number={9}, journal={ULTRASOUND IN MEDICINE AND BIOLOGY}, author={Sheeran, Paul S. and Wong, Vincent P. and Luois, Samantha and McFarland, Ryan J. and Ross, William D. and Feingold, Steven and Matsunaga, Terry O. and Dayton, Paul A.}, year={2011}, month={Sep}, pages={1518–1530} }
 @article{seiler_salmon_mantuo_feingold_dayton_gilger_2011, title={Effect and Distribution of Contrast Medium after Injection into the Anterior Suprachoroidal Space in Ex Vivo Eyes}, volume={52}, ISSN={1552-5783}, url={http://dx.doi.org/10.1167/iovs.11-7525}, DOI={10.1167/iovs.11-7525}, abstractNote={PURPOSE
To determine the effects and posterior distribution of injections made into the anterior suprachoroidal space (SCS).


METHODS
The anterior SCS of adult porcine and canine ex vivo eyes was cannulated. Latex injections and high frequency ultrasound (50 MHz) was used to image the effect and distension of the SCS. Flow characteristics and percentage maximal distribution of microbubble contrast injection into the SCS were assessed by 2D and 3D ultrasound.


RESULTS
Mean (SD) distension of the SCS with PBS increased from 1.57 (0.48) mm after injection of 250 μL to 3.28 (0.57) mm with 1000 μL PBS. Eyes injected at physiologic IOP had no significant difference in SCS distension. In real-time 2D ultrasound, the contrast agent flowed from the injection site to the opposite ventral anterior SCS and the posterior SCS. Contrast arrived at the opposite and posterior SCS 7.8 (4.6) and 7.7 (4.6) seconds after injection, respectively. In sagittal images, contrast was visible in 24.0%to 27.2% of the SCS; in 10 of 12 eyes, contrast reached the posterior pole of the eye. In 3D images, contrast medium occupied 39.0% to 52.1% of the entire SCS.


CONCLUSIONS
These results suggest that the SCS can expand, in a dose-dependent manner, to accommodate various volumes of fluid and that it is possible to image the SCS with ultrasound contrast. The authors' hypothesis that a single anterior SCS injection can reach the ocular posterior segment was supported. Further development of SCS injections for treatment of the ocular posterior segment is warranted.}, number={8}, journal={Investigative Opthalmology & Visual Science}, publisher={Association for Research in Vision and Ophthalmology (ARVO)}, author={Seiler, Gabriela S. and Salmon, Jacklyn H. and Mantuo, Rebecca and Feingold, Steven and Dayton, Paul A. and Gilger, Brian C.}, year={2011}, month={Jul}, pages={5730} }
 @article{mullin_gessner_kwan_kaya_borden_dayton_2011, title={Effect of anesthesia carrier gas on in vivo circulation times of ultrasound microbubble contrast agents in rats}, volume={6}, ISSN={["1555-4317"]}, DOI={10.1002/cmmi.414}, abstractNote={Purpose:Microbubble contrast agents are currently implemented in a variety of both clinical and preclinical ultrasound imaging studies. The therapeutic and diagnostic capabilities of these contrast agents are limited by their short in‐vivo lifetimes, and research to lengthen their circulation times is on going. In this manuscript, observations are presented from a controlled experiment performed to evaluate differences in circulation times for lipid shelled perfluorocarbon‐filled contrast agents circulating within rodents as a function of inhaled anesthesia carrier gas.}, number={3}, journal={CONTRAST MEDIA & MOLECULAR IMAGING}, author={Mullin, Lee and Gessner, Ryan and Kwan, James and Kaya, Mehmet and Borden, Mark A. and Dayton, Paul A.}, year={2011}, pages={126–131} }
 @article{sheeran_luois_dayton_matsunaga_2011, title={Formulation and Acoustic Studies of a New Phase-Shift Agent for Diagnostic and Therapeutic Ultrasound}, volume={27}, ISSN={["0743-7463"]}, DOI={10.1021/la2013705}, abstractNote={Recent efforts in the area of acoustic droplet vaporization with the objective of designing extravascular ultrasound contrast agents has led to the development of stabilized, lipid-encapsulated nanodroplets of the highly volatile compound decafluorobutane (DFB). We developed two methods of generating DFB droplets, the first of which involves condensing DFB gas (boiling point from -1.1 to -2 °C) followed by extrusion with a lipid formulation in HEPES buffer. Acoustic droplet vaporization of micrometer-sized lipid-coated droplets at diagnostic ultrasound frequencies and mechanical indices were confirmed optically. In our second formulation methodology, we demonstrate the formulation of submicrometer-sized lipid-coated nanodroplets based upon condensation of preformed microbubbles containing DFB. The droplets are routinely in the 200-300 nm range and yield microbubbles on the order of 1-5 μm once vaporized, consistent with ideal gas law expansion predictions. The simple and effective nature of this methodology allows for the development of a variety of different formulations that can be used for imaging, drug and gene delivery, and therapy. This study is the first to our knowledge to demonstrate both a method of generating ADV agents by microbubble condensation and formulation of primarily submicrometer droplets of decafluorobutane that remain stable at physiological temperatures. Finally, activation of DFB nanodroplets is demonstrated using pressures within the FDA guidelines for diagnostic imaging, which may minimize the potential for bioeffects in humans. This methodology offers a new means of developing extravascular contrast agents for diagnostic and therapeutic applications.}, number={17}, journal={LANGMUIR}, author={Sheeran, Paul S. and Luois, Samantha and Dayton, Paul A. and Matsunaga, Terry O.}, year={2011}, month={Sep}, pages={10412–10420} }
 @article{bardin_martz_sheeran_shih_dayton_lee_2011, title={High-speed, clinical-scale microfluidic generation of stable phase-change droplets for gas embolotherapy}, volume={11}, ISSN={["1473-0197"]}, DOI={10.1039/c1lc20615j}, abstractNote={In this study we report on a microfluidic device and droplet formation regime capable of generating clinical-scale quantities of droplet emulsions suitable in size and functionality for in vivo therapeutics. By increasing the capillary number-based on the flow rate of the continuous outer phase-in our flow-focusing device, we examine three modes of droplet breakup: geometry-controlled, dripping, and jetting. Operation of our device in the dripping regime results in the generation of highly monodisperse liquid perfluoropentane droplets in the appropriate 3-6 μm range at rates exceeding 10(5) droplets per second. Based on experimental results relating droplet diameter and the ratio of the continuous and dispersed phase flow rates, we derive a power series equation, valid in the dripping regime, to predict droplet size, D(d) approximately equal 27(Q(C)/Q(D))(-5/12). The volatile droplets in this study are stable for weeks at room temperature yet undergo rapid liquid-to-gas phase transition, and volume expansion, above a uniform thermal activation threshold. The opportunity exists to potentiate locoregional cancer therapies such as thermal ablation and percutaneous ethanol injection using thermal or acoustic vaporization of these monodisperse phase-change droplets to intentionally occlude the vessels of a cancer.}, number={23}, journal={LAB ON A CHIP}, author={Bardin, David and Martz, Thomas D. and Sheeran, Paul S. and Shih, Roger and Dayton, Paul A. and Lee, Abraham P.}, year={2011}, pages={3990–3998} }
 @article{martz_sheeran_bardin_lee_dayton_2011, title={PRECISION MANUFACTURE OF PHASE-CHANGE PERFLUOROCARBON DROPLETS USING MICROFLUIDICS}, volume={37}, ISSN={["0301-5629"]}, DOI={10.1016/j.ultrasmedbio.2011.08.012}, abstractNote={Liquid perfluorocarbon droplets have been of interest in the medical acoustics community for use as acoustically activated particles for tissue occlusion, imaging and therapeutics. To date, methods to produce liquid perfluorocarbon droplets typically result in a polydisperse size distribution. Because the threshold of acoustic activation is a function of diameter, there would be benefit from a monodisperse population to preserve uniformity in acoustic activation parameters. Through use of a microfluidic device with flow-focusing technology, the production of droplets of perfluoropentane with a uniform size distribution is demonstrated. Stability studies indicate that these droplets are stable in storage for at least two weeks. Acoustic studies illustrate the thresholds of vaporization as a function of droplet diameter, and a logarithmic relationship is observed between acoustic pressure and vaporization threshold within the size ranges studied. Droplets of uniform size have very little variability in acoustic vaporization threshold. Results indicate that microfluidic technology can enable greater manufacturing control of phase-change perfluorocarbons for acoustic droplet vaporization applications.}, number={11}, journal={ULTRASOUND IN MEDICINE AND BIOLOGY}, author={Martz, Thomas D. and Sheeran, Paul S. and Bardin, David and Lee, Abraham P. and Dayton, Paul A.}, year={2011}, month={Nov}, pages={1952–1957} }
 @article{kogan_johnson_feingold_garrett_guracar_arendshorst_dayton_2011, title={VALIDATION OF DYNAMIC CONTRAST-ENHANCED ULTRASOUND IN RODENT KIDNEYS AS AN ABSOLUTE QUANTITATIVE METHOD FOR MEASURING BLOOD PERFUSION}, volume={37}, ISSN={["0301-5629"]}, DOI={10.1016/j.ultrasmedbio.2011.03.011}, abstractNote={Contrast-enhanced ultrasound (CEUS) has demonstrated utility in the monitoring of blood flow in tissues, organs and tumors. However, current CEUS methods typically provide only relative image-derived measurements, rather than quantitative values of blood flow in milliliters/minute per gram of tissue. In this study, CEUS derived parameters of blood flow are compared with absolute measurements of blood flow in rodent kidneys. Additionally, the effects of contrast agent infusion rate and transducer orientation on image-derived perfusion measurements are assessed. Both wash-in curve and time-to-refill algorithms are examined. Data illustrate that for all conditions, image-derived flow measurements were well-correlated with transit-time flow probe measurements (R > 0.9). However, we report differences in the sensitivity to flow across different transducer orientations as well as the contrast analysis algorithm utilized. Results also indicate that there exists a range of contrast agent flow rates for which image-derived estimates are consistent.}, number={6}, journal={ULTRASOUND IN MEDICINE AND BIOLOGY}, author={Kogan, Paul and Johnson, Kennita A. and Feingold, Steven and Garrett, Nicholas and Guracar, Ismayil and Arendshorst, William J. and Dayton, Paul A.}, year={2011}, month={Jun}, pages={900–908} }
 @misc{gessner_dayton_2010, title={Advances in molecular imaging with ultrasound}, volume={9}, number={3}, journal={Molecular Imaging}, author={Gessner, R. and Dayton, P. A.}, year={2010}, pages={117–127} }
 @article{gessner_lukacs_lee_cherin_foster_dayton_2010, title={High-Resolution, High-Contrast Ultrasound Imaging Using a Prototype Dual-Frequency Transducer: In Vitro and In Vivo Studies}, volume={57}, ISSN={["1525-8955"]}, DOI={10.1109/tuffc.2010.1615}, abstractNote={With recent advances in animal models of disease, there has been great interest in capabilities for highresolution contrast-enhanced ultrasound imaging. Microbubble contrast agents are unique in that they scatter broadband ultrasound energy because of their nonlinear behavior. For optimal response, it is desirable to excite the microbubbles near their resonant frequency. To date, this has been challenging with high-frequency imaging systems because most contrast agents are resonant at frequencies in the order of several megahertz. Our team has developed a unique dual-frequency confocal transducer which enables low-frequency excitation of bubbles near their resonance with one element, and detection of their emitted high-frequency content with the second element. Using this imaging approach, we have attained an average 12.3 dB improvement in contrast-to-tissue ratios over fundamental mode imaging, with spatial resolution near that of the high-frequency element. Because this detection method does not rely on signal decorrelation, it is not susceptible to corruption by tissue motion. This probe demonstrates contrast imaging capability with significant tissue suppression, enabling high-resolution contrast-enhanced images of microvascular blood flow. Additionally, this probe can readily produce radiation force on flowing contrast agents, which may be beneficial for targeted imaging or therapy.}, number={8}, journal={IEEE TRANSACTIONS ON ULTRASONICS FERROELECTRICS AND FREQUENCY CONTROL}, author={Gessner, Ryan and Lukacs, Marc and Lee, Mike and Cherin, Emmanuel and Foster, F. Stuart and Dayton, Paul A.}, year={2010}, month={Aug}, pages={1772–1781} }
 @article{streeter_gessner_miles_dayton_2010, title={Improving sensitivity in ultrasound molecular imaging by tailoring contrast agent size distribution: In vivo studies}, volume={9}, number={2}, journal={Molecular Imaging}, author={Streeter, J. E. and Gessner, R. and Miles, I. and Dayton, P. A.}, year={2010}, pages={87–95} }
 @article{feingold_gessner_guracar_dayton_2010, title={Quantitative Volumetric Perfusion Mapping of the Microvasculature Using Contrast Ultrasound}, volume={45}, ISSN={["1536-0210"]}, DOI={10.1097/rli.0b013e3181ef0a78}, abstractNote={Objectives:Contrast-enhanced ultrasound imaging has demonstrated significant potential as a noninvasive technology for monitoring blood flow in the microvasculature. With the application of nondestructive contrast imaging pulse sequences combined with a clearance-refill approach, it is possible to create quantitative time-to-refill maps of tissue correlating to blood perfusion rate. One limitation to standard two-dimensional (2D) perfusion imaging is that the narrow elevational beamwidth of 1- or 1.5-D ultrasound transducers provides information in only a single slice of tissue, and thus it is difficult to image exactly the same plane from study to study. We hypothesize that inhomogeneity in vascularization, such as that common in many types of tumors, makes serial perfusion estimates inconsistent unless the same region can be imaged repeatedly. Our objective was to evaluate error in 2D quantitative perfusion estimation in an in vivo sample volume because of differences in transducer positioning. To mitigate observed errors due to imaging plane misalignment, we propose and demonstrate the application of quantitative 3-dimensional (3D) perfusion imaging. We also evaluate the effect of contrast agent concentration and infusion rate on perfusion estimates. Materials and Methods:Contrast-enhanced destruction-reperfusion imaging was performed using parametric mapping of refill times and custom software for image alignment to compensate for tissue motion. Imaging was performed in rats using a Siemens Sequoia 512 imaging system with a 15L8 transducer. A custom 3D perfusion mapping system was designed by incorporating a computer-controlled positioning system to move the transducer in the elevational direction, and the Sequoia was interfaced to the motion system for timing of the destruction-reperfusion sequence and data acquisition. Perfusion estimates were acquired from rat kidneys as a function of imaging plane and in response to the vasoactive drug dopamine. Results:Our results indicate that perfusion estimates generated by 2D imaging in the rat kidney have mean standard deviations on the order of 10%, and as high as 22%, because of differences in initial transducer position. This difference was larger than changes in kidney perfusion induced by dopamine. With application of 3D perfusion mapping, repeatability in perfusion estimated in the kidney is reduced to a standard deviation of less than 3%, despite random initial transducer positioning. Varying contrast agent administration rate was also observed to bias measured perfusion time, especially at low concentrations; however, we observed that contrast administration rates between 2.7 × 108 and 3.9 × 108 bubbles/min provided results that were consistent within 3% for the contrast agent type evaluated. Conclusions:Three-dimensional perfusion imaging allows a significant reduction in the error caused by transducer positioning, and significantly improves the reliability of quantitative perfusion time estimates in a rat kidney model. When performing perfusion imaging, it is important to use appropriate and consistent contrast agent infusion rates to avoid bias.}, number={10}, journal={INVESTIGATIVE RADIOLOGY}, author={Feingold, Steven and Gessner, Ryan and Guracar, Ismayil M. and Dayton, Paul A.}, year={2010}, month={Oct}, pages={669–674} }
 @article{marvel_okrasinski_bernacki_loboa_dayton_2010, title={The Development and Validation of a LIPUS System With Preliminary Observations of Ultrasonic Effects on Human Adult Stem Cells}, volume={57}, ISSN={["1525-8955"]}, DOI={10.1109/tuffc.2010.1645}, abstractNote={To study the potential effects of low-intensity pulsed ultrasound (LIPUS) on cell response in vitro, the ability to alter LIPUS parameters is required. However, commercial LIPUS systems have very little control over parameter selection. In this study, a custom LIPUS system was designed and validated by exploring the effects of using different pulse repetition frequency (PRF) parameters on human adipose derived adult stem cells (hASCs) and bone marrow derived mesenchymal stem cells (hMSCs), two common stem cell sources for creating bone constructs in vitro. Changing the PRF was found to affect cellular response to LIPUS stimulation for both cell types. Proliferation of LIPUS-stimulated cells was found to decrease for hASCs by d 7 for all three groups compared with unstimulated control cells (P = 0.008, 0.011, 0.014 for 1 Hz, 100 Hz and 1 kHz PRF, respectively) and for hMSCs by d 14 (donor 1: P = 0.0005, 0.0002, 0.0003; donor 2: P = 0.0003, 0.0002, 0.0001; for PRFs of 1 Hz, 100 Hz, and 1 kHz, respectively). Additionally, LIPUS was shown to strongly accelerate osteogenic differentiation of hASCs based on amount of calcium accretion normalized by total DNA (P = 0.003, 0.001, 0.003, and 0.032 between control/100 Hz, control/1 kHz, 1 Hz/1 kHz, and 100 Hz/1 kHz pulse repetition frequencies, respectively). These findings promote the study of using LIPUS to induce osteogenic differentiation and further encourage the exploration of LIPUS parameter optimization. The custom LIPUS system was successfully designed to allow extreme parameter variation, specifically PRF, and encourages further studies.}, number={9}, journal={IEEE TRANSACTIONS ON ULTRASONICS FERROELECTRICS AND FREQUENCY CONTROL}, author={Marvel, Skylar and Okrasinski, Stan and Bernacki, Susan H. and Loboa, Elizabeth and Dayton, Paul A.}, year={2010}, month={Sep}, pages={1977–1984} }
 @article{kaya_gregory_dayton_2009, title={CHANGES IN LIPID-ENCAPSULATED MICROBUBBLE POPULATION DURING CONTINUOUS INFUSION AND METHODS TO MAINTAIN CONSISTENCY}, volume={35}, ISSN={["1879-291X"]}, DOI={10.1016/j.ultrasmedbio.2009.04.023}, abstractNote={Stabilized microbubbles are used as ultrasound contrast agents. These micron-sized gas capsules are injected into the bloodstream to provide contrast enhancement during ultrasound imaging. Some contrast imaging strategies, such as destruction-reperfusion, require a continuous injection of microbubbles over several minutes. Most quantitative imaging strategies rely on the ability to administer a consistent dose of contrast agent. Because of the buoyancy of these gas-filled agents, their spatial distribution within a syringe changes over time. The population of microbubbles that is pumped from a horizontal syringe outlet differs from initial population as the microbubbles float to the syringe top. In this manuscript, we study the changes in the population of a contrast agent that is pumped from a syringe caused by microbubble flotation. Results are presented in terms of change in concentration and change in mean diameter, as a function of time, suspension medium and syringe diameter. Data illustrate that the distribution of contrast agents injected from a syringe changes in both concentration and mean diameter over several minutes without mixing. We discuss the application of a mixing system and viscosity agents to keep the contrast solution more evenly distributed in a syringe. These results are significant for researchers using microbubble contrast agents in continuous-infusion applications where it is important to maintain consistent contrast agent delivery rate, or in situations where the injection syringe cannot be mixed immediately before administration.}, number={10}, journal={ULTRASOUND IN MEDICINE AND BIOLOGY}, author={Kaya, Mehmet and Gregory, Thomas S. and Dayton, Paul A.}, year={2009}, month={Oct}, pages={1748–1755} }
 @article{hettiarachchi_lee_zhang_feingold_dayton_2009, title={Controllable Microfluidic Synthesis of Multiphase Drug-Carrying Lipospheres for Site-Targeted Therapy}, volume={25}, ISSN={["1520-6033"]}, DOI={10.1002/btpr.214}, abstractNote={Abstract}, number={4}, journal={BIOTECHNOLOGY PROGRESS}, author={Hettiarachchi, Kanaka and Lee, Abraham P. and Zhang, Shirley and Feingold, Steven and Dayton, Paul A.}, year={2009}, pages={938–945} }
 @article{bonadio_pollard_dayton_leonard_marks_2009, title={Effects of Body Positioning on Swallowing and Esophageal Transit in Healthy Dogs}, volume={23}, ISSN={["1939-1676"]}, DOI={10.1111/j.1939-1676.2009.0325.x}, abstractNote={Background:  Contrast videofluoroscopy is the imaging technique of choice for evaluating dysphagic dogs. In people, body position alters the outcome of videofluoroscopic assessment of swallowing.}, number={4}, journal={JOURNAL OF VETERINARY INTERNAL MEDICINE}, author={Bonadio, C. M. and Pollard, R. E. and Dayton, P. A. and Leonard, C. D. and Marks, S. L.}, year={2009}, pages={801–805} }
 @article{caskey_qin_dayton_ferrara_2009, title={Microbubble tunneling in gel phantoms}, volume={125}, ISSN={["1520-8524"]}, DOI={10.1121/1.3097679}, abstractNote={Insonified microbubbles were observed in vessels within a gel with a Young’s modulus similar to that of tissue, demonstrating shape instabilities, liquid jets, and the formation of small tunnels. In this study, tunnel formulation occurred in the direction of the propagating ultrasound wave, where radiation pressure directed the contact of the bubble and gel, facilitating the activity of the liquid jets. Combinations of ultrasonic parameters and microbubble concentrations that are relevant for diagnostic imaging and drug delivery and that lead to tunnel formation were applied and the resulting tunnel formation was quantified.}, number={5}, journal={JOURNAL OF THE ACOUSTICAL SOCIETY OF AMERICA}, author={Caskey, Charles F. and Qin, Shengping and Dayton, Paul A. and Ferrara, Katherine W.}, year={2009}, month={May}, pages={EL183–EL189} }
 @article{bouchard_palmeri_pinton_trahey_streeter_dayton_2009, title={Optical tracking of acoustic radiation force impulse-induced dynamics in a tissue-mimicking phantom}, volume={126}, ISSN={["1520-8524"]}, DOI={10.1121/1.3238235}, abstractNote={Optical tracking was utilized to investigate the acoustic radiation force impulse (ARFI)-induced response, generated by a 5-MHz piston transducer, in a translucent tissue-mimicking phantom. Suspended 10-μm microspheres were tracked axially and laterally at multiple locations throughout the field of view of an optical microscope with 0.5-μm displacement resolution, in both dimensions, and at frame rates of up to 36 kHz. Induced dynamics were successfully captured before, during, and after the ARFI excitation at depths of up to 4.8 mm from the phantom’s proximal boundary. Results are presented for tracked axial and lateral displacements resulting from on-axis and off-axis (i.e., shear wave) acquisitions; these results are compared to matched finite element method modeling and independent ultrasonically based empirical results and yielded reasonable agreement in most cases. A shear wave reflection, generated by the proximal boundary, consistently produced an artifact in tracked displacement data later in time (i.e., after the initial ARFI-induced displacement peak). This tracking method provides high-frame-rate, two-dimensional tracking data and thus could prove useful in the investigation of complex ARFI-induced dynamics in controlled experimental settings.}, number={5}, journal={JOURNAL OF THE ACOUSTICAL SOCIETY OF AMERICA}, author={Bouchard, Richard R. and Palmeri, Mark L. and Pinton, Gianmarco F. and Trahey, Gregg E. and Streeter, Jason E. and Dayton, Paul A.}, year={2009}, month={Nov}, pages={2733–2745} }
 @article{ounkomol_xie_dayton_heinrich_2009, title={Versatile Horizontal Force Probe for Mechanical Tests on Pipette-Held Cells, Particles, and Membrane Capsules}, volume={96}, ISSN={["1542-0086"]}, DOI={10.1016/j.bpj.2008.10.047}, abstractNote={We present a multipurpose nanomechanical force probe that combines a sideways-mounted elastic cantilever and an optical-lever detection module with automated micropipette manipulation. It allows us to apply and measure compression, stretching, adhesion, and dissociation forces in the horizontal direction while providing a "side view" of ongoing experiments. The integrated micropipette setup facilitates the easy manipulation and mechanical interrogation of individual cells, functionalized particles, and synthetic membrane capsules. Pipette-held test objects are translated perpendicularly to and from the stationary cantilever, eliminating the need to attach them to a carrier surface and substantially reducing unwanted hydrodynamic coupling effects. Moreover, the test objects can be brought into contact with the cantilever anywhere along its length, which considerably enlarges the range of forces that can be applied with a single cantilever. Advantages of this instrument are demonstrated in example measurements of single-cell compression, membrane-tether extrusion, oligonucleotide stretching, and extraction of individual lipids from surfactant-monolayer surfaces of microbubbles.}, number={3}, journal={BIOPHYSICAL JOURNAL}, author={Ounkomol, Chawin and Xie, Hongtao and Dayton, Paul A. and Heinrich, Volkmar}, year={2009}, month={Feb}, pages={1218–1231} }
 @article{streeter_gessner_tsuruta_feingold_dayton, title={Assessment of molecular imaging of angiogenesis with three-dimensional ultrasonography}, volume={10}, number={6}, journal={Molecular Imaging}, author={Streeter, J. E. and Gessner, R. C. and Tsuruta, J. and Feingold, S. and Dayton, P. A.}, pages={460–468} }