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Bioparticle Manipulation using Acoustophoresis and Inertial Microfluidics
KTH, School of Biotechnology (BIO), Proteomics and Nanobiotechnology. (Clinical Microfluidics)ORCID iD: 0000-0003-1176-0905
2017 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Despite the many promising advances made in microfluidics, sample preparation remains the single largest challenge and bottleneck in the field of miniaturised diagnostics. This thesis is focused on the development of sample preparation methods using active and passive particle manipulation techniques for point of care diagnostic applications. The active technique is based on acoustophoresis (acoustic manipulation) while the passive method is based on inertial microfluidics (hydrodynamic manipulation). In paper I, acoustic capillary-based cavity resonator was used to study aggregation of silica and polystyrene particles. We found that silica particles show faster aggregation time (5.5 times) and larger average area of aggregates (3.4 times) in comparison to polystyrene particles under the same actuation procedure. The silica particles were then used for acoustic based bacteria up-concentration. In paper II, a microfluidic-based microbubbles activated acoustic cell sorting technique was developed for affinity based cell separation. As a proof of principle, separation of cancer cell line in a suspension with better than 75% efficiency is demonstrated. For the passive sample preparation, inertial and elasto-inertial microfluidic approach that uses geometry-induced hydrodynamic forces for continuous size-based sorting of particles in a flow-through fashion were studied and applied for blood processing (paper III-V). In paper III, a simple ushaped curved channel was used for inertial microfluidics based enrichment of white blood cells from diluted whole blood. A filtration efficiency of 78% was achieved at a flow rate of 2.2 ml/min. In paper IV, elasto-inertial microfluidics where viscoelastic flow enables size-based migration of cells into a non- Newtonian solution, was used to continuously separate bacteria from unprocessed whole blood for sepsis diagnostics. Bacteria were continuously separated at an efficiency of 76% from undiluted whole blood sample. Finally, in paper V, the inertial and elasto-inertial techniques were combined with a detection platform to demonstrate an integrated miniaturized flow cytometer. The all-optical-fiber technology based system allows for simultaneous measurements of fluorescent and scattering data at 2500 particles/s. The use of inertial and acoustic techniques for sample preparation and development of an integrated detection platform may allow for further development and realization of point of care testing (POCT) systems.

Place, publisher, year, edition, pages
Stockholm, Sweden: Kungliga Tekniska högskolan, 2017. , p. 68
Series
TRITA-BIO-Report, ISSN 1654-2312 ; 2017:4
National Category
Medical Biotechnology
Research subject
Biotechnology
Identifiers
URN: urn:nbn:se:kth:diva-200304ISBN: 978-91-7729-264-7 (print)OAI: oai:DiVA.org:kth-200304DiVA, id: diva2:1068019
Public defence
2017-02-16, Gard-Aulan, Nobels vägen 18, Solna, Stockholm, 10:00 (English)
Opponent
Supervisors
Note

QC 20170124

Available from: 2017-01-24 Created: 2017-01-24 Last updated: 2017-01-24Bibliographically approved
List of papers
1. Glass Capillary based cavity resonator for particle trapping study and bacteria up-concentration
Open this publication in new window or tab >>Glass Capillary based cavity resonator for particle trapping study and bacteria up-concentration
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(English)In: Biomedical microdevices (Print), ISSN 1387-2176, E-ISSN 1572-8781Article in journal (Refereed) Submitted
Abstract [en]

We have performed particle aggregation characterization on the basis of their material and suspending

medium in a capillary-based cavity resonator used for acoustophoresis. We have investigated the experimental

aggregation time of 5μm polystyrene and silica particles, size of aggregate, number of trapped particles and upconcentration

factor in water, 0.01M phosphate buffered saline (PBS) and 0.005M PBS at 1.97MHz and with

actuation voltages between 4, 8 and 12Vpp. We have found that there is little difference between using water and

PBS as suspension medium, approximately 5-10% longer trapping times with PBS compared with water.

However we get approx. 5.5 times faster trapping time for silica than for polystyrene. It is also observed and

calculated that silica particle aggregates have 3.4 times larger area than the polystyrene aggregates using the same

starting particle concentrations, revealing similar amount of difference in trapped number of particles. The upconcentration

factor for silica is also about 3.2 times higher than that of polystyrene due to larger aggregate area

of silica particles. Based on theoretical predictions and experimental characterization of the particle aggregation

pattern, we note that the particle-particle interaction force contribution to the total acoustic radiation force is more

pronounced for silica than for polystyrene. Finally as a proof of principle for biomedical sample preparation

application we demonstrate the capillary-based silica particles mediated bacteria acoustophoretic upconcentration.

This setup could potentially be utilized not only for sample preparation application but also for

bead based affinity immunoassays.

National Category
Medical Biotechnology
Identifiers
urn:nbn:se:kth:diva-200301 (URN)
Funder
EU, FP7, Seventh Framework Programme, 115153-2Swedish Research Council, 2011-5230Stockholm County Council, HMT-20140722
Note

QCR 20170124

Available from: 2017-01-24 Created: 2017-01-24 Last updated: 2017-11-29Bibliographically approved
2. MicroBubble Activated Acoustic Cell Sorting: BAACS
Open this publication in new window or tab >>MicroBubble Activated Acoustic Cell Sorting: BAACS
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(English)In: Biomedical microdevices (Print), ISSN 1387-2176, E-ISSN 1572-8781Article in journal (Refereed) Submitted
Abstract [en]

Acoustophoresis, the ability to acoustically manipulate particles and cells inside a microfluidic channel, is a critical enabling technology for cell-sorting applications. However, one of the major impediments for routine use of acoustophoresis at clinical laboratory has been the reliance on the inherent physical properties of cells for separation. Here, we present a microfluidic-based microBubble-Activated Acoustic Cell Sorting (BAACS) method that rely on the specific binding of target cells to microbubbles conjugated with specific antibodies on their surface for continuous cell separation using ultrasonic standing wave. In acoustophoresis, cells being positive acoustic contrast particles migrate to pressure nodes. On the contrary we show that air-filled polymer-shelled microbubbles being strong negative acoustic contrast particles migrate to pressure antinodes at acoustic pressure amplitudes as low as 60 kPa. As a proof of principle, using the BAACS strategy, we demonstrate the separation of cancer cell line in a suspension with better than 75% efficiency. Moreover, 100% of the microbubble-cell conjugates migrated to the anti-node. Hence a better upstream affinity-capture has the potential to provide higher sorting efficiency. The BAACS technique may potentially provide a simplistic approach for similar sized selective isolation of cells, and is suited for applications in point of care.

Keywords
Cell sorting, acoustophoresis, microbubble, contrast agent, microfluidic separation
National Category
Medical Biotechnology
Identifiers
urn:nbn:se:kth:diva-200302 (URN)
Funder
EU, FP7, Seventh Framework Programme, 115153
Note

QC 20170124

Available from: 2017-01-24 Created: 2017-01-24 Last updated: 2017-11-29Bibliographically approved
3. Dean flow-coupled inertial focusing in curved channels
Open this publication in new window or tab >>Dean flow-coupled inertial focusing in curved channels
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2014 (English)In: Biomicrofluidics, ISSN 1932-1058, E-ISSN 1932-1058, Vol. 8, no 3, p. 034117-Article in journal (Refereed) Published
Abstract [en]

Passive particle focusing based on inertial microfluidics was recently introduced as a high-throughput alternative to active focusing methods that require an external force field to manipulate particles. In inertial microfluidics, dominant inertial forces cause particles to move across streamlines and occupy equilibrium positions along the faces of walls in flows through straight micro channels. In this study, we systematically analyzed the addition of secondary Dean forces by introducing curvature and show how randomly distributed particles entering a simple u-shaped curved channel are focused to a fixed lateral position exiting the curvature. We found the lateral particle focusing position to be fixed and largely independent of radius of curvature and whether particles entering the curvature are pre-focused (at equilibrium) or randomly distributed. Unlike focusing in straight channels, where focusing typically is limited to channel cross-sections in the range of particle size to create single focusing point, we report here particle focusing in a large cross-section area (channel aspect ratio 1: 10). Furthermore, we describe a simple u-shaped curved channel, with single inlet and four outlets, for filtration applications. We demonstrate continuous focusing and filtration of 10 mu m particles (with > 90% filtration efficiency) from a suspension mixture at throughputs several orders of magnitude higher than flow through straight channels (volume flow rate of 4.25ml/min). Finally, as an example of high throughput cell processing application, white blood cells were continuously processed with a filtration efficiency of 78% with maintained high viability. We expect the study will aid in the fundamental understanding of flow through curved channels and open the door for the development of a whole set of bio-analytical applications.

Keywords
Continuous Particle Separation, Microfluidic Device, Poiseuille Flow, Tumor-Cells, Microchannels, Filtration, Filter
National Category
Biochemistry and Molecular Biology
Identifiers
urn:nbn:se:kth:diva-149227 (URN)10.1063/1.4884306 (DOI)000339004500017 ()
Funder
EU, FP7, Seventh Framework ProgrammeSwedish Research CouncilScience for Life Laboratory - a national resource center for high-throughput molecular bioscience
Note

QC 20140819

Available from: 2014-08-19 Created: 2014-08-18 Last updated: 2017-12-05Bibliographically approved
4. Elasto-inertial microfluidics for bacteria separation from whole blood for sepsis diagnostics
Open this publication in new window or tab >>Elasto-inertial microfluidics for bacteria separation from whole blood for sepsis diagnostics
Show others...
2017 (English)In: Journal of Nanobiotechnology, ISSN 1477-3155, E-ISSN 1477-3155, Vol. 15, article id 3Article in journal (Refereed) Published
Abstract [en]

Background: Bloodstream infections (BSI) remain a major challenge with high mortality rate, with an incidence that is increasing worldwide. Early treatment with appropriate therapy can reduce BSI-related morbidity and mortality. However, despite recent progress in molecular based assays, complex sample preparation steps have become critical roadblock for a greater expansion of molecular assays. Here, we report a size based, label-free, bacteria separation from whole blood using elasto-inertial microfluidics.

Results: In elasto-inertial microfluidics, the viscoelastic flow enables size based migration of blood cells into a non- Newtonian solution, while smaller bacteria remain in the streamline of the blood sample entrance and can be sepa- rated. We first optimized the flow conditions using particles, and show continuous separation of 5 μm particles from 2 μm at a yield of 95% for 5 μm particle and 93% for 2 μm particles at respective outlets. Next, bacteria were continu- ously separated at an efficiency of 76% from undiluted whole blood sample.

Conclusion: We demonstrate separation of bacteria from undiluted while blood using elasto-inertial microfluidics. The label-free, passive bacteria preparation method has a great potential for downstream phenotypic and molecular analysis of bacteria. 

Place, publisher, year, edition, pages
BioMed Central, 2017
Keywords
Micro particle separation, Elasto-inertial microfluidics, Sepsis, Sample preparation
National Category
Medical Biotechnology
Identifiers
urn:nbn:se:kth:diva-200300 (URN)10.1186/s12951-016-0235-4 (DOI)000391073000001 ()2-s2.0-85008198016 (Scopus ID)
Projects
RAPP_ID
Funder
EU, European Research Council, 115153
Note

QC 20170124

Available from: 2017-01-24 Created: 2017-01-24 Last updated: 2017-11-29Bibliographically approved
5. Optical Fiber inertial focusing based micro Flowcytometer
Open this publication in new window or tab >>Optical Fiber inertial focusing based micro Flowcytometer
Show others...
(English)In: Nature Communications, ISSN 2041-1723, E-ISSN 2041-1723Article in journal (Refereed) Submitted
Abstract [en]

Flow cytometry is a powerful method for analysis of cells and particles. Fueled by the need for point of care diagnostic applications, a significant effort has been made to miniaturize flow cytometry. However, despite recent advances, current microflow cytometers remain less versatile and much slower than their large-scale counterparts. Here, we present a portable all-silica optofluidic device that integrates particle focusing in flow through cylindrical silica capillaries and light delivery in optical fibers to simultaneously measure fluorescence and scattering from cells and particles at a rate of 2500 particles/s – a throughput comparable to conventional cytometers. Precise 3D cell focusing and ordering is accomplished using extended elasto-inertial focusing (EEF), a key enabler for eliminating the sheath fluid commonly employed in flow cytometry with maintained high throughput. We demonstrate simultaneously two-color fluorescence and scattering measurement of different sized particles and cells. This robust and low-cost optofluidic device, assembled without the need of clean-room facilities, is ideal suited for point of care applications.

National Category
Medical Biotechnology
Identifiers
urn:nbn:se:kth:diva-200303 (URN)
Funder
Swedish Research CouncilSwedish Childhood Cancer Foundation
Note

QCR 20170124

Available from: 2017-01-24 Created: 2017-01-24 Last updated: 2017-11-29Bibliographically approved

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