Jacob D. Dove

High contrast three-dimensional photoacoustic imaging through scattering media by localized optical fluence enhancement

We demonstrate enhanced three-dimensional photoacoustic imaging behind a scattering material by increasing the fluence in the ultrasound transducer focus. We enhance the optical intensity using wavefront shaping before the scatterer. The photoacoustic signal induced by an object placed behind the scattering medium serves as feedback to optimize the wavefront, enabling one order of magnitude enhancement of the photoacoustic amplitude. Using the enhanced optical intensity, we scan the object in two-dimensions before post-processing of the data to reconstruct the image. The temporal profile of the photoacoustic signal provides the information used to reconstruct the third dimension.

Super-resolution photoacoustic imaging through a scattering wall.

The use of wavefront shaping to compensate for scattering has brought a renewed interest as a potential solution to imaging through scattering walls. A key to the practicality of any imaging through scattering technique is the capability to focus light without direct access behind the scattering wall. Here we address this problem using photoacoustic feedback for wavefront optimization. By combining the spatially non-uniform sensitivity of the ultrasound transducer to the generated photoacoustic waves with an evolutionary competition among optical modes, the speckle field develops a single, high intensity focus significantly smaller than the acoustic focus used for feedback. Notably, this method is not limited by the size of the absorber to form a sub-acoustic optical focus. We demonstrate imaging behind a scattering medium using two different imaging modalities with up to ten times improvement in signal-to-noise ratio and five to six times sub-acoustic resolution.

Enhanced photoacoustic response with plasmonic nanoparticle-templated microbubbles

We report a versatile approach for the generation of novel nanoparticle-templated microbubbles capable of simultaneous contrast enhancement in both ultrasound and photoacoustic imaging. Fabrication of the dual modality contrast agent relies on specific binding of avidinated gold nanoparticles to a biotinylated microbubble shell, providing stoichiometric control over nanoparticle surface density and optical absorption, while still retaining the essential acoustic properties of the microbubble. Nanoparticle laden microbubbles were shown to be exceptionally efficient photoacoustic agents, with an enhanced photoacoustic response compared to free nanoparticles or unconjugated mixtures of nanoparticles and microbubbles. Upon destruction of the microbubble gas core, a marked reduction in photoacoustic signal amplitude was observed, demonstrating the importance of placing the nanoparticles onto a compressible gas core in achieving the photoacoustic enhancement. We further demonstrate dual modality contrast enhanced photoacoustic and ultrasound imaging in a flow-through tissue phantom. Our results show that nanoparticle-templated microbubbles are promising for imaging, biosensing and theranostic applications.

Engineering optically triggered droplets for photoacoustic imaging and therapy

Liquid perfluorocarbon (PFC) droplets incorporating optical absorbers can be vaporized through photothermal heating using a pulsed laser source. Here, we report on the effect of droplet core material on the optical fluence required to produce droplet vaporization. We fabricate gold nanoparticle templated microbubbles filled with various PFC gases (C3F8, C4F10, and C5F12) and apply pressure to condense them into droplets. The core material is found to have a strong effect on the threshold optical fluence, with lower boiling point droplets allowing for vaporization at lower laser fluence. The impact of droplet size on vaporization threshold is discussed, as well as a proposed mechanism for the relatively broad distribution of vaporization thresholds observed within a droplet population with the same core material. We propose that the control of optical vaporization threshold enabled by engineering the droplet core may find application in contrast enhanced photoacoustic imaging and therapy.

Single-Particle Optical Sizing of Microbubbles

Single-particle optical sizing techniques are being used to determine the size distributions of microbubble ultrasound contrast agents and to study the dynamics of individual microbubbles during ultrasound stimulation. The goal of this study was to compare experimental light obscuration and scattering measurements of microbubble size distributions with predictions from generalized Lorenz-Mie scattering theory (GLMT). First, we illustrate that a mono-modal size distribution can be misrepresented by single-particle light obscuration measurements as multi-modal peaks because of non-linearities in the extinction cross section-versus-diameter curve. Next, polymer bead standards are measured to provide conversion factors between GLMT calculations and experimental flow cytometry scatter plots. GLMT calculations with these conversion factors accurately predict the characteristic Lissajous-like serpentine scattering plot measured by flow cytometry for microbubbles. We conclude that GLMT calculations can be combined with optical forward and side scatter measurements to accurately determine microbubble size.

Optically induced resonance of nanoparticle-loaded microbubbles

We report on the optical excitation and detection of resonant microbubble oscillations. Optically absorbing nanoparticles were attached to the shell of a lipid-encapsulated microbubble, allowing for optical pulsing to photothermally drive the microbubble into resonance. A modified optical microscope was used to track the bubble wall radius as a function of time using light scattering. The microbubble response from a nanosecond laser pulse was measured, and the eigenfrequency and vibrational amplitude were determined and compared to theory. The ability to optically drive microbubble oscillations may have applications in basic studies of bubble dynamics and biomedical imaging and therapy.

Single Microbubble Measurements of Lipid Monolayer Viscoelastic Properties for Small-Amplitude Oscillations

Lipid monolayer rheology plays an important role in a variety of interfacial phenomena, the physics of biological membranes, and the dynamic response of acoustic bubbles and drops. We show here measurements of lipid monolayer elasticity and viscosity for very small strains at megahertz frequency. Individual plasmonic microbubbles of 2-6 μm radius were photothermally activated with a short laser pulse, and the subsequent nanometer-scale radial oscillations during ring-down were monitored by optical scatter. This method provided average dynamic response measurements of single microbubbles. Each microbubble was modeled as an underdamped linear oscillator to determine the damping ratio and eigenfrequency, and thus the lipid monolayer viscosity and elasticity. Our nonisothermal measurement technique revealed viscoelastic trends for different lipid shell compositions. We observed a significant increase in surface elasticity with the lipid acyl chain length for 16 to 20 carbons, and this effect was explained by an intermolecular forces model that accounts for the lipid composition, packing, and hydration. The surface viscosity was found to be equivalent for these lipid shells. We also observed an anomalous decrease in elasticity and an increase in viscosity when increasing the acyl chain length from 20 to 22 carbons. These results illustrate the use of a novel nondestructive optical technique to investigate lipid monolayer rheology in new regimes of frequency and strain, possibly elucidating the phase behavior, as well as how the dynamic response of a microbubble can be tuned by the lipid intermolecular forces.

Microbubble lipid shell elasticity: Simulation and measurement

We show here that the phospholipid composition of a microbubble shell can significantly affect microbubble dynamics by changing shell viscoelastic properties. We fabricate gold nanoparticle templated microbubbles with varying lipid shells (DPPC, DSPC, DAPC and DBPC). Individual microbubbles undergo nanometer scale radial oscillations that are photothermally activated using a short laser pulse and monitored using forward light scattering. Shell elasticity and viscosity were determined for each microbubble by finding the eigenfrequency and damping ratio when modelling the microbubble as an underdamped, linear oscillator. Elasticity was found to increase with longer lipid acyl chain length from 16 to 20 carbons, and modeled by considering the intermolecular forces. Viscosity, on the other hand, was not found to change significantly for these shells. Interestingly, we observed an increase in elasticity and decrease in viscosity for lipid shells of 22 carbons. These results illustrate key interrelationships between microbubble composition, structure and dynamic behavior that may be used to facilitate their rational design for contrast-enhanced ultrasound and other applications.

Three-dimensional photoacoustic imaging through scattering media

We demonstrate three-dimensional photoacoustic imaging behind a scattering material by scanning an absorbing object through an optimized focus. We optimize the wavefront to create an optical focus using the photoacoustic effect as feedback.