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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