Microbubble Acoustic Resonance Interference Spectroscopy

CSIRO MANUFACTURING

Steven Spencer and Andrea Sosa-Pintos

ESTS’16 – 7-9 December 2016

Medical Microbubble Acoustic Resonance Interference Spectroscopy

Bubbles and Acoustics

• Acoustic waves are generated and radiated as pressure waves in liquid media by pulsations ofthe surfaces of gaseous bubbles.

• Bubbles can oscillate passively ( e.g. due to formation, motion, coalescence or bursting) or actively due to an acoustic source.

• Gas bubbles of ~m - cm sizes (and nanobubbles?) are known to be powerful sources and sinks of ultrasonics / acoustics in liquids.

Medical Microbubbles• Medical imaging - Contrast Enhanced UltraSound (CEUS)

• Ultrasound contrast agent (UCA) – O(1-10) m-sized lipid or polymer coated bubbles for enhancement of ultrasound scattering

Medical Microbubble Acoustic Resonance Interference Spectroscopy

Monodisperse coated microbubbles (Boston University Mechanical Engineering)

Blood vessels + dirn of flow (~10 m capillaries) of mouse ear (Christensen-Jeffries et al, 2015)

Untargetted (in clinical use) - echocardiography (organ edge delineation), radiology

(lesion characterisation), blood volume and perfusion

Targetted (pre-clinical development) - thrombosis, inflammation, tumours

• Therapeutic payload delivery (pre-clinical research) Loading of therapeutic compound (antibodies, drugs or genes) into nanoparticles selectively attached to microbubble shell

Targetted delivery of payload to areas of interest in body

•

Medical Microbubble Acoustic Resonance Interference Spectroscopy

Schematic of a therapeutic microbubble: 1-2 m bubble & 100-200 nm liposomes(Peyman et al., 2012)

Medical Microbubble Acoustic Resonance Interference Spectroscopy

Acoustic Methods for Bubble Detection and Characterisation

• Geometric scattering (imaging of intensity & Doppler)

• Sound speed and attenuation (gas fraction, number density & bubble size distribution)

• Resonance harmonic excitation (bsd)

• Combination frequency methods (bsd & number density)

Acoustic Resonance Interference Spectroscopy

• Bubble active acoustic spectral features:low intensity source + bubble response [O(1 kPa), kHz – MHz]

• Goal - Development of new methods for characterising (mass-loaded) gaseous bubble and liquid medium properties

• Theory - Bubble active acoustic response to mild acoustic excitation for robust estimation of bubble, liquid and gaseous medium properties based on spectral features

• Experiments – Active acoustic estimation of key properties of a variety of surface mass-loaded (micro/macro)bubbles and supporting liquids (spectroscopic work - ‘pre-imaging’)

Medical Microbubble Acoustic Resonance Interference Spectroscopy

Theoretical Modelling• Single bubble in ‘liquid-like’ medium

i. Elastic encapsulating layer (medical microbubbles)ii. Surface mass loading (therapeutic/industrial payload)

• Response to acoustic / ultrasonic source –

i. Spherical oscillations of bubble wall - ‘Rayleigh-Plesset’-like ODE ii. Acoustic wave propagation in liquid – Euler eqn derived ODE

Bubble Acoustic Resonance Interference Spectroscopy (ARIS)

Medical Microbubble Acoustic Resonance Interference Spectroscopy

Perturbation analysis

(low power acoustic insonation)

Medical Microbubble Acoustic Resonance Interference Spectroscopy

Acoustic response

Spencer, S.J. (2015). “Mathematical models for the

acoustic response of a solids-loaded encapsulated

bubble”. J. Acoust. Soc. Am., 137 (5), 2623-2641.

• Bubble resonance + source / bubble interference

acoustic spectral features

bubble and liquid medium properties

Resonance

Destructive

interference

•Sensitivity Limits- Bubble radius O(m)- Surface mass loading O(pg)

How Does It Work?

Transmission configuration

Candidates for ARIS Estimation

Medical Microbubble Acoustic Resonance Interference Spectroscopy

Range of Estimator Validity

[~0.01 pg large poxvirus, ~0.3 pg small cyanobacteria, ~1 g small mineral particle in flotation ]

Bubble location

Bubble Radius ~m - mm

Bubble Mass Loading ~pg – 100 mg

What Do We See in the Lab?

Medical Microbubble Acoustic Resonance Interference Spectroscopy

•Schematic of equipment setup for transmission mode active acoustic

measurements of particle-laden oscillations of large [O(1 mm) radius] solid particle

loaded bubbles (Zhang, Spencer & Coghill, 2012).

Power

AmplifierSignal

Generator

Syringe

Pump

Light

Amplifier Data Logger

Acoustic

Transducer

Bubble

Hydrophone

Particles

Macrobubble Acoustic Monitoring

Medical Microbubble Acoustic Resonance Interference Spectroscopy

Active Acoustic Response

Single Bubble

Swept-frequency insonation

Acoustic Features

Raw Power Spectrum Bubble Response Spectrum

• Bubble size and attached solids mass loading from passive and active bubble AE monitoring

estimate of single bubble attached solids mass loading from AE resonance frequency and bubble size

Medical Microbubble Acoustic Resonance Interference Spectroscopy

Attached solids mass loading with squared ratio of AE resonance frequency

Image of single bubble in tankwith attached solids

Medical Microbubble Acoustic Resonance Interference Spectroscopy

Stream Swarm

Estimation of Macrobubble Properties –Monitoring Industrial Liquid/Solid Processing

Medical Microbubble Acoustic Resonance Interference Spectroscopy

• 1 mm radius + attached mineral

particles (mg mass)

Estimation of Microbubble Properties -Monitoring Targetted Therapeutics Delivery

Medical Microbubble Acoustic Resonance Interference Spectroscopy

• 1.0 m radius microbubble + attached mass

loading (Definity encapsulating layer)

(ARIS model results)

Optison – GE Healthcare

Definity – Lantheus

SonoVue – Bracco

1st harmonic

ARIS Signature of Commercially Available UCAs

Medical Microbubble Acoustic Resonance Interference Spectroscopy

(ARIS model results)

Estimation of Liquid Properties – Monitoring Rheology of Biomedical Liquids• Unloaded microbubble with known surface elastic properties.

• Liquid medium viscosity, (density and bubble equilibrium radius) as a function of acoustic feature frequencies (fmax,fmin,fmax2).

Medical Microbubble Acoustic Resonance Interference Spectroscopy

Haemorheology – local / global cardiovascular risk due to disease /

prosthetic devices

(ARIS model results)

Medical Microbubble Acoustic Resonance Interference Spectroscopy

• Medical UCA properties (size & shell elastic)

• Surface activated microbubble properties - Therapeutics progressive delivery - Trace analyte attachment

• Liquid medium rheological analysis (viscosity, pressure, density)

• (Coated) nanobubbles – monitoring for new medical, environmental and industrial applications?

Fine Bubble Monitoring Applications

Conclusion

• Acoustic Resonance Interference Spectroscopy is a promising new method for active acoustic monitoring of microbubble (and macrobubble) properties + liquid rheological properties

• Highly sensitive to bubble size and surface mass loading

• Sensitive to liquid viscosity

• Broad suite of possible medical, industrial and environmental monitoring applications

Medical Microbubble Acoustic Resonance Interference Spectroscopy

Acknowledgements

• Dr Wen Zhang, formerly CSIRO OCE Postdoctoral Fellow

• Dr Peter Coghill, Research Scientist, CSIRO Mineral Resources

• Mr Sam Magin, formerly Honours Student, UNSW

• Dr Pavel Yaroshchyk, formerly Research Scientist, CSIRO Mineral Resources

• Ms Catherine Jackson, Project Scientist, CSIRO Mineral Resources

Medical Microbubble Acoustic Resonance Interference Spectroscopy

MANUFACTURING

Thank you

Steven SpencerPrincipal Research Scientist