Current clinical investigations of focused ultrasound blood-brain barrier disruption: A review.

The blood-brain barrier (BBB) presents a formidable challenge in delivering therapeutic agents to the central nervous system. Ultrasound-mediated BBB disruption has emerged as a promising non-invasive technique to enhance drug delivery to the brain. This manuscript reviews fundamental principles of ultrasound-based techniques and their mechanisms of action in temporarily permeabilizing the BBB. Clinical trials employing ultrasound for BBB disruption are discussed, summarizing diverse applications ranging from the treatment of neurodegenerative diseases to targeted drug delivery for brain tumors. The review also addresses safety considerations, outlining the current understanding of potential risks and mitigation strategies associated with ultrasound exposure, including real-time monitoring and assessment of treatment efficacy. Among the large number of studies, significant successes are highlighted thus providing perspective on the future direction of the field.

Element Position Calibration for Matrix Array Transducers with Multiple Disjoint Piezoelectric Panels.

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.

Design and Fabrication of 1-D CMUT Arrays for Dual-Mode Dual-Frequency Acoustic Angiography Applications.

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.

The Performance of Flash Replenishment Contrast-Enhanced Ultrasound for the Qualitative Assessment of Kidney Lesions in Patients with Chronic Kidney Disease.

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.

Longitudinal 3-D Visualization of Microvascular Disruption and Perfusion Changes in Mice During the Evolution of Glioblastoma Using Super-Resolution Ultrasound.

Glioblastoma is an aggressive brain cancer with a very poor prognosis in which less than 6% of patients survive more than five-year post-diagnosis. The outcome of this disease for many patients may be improved by early detection. This could provide clinicians with the information needed to take early action for treatment. In this work, we present the utilization of a non-invasive, fully volumetric ultrasonic imaging method to assess microvascular change during the evolution of glioblastoma in mice. Volumetric ultrasound localization microscopy (ULM) was used to observe statistically significant ( ) reduction in the appearance of functional vasculature over the course of three weeks. We also demonstrate evidence suggesting the reduction of vascular flow for vessels peripheral to the tumor. With an 82.5% consistency rate in acquiring high-quality vascular images, we demonstrate the possibility of volumetric ULM as a longitudinal method for microvascular characterization of neurological disease.

Superharmonic and Microultrasound Imaging With Plane Wave Beamforming Techniques.

Superharmonic contrast imaging (SpHI) suppresses tissue clutter and allows high-contrast visualization of the vasculature. An array-based dual-frequency (DF) probe has been developed for SpHI, integrating a 21-MHz, 256-element microultrasound imaging array with a 2-MHz, 32-element array to take advantage of the broadband nonlinear responses from microbubble (MB) contrast agents. In this work, ultrafast imaging with plane waves was implemented for SpHI to increase the acquisition frame rate. Ultrafast imaging was also implemented for microultrasound B-mode imaging (HFPW B-mode) to enable high-resolution visualization of the tissue structure. Coherent compounding was demonstrated in vitro and in vivo in both imaging modes. Acquisition frame rates of 4.5 kHz and 187 Hz in HFPW B-mode imaging were achieved for imaging up to 21 mm with one and 25 angles, respectively, and 3.5 kHz and 396 Hz in the SpHI mode with one and nine coherently compounded angles, respectively. SpHI images showed suppression of tissue clutter prior to and after the introduction of MBs in vitro and in vivo. The nine-angle coherently compounded 2-D SpHI images of contrast-filled flow channel showed a contrast-to-tissue ratio (CTR) of 26.0 dB, a 2.5-dB improvement relative to images reconstructed from 0° steering. Consistent with in vitro imaging, the nine-angle compounded 2-D SpHI of a Lewis lung cancer tumor showed a 2.6-dB improvement in contrast enhancement, relative to 0° steering, and additionally revealed a region of nonviable tissue. The 3-D display of the volumetric SpHI data acquired from a xenograft mouse tumor using both 0° steering and nine-angle compounding allowed the visualization of the tumor vasculature. A small vessel visible in the compounded SpHI image, measuring around [Formula: see text], is not visualized in the 0° steering SpHI image, demonstrating the superiority of the latter in detecting fine structures within the tumor.

Nanoparticle-Epoxy Composite Molding for Undeformed Acoustic Holograms With Tailored Acoustic Properties.

Acoustic hologram (AH) lenses are typically produced by high-resolution 3-D printing methods, such as stereolithography (SLA) printing. However, SLA printing of thin, plate-shaped lens structures has major limitations, including vulnerability to deformation during photocuring and limited control of acoustic impedance. To overcome these limitations, we demonstrated a nanoparticle-epoxy composite (NPEC) molding technique, and we tested its feasibility for AH lens fabrication. The characterized acoustic impedance of the 22.5% NPEC was 4.64 MRayl, which is 55% higher than the clear photopolymer (2.99 MRayl) used by SLA. Simulations demonstrated that the improved pressure transmission by the higher acoustic impedance of the NPEC resulted in 21% higher pressure amplitude in the region of interest (ROI, -6-dB pressure amplitude pixels) than the photopolymer. This improvement was experimentally demonstrated after prototyping NPEC lenses through a molding process. The NPEC lens showed no significant deformation and 72% lower thickness profile errors than the photopolymer, which otherwise experienced deformed edges due to thermal bending. Beam mapping results using the NPEC lens validated the predicted improvement, demonstrating 24% increased pressure amplitude on average and 10% improved structural similarity (SSIM) with the simulated pressure pattern compared to the photopolymer lens. This method can be used for AH lens applications with improved pressure output and accurate pressure field formation.

Effect of Anesthetic Carrier Gas on In Vivo Circulation Times of Intravenously Administered Phospholipid Oxygen Microbubbles in Rats.

OBJECTIVE: 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. METHODS: 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: 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. CONCLUSION: 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.

Overcoming biological barriers to improve treatment of a Staphylococcus aureus wound infection.

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 in vivo biofilm model. This dual approach dramatically improved antibiotic efficacy against a methicillin-resistant Staphylococcus aureus (MRSA) wound infection in diabetic mice.

An open-source framework for synthetic post-dive Doppler ultrasound audio generation.

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.

A Model of High-Speed Endovascular Sonothrombolysis with Vortex Ultrasound-Induced Shear Stress to Treat Cerebral Venous Sinus Thrombosis.

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.

Loading Intracranial Drug-Eluting Reservoirs Across the Blood-Brain Barrier With Focused Ultrasound.

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.

Current Status of Sub-micron Cavitation-Enhancing Agents for Sonothrombolysis.

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.

Non-invasive transcranial volumetric ultrasound localization microscopy of the rat brain with continuous, high volume-rate acquisition.

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.

A fully automated algorithm for heart rate detection in post-dive precordial Doppler ultrasound.

Background: Doppler ultrasound is used currently in decompression research for the evaluation of venous gas emboli (VGE). Estimation of heart rate from post-dive Doppler ultrasound recordings can provide a tool for the evaluation of physiological changes from decompression stress, as well as aid in the development of automated VGE detection algorithms that relate VGE presence to cardiac activity. Method: An algorithm based on short-term autocorrelation was developed in MATLAB to estimate the heart rate in post-dive precordial Doppler ultrasound. The algorithm was evaluated on 21 previously acquired and labeled precordial recordings spanning Kisman-Masurel (KM) codes of 111-444 (KM I-IV) with manually derived instantaneous heart rates. Results: A window size of at least two seconds was necessary for robust and accurate instantaneous heart rate estimation with a mean error of 1.56 ± 7.10 bpm. Larger window sizes improved the algorithm performance, at the cost of beat-to-beat heart rate estimates. We also found that our algorithm provides good results for low KM grade Doppler recordings with and without flexion, and high KM grades without flexion. High KM grades observed after movement produced the greatest mean absolute error of 6.12 ± 8.40 bpm. Conclusion: We have developed a fully automated algorithm for the estimation of heart rate in post-dive precordial Doppler ultrasound recordings.

Deep Learning-Based Venous Gas Emboli Grade Classification in Doppler Ultrasound Audio Recordings.

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.

Hyperbaric exposure in rodents with non-invasive imaging assessment of decompression bubbles: A scoping review protocol.

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.

Low-Intensity Focused Ultrasound Produces Immune Response in Pancreatic Cancer.

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.

Low-boiling Point Perfluorocarbon Nanodroplets as Dual-Phase Dual-Modality MR/US Contrast Agent.

Detection of bare gas microbubbles by magnetic resonance (MR) at low concentrations typically used in clinical contrast-ultrasound studies was recently demonstrated using hyperCEST. Despite the enhanced sensitivity achieved with hyperCEST, in vivo translation is challenging as on-resonance saturation of the gas-phase core of microbubbles consequently results in saturation of the gas-phase hyperpolarized 129 Xe within the lungs. Alternatively, microbubbles can be condensed into the liquid phase to form perfluorocarbon nanodroplets, where 129 Xe resonates at a chemical shift that is separated from the gas-phase signal in the lungs. For ultrasound applications, nanodroplets can be acoustically reverted back into their microbubble form to act as a phase-change contrast agent. Here, we show that low-boiling point perfluorocarbons, both in their liquid and gas form, generate phase-dependent hyperCEST contrast. Magnetic resonance detection of ultrasound-mediated phase transition demonstrates that these perfluorocarbons could be used as a dual-phase dual-modality MR/US contrast agent.