Publications by authors named "Robert F Mattrey"

68 Publications

Catalase-Loaded Silica Nanoparticles Formulated via Direct Surface Modification as Potential Oxygen Generators for Hypoxia Relief.

ACS Appl Mater Interfaces 2021 Feb 26;13(5):5945-5954. Epub 2021 Jan 26.

Department of Radiology, Translational Research in Ultrasound Theranostics (TRUST) Program, University of Texas Southwestern Medical Center, Dallas, Texas 75390, United States.

Enzymes are biological catalysts that have many potential industrial and biomedical applications. However, the widespread use of enzymes in the industry has been limited by their instability and poor recovery. In biomedical applications, systemic administration of enzymes has faced two main challenges: limited bioactivity mostly due to rapid degradation by proteases and immunogenic activity, since most enzymes are from nonhuman sources. Herein, we propose a robust enzyme-encapsulation strategy to mitigate these limitations. Catalase (CAT) was encapsulated in nanoporous silica nanoparticles (CAT-SiNPs) by first chemically modifying the enzyme surface with a silica precursor, followed by silica growth and finally poly(ethylene glycol) (PEG) conjugation. The formulation was carried out in mild aqueous conditions and yielded nanoparticles (NPs) with a mean diameter of 230 ± 10 nm and a concentration of 1.3 ± 0.8 × 10 NPs/mL. CAT-SiNPs demonstrated high enzyme activity, optimal protection from proteolysis by proteinase K and trypsin, and excellent stability over time. In addition, a new electrochemical assay was developed to measure CAT activity in a rapid, simple, and accurate manner without interference from chromophore usually present in biological samples. Concentrations of 2.5 × 10 to 80 × 10 CAT-SiNPs/mL not only proved to be nontoxic in cell cultures using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay but also conferred cell protection when cells were exposed to 1 mM hydrogen peroxide (HO). Finally, the ability of CAT-SiNPs to release oxygen (O) when exposed to HO was demonstrated using a rat model. Following the direct injection of CAT-SiNPs in the left kidney, partial pressure of oxygen (pO) increased by more than 30 mmHg compared to the contralateral control kidney during the systemic infusion of safe levels of HO. This pilot study highlights the potential of CAT-SiNPs to generate O to relieve hypoxia in tissues and potentially sensitize tumors against radiation therapy.
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http://dx.doi.org/10.1021/acsami.0c19633DOI Listing
February 2021

Microbubbles Cloaked with Hydrogels as Activatable Ultrasound Contrast Agents.

ACS Appl Mater Interfaces 2020 Nov 10;12(47):52298-52306. Epub 2020 Nov 10.

Department of Radiology, Translational Research in Ultrasound Theranostics (TRUST) Program, University of Texas Southwestern Medical Center, Dallas, Texas 75390, United States.

Microbubbles (MBs) are optimal ultrasound contrast agents because their unique acoustic response allows for exquisite sensitivity . This unique response is derived from MBs' elasticity that allows them to oscillate differently from surrounding tissues. While the main use of MBs in the clinic is for cardiac and perfusion imaging, imparting MBs with bioresponsive properties would expand their use to detect pathophysiologic changes. This can be achieved by damping MBs' oscillations to silence their signal and rescuing it when they encounter the biomarker of interest to improve detection and specificity of diseases such as deep vein thrombosis (DVT). Here, we demonstrate that conjugating perfluorobutane-filled MBs with hyaluronic acid (HA) and cross-linking HA with biodegradable linkers eliminates harmonic signal because of increased MB stiffness and decreased oscillation. In this proof-of-concept study, we used a reversible pH-sensitive cross-linker to establish and validate this targeted and activatable pH-sensitive MB (pH-MB) platform. Conjugation of HA to MBs and targeting of pH-MBs to CD44-positive cells were validated. Harmonic signal loss due to stiffening of pH-MBs' shell was confirmed using a clinical ultrasound scanner equipped with Cadence contrast pulse sequencing. pH-MBs imaged before and after acidification increased harmonic signal fivefold. Because the cleavage of the cross-linker we used is reversible, harmonic signal was silenced again when the acidic suspension was neutralized, confirming that harmonic signal is dependent on the cross-linked HA. The rate of rise and the magnitude of harmonic signal increase could be manipulated by varying the phospholipid composition and the number of HA cross-linkers, indicating that the platform can be tuned to the desired response needed. In this study, we established the feasibility of using targeted and activatable MBs and plan to apply this platform to aid in the diagnosis and management of patients with DVT and potentially other conditions.
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http://dx.doi.org/10.1021/acsami.0c12043DOI Listing
November 2020

Bubble Inflation Using Phase-Change Perfluorocarbon Nanodroplets as a Strategy for Enhanced Ultrasound Imaging and Therapy.

Langmuir 2020 03 9;36(11):2954-2965. Epub 2020 Mar 9.

Translational Research in Ultrasound Theranostics (TRUST) Program, Department of Radiology, University of Texas Southwestern Medical Center, Dallas, Texas 75390, United States.

Phase-change perfluorocarbon microdroplets were introduced over 2 decades ago to occlude downstream vessels in vivo. Interest in perfluorocarbon nanodroplets has recently increased to enable extravascular targeting, to rescue the weak ultrasound signal of perfluorocarbon droplets by converting them to microbubbles and to improve ultrasound-based therapy. Despite great scientific interest and advances, applications of phase-change perfluorocarbon agents have not reached clinical testing because of efficacy and safety concerns, some of which remain unexplained. Here, we report that the coexistence of perfluorocarbon droplets and microbubbles in blood, which is inevitable when droplets spontaneously or intentionally vaporize to form microbubbles, is a major contributor to the observed side effects. We develop the theory to explain why the coexistence of droplets and microbubbles results in microbubble inflation induced by perfluorocarbon transfer from droplets to adjacent microbubbles. We also present the experimental data showing up to 6 orders of magnitude microbubble volume expansion, which occludes a 200 μm tubing in the presence of perfluorocarbon nanodroplets. More importantly, we demonstrate that the rate of microbubble inflation and ultimate size can be controlled by manipulating formulation parameters to tailor the agent's design for the potential theranostic application while minimizing the risk to benefit ratio.
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http://dx.doi.org/10.1021/acs.langmuir.9b03647DOI Listing
March 2020

Characterizing Breast Lesions Using Quantitative Parametric 3D Subharmonic Imaging: A Multicenter Study.

Acad Radiol 2020 08 16;27(8):1065-1074. Epub 2019 Dec 16.

Department of Radiology, Thomas Jefferson University, 763H Main Building, 132 South 10th Street, Philadelphia, PA 19107. Electronic address:

Rationale And Objectives: Breast cancer is the leading type of cancer among women. Visualization and characterization of breast lesions based on vascularity kinetics was evaluated using three-dimensional (3D) contrast-enhanced ultrasound imaging in a clinical study.

Materials And Methods: Breast lesions (n = 219) were imaged using power Doppler imaging (PDI), 3D contrast-enhanced harmonic imaging (HI), and 3D contrast-enhanced subharmonic imaging (SHI) with a modified Logiq 9 ultrasound scanner using a 4D10L transducer. Quantitative metrics of vascularity derived from 3D parametric volumes (based on contrast perfusion; PER and area under the curve; AUC) were generated by off-line processing of contrast wash-in and wash-out. Diagnostic accuracy of these quantitative vascular parameters was assessed with biopsy results as the reference standard.

Results: Vascularity was observed with PDI in 93 lesions (69 benign and 24 malignant), 3D HI in 8 lesions (5 benign and 3 malignant), and 3D SHI in 83 lesions (58 benign and 25 malignant). Diagnostic accuracy for vascular heterogeneity, PER, and AUC ranged from 0.52 to 0.75, while the best logistical regression model (vascular heterogeneity ratio, central PER, and central AUC) reached 0.90.

Conclusion: 3D SHI successfully detects contrast agent flow in breast lesions and characterization of these lesions based on quantitative measures of vascular heterogeneity and 3D parametric volumes is promising.
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http://dx.doi.org/10.1016/j.acra.2019.10.029DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7295667PMC
August 2020

Fluorous-phase iron oxide nanoparticles as enhancers of acoustic droplet vaporization of perfluorocarbons with supra-physiologic boiling point.

J Control Release 2019 05 27;302:54-62. Epub 2019 Mar 27.

Department of Radiology, Translational Research in Ultrasound Theranostics (TRUST) Program, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA. Electronic address:

Perfluorocarbon emulsion nanodroplets containing iron oxide nanoparticles (IONPs) within their inner perfluorohexane (PFH) core were prepared to investigate potential use as an acoustically activatable ultrasound contrast agent, with the hypothesis that incorporation of IONPs into the fluorous phase of a liquid perfluorocarbon emulsion would potentiate acoustic vaporization. IONPs with an oleic acid (OA) hydrophobic coating were synthesized through chemical co-precipitation. To suspend IONP in PFH, OA was exchanged with perfluorononanoic acid (PFNA) via ligand exchange to yield fluorophilic PFNA-coated IONPs (PFNA-IONPs). Suspensions with various amounts of PFNA-IONPs (0-15% w/v) in PFH were emulsified in saline by sonication, using 5% (w/v) egg yolk phospholipid as an emulsifier. PFNA-IONPs were characterized with transmission electron microscopy (TEM), transmission electron cryomicroscopy (cryoTEM), and thermogravimetric analysis (TGA) with Fourier transform infrared spectroscopy (FTIR). IONP were between 5 and 10 nm in diameter as measured by electron microscopy, and hydrodynamic size of the PFH nanodroplets were 150 to 230 nm as measured by dynamic light scattering (DLS). Acoustic droplet vaporization of PFH nanodroplets (PFH-NDs) was induced using conversion pulses (100 cycle at 1.1 MHz and 50% duty cycle) provided by a focused ultrasound transducer, and formed microbubbles were imaged using a clinical ultrasound scanner. The acoustic pressure threshold needed for PFH-NDs vaporization decreased with increasing temperature and IONP content. PFH-NDs containing 5% w/v IONP converted to microbubbles at 42 °C at 2.18 MI, which is just above the exposure limits of 1.9 MI allowed by the FDA for clinical ultrasound scanners, whereas 10 and 15% emulsion vaporized at 1.87 and 1.24 MI, respectively. Furthermore, 5% IONP-loaded PFH-NDs injected intravenously into melanoma-bearing mice at a dose of 120 mg PFH/kg, converted into detectable microbubbles in vivo 5 h, but not shortly after injection, indicating that this technique detects NDs accumulated in tumors.
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http://dx.doi.org/10.1016/j.jconrel.2019.03.013DOI Listing
May 2019

Catalase-Containing Silica Particles as Ultrasound-Based Hydrogen Peroxide Sensors to Determine Infected From Noninfected Fluid Collections in Humans.

AJR Am J Roentgenol 2019 Jul 12;213(1):W9-W16. Epub 2019 Mar 12.

Department of Radiology, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd, Dallas, TX 75390-8514.

Hydrogen peroxide (HO) plays a key role in neutrophil oxidative defense against infection. Catalase-containing silica nanoshells are nanoparticles that generate O microbubbles imaged with ultrasound in the presence of elevated HO. We aimed to determine whether ultrasound-detectable O microbubbles produced by catalase-containing silica nanoshells can determine whether fluid collections drained from patients are infected. During this HIPAA-compliant, institutional review board-approved study, 52 human fluid samples were collected from clinically required image-guided percutaneous drainage procedures. Catalase-containing silica nanoshells were added to the fluid samples during imaging in real time using a Sequoia-512 15L8-S linear transducer (Siemens Healthcare). Production of detectable microbubbles was graded subjectively as negative (noninfected) or positive (infected) with low, moderate, or high confidence by a single observer blinded to all clinical data. The truth standard was microbiology laboratory culture results. Performance characteristics including ROC curves were calculated. Microbubble detection to distinguish infected from noninfected fluids was 84% sensitive and 72% specific and offered negative and positive predictive values of 89% and 64%, respectively. The AUC was 0.79. Six of nine false-positive samples were peritoneal fluid collections that were all collected from patients with decompensated cirrhosis. The presence of elevated HO indicated by microbubble formation in the presence of catalase-containing silica nanoshells is sensitive in distinguishing infected from noninfected fluids and offers a relatively high negative predictive value. False-positive cases may result from noninfectious oxidative stress. Catalase-containing silica nanoshells may constitute a novel point-of-care test performed at time of percutaneous drainage, potentially obviating placement of drains into otherwise sterile collections and minimizing risk of secondary infection or other complication.
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http://dx.doi.org/10.2214/AJR.18.20779DOI Listing
July 2019

Accomplishments and challenges in stem cell imaging in vivo.

Drug Discov Today 2019 02 17;24(2):492-504. Epub 2018 Oct 17.

Department of Radiology and Advanced Imaging Research Center, 5323 Harry Hines Blvd, UT Southwestern Medical Center, Dallas, TX 75390-8514, USA. Electronic address:

Stem cell therapies have demonstrated promising preclinical results, but very few applications have reached the clinic owing to safety and efficacy concerns. Translation would benefit greatly if stem cell survival, distribution and function could be assessed in vivo post-transplantation, particularly in patients. Advances in molecular imaging have led to extraordinary progress, with several strategies being deployed to understand the fate of stem cells in vivo using magnetic resonance, scintigraphy, PET, ultrasound and optical imaging. Here, we review the recent advances, challenges and future perspectives and opportunities in stem cell tracking and functional assessment, as well as the advantages and challenges of each imaging approach.
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http://dx.doi.org/10.1016/j.drudis.2018.10.007DOI Listing
February 2019

Hyposialylated IgG activates endothelial IgG receptor FcγRIIB to promote obesity-induced insulin resistance.

J Clin Invest 2018 01 27;128(1):309-322. Epub 2017 Nov 27.

Center for Pulmonary and Vascular Biology, Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, Texas, USA.

Type 2 diabetes mellitus (T2DM) is a common complication of obesity. Here, we have shown that activation of the IgG receptor FcγRIIB in endothelium by hyposialylated IgG plays an important role in obesity-induced insulin resistance. Despite becoming obese on a high-fat diet (HFD), mice lacking FcγRIIB globally or selectively in endothelium were protected from insulin resistance as a result of the preservation of insulin delivery to skeletal muscle and resulting maintenance of muscle glucose disposal. IgG transfer in IgG-deficient mice implicated IgG as the pathogenetic ligand for endothelial FcγRIIB in obesity-induced insulin resistance. Moreover, IgG transferred from patients with T2DM but not from metabolically healthy subjects caused insulin resistance in IgG-deficient mice via FcγRIIB, indicating that similar processes may be operative in T2DM in humans. Mechanistically, the activation of FcγRIIB by IgG from obese mice impaired endothelial cell insulin transcytosis in culture and in vivo. These effects were attributed to hyposialylation of the Fc glycan, and IgG from T2DM patients was also hyposialylated. In HFD-fed mice, supplementation with the sialic acid precursor N-acetyl-D-mannosamine restored IgG sialylation and preserved insulin sensitivity without affecting weight gain. Thus, IgG sialylation and endothelial FcγRIIB may represent promising therapeutic targets to sever the link between obesity and T2DM.
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http://dx.doi.org/10.1172/JCI89333DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5749535PMC
January 2018

Focal Liver Lesions: Computer-aided Diagnosis by Using Contrast-enhanced US Cine Recordings.

Radiology 2018 03 25;286(3):1062-1071. Epub 2017 Oct 25.

From the Department of Electrical and Computer Engineering (C.N.T.), Departments of Medicine and Radiology (Y.K.), Department of Radiology (M.E.), and Department of Chemistry and Biochemistry (A.C.K.), University of California, San Diego, La Jolla, Calif; Department of Radiology and Research Institute of Radiological Science, Severance Hospital, Yonsei University College of Medicine, Seoul, Korea (Y.T.O.); Department of Radiology, University of Alabama at Birmingham, Birmingham, Ala (M.L.R.); Southwoods Imaging, Youngstown, Ohio and Northeastern Ohio Medical University, Rootstown, Ohio (R.G.B.); and Department of Radiology, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd, Room D1.204, Dallas, TX 75390-8514 (R.F.M.).

Purpose To assess the performance of computer-aided diagnosis (CAD) systems and to determine the dominant ultrasonographic (US) features when classifying benign versus malignant focal liver lesions (FLLs) by using contrast material-enhanced US cine clips. Materials and Methods One hundred six US data sets in all subjects enrolled by three centers from a multicenter trial that included 54 malignant, 51 benign, and one indeterminate FLL were retrospectively analyzed. The 105 benign or malignant lesions were confirmed at histologic examination, contrast-enhanced computed tomography (CT), dynamic contrast-enhanced magnetic resonance (MR) imaging, and/or 6 or more months of clinical follow-up. Data sets included 3-minute cine clips that were automatically corrected for in-plane motion and automatically filtered out frames acquired off plane. B-mode and contrast-specific features were automatically extracted on a pixel-by-pixel basis and analyzed by using an artificial neural network (ANN) and a support vector machine (SVM). Areas under the receiver operating characteristic curve (AUCs) for CAD were compared with those for one experienced and one inexperienced blinded reader. A third observer graded cine quality to assess its effects on CAD performance. Results CAD, the inexperienced observer, and the experienced observer were able to analyze 95, 100, and 102 cine clips, respectively. The AUCs for the SVM, ANN, and experienced and inexperienced observers were 0.883 (95% confidence interval [CI]: 0.793, 0.940), 0.829 (95% CI: 0.724, 0.901), 0.843 (95% CI: 0.756, 0.903), and 0.702 (95% CI: 0.586, 0.782), respectively; only the difference between SVM and the inexperienced observer was statistically significant. Accuracy improved from 71.3% (67 of 94; 95% CI: 60.6%, 79.8%) to 87.7% (57 of 65; 95% CI: 78.5%, 93.8%) and from 80.9% (76 of 94; 95% CI: 72.3%, 88.3%) to 90.3% (65 of 72; 95% CI: 80.6%, 95.8%) when CAD was in agreement with the inexperienced reader and when it was in agreement with the experienced reader, respectively. B-mode heterogeneity and contrast material washout were the most discriminating features selected by CAD for all iterations. CAD selected time-based time-intensity curve (TIC) features 99.0% (207 of 209) of the time to classify FLLs, versus 1.0% (two of 209) of the time for intensity-based features. None of the 15 video-quality criteria had a statistically significant effect on CAD accuracy-all P values were greater than the Holm-Sidak α-level correction for multiple comparisons. Conclusion CAD systems classified benign and malignant FLLs with an accuracy similar to that of an expert reader. CAD improved the accuracy of both readers. Time-based features of TIC were more discriminating than intensity-based features. RSNA, 2017 Online supplemental material is available for this article.
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http://dx.doi.org/10.1148/radiol.2017170365DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5831265PMC
March 2018

Spatial Angular Compounding Technique for H-Scan Ultrasound Imaging.

Ultrasound Med Biol 2018 Jan 12;44(1):267-277. Epub 2017 Oct 12.

Department of Bioengineering, University of Texas at Dallas, Richardson, Texas, USA; Department of Radiology, University of Texas Southwestern Medical Center, Dallas, Texas, USA. Electronic address:

H-Scan is a new ultrasound imaging technique that relies on matching a model of pulse-echo formation to the mathematics of a class of Gaussian-weighted Hermite polynomials. This technique may be beneficial in the measurement of relative scatterer sizes and in cancer therapy, particularly for early response to drug treatment. Because current H-scan techniques use focused ultrasound data acquisitions, spatial resolution degrades away from the focal region and inherently affects relative scatterer size estimation. Although the resolution of ultrasound plane wave imaging can be inferior to that of traditional focused ultrasound approaches, the former exhibits a homogeneous spatial resolution throughout the image plane. The purpose of this study was to implement H-scan using plane wave imaging and investigate the impact of spatial angular compounding on H-scan image quality. Parallel convolution filters using two different Gaussian-weighted Hermite polynomials that describe ultrasound scattering events are applied to the radiofrequency data. The H-scan processing is done on each radiofrequency image plane before averaging to get the angular compounded image. The relative strength from each convolution is color-coded to represent relative scatterer size. Given results from a series of phantom materials, H-scan imaging with spatial angular compounding more accurately reflects the true scatterer size caused by reductions in the system point spread function and improved signal-to-noise ratio. Preliminary in vivo H-scan imaging of tumor-bearing animals suggests this modality may be useful for monitoring early response to chemotherapeutic treatment. Overall, H-scan imaging using ultrasound plane waves and spatial angular compounding is a promising approach for visualizing the relative size and distribution of acoustic scattering sources.
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http://dx.doi.org/10.1016/j.ultrasmedbio.2017.09.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5712267PMC
January 2018

Thrombin-Activatable Microbubbles as Potential Ultrasound Contrast Agents for the Detection of Acute Thrombosis.

ACS Appl Mater Interfaces 2017 Nov 20;9(43):37587-37596. Epub 2017 Oct 20.

Department of Radiology, Translational Research in Ultrasound Theranostics (TRUST) Program, University of Texas Southwestern Medical Center , 5323 Harry Hines Boulevard, Dallas, Texas 75390-8514, United States.

Acute deep vein thrombosis (DVT) is the formation of a blood clot in the deep veins of the body that can lead to fatal pulmonary embolism. Acute DVT is difficult to distinguish from chronic DVT by ultrasound (US), the imaging modality of choice, and is therefore treated aggressively with anticoagulants, which can lead to internal bleeding. Here we demonstrate that conjugating perfluorobutane-filled (PFB-filled) microbubbles (MBs) with thrombin-sensitive activatable cell-penetrating peptides (ACPPs) could lead to the development of contrast agents that detect acute thrombosis with US imaging. Successful conjugation of ACPP to PFB-filled MBs was confirmed by fluorescence microscopy and flow cytometry. Fluorescein-labeled ACPP was used to evaluate the efficiency of thrombin-triggered cleavage by measuring the mean fluorescence intensity of ACPP-labeled MBs (ACPP-MBs) before and after incubation at 37 °C with thrombin. Lastly, control MBs and ACPP-MBs were infused through a tube containing a clot, and US contrast enhancement was measured with or without the presence of a thrombin inhibitor after washing the clot with saline. With thrombin activity, 91.7 ± 14.2% of the signal was retained after ACPP-MB infusion and washing, whereas only 16.7 ± 4% of the signal was retained when infusing ACPP-MBs in the presence of hirudin, a potent thrombin inhibitor.
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http://dx.doi.org/10.1021/acsami.7b10592DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5691601PMC
November 2017

Toward optimization of in vivo super-resolution ultrasound imaging using size-selected microbubble contrast agents.

Med Phys 2017 Dec 27;44(12):6304-6313. Epub 2017 Oct 27.

Department of Bioengineering, University of Texas at Dallas, Richardson, TX, 75080, USA.

Purpose: Microvascular processes play key roles in many diseases including diabetes. Improved understanding of the microvascular changes involved in disease development could offer crucial insight into the relationship of these changes to disease pathogenesis. Super-resolution ultrasound (SR-US) imaging has showed the potential to visualize microvascular detail down to the capillary level (i.e., subwavelength resolution), but optimization is still necessary. The purpose of this study was to investigate in vivo SR-US imaging of skeletal muscle microvascularity using microbubble (MB) contrast agents of various size and concentration while evaluating different ultrasound (US) system level parameters such as imaging frame rate and image acquisition length.

Methods: An US system equipped with a linear array transducer was used in a harmonic imaging mode at low transmit power. C57BL/6J mice fed a normal diet were used in this study. An assortment of size-selected MB contrast agents (1-2 μm, 3-4 μm, and 5-8 μm in diameter) were slowly infused in the tail vein at various doses (1.25 × 10 , 2.5 × 10 , or 5 × 10  MBs). US image data were collected before MB injection and thereafter for 10 min at 30 frames per s (fps). The US transducer was fixed throughout and between each imaging period to help capture microvascular patterns along the same image plane. An adaptive SR-US image processing technique was implemented using custom Matlab software.

Results: Experimental findings illustrate the use of larger MB results in better SR-US images in terms of skeletal muscle microvascular detail. A dose of 2.5 × 10  MBs resulted in SR-US images with optimal spatial resolution. An US imaging rate of at least 20 fps and image acquisition length of at least 8 min also resulted in SR-US images with pronounced microvascular detail.

Conclusions: This study indicates that MB size and dose and US system imaging rate and data acquisition length have significant impact on the quality of in vivo SR-US images of skeletal muscle microvascularity.
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http://dx.doi.org/10.1002/mp.12606DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5734623PMC
December 2017

Extended Lifetime In Vivo Pulse Stimulated Ultrasound Imaging.

IEEE Trans Med Imaging 2018 01 17;37(1):222-229. Epub 2017 Aug 17.

An on-demand long-lived ultrasound contrast agent that can be activated with single pulse stimulated imaging (SPSI) has been developed using hard shell liquid perfluoropentane filled silica 500-nm nanoparticles for tumor ultrasound imaging. SPSI was tested on LnCAP prostate tumor models in mice; tumor localization was observed after intravenous (IV) injection of the contrast agent. Consistent with enhanced permeability and retention, the silica nanoparticles displayed an extended imaging lifetime of 3.3±1 days (mean±standard deviation). With added tumor specific folate functionalization, the useful lifetime was extended to 12 ± 2 days; in contrast to ligand-based tumor targeting, the effect of the ligands in this application is enhanced nanoparticle retention by the tumor. This paper demonstrates for the first time that IV injected functionalized silica contrast agents can be imaged with an in vivo lifetime ~500 times longer than current microbubble-based contrast agents. Such functionalized long-lived contrast agents may lead to new applications in tumor monitoring and therapy.
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http://dx.doi.org/10.1109/TMI.2017.2740784DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5868352PMC
January 2018

Polymer-Stabilized Perfluorobutane Nanodroplets for Ultrasound Imaging Agents.

J Am Chem Soc 2017 01 29;139(1):15-18. Epub 2016 Dec 29.

Materials Science & Engineering Program, ‡Department of Radiology, and §Department of Chemistry & Biochemistry, University of California-San Diego , La Jolla, California 92093, United States.

In this paper, we describe a method for the stabilization of low-boiling point (low-bp) perfluorocarbons (PFCs) at physiological temperatures by an amphiphilic triblock copolymer which can emulsify PFCs and be cross-linked. After UV-induced thiol-ene cross-linking, the core of the PFC emulsion remains in liquid form even at temperatures exceeding their boiling points. Critically, the formulation permits vaporization at rarefactional pressures relevant for clinical ultrasound.
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http://dx.doi.org/10.1021/jacs.6b08800DOI Listing
January 2017

Polymeric Gd-DOTA amphiphiles form spherical and fibril-shaped nanoparticle MRI contrast agents.

Chem Sci 2016 Jul 22;7(7):4230-4236. Epub 2016 Mar 22.

Department of Chemistry and Biochemistry , University of California , 9500 Gilman Dr., La Jolla , San Diego , CA 92093 , USA . Email: ; Email:

A Gd-coordinated polymerizable analogue of the MRI contrast agent Gd-DOTA was used to prepare amphiphilic block copolymers, with hydrophilic blocks composed entirely of the polymerized contrast agent. The resulting amphiphilic block copolymers assemble into nanoparticles (NPs) of spherical- or fibril-shape, each demonstrating enhanced relaxivity over Gd-DOTA. As an initial examination of their behavior , intraperitoneal (IP) injection of NPs into live mice was performed, showing long IP residence times, observed by MRI. Extended residence times for particles of well-defined morphology may represent a valuable design paradigm for treatment or diagnosis of peritoneal malignances.
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http://dx.doi.org/10.1039/c6sc00342gDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6013922PMC
July 2016

Staging of fibrosis in experimental non-alcoholic steatohepatitis by quantitative molecular imaging in rat models.

Nucl Med Biol 2016 Feb 2;43(2):179-87. Epub 2015 Dec 2.

UCSD In Vivo Cancer & Molecular Imaging Program, University of California, San Diego, La Jolla, CA; Department of Radiology, University of California, San Diego, La Jolla, CA; Moores UCSD Cancer Center, University of California, San Diego, La Jolla, CA; Department of Surgery, University of California, San Diego, La Jolla, CA. Electronic address:

Objectives: The aim of this study was to test the ability of hepatocyte-specific functional imaging to stage fibrosis in experimental rat models of liver fibrosis and progressive NASH. Using ROC analysis we tested the ability of a functional imaging metric to discriminate early (F1) from moderate (F2) fibrosis in the absence and presence of non-alcoholic steatohepatitis, which has not been achieved by any modality other than biopsy.

Methods: Galactosyl Human Serum Albumin (GSA) was radiolabeled with the positron-emitter, (68)Ga, and injected (i.v., 45-95 μCi, 1.5 pmol/g TBW) into 44 healthy, 19 DEN-, and 22 CDAA-treated male rats. Quantification of liver function was achieved by calculating T90, defined as the time for the liver to accumulate 90 percent of the [(68)Ga]GSA plateau value. All livers were excised immediately after imaging and prepared for a "blinded" histologic examination, which included fibrosis and fat content scores. Two sets of fibrosis scores were recorded for all of animals. The dominant fibrosis stage was recorded as the "Dominant Pattern" score and the "Maximum Pattern" score was assigned if a smaller distinct region with a higher fibrosis score was observed.

Results: Animals with Dominant Pattern F0-F1 liver fibrosis (D(-)=39) demonstrated significantly (P<0.0001) faster accumulation of [(68)Ga]GSA (2.40 ± 0.52 min) than those with moderate to advanced Dominant Pattern fibrosis F2 and F4 (D(+)=26) (3.48 ± 1.01 min). ROC analysis (F0-F1 vs F2-F4) produced an area under the binormal curve (AUC) of 0.867 ± 0.045. Twenty-seven of the 65 rats had small regions with higher fibrosis scores. Six of these Maximum Pattern scores reclassified the animals from D(-) to D(+). ROC analysis of F0-F1 versus F2-F4 rats without liver fat produced AUCs of 0.881 ± 0.053 for the Dominant Pattern Score and 0.944 ± 0.035 for the Maximum Pattern Score.

Conclusions: PET Functional Imaging of [(68)Ga]GSA accurately discriminates early from moderate experimental fibrosis independent of steatosis grade. If validated in human studies, molecular imaging may emerge as a potential alternative to invasive liver biopsy.
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http://dx.doi.org/10.1016/j.nucmedbio.2015.11.009DOI Listing
February 2016

Tumor Detection at 3 Tesla with an Activatable Cell Penetrating Peptide Dendrimer (ACPPD-Gd), a T1 Magnetic Resonance (MR) Molecular Imaging Agent.

PLoS One 2015 3;10(9):e0137104. Epub 2015 Sep 3.

Department of Otolaryngology-Head and Neck Surgery University of California, San Diego, San Diego, CA, United States of America.

Purpose: The ability to detect small malignant lesions with magnetic resonance imaging (MRI) is limited by inadequate accumulations of Gd with standard chelate agents. To date, no T1-targeted agents have proven superiority to Gd chelates in their ability to detect small tumors at clinically relevant field strengths. Activatable cell-penetrating peptides and their Gd-loaded dendrimeric form (ACPPD-Gd) have been shown to selectively accumulate in tumors. In this study we compared the performance of ACPPD-Gd vs. untargeted Gd chelates to detect small tumors in rodent models using a clinical 3T-MR system.

Materials And Methods: This study was approved by the Institutional-Animal Care-and-Use Committee. 2 of 4 inguinal breast fat pads of 16 albino-C57BL/6 mice were inoculated with tumor Py8119 cells and the other 2 with saline at random. MRI at 3T was performed at 4, 9, and 14 days after inoculation on 8 mice 24-hours after injection of 0.036mmol Gd/kg (ACPPD-Gd), and before and 2-3 minutes after 0.1 mmol/kg gadobutrol on the other 8 mice. T1-weighted (T1w) tumor signal normalized to muscle, was compared among the non-contrast, gadobutrol, and ACPPD-Gd groups using ANOVA. Experienced and trainee readers blinded to experimental conditions assessed for the presence of tumor in each of the 4 breast regions. Receiver operator characteristic (ROC) curves and area-under-curve (AUC) values were constructed and analyzed.

Results: Tumors ≥1mm3 were iso-intense to muscle without contrast on T1w sequences. They enhanced diffusely and homogeneously by 57±20% (p<0.001) 24 hours after ACPPD-Gd and by 25±13% (p<0.001) immediately after gadobutrol. The nearly 2-fold difference was similar for small tumors (1-5mm3) (45±19% vs. 19±18%, p = 0.03). ACPPD-Gd tended to improve tumor detection by an experienced reader (AUC 0.98 vs 0.91) and significantly more for a trainee (0.93 vs. 0.82, p = 0.02) compared to gadobutrol. This improvement was more pronounced when obvious tumors (>5mm3) were removed from the ROC analysis for both the experienced observer (0.96 vs. 0.86) and more so for the trainee (0.86 vs. 0.69, p = 0.04).

Conclusion: ACPPD-Gd enhances MMP-expressing tumors of any size at 3T 24 hours after administration, improving their detection by blinded observers when compared to non-contrast and contrast groups given commercial Gd-chelates and imaged during the equilibrium phase.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0137104PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4559389PMC
May 2016

Therapeutic Enzyme-Responsive Nanoparticles for Targeted Delivery and Accumulation in Tumors.

Adv Mater 2015 Aug 14;27(31):4611-5. Epub 2015 Jul 14.

Department of Chemistry and Biochemistry, University of California San Diego, La Jolla, CA, 92093, USA.

An enzyme-responsive, paclitaxel-loaded nanoparticle is described and assessed in vivo in a human fibrosarcoma murine xenograft. This work represents a proof-of-concept study demonstrating the utility of enzyme-responsive nanoscale drug carriers capable of targeted accumulation and retention in tumor tissue in response to overexpressed endogenous enzymes.
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http://dx.doi.org/10.1002/adma.201501803DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4699560PMC
August 2015

Quantitative analysis of vascular heterogeneity in breast lesions using contrast-enhanced 3-D harmonic and subharmonic ultrasound imaging.

IEEE Trans Ultrason Ferroelectr Freq Control 2015 Mar;62(3):502-10

Ability to visualize breast lesion vascularity and quantify the vascular heterogeneity using contrast-enhanced 3-D harmonic (HI) and subharmonic (SHI) ultrasound imaging was investigated in a clinical population. Patients (n = 134) identified with breast lesions on mammography were scanned using power Doppler imaging, contrast-enhanced 3-D HI, and 3-D SHI on a modified Logiq 9 scanner (GE Healthcare). A region of interest corresponding to ultrasound contrast agent flow was identified in 4D View (GE Medical Systems) and mapped to raw slice data to generate a map of time-intensity curves for the lesion volume. Time points corresponding to baseline, peak intensity, and washout of ultrasound contrast agent were identified and used to generate and compare vascular heterogeneity plots for malignant and benign lesions. Vascularity was observed with power Doppler imaging in 84 lesions (63 benign and 21 malignant). The 3-D HI showed flow in 8 lesions (5 benign and 3 malignant), whereas 3-D SHI visualized flow in 68 lesions (49 benign and 19 malignant). Analysis of vascular heterogeneity in the 3-D SHI volumes found benign lesions having a significant difference in vascularity between central and peripheral sections (1.71 ± 0.96 vs. 1.13 ± 0.79 dB, p < 0.001, respectively), whereas malignant lesions showed no difference (1.66 ± 1.39 vs. 1.24 ± 1.14 dB, p = 0.24), indicative of more vascular coverage. These preliminary results suggest quantitative evaluation of vascular heterogeneity in breast lesions using contrast-enhanced 3-D SHI is feasible and able to detect variations in vascularity between central and peripheral sections for benign and malignant lesions.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4607037PMC
http://dx.doi.org/10.1109/tuffc.2014.006886DOI Listing
March 2015

In Vivo Transfection and Detection of Gene Expression of Stem Cells Preloaded with DNA-carrying Microbubbles.

Radiology 2015 Aug 26;276(2):518-25. Epub 2015 Mar 26.

From the Department of Radiology, University of California-San Diego, 200 W Arbor Dr, San Diego, CA 92103.

Purpose: To determine whether (a) stem cells loaded with DNA-carrying microbubbles (MBs) can be transfected in vivo, (b) the cells remain alive to express the gene, and (c) gene expression is sufficiently robust to be detected in vivo.

Materials And Methods: The study was approved by the Institutional Animal Care and Use Committee. Cationic MBs were prepared, characterized, and loaded with pLuciferase green fluorescent protein (GFP) plasmid. Loading was confirmed with SYBR Gold staining (Life Technologies, Carlsbad, Calif). C17.2 cells were loaded with the DNA-carrying MBs. Two hundred thousand cells suspended in 20 μL phosphate-buffered saline were mixed with 200 μL Matrigel (BD Biosciences, San Jose, Calif) and injected in both flanks of eight nude mice. One of the Matrigel (BD Biosciences) injections contained 50 000 cells pretransfected in vitro by using lipofectamine as a positive control. Nine flanks were exposed to 2.25-MHz ultrasonic pulses at 50% duty cycle for 1 minute at 1 W/cm(2) (n = 3) or 2 W/cm(2) (n = 6), and six flanks served as the negative control. Two days later, bioluminescent images were acquired in each mouse every 3 minutes for 1 hour after the intraperitoneal injection of d-luciferin (Perkin Elmer, Waltham, Mass). Differences between groups were assessed by using the nonparametric Kruskal-Wallis test with Wilcoxon rank sum tests for follow-up comparisons. Mice were then killed, plugs were explanted, and alternate sections were stained with hematoxylin-eosin or stained for GFP expression.

Results: Mean DNA-loaded MB diameter ± standard deviation was 2.87 μm ± 1.69 with the DNA associated with the MB shell. C17.2 cells were associated with 2-4 MBs each, and more than 90% were viable. Peak background subtracted bioluminescent signal was fourfold higher when cells were exposed to 2 W/cm(2) pulses as compared with 1 W/cm(2) pulses (P = .02) and negative controls (P = .002). Histologic examination showed cells within the Matrigel (BD Biosciences) with robust GFP expression only after 2 W/cm(2) ultrasound exposure and lipofectamine transfection.

Conclusion: Stem cells loaded with DNA-carrying MBs can be transfected in vivo with ultrasonic pulses and remain alive to demonstrate robust gene expression.
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http://dx.doi.org/10.1148/radiol.15141380DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4521611PMC
August 2015

MRI-Derived Restriction Spectrum Imaging Cellularity Index is Associated with High Grade Prostate Cancer on Radical Prostatectomy Specimens.

Front Oncol 2015 17;5:30. Epub 2015 Feb 17.

Department of Radiology, University of California San Diego School of Medicine , San Diego, CA , USA.

Purpose: We evaluate a novel magnetic resonance imaging (MRI) technique to improve detection of aggressive prostate cancer (PCa).

Materials And Methods: We performed a retrospective analysis of pre-surgical prostate MRI scans using an advanced diffusion-weighted imaging technique called restriction spectrum imaging (RSI), which can be presented as a normalized z-score statistic. Scans were acquired prior to radical prostatectomy. Prostatectomy specimens were processed using whole-mount sectioning and regions of interest (ROIs) were drawn around individual PCa tumors. Corresponding ROIs were drawn on the MRI imaging and paired with ROIs in regions with no pathology. RSI z-score and conventional apparent diffusion coefficient (ADC) values were recorded for each ROI. Paired t-test, ANOVA, and logistic regression analyses were performed.

Results: We evaluated 28 patients with 64 ROIs (28 benign and 36 PCa). The mean difference in RSI z-score (PCa ROI-Benign ROI) was 2.17 (SE = 0.11; p < 0.001) and in ADC was 551 mm(2)/s (SE = 80 mm(2)/s; paired t-test, p < 0.001). The differences in the means among all groups (benign, primary Gleason 3, and primary Gleason 4) was significant for both RSI z-score (F 3,64 = 97.7, p < 0.001) and ADC (F 3,64 = 13.9, p < 0.001). A t-test was performed on only PCa tumor ROIs (n = 36) to determine PCa aggressiveness (Gleason 3 vs. Gleason 4) revealing that RSI z-score was still significant (p = 0.03), whereas, ADC values were no longer significant (p = 0.08). In multivariable analysis adjusting for age and race, RSI z-score was associated with PCa aggressiveness (OR 10.3, 95% CI: 1.4-78.0, p = 0.02) while ADC trended to significance (p = 0.07).

Conclusion: The RSI-derived normalized cellularity index is associated with aggressive PCa as determined by pathologic Gleason scores. Further utilization of RSI techniques may serve to enhance standardized reporting systems for PCa in the future.
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http://dx.doi.org/10.3389/fonc.2015.00030DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4330697PMC
March 2015

Stimulus-responsive ultrasound contrast agents for clinical imaging: motivations, demonstrations, and future directions.

Wiley Interdiscip Rev Nanomed Nanobiotechnol 2015 Jan-Feb;7(1):111-23. Epub 2014 Sep 6.

Department of Chemical and Biological Engineering, University of Colorado Boulder, Boulder, CO, USA.

Microbubble ultrasound contrast agents allow imaging of the vasculature with excellent resolution and signal-to-noise ratios. Contrast in microbubbles derives from their interaction with an ultrasound wave to generate signal at harmonic frequencies of the stimulating pulse; subtracting the elastic echo caused by the surrounding tissue can enhance the specificity of these harmonic signals significantly. The nonlinear acoustic emission is caused by pressure-driven microbubble size fluctuations, which in both theoretical descriptions and empirical measurements was found to depend on the mechanical properties of the shell that encapsulates the microbubble as well as stabilizes it against the surrounding aqueous environment. Thus biochemically induced switching between a rigid 'off' state and a flexible 'on' state provides a mechanism for sensing chemical markers for disease. In our research, we coupled DNA oligonucleotides to a stabilizing lipid monolayer to modulate stiffness of the shell and thereby induce stimulus-responsive behavior. In initial proof-of-principle studies, it was found that signal modulation came primarily from DNA crosslinks preventing the microbubble size oscillations rather than merely damping the signal. Next, these microbubbles were redesigned to include an aptamer sequence in the crosslinking strand, which not only allowed the sensing of the clotting enzyme thrombin but also provided a general strategy for sensing other soluble biomarkers in the bloodstream. Finally, the thrombin-sensitive microbubbles were validated in a rabbit model, presenting the first example of an ultrasound contrast agent that could differentiate between active and inactive clots for the diagnosis of deep venous thrombosis.
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http://dx.doi.org/10.1002/wnan.1285DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4268373PMC
August 2015

Hollow iron-silica nanoshells for enhanced high intensity focused ultrasound.

J Surg Res 2014 Aug 10;190(2):391-8. Epub 2014 May 10.

Moores Cancer Center, University of California, San Diego; Department of Surgery, University of California, San Diego. Electronic address:

Background: High intensity-focused ultrasound (HIFU) is an alterative ablative technique currently being investigated for local treatment of breast cancer and fibroadenomas. Current HIFU therapies require concurrent magnetic resonance imaging monitoring. Biodegradable 500 nm perfluoropentane-filled iron-silica nanoshells have been synthesized as a sensitizing agent for HIFU therapies, which aid both mechanical and thermal ablation of tissues. In low duty cycle high-intensity applications, rapid tissue damage occurs from mechanical rather than thermal effects, which can be monitored closely by ultrasound obviating the need for concurrent magnetic resonance imaging.

Materials And Methods: Iron-silica nanoshells were synthesized by a sol-gel method on polystyrene templates and calcined to yield hollow nanoshells. The nanoshells were filled with perfluoropentane and injected directly into excised human breast tumor, and intravenously (IV) into healthy rabbits and Py8119 tumor-bearing athymic nude mice. HIFU was applied at 1.1 MHz and 3.5 MPa at a 2% duty cycle to achieve mechanical ablation.

Results: Ex vivo in excised rabbit livers, the time to visually observable damage with HIFU was 20 s without nanoshells and only 2 s with nanoshells administered IV before sacrifice. Nanoshells administered IV into nude mice with xenograft tumors were activated in vivo by HIFU 24 h after administration. In this xenograft model, applied HIFU resulted in a 13.6 ± 6.1 mm(3) bubble cloud with the IV injected particles and no bubble cloud without particles.

Conclusions: Iron-silica nanoshells can reduce the power and time to perform HIFU ablative therapy and can be monitored by ultrasound during low duty cycle operation.
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http://dx.doi.org/10.1016/j.jss.2014.05.009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4141695PMC
August 2014

2-tier in-plane motion correction and out-of-plane motion filtering for contrast-enhanced ultrasound.

Invest Radiol 2014 Nov;49(11):707-19

From the *Department of Electrical and Computer Engineering, University of California, San Diego, La Jolla; †University of Texas MD Anderson Cancer Center, Houston; ‡MRI Institute, Department of Radiology, University of California, San Diego, Medical Center; §Moores Cancer Center, University of California, San Diego, La Jolla; ∥Departments of Medicine and Radiology, University of California, San Diego, Medical Center; and ¶Department of Chemistry and Biochemistry, University of California, San Diego, La Jolla.

Objectives: Contrast-enhanced ultrasound (CEUS) cines of focal liver lesions (FLLs) can be quantitatively analyzed to measure tumor perfusion on a pixel-by-pixel basis for diagnostic indication. However, CEUS cines acquired freehand and during free breathing cause nonuniform in-plane and out-of-plane motion from frame to frame. These motions create fluctuations in the time-intensity curves (TICs), reducing the accuracy of quantitative measurements. Out-of-plane motion cannot be corrected by image registration in 2-dimensional CEUS and degrades the quality of in-plane motion correction (IPMC). A 2-tier IPMC strategy and adaptive out-of-plane motion filter (OPMF) are proposed to provide a stable correction of nonuniform motion to reduce the impact of motion on quantitative analyses.

Materials And Methods: A total of 22 cines of FLLs were imaged with dual B-mode and contrast specific imaging to acquire a 3-minute TIC. B-mode images were analyzed for motion, and the motion correction was applied to both B-mode and contrast images. For IPMC, the main reference frame was automatically selected for each cine, and subreference frames were selected in each respiratory cycle and sequentially registered toward the main reference frame. All other frames were sequentially registered toward the local subreference frame. Four OPMFs were developed and tested: subsample normalized correlation (NC), subsample sum of absolute differences, mean frame NC, and histogram. The frames that were most dissimilar to the OPMF reference frame using 1 of the 4 above criteria in each respiratory cycle were adaptively removed by thresholding against the low-pass filter of the similarity curve. Out-of-plane motion filter was quantitatively evaluated by an out-of-plane motion metric (OPMM) that measured normalized variance in the high-pass filtered TIC within the tumor region-of-interest with low OPMM being the goal. Results for IPMC and OPMF were qualitatively evaluated by 2 blinded observers who ranked the motion in the cines before and after various combinations of motion correction steps.

Results: Quantitative measurements showed that 2-tier IPMC and OPMF improved imaging stability. With IPMC, the NC B-mode metric increased from 0.504 ± 0.149 to 0.585 ± 0.145 over all cines (P < 0.001). Two-tier IPMC also produced better fits on the contrast-specific TIC than industry standard IPMC techniques did (P < 0.02). In-plane motion correction and OPMF were shown to improve goodness of fit for pixel-by-pixel analysis (P < 0.001). Out-of-plane motion filter reduced variance in the contrast-specific signal as shown by a median decrease of 49.8% in the OPMM. Two-tier IPMC and OPMF were also shown to qualitatively reduce motion. Observers consistently ranked cines with IPMC higher than the same cine before IPMC (P < 0.001) as well as ranked cines with OPMF higher than when they were uncorrected.

Conclusion: The 2-tier sequential IPMC and adaptive OPMF significantly reduced motion in 3-minute CEUS cines of FLLs, thereby overcoming the challenges of drift and irregular breathing motion in long cines. The 2-tier IPMC strategy provided stable motion correction tolerant of out-of-plane motion throughout the cine by sequentially registering subreference frames that bypassed the motion cycles, thereby overcoming the lack of a nearly stationary reference point in long cines. Out-of-plane motion filter reduced apparent motion by adaptively removing frames imaged off-plane from the automatically selected OPMF reference frame, thereby tolerating nonuniform breathing motion. Selection of the best OPMF by minimizing OPMM effectively reduced motion under a wide variety of motion patterns applicable to clinical CEUS. These semiautomated processes only required user input for region-of-interest selection and can improve the accuracy of quantitative perfusion measurements.
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http://dx.doi.org/10.1097/RLI.0000000000000074DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4184933PMC
November 2014

In vivo ultrasound visualization of non-occlusive blood clots with thrombin-sensitive contrast agents.

Biomaterials 2013 Dec 10;34(37):9559-65. Epub 2013 Sep 10.

Department of Nanoengineering, University of California, San Diego, 9500 Gilman Dr. #0448, La Jolla, CA 92093-0448, USA.

The use of microbubbles as ultrasound contrast agents is one of the primary methods to diagnose deep venous thrombosis. However, current microbubble imaging strategies require either a clot sufficiently large to produce a circulation filling defect or a clot with sufficient vascularization to allow for targeted accumulation of contrast agents. Previously, we reported the design of a microbubble formulation that modulated its ability to generate ultrasound contrast from interaction with thrombin through incorporation of aptamer-containing DNA crosslinks in the encapsulating shell, enabling the measurement of a local chemical environment by changes in acoustic activity. However, this contrast agent lacked sufficient stability and lifetime in blood to be used as a diagnostic tool. Here we describe a PEG-stabilized, thrombin-activated microbubble (PSTA-MB) with sufficient stability to be used in vivo in circulation with no change in biomarker sensitivity. In the presence of actively clotting blood, PSTA-MBs showed a 5-fold increase in acoustic activity. Specificity for the presence of thrombin and stability under constant shear flow were demonstrated in a home-built in vitro model. Finally, PSTA-MBs were able to detect the presence of an active clot within the vena cava of a rabbit sufficiently small as to not be visible by current non-specific contrast agents. By activating in non-occlusive environments, these contrast agents will be able to detect clots not diagnosable by current contrast agents.
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http://dx.doi.org/10.1016/j.biomaterials.2013.08.040DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3788116PMC
December 2013

Toward in vivo detection of hydrogen peroxide with ultrasound molecular imaging.

Biomaterials 2013 Nov 16;34(35):8918-24. Epub 2013 Aug 16.

Department of Radiology, University of California, 410 Dickinson St., San Diego, CA 92103, United States.

We present a new class of ultrasound molecular imaging agents that extend upon the design of micromotors that are designed to move through fluids by catalyzing hydrogen peroxide (H₂O₂) and propelling forward by escaping oxygen microbubbles. Micromotor converters require 62 mm of H₂O₂ to move - 1000-fold higher than is expected in vivo. Here, we aim to prove that ultrasound can detect the expelled microbubbles, to determine the minimum H₂O₂ concentration needed for microbubble detection, explore alternate designs to detect the H₂O₂ produced by activated neutrophils and perform preliminary in vivo testing. Oxygen microbubbles were detected by ultrasound at 2.5 mm H₂O₂. Best results were achieved with a 400-500 nm spherical design with alternating surface coatings of catalase and PSS over a silica core. The lowest detection limit of 10-100 μm was achieved when assays were done in plasma. Using this design, we detected the H₂O₂ produced by freshly isolated PMA-activated neutrophils allowing their distinction from naïve neutrophils. Finally, we were also able to show that direct injection of these nanospheres into an abscess in vivo enhanced ultrasound signal only when they contained catalase, and only when injected into an abscess, likely because of the elevated levels of H₂O₂ produced by inflammatory mediators.
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http://dx.doi.org/10.1016/j.biomaterials.2013.06.055DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3794895PMC
November 2013

Color Doppler ultrasound and gamma imaging of intratumorally injected 500 nm iron-silica nanoshells.

ACS Nano 2013 Jul 1;7(7):6367-77. Epub 2013 Jul 1.

Materials Science and Engineering Program, University of California, San Diego, 9500 Gilman Drive, #0358 La Jolla, California 92093, USA.

Perfluoropentane gas filled iron-silica nanoshells have been developed as stationary ultrasound contrast agents for marking tumors to guide surgical resection. It is critical to establish their long-term imaging efficacy, as well as biodistribution. This work shows that 500 nm Fe-SiO2 nanoshells can be imaged by color Doppler ultrasound over the course of 10 days in Py8119 tumor bearing mice. The 500 nm nonbiodegradable SiO2 and biodegradable Fe-SiO2 nanoshells were functionalized with diethylenetriamine pentaacetic acid (DTPA) ligand and radiolabeled with (111)In(3+) for biodistribution studies in nu/nu mice. The majority of radioactivity was detected in the liver and kidneys following intravenous (IV) administration of nanoshells to healthy animals. By contrast, after nanoshells were injected intratumorally, most of the radioactivity remained at the injection site; however, some nanoshells escaped into circulation and were distributed similarly as those given intravenously. For intratumoral delivery of nanoshells and IV delivery to healthy animals, little difference was seen between the biodistribution of SiO2 and biodegradable Fe-SiO2 nanoshells. However, when nanoshells were administered IV to tumor bearing mice, a significant increase was observed in liver accumulation of SiO2 nanoshells relative to biodegradable Fe-SiO2 nanoshells. Both SiO2 and Fe-SiO2 nanoshells accumulate passively in proportion to tumor mass, during intravenous delivery of nanoshells. This is the first report of the biodistribution following intratumoral injection of any biodegradable silica particle, as well as the first report demonstrating the utility of DTPA-(111)In labeling for studying silica nanoparticle biodistributions.
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http://dx.doi.org/10.1021/nn402507dDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3777724PMC
July 2013

Integrated processing of contrast pulse sequencing ultrasound imaging for enhanced active contrast of hollow gas filled silica nanoshells and microshells.

J Vac Sci Technol B Nanotechnol Microelectron 2012 Mar 23;30(2):2C104. Epub 2012 Mar 23.

University of California, San Diego, Department of Electrical and Computer Engineering, 9500 Gilman Drive Mail Code 0407, La Jolla, California 92093.

In recent years, there have been increasing developments in the field of contrast-enhanced ultrasound both in the creation of new contrast agents and in imaging modalities. These contrast agents have been employed to study tumor vasculature in order to improve cancer detection and diagnosis. An in vivo study is presented of ultrasound imaging of gas filled hollow silica microshells and nanoshells which have been delivered intraperitoneally to an IGROV-1 tumor bearing mouse. In contrast to microbubbles, this formulation of microshells provided strong ultrasound imaging signals by shell disruption and release of gas. Imaging of the microshells in an animal model was facilitated by novel image processing. Although the particle signal could be identified by eye under live imaging, high background obfuscated the particle signal in still images and near the borders of the tumor with live images. Image processing techniques were developed that employed the transient nature of the particle signal to selectively filter out the background signal. By applying image registration, high-pass, median, threshold, and motion filtering, a short video clip of the particle signal was compressed into a single image, thereby resolving the silica shells within the tumor. © 2012 American Vacuum Society.
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http://dx.doi.org/10.1116/1.3694835DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3463889PMC
March 2012

Automating tumor classification with pixel-by-pixel contrast-enhanced ultrasound perfusion kinetics.

J Vac Sci Technol B Nanotechnol Microelectron 2012 Mar 22;30(2):2C103. Epub 2012 Mar 22.

University of California, San Diego, Department of Electrical and Computer Engineering, 9500 Gilman Drive Mail Code 0407, La Jolla, California 92093.

Contrast-enhanced ultrasound (CEUS) enables highly specific time-resolved imaging of vasculature by intravenous injection of ∼2 μm gas filled microbubbles. To develop a quantitative automated diagnosis of breast tumors with CEUS, breast tumors were induced in rats by administration of N-ethyl-N-nitrosourea. A bolus injection of microbubbles was administered and CEUS videos of each tumor were acquired for at least 3 min. The time-intensity curve of each pixel within a region of interest (ROI) was analyzed to measure kinetic parameters associated with the wash-in, peak enhancement, and wash-out phases of microbubble bolus injections since it was expected that the aberrant vascularity of malignant tumors will result in faster and more diverse perfusion kinetics versus those of benign lesions. Parameters were classified using linear discriminant analysis to differentiate between benign and malignant tumors and improve diagnostic accuracy. Preliminary results with a small dataset (10 tumors, 19 videos) show 100% accuracy with fivefold cross-validation testing using as few as two choice variables for training and validation. Several of the parameters which provided the best differentiation between malignant and benign tumors employed comparative analysis of all the pixels in the ROI including enhancement coverage, fractional enhancement coverage times, and the standard deviation of the envelope curve difference normalized to the mean of the peak frame. Analysis of combinations of five variables demonstrated that pixel-by-pixel analysis produced the most robust information for tumor diagnostics and achieved 5 times greater separation of benign and malignant cases than ROI-based analysis.
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http://dx.doi.org/10.1116/1.3692962DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3463888PMC
March 2012

Neural progenitor cells labeling with microbubble contrast agent for ultrasound imaging in vivo.

Biomaterials 2013 Jul 8;34(21):4926-35. Epub 2013 Apr 8.

Department of Radiology, University of California, San Diego, La Jolla, San Diego, CA 92093, USA.

Tracking neuroprogenitor cells (NPCs) that are used to target tumors, infarction or inflammation, is paramount for cell-based therapy. We employed ultrasound imaging that can detect a single microbubble because it can distinguish its unique signal from those of surrounding tissues. NPCs efficiently internalized positively charged microbubbles allowing a clinical ultrasound system to detect a single cell at 7 MHz. When injected intravenously, labeled NPCs traversed the lungs to be imaged in the left ventricle and the liver where they accumulated. Internalized microbubbles were not only less sensitive to destruction by ultrasound, but remained visible in vivo for days as compared to minutes when given free. The extended longevity provides ample time to allow cells to reach their intended target. We were also able to transfect NPCs in vitro when microbubbles were preloaded with GFP plasmid only when cells were insonated. Transfection efficiency and cell viability were both greater than 90%.
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http://dx.doi.org/10.1016/j.biomaterials.2013.03.020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3742341PMC
July 2013