Accomplishments and challenges in stem cell imaging in vivo.

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

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

OBJECTIVE. Hydrogen peroxide (H2O2) plays a key role in neutrophil oxidative defense against infection. Catalase-containing silica nanoshells are nanoparticles that generate O2 microbubbles imaged with ultrasound in the presence of elevated H2O2. We aimed to determine whether ultrasound-detectable O2 microbubbles produced by catalase-containing silica nanoshells can determine whether fluid collections drained from patients are infected. SUBJECTS AND METHODS. 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. RESULTS. 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. CONCLUSION. The presence of elevated H2O2 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

Toward in vivo detection of hydrogen peroxide with ultrasound molecular imaging

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 (H_2O_2) and propelling forward by escaping oxygen microbubbles. Micromotor converters require 62 mm of H_2O_2 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 H_2O_2 concentration needed for microbubble detection, explore alternate designs to detect the H_2O_2 produced by activated neutrophils and perform preliminary in vivo testing. Oxygen microbubbles were detected by ultrasound at 2.5 mm H_2O_2. 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 H_2O_2 produced by inflammatory mediators

Characterization of indeterminate breast lesions on B-mode ultrasound using automated machine learning models

Purpose: While mammography has excellent sensitivity for the detection of breast lesions, its specificity is limited. Adjunct screening with ultrasound may partially alleviate this issue, but also increases false positives, resulting in unnecessary biopsies. This study investigated the use of Google AutoML Vision (Mountain View, CA), a commercially available machine learning service, to both identify and characterize indeterminate breast lesions on ultrasound. Methods: B-mode images from 253 independent cases of indeterminate breast lesions scheduled for core biopsy were used for model creation and validation. The performances of two sub-models from AutoML Vision, the image classification model and object detection model were evaluated, while also investigating training strategies to enhance model performances. Pathology from the patient’s biopsy were used as a reference standard. Results: The image classification models trained under different conditions demonstrated areas under the precision recall curve (AUC) ranging from 0.85 to 0.96 during internal validation. Once deployed, the model with highest internal performance demonstrated a sensitivity of 100% (95% confidence interval (CI) of 73.5-100%), specificity of 83.3% (CI=51.6-97.9%), positive predictive value (PPV) of 85.7% (CI=62.9-95.5%), and negative predictive value (NPV) of 100% (CI non-evaluable) in an independent dataset. The object detection model demonstrated lower performance internally during development (AUC=0.67) and during prediction in the independent dataset (sensitivity=75.0% (CI=42.8-94.5), specificity=80.0% (CI=51.9-95.7), PPV=75.0% (CI=50.8-90.0), NPV=80.0% (CI=59.3-91.7%)), but was able to demonstrate the location of the lesion within the image. Conclusions: Two models appear to be useful tools for identifying and classifying suspicious areas on B-mode images of indeterminate breast lesions

Feature-interaction detection based on feature-based specifications

A Gd3+-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 in vivo, 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

The Effect of Inhaled Gases on Ultrasound Contrast Agent Longevity In Vivo

Purpose: The purpose of this study is to investigate the effect of the inhaled gas used alongside isoflurane in the anesthetization of small animals on the time-intensity curves (TICs) acquired from ultrasound contrast agents—microbubbles. Procedures: TICs were recorded over the common iliac vein of 12 mice receiving Definity®. Animals were anesthetized with isoflurane, the ventilator was driven by medical air (MA), then in random order, the driving gas was changed for 3 min to: MA (control); pure oxygen (O2); O2+ perfluorohexane (PFH:O2); or O2+octafluoropropane (OFP:O2), the perfluorocarbon (PFC) in Definity, followed by a return to MA 3 min later. Results: The mean slope of signal decay was −0.47, −1.05, −1.16, and −1.42 video-intensity units/s for MA, OFP:O2, PFH:O2, and O2, respectively; MA had the slowest decay (pG0.0001). Both PFC mixtures had slower signal decay than O2, but only OFP:O2 was significant (pG0.01). When MA was used immediately following dosing, slope gradually decreased (p=0.032) and was two times slower by the fourth injection (p=0.012). Conclusions: Microbubble kinetics are closely associated with the driving gas for inhaled anesthesia. MA has the least effect and should be used when inhaled anesthesia is used. Furthermore, when animals are given multiple injections in the same session, microbubbles last longer with subsequent injections

Accomplishments and challenges in stem cell imaging in vivo.

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