Medical Microbubbles and Industrial Flotation

CSIRO MANUFACTURING

Dr Steven Spencer Principal Research Scientist 7th International Symposium of Fine Bubble Technology - 25th July 2016

Medical Microbubbles and Industrial Flotation

Bubbles and Acoustics

• Acoustic waves are generated and radiated in

liquid media by pulsations of the 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 ~µm - cm sizes (and nanobubbles?) are known to be powerful sources and sinks of ultrasonics / acoustics in liquids.

Bubbles in Industrial Processes

Medical Microbubbles and Industrial Flotation

Flotation cells in a mineral concentrator

Froth Flotation – selectively separating hydrophobic from hydrophilic materials O(10-103) µm-sized surface loaded bubbles.

Schematic of flotation cell

Applications – mineral separation, wastewater treatment (DAF), paper recycling

Medical Microbubbles and Industrial Flotation

Photobioreactor for microalgae cultivation (University of Alicante, Spain)

•Bubble Column Reactors – columns for mixing or reaction of bubbles of gas within a supporting liquid (& solid catalyst). Applications – chemical, biochemical, metallurgical and petrochemical industries (chlorination, phosgenation, oxidation, hydrogenation, polymerisation , alkylation, Fischer-Tropsch synthesis)

Schematic of bubble column

Acoustic Monitoring of Flotation

Medical Microbubbles and Industrial Flotation

Jameson Cell

Jameson Cell passive AE monitoring array

Medical Microbubbles • Medical imaging (clinically approved in many countries)

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

21st European Symposium on Ultrasound Contrast Imaging (21-22 January 2016, Rotterdam, The Netherlands)

Monodisperse coated microbubbles (Boston University Mechanical Engineering)

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

Applications: General cardiovascular & echocardiography, lesion characterisation and organ delineation. Untargeted / targeted (molecular imaging)

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

•

21st European Symposium on Ultrasound Contrast Imaging (21-22 January 2016, Rotterdam, The Netherlands)

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

Medical Microbubbles and Industrial Flotation

Acoustic Methods for Bubble Detection and Characterisation

• Geometric scattering

• Sound speed and attenuation

• Resonance harmonic excitation

• Combination frequency methods

Acoustic Resonance Interference Spectroscopy

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

• Goal - Development of new methods for characterising bubble properties applicable to encapsulated microbubbles and (free surface loaded) macrobubbles

• Theory - solutions of bubble active acoustic response problem that permit robust estimation of bubble, liquid and gaseous medium properties based on spectral features

• Experiments – Demonstrate laboratory techniques for active acoustic

estimation of key properties of variety of surface mass-loaded (micro)bubbles and supporting liquid

Medical Microbubbles and Industrial Flotation

Modelling Approach • Mathematical models based on acoustic physics →

Single bubble oscillation (Rayleigh-Plesset) + acoustic wave propgn

Perturbation analysis (low intensity activation)

Bubble Acoustic Resonance Interference Spectroscopy (ARIS) Active acoustic spectral feature frequencies to estimate properties of A) Encapsulated and surface mass-loaded gaseous bubbles B) ‘Liquid-like’ supporting medium

Medical Microbubbles and Industrial Flotation

Medical Microbubbles and Industrial Flotation

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(µm) - Surface mass loading O(pg)

How Does It Work?

⇒ ⇒

Candidates for ARIS Estimation

Medical Microbubbles and Industrial Flotation

Range of Estimator Validity

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

Source location

What Do We See in the Lab?

Medical Microbubbles and Industrial Flotation

•Schematic of equipment setup for transmission mode active acoustic measurements of particle-laden oscillations of large [O(1 mm)] solid particle loaded bubbles (Zhang, Spencer & Coghill, 2012).

Power Amplifier

Signal Generator

Syringe Pump

Light

Amplifier Data Logger Acoustic Transducer

Bubble

Hydrophone

Particles

Medical Microbubbles and Industrial Flotation

• Active acoustic response (mm size air macrobubbles)

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 Microbubbles and Industrial Flotation

Attached solids mass loading with squared ratio of AE resonance frequency

Image of single bubble in tank with attached solids

Medical Microbubbles and Industrial Flotation

Stream Swarm

Model Estimation of Macrobubble Properties

Medical Microbubbles and Industrial Flotation

• 1 mm radius + attached mineral particles

Model Estimation of Microbubble Properties

Medical Microbubbles and Industrial Flotation

• 2.5 µm radius + attached mass loading (Sonovue encapsulating layer)

Optison – GE Healthcare Definity – Lantheus SonoVue – Bracco

1st harmonic

Modelling Results (Commercially Available UCAs)

Medical Microbubbles and Industrial Flotation

• Medical UCA properties (size & shell properties) • Surface activated medical microbubble properties

(detection of therapeutics delivery and trace analyte attachment)

• Flotation cell process performance (solids attachment and species separation)

• Bubble column reactor performance (flow regime, phase mass transfer, catalyst content)

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

• Detection of (coated) nanobubble properties?

Some Possible Monitoring Applications

Conclusion

• Active acoustics (ultrasonics) is a widely used method for detection and characterisation of bubbles

• Acoustic Resonance Interference Spectroscopy is a promising new method for active acoustic monitoring of microbubble and macrobubble properties

• Highly sensitive to bubble size and surface mass loading

• Broad suite of possible medical, industrial and environmental monitoring applications Medical Microbubbles and Industrial Flotation

Acknowledgements

• Dr Wen Zhang, formerly CSIRO OCE Postdoctoral Fellow • Dr Peter Coghill, Research Scientist, CSIRO Mineral Resources • Sam Magin, formerly Honours Student, UNSW • Dr Pavel Yaroshchyk, formerly Research Scientist, CSIRO Mineral

Resources • Catherine Jackson, Project Scientist, CSIRO Mineral Resources • Andrea Sosa Pintos, Engineer, CSIRO Manufacturing

Medical Microbubbles and Industrial Flotation

MANUFACTURING

Thank you

Steven Spencer Principal Research Scientist