Connor Puett

Phase-shift perfluorocarbon agents enhance high intensity focused ultrasound thermal delivery with reduced near-field heating

Ultrasound contrast agents are known to enhance high intensity focused ultrasound (HIFU) ablation, but these perfluorocarbon microbubbles are limited to the vasculature, have a short half-life in vivo, and may result in unintended heating away from the target site. Herein, a nano-sized (100-300 nm), dual perfluorocarbon (decafluorobutane/dodecafluoropentane) droplet that is stable, is sufficiently small to extravasate, and is convertible to micron-sized bubbles upon acoustic activation was investigated. Microbubbles and nanodroplets were incorporated into tissue-mimicking acrylamide-albumin phantoms. Microbubbles or nanodroplets at 0.1 × 10(6) per cm(3) resulted in mean lesion volumes of 80.4 ± 33.1 mm(3) and 52.8 ± 14.2 mm(3) (mean ± s.e.), respectively, after 20 s of continuous 1 MHz HIFU at a peak negative pressure of 4 MPa, compared to a lesion volume of 1.0 ± 0.8 mm(3) in agent-free control phantoms. Magnetic resonance thermometry mapping during HIFU confirmed undesired surface heating in phantoms containing microbubbles, whereas heating occurred at the acoustic focus of phantoms containing the nanodroplets. Maximal change in temperature at the target site was enhanced by 16.9% and 37.0% by microbubbles and nanodroplets, respectively. This perfluorocarbon nanodroplet has the potential to reduce the time to ablate tumors by one-third during focused ultrasound surgery while also safely enhancing thermal deposition at the target site.

Pulse sequences for uniform perfluorocarbon droplet vaporization and ultrasound imaging.

Phase-change contrast agents (PCCAs) consist of liquid perfluorocarbon droplets that can be vaporized into gas-filled microbubbles by pulsed ultrasound waves at diagnostic pressures and frequencies. These activatable contrast agents provide benefits of longer circulating times and smaller sizes relative to conventional microbubble contrast agents. However, optimizing ultrasound-induced activation of these agents requires coordinated pulse sequences not found on current clinical systems, in order to both initiate droplet vaporization and image the resulting microbubble population. Specifically, the activation process must provide a spatially uniform distribution of microbubbles and needs to occur quickly enough to image the vaporized agents before they migrate out of the imaging field of view. The development and evaluation of protocols for PCCA-enhanced ultrasound imaging using a commercial array transducer are described. The developed pulse sequences consist of three states: (1) initial imaging at sub-activation pressures, (2) activating droplets within a selected region of interest, and (3) imaging the resulting microbubbles. Bubble clouds produced by the vaporization of decafluorobutane and octafluoropropane droplets were characterized as a function of focused pulse parameters and acoustic field location. Pulse sequences were designed to manipulate the geometries of discrete microbubble clouds using electronic steering, and cloud spacing was tailored to build a uniform vaporization field. The complete pulse sequence was demonstrated in the water bath and then in vivo in a rodent kidney. The resulting contrast provided a significant increase (>15 dB) in signal intensity.

In vitro parameter optimization for spatial control of focused ultrasound ablation when using low boiling point phase-change nanoemulsions

BackgroundPhase-shift nanoemulsions (PSNEs) provide cavitation sites when the perfluorocarbon (PFC) nanodroplets (ND) are vaporized to microbubbles by acoustic energy. Their presence lowers the power required to ablate tissue by high-intensity focused ultrasound (HIFU), potentially making it a safer option for a broader range of treatment sites. However, spatial control over the ablation region can be problematic when cavitation is used to enhance heating. This study explored relationships between vaporization, ablation, and the PSNE concentration in vitro to optimize the acoustic intensity and insonation time required for spatially controlled ablation enhancement using a PSNE that included a volatile PFC component.MethodsHIFU (continuous wave at 1 MHz; insonation times of 5, 10, 15, and 20 s; cool-down times of 2, 4, and 6 s; peak negative pressures of 2, 3, and 4 MPa) was applied to albumin-acrylamide gels containing PFC agents (1:1 mix of volatile decafluorobutane and more stable dodecafluoropentane at 105 to 108 PFC ND per milliliter) or agent-free controls. Vaporization fields (microbubble clouds) were imaged by conventional ultrasound, and ablation lesions were measured directly by calipers. Controlled ablation was defined as the production of ‘cigar’-shaped lesions corresponding with the acoustic focal zone. This control was considered to be lost when ablation occurred in prefocal vaporization fields having a predominantly ‘tadpole’ or oblong shape.ResultsChanges in the vaporization field shape and location occurred on a continuum with increasing PSNE concentration and acoustic intensity. Working with the maximum concentration-intensity combinations resulting in controlled ablation demonstrated a dose-responsive relationship between insonation time and volumes of both the vaporization fields (approximately 20 to 240 mm3) and the ablation lesions (1 to 135 mm3) within them.ConclusionsHIFU ablation was enhanced by this PSNE and could be achieved using intensities ≤650 W/cm2. Although the ablation lesions were located within much larger microbubble clouds, optimum insonation times and intensities could be selected to achieve an ablation lesion of desired size and location for a given PSNE concentration. This demonstration of controllable enhancement using a PSNE that contained a volatile PFC component is another step toward developing phase-shift nanotechnology as a potential clinical tool to improve HIFU.

Dual perfluorocarbon nanodroplets enhance high intensity focused ultrasound heating and extend therapeutic window in vivo

Perfluorocarbon microbubbles are known to enhance high intensity focused ultrasound (HIFU) ablation by cavitation. However, they can result in superficial skin heating, minimizing their clinical translation. Perfluorocarbon nanodroplets activate only at the higher pressures present at the acoustic focus. We hypothesized that a mixed perfluorocarbon nanodroplet formulation would minimize surface heating while still enhancing ablation. Tissue-mimicking phantoms containing microbubbles or nanodroplets were sonicated (1 MHz, 15 W, 60 s) to assess heating and lesion formation in vitro. Microbubbles or nanodroplets were injected into rats (n = 3) and HIFU (1 MHz, 15 W, 15 s) was focused into each liver while under MRI guidance. Temperature throughout the liver was tracked by MR thermometry. In vitro, microbubbles caused excess surface heating during HIFU, whereas nanodroplets did not. In vivo, microbubbles typically circulate for less than 15 min. In comparison, the nanodroplets remained viable in circulation f...

An update on carbon nanotube-enabled X-ray sources for biomedical imaging

A new imaging technology has emerged that uses carbon nanotubes (CNT) as the electron emitter (cathode) for the X-ray tube. Since the performance of the CNT cathode is controlled by simple voltage manipulation, CNT-enabled X-ray sources are ideal for the repetitive imaging steps needed to capture three-dimensional information. As such, they have allowed the development of a gated micro-computed tomography (CT) scanner for small animal research as well as stationary tomosynthesis, an experimental technology for large field-of-view human imaging. The small animal CT can acquire images at specific points in the respiratory and cardiac cycles. Longitudinal imaging therefore becomes possible and has been applied to many research questions, ranging from tumor response to the noninvasive assessment of cardiac output. Digital tomosynthesis (DT) is a low-dose and low-cost human imaging tool that captures some depth information. Known as three-dimensional mammography, DT is now used clinically for breast imaging. However, the resolution of currently-approved DT is limited by the need to swing the X-ray source through space to collect a series of projection views. An array of fixed and distributed CNT-enabled sources provides the solution and has been used to construct stationary DT devices for breast, lung, and dental imaging. To date, over 100 patients have been imaged on Institutional Review Board-approved study protocols. Early experience is promising, showing an excellent conspicuity of soft-tissue features, while also highlighting technical and post-acquisition processing limitations that are guiding continued research and development. Additionally, CNT-enabled sources are being tested in miniature X-ray tubes that are capable of generating adequate photon energies and tube currents for clinical imaging. Although there are many potential applications for these small field-of-view devices, initial experience has been with an X-ray source that can be inserted into the mouth for dental imaging. Conceived less than 20 years ago, CNT-enabled X-ray sources are now being manufactured on a commercial scale and are powering both research tools and experimental human imaging devices. WIREs Nanomed Nanobiotechnol 2018, 10:e1475. doi: 10.1002/wnan.1475 This article is categorized under: Diagnostic Tools > Diagnostic Nanodevices Diagnostic Tools > In Vivo Nanodiagnostics and Imaging.

Contrast enhanced imaging with a stationary digital breast tomosynthesis system

Digital breast tomosynthesis (DBT) captures some depth information and thereby improves the conspicuity of breast lesions, compared to standard mammography. Using contrast during DBT may also help distinguish malignant from benign sites. However, adequate visualization of the low iodine signal requires a subtraction step to remove background signal and increase lesion contrast. Additionally, attention to factors that limit contrast, including scatter, noise, and artifact, are important during the image acquisition and post-acquisition processing steps. Stationary DBT (sDBT) is an emerging technology that offers a higher spatial and temporal resolution than conventional DBT. This phantom-based study explored contrast-enhanced sDBT (CE sDBT) across a range of clinically-appropriate iodine concentrations, lesion sizes, and breast thicknesses. The protocol included an effective scatter correction method and an iterative reconstruction technique that is unique to the sDBT system. The study demonstrated the ability of this CE sDBT system to collect projection images adequate for both temporal subtraction (TS) and dual-energy subtraction (DES). Additionally, the reconstruction approach preserved the improved contrast-to-noise ratio (CNR) achieved in the subtraction step. Finally, scatter correction increased the iodine signal and CNR of iodine-containing regions in projection views and reconstructed image slices during both TS and DES. These findings support the ongoing study of sDBT as a potentially useful tool for contrast-enhanced breast imaging and also highlight the significant effect that scatter has on image quality during DBT.

Stationary digital intraoral tomosynthesis: Demonstrating the clinical potential of the first-generation system

Stationary intraoral tomosynthesis (sIOT) is an experimental imaging approach using a fixed array of carbon nanotubeenabled x-ray sources to produce a series of projections from which three-dimensional information can be reconstructed and displayed. Customized to the dental workspace, the first-generation sIOT tube is compact, easy-to-operate, and designed to interface with standard digital intraoral detectors. The purpose of this work was to explore the utility of the sIOT device across a range of dental pathologies and thereby identify limitations potentially amenable to correction through post-acquisition processing. Phantoms, extracted human teeth, and cadaveric specimens containing caries, fractures, and dilacerated roots, often associated with amalgam restorations, were imaged using tube settings that match the kVp and mA used in conventional clinical 2D intraoral imaging. An iterative reconstruction approach generated a stack of image slices through which the reader scrolls to appreciate depth relationships. Initial experience demonstrated an improved ability to visualize occlusal caries, interproximal caries, crown and root fractures, and root dilacerations when compared to 2D imaging. However, artifacts around amalgam restorations and metal implants proved problematic, leading to the incorporation of an artifact reduction step in the post-acquisition processing chain. These findings support the continued study of sIOT as a viable limited-angle tomography tool for dental applications and provide a foundation for the ongoing development of image processing steps to maximize the diagnostic utility of the displayed images.

Initial clinical evaluation of gated stationary digital chest tomosynthesis

High resolution imaging of the chest is dependent on a breath hold maintained throughout the imaging time. However, pediatric and comatose patients are unable to follow respiration commands. Gated tomosynthesis could offer a lower dose, high in-plane resolution imaging modality, but current systems are unable to prospectively gate in a reasonable scan time. In contrast, a carbon nanotube (CNT) based linear x-ray source array offers both the angular span and precise control necessary to generate x-ray projections for gated tomosynthesis. The goal of this study was to explore the first clinical use of the CNT linear x-ray source array for gated clinical chest imaging. Eighteen pediatric cystic fibrosis patients were recruited for this study, with 13 usable image sets. The s-GDCT system consists of a CNT linear x-ray source array coupled with a digital detector. A respiration signal derived from a respiratory belt served as a gating signal with sources fired sequentially when the imaging window and maximum inspiration window coincided. Images were reconstructed and reviewed for motion blur and ability to identify major anatomical structures. Image quality was highly dependent on quality of the respiration gating signal, and a correlation was found between qualitative image quality and height of the respiration peak. We demonstrate the first prospectively gated evaluation of the stationary digital chest tomosynthesis patients in pediatric patients. Though further refinements in projection selection and respiratory gating approaches are necessary, this study demonstrates the potential utility of this low dose imaging approach.

Enhanced in vivo and in vitro high intensity focused ultrasound ablation via phase-shift nanodroplets compared to microbubbles

Both pefluorocarbon microbubbles and nanodroplets have been investigated as enhancers of high intensity focused ultrasound (HIFU) thermal ablation, however microbubbles often lead to surface or skin lesions. We have designed and investigated a dual-perfluorocarbon (PFC) nanodroplet which has the benefits of sufficiently small size to extravasate from tumors, enhanced stability at body temperature, and sufficiently low acoustic threshold for vaporization. In vitro, microbubbles enhanced thermal depostion at the target site by 21%, but were found to cause surface heating up to 60.2±2.2°C. Nanodroplets caused no more surface heating (10.1±1.1°C) than the temperature rise observed in agent-free controls (9.8±0.8°C), and enhanced heating at the target by 51%. Circulation time of the nanodroplets was investigated in vivo. HIFU (1 MHz, 4.06 MPa, CW, 15 seconds) was applied to rat livers (n=3) up to 95 minutes after nanodroplet injection, and any thermal enhancement was detected simultaneously by MR thermometry. Temperature rises of up to 55 degrees above body temperature were observed out to 95 minutes. HIFU applied to control livers without nanodroplets induced only a 22°C maximal temperature rise. These results suggest that the nanodroplets are sufficiently stable to enhance HIFU ablation in vivo for at least 1.5 hours and could reduce focused ultrasound surgical procedure times by as much as 5 fold by more quickly ablating a larger region of tissue, without compromising safety.