Medical Microbubbles and. Industrial Flotation

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1 Medical Microbubbles and Dr Steven Spencer Principal Research Scientist CSIRO MANUFACTURING Industrial Flotation 7 th International Symposium of Fine Bubble Technology - 25 th July 2016

2 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.

3 Bubbles in Industrial Processes Froth Flotation selectively separating hydrophobic from hydrophilic materials O( ) µm-sized surface loaded bubbles. Applications mineral separation, wastewater treatment (DAF), paper recycling Flotation cells in a mineral concentrator Schematic of flotation cell

4 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) Photobioreactor for microalgae cultivation (University of Alicante, Spain) Schematic of bubble column

5 Acoustic Monitoring of Flotation Jameson Cell Jameson Cell passive AE monitoring array

6 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 Applications: General cardiovascular & echocardiography, lesion characterisation and organ delineation. Untargeted / targeted (molecular imaging) Monodisperse coated microbubbles (Boston University Mechanical Engineering) Blood vessels + dirn of flow (~10 µm capillaries) of mouse ear (Christensen-Jeffries et al, 2015) 21st European Symposium on Ultrasound Contrast Imaging (21-22 January 2016, Rotterdam, The Netherlands)

7 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 Schematic of a therapeutic microbubble: 1-2 µm bubble & nm liposomes (Peyman et al., 2012) 21st European Symposium on Ultrasound Contrast Imaging (21-22 January 2016, Rotterdam, The Netherlands)

8 Acoustic Methods for Bubble Detection and Characterisation Geometric scattering Sound speed and attenuation Resonance harmonic excitation Combination frequency methods

9 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

10 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

11 How Does It Work? Bubble resonance + source / bubble interference acoustic spectral features bubble and liquid medium properties Resonance Acoustic response Destructive interference Spencer, S.J. (2015). Mathematical models for the acoustic response of a solids-loaded encapsulated bubble. J. Acoust. Soc. Am., 137 (5), Sensitivity Limits - Bubble radius O(µm) - Surface mass loading O(pg)

12 Candidates for ARIS Estimation Source location Range of Estimator Validity [~0.01 pg large poxvirus, ~0.3 pg small cyanobacteria, ~1 µg small mineral particle in flotation ]

13 What Do We See in the Lab? Syringe Pump Power Amplifier Signal Generator Acoustic Transducer Light Amplifier Particles Hydrophone Bubble Data Logger 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).

14 Active acoustic response (mm size air macrobubbles) Single Bubble Raw Power Spectrum Bubble Response Spectrum Acoustic Features Swept-frequency insonation

15 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 Image of single bubble in tank with attached solids Attached solids mass loading with squared ratio of AE resonance frequency

16 Stream Swarm

17 Model Estimation of Macrobubble Properties 1 mm radius + attached mineral particles

18 Model Estimation of Microbubble Properties 2.5 µm radius + attached mass loading (Sonovue encapsulating layer)

19 Modelling Results (Commercially Available UCAs) 1 st harmonic Optison GE Healthcare Definity Lantheus SonoVue Bracco

20 Some Possible Monitoring Applications 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?

21 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

22 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

23 Thank you Steven Spencer Principal Research Scientist MANUFACTURING