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Point of care microfluidic tool development for resource limited settings
KTH, School of Engineering Sciences in Chemistry, Biotechnology and Health (CBH), Protein Science, Nano Biotechnology.ORCID iD: 0000-0001-9869-7181
2019 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

The development of point of care diagnostics using recent advances in microfluidics have the potential to transform health care in several ways, especially in resource limited settings with limited access to advanced health care infrastructure. However, translating a point of care device to reality is often a challenging task because of the complexities involved in integrating a number of diverse engineering concepts into an easy to use, accurate and portable device. This thesis focuses on miniaturization of crucial diagnostic laboratory tools, that can be used in a portable point of care format without compromising on the accuracy or performance. The first part of the thesis (Paper I-III) focuses on understanding and applying elasto-inertial microfluidics, which is a label-free and passive bio-particle sorting and separation method. A basic understanding of particle trajectories in both inertial (Paper I) and visco-elastic flows (Paper II) is established, followed by an investigation on the combined effects of inertia and elasticity (Paper III). The second part of the thesis (Paper IV-VI) focuses on developing integrated microfluidic platforms, each of which addresses different aspects of point of care diagnostic applications. The applications include neonatal diagnostics using a hand-driven Slipdisc technique (Paper IV), rapid nucleic acid quantification using a novel precipitate-based detection on a centrifugal microfluidics platform (Paper V), and hematocrit level measurement in blood using a portable lab-on- Disc platform operated by a mobile phone (Paper VI). The proof of concept microfluidic tools presented in the scope of this thesis have the potential to replace a number of functions of standard laboratory equipment, at a fraction of the price and without compromising performance. Hence, the different methods developed should contribute towards decentralization of medical testing laboratories, making healthcare accessible to one and all.

Place, publisher, year, edition, pages
Stockholm: KTH Royal Institute of Technology, 2019. , p. 63
Series
TRITA-CBH-FOU ; 2019:15
Keywords [en]
Blood, control, cell separation, centrifugal microfluidics, diagnostics, elasto-inertial, hematocrit level, microfluidics, neonatal diagnostics, nucleic acid quantification, point of care, particle focusing, resource limited settings.
National Category
Medical and Health Sciences Engineering and Technology
Research subject
Biotechnology
Identifiers
URN: urn:nbn:se:kth:diva-244825ISBN: 978-91-7873-122-0 (print)OAI: oai:DiVA.org:kth-244825DiVA, id: diva2:1292583
Public defence
2019-03-29, Air & Fire auditorium, Science for Life Laboratory, Tomtebodavägen 23, Solna, 10:00 (English)
Opponent
Supervisors
Note

QC 20190228

Available from: 2019-02-28 Created: 2019-02-28 Last updated: 2019-02-28Bibliographically approved
List of papers
1. Inertial migration of spherical and oblate particles in straight ducts
Open this publication in new window or tab >>Inertial migration of spherical and oblate particles in straight ducts
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(English)In: Journal of Fluid Mechanics, ISSN 0022-1120, E-ISSN 1469-7645Article in journal (Refereed) Accepted
Abstract [en]

We study numerically the inertial migration of a single rigid sphere and an oblate spheroid in straight square and rectangular ducts. A highly accurate interface-resolved numerical algorithm is employed to analyse the entire migration dynamics of the oblate particle and compare it with that of the sphere. Similarly to the inertial focusing of spheres, the oblate particle reaches one of the four face-centred equilibrium positions, however they are vertically aligned with the axis of symmetry in the spanwise direction. In addition, the lateral trajectories of spheres and oblates collapse into an equilibrium manifold before ending at the equilibrium positions, with the equilibrium manifold tangential to lines of constant background shear for both sphere and oblate particles. The differences between the migration of the oblate and sphere are also presented, in particular the oblate may focus on the diagonal symmetry line of the duct cross-section, close to one of the corners, if its diameter is larger than a certain threshold. Moreover, we show that the final orientation and rotation of the oblate exhibit a chaotic behaviour for Reynolds numbers beyond a critical value. Finally, we document that the lateral motion of the oblate particle is less uniform than that of the spherical particle due to its evident tumbling motion throughout the migration. In a square duct, the strong tumbling motion of the oblate in the first stage of the migration results in a lower lateral velocity and consequently longer focusing length with respect to that of the spherical particle. The opposite is true in a rectangular duct where the higher lateral velocity of the oblate in the second stage of the migration, with negligible tumbling, gives rise to shorter focusing lengths.These results can help the design of microfluidic systems for bio-applications.

National Category
Fluid Mechanics and Acoustics
Identifiers
urn:nbn:se:kth:diva-204162 (URN)10.1017/jfm.2017.189 (DOI)000405373500005 ()2-s2.0-85018317724 (Scopus ID)
Note

QC 20170328

Available from: 2017-03-23 Created: 2017-03-23 Last updated: 2019-02-28Bibliographically approved
2. 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
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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: 2019-02-28Bibliographically approved
3. Analog particle position tuning in Elasto-inertial microfluidic flows
Open this publication in new window or tab >>Analog particle position tuning in Elasto-inertial microfluidic flows
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(English)Manuscript (preprint) (Other academic)
Abstract [en]

We observe for the first time an analog trend in particle focusing in a high throughput weakly viscoelastic regime, where it is possible to tune particles into multiple intermediate focusing positions that lie between the "Segre-Silberberg annulus" and the center of a circular microcapillary. The "Segre-Silberberg annulus" (0.6 times the pipe radius), that describes particle equilibrium in a predominantly inertial flow, shrinks consistently closer to the center for increasing elasticity in extremely dilute PEO concentrations (ranging from 0.001 wt% to 0.05wt%). The experimental observations are supported by direct numerical simulations, where an Immersed Boundary Method is used to account for the presence of particles and a FENE-P model is used to simulate the presence of polymers in a Non-Newtonian fluid. The numerical simulations study the dynamics and stability of finite size particles and are further used to analyze particle behavior at Reynolds number higher than what is allowed by the present experimental setup. In particular, we are able to report the entire migration trajectories of the particles as they reach their final equilibrium positions and extend our predictions to other geometries such as the square cross-section. We believe complex effects originate due to a combination of inertia and elasticity in a weakly viscoelastic regime, where neither inertia nor elasticity are able to mask each other's effect completely, thus leading to a number of intermediate focusing positions. The present study provides a new understanding into the mechanism of particle focusing in elasto-inertial flows and opens up new possibilities for exercising analog control in tuning the particle focusing positions.

National Category
Fluid Mechanics and Acoustics
Research subject
Biotechnology
Identifiers
urn:nbn:se:kth:diva-244824 (URN)
Note

QC 20190228

Available from: 2019-02-28 Created: 2019-02-28 Last updated: 2019-03-12Bibliographically approved
4. Slipdisc: A versatile sample preparation platform for point of care diagnostics
Open this publication in new window or tab >>Slipdisc: A versatile sample preparation platform for point of care diagnostics
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2017 (English)In: RSC Advances, ISSN 2046-2069, E-ISSN 2046-2069, Vol. 7, no 56, p. 35048-35054Article in journal (Refereed) Published
Abstract [en]

We report a microfluidic sample preparation platform called "Slipdisc" based on slipchip technology. Slipdisc is a rotational slipchip that uses a unique hand-wound clockwork mechanism for precise movement of specially fabricated polycarbonate discs. In operation, the microchannels and microchambers carved on the closely aligned microfluidic discs convert from continuous filled paths to defined compartments using the slip movement. The clockwork mechanism introduced here is characterised by a food dye experiment and a conventional HRP TMB reaction before measuring lactate dehydrogenase (LDH) enzyme levels, which is a crucial biomarker for neonatal diagnostics. The colorimetry based detection of LDH was performed with an unmodified camera and an image analysis procedure based on normalising images and observing changes in red channel intensity. The analysis showed a close to unity coefficient of determination (R2 = 0.96) in detecting the LDH concentration when compared with a standard Chemical Analyser, demonstrating the excellent performance of the slipdisc platform with colorimetric detection. The versatile point of care sample preparation platform should ideally be suited for a multitude of applications at resource-limited settings.

Place, publisher, year, edition, pages
Royal Society of Chemistry, 2017
Keywords
Chemical analysis, Chemical detection, Clocks, Colorimetric analysis, Colorimetry, Coefficient of determination, Colorimetric detection, Lactate dehydrogenase, Micro-chambers, Point of care, Point of care diagnostic, Red channels, Sample preparation, Microfluidics
National Category
Analytical Chemistry
Identifiers
urn:nbn:se:kth:diva-219077 (URN)10.1039/c7ra05209j (DOI)000405811400015 ()2-s2.0-85025080747 (Scopus ID)
Note

QC 20171201

Available from: 2017-12-01 Created: 2017-12-01 Last updated: 2019-11-06Bibliographically approved
5. Microfluidic Centrifugation Assisted Precipitation based DNA Quantification
Open this publication in new window or tab >>Microfluidic Centrifugation Assisted Precipitation based DNA Quantification
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(English)Manuscript (preprint) (Other academic)
Abstract [en]

Nucleic acid amplification methods are increasingly being used to detect trace quantities of DNA in samples for various diagnostic applications. However, quantifying the amount of DNA from such methods often require time consuming purification, washing or labeling step. Here, we report a novel microfluidic centrifugation assisted precipitation (uCAP) method for single-step DNA quantification. The method is based on formation of a visible precipitate, that can be quantified, when an intercalating dye (GelRed) is added to DNA sample and centrifuged for few seconds. We describe the mechanism leading to the precipitation phenomenon. We utilize centrifugal microfluidics to precisely control the formation of visible and quantifiable mass. Using a standard CMOS sensor for imaging, we report a detection limit of 45 ng/ul. Furthermore, using an integrated Lab-on-DVD platform we recently developed, the detection limit was lowered to 10 ng/ul, which is comparable to current commercially available instruments for DNA quantification. As a proof of principle, we demonstrate the quantification of LAMP products for a HIV-1B type genome containing plasmid on the Lab-on-DVD platform. The simple DNA quantification system could facilitate advanced molecular diagnosis at point of care.

National Category
Medical and Health Sciences
Research subject
Biotechnology
Identifiers
urn:nbn:se:kth:diva-244820 (URN)
Note

QC 20190228

Available from: 2019-02-27 Created: 2019-02-27 Last updated: 2019-03-12Bibliographically approved
6. Mobile-LabDisc for Point-of-Care Diagnostics
Open this publication in new window or tab >>Mobile-LabDisc for Point-of-Care Diagnostics
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(English)Manuscript (preprint) (Other academic)
Abstract [en]

At resource limited settings, point of care devices require a very low-cost, robust and easy to use platform that is preferably capable of automating and multiplexing intricate bioassays. We report on a mobile lab-disc platform that is specifically designed to meet the needs at resource- limited settings. It uses a smartphone as an electrical power source and a disposable, rigid and portable casing made of cardboard that securely accommodate the entire lab-disc system rotor, lightning and wiring and other accessories. The mobile lab-disc is light, less-expensive and functional at places where the electrical power infrastructure is not available. We show that the electrical energy stored in most mobile phones can be used for spinning a lab-Disc at up to 5500 rpm, a speed sufficient for most of the required functional steps in a bioassay including ELISA. We develop individual components of the mobile lab-disc system by experimentally conducting colorimetric assays using HRP and sandwich immunoassay. Finally, the full potential of the mobile lab-disc for integrating and multiplexing bioassays is demonstrated by measuring the hematocrit level in whole blood. The mobile phone-operated process integrates sample preparation i.e., blood-plasma separation, imaging and image analysis. The total cost of our prototype system for the tests, excluding the phone is ~$5, assuming that a lab-disc unit is worth $1.

National Category
Biomedical Laboratory Science/Technology
Research subject
Biotechnology
Identifiers
urn:nbn:se:kth:diva-244821 (URN)
Note

QC 20180228

Available from: 2019-02-28 Created: 2019-02-28 Last updated: 2019-02-28Bibliographically approved

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More languages
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