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From Lab to Chip – and back: Polymer microfluidic systems for sample handling in point-of-care diagnostics
KTH, School of Electrical Engineering (EES), Micro and Nanosystems.ORCID iD: 0000-0001-8531-5607
2016 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

This thesis contributes to the development of Lab-on-a-Chip systems that enables reliable, rapid medical diagnostics at the point-of-care. These contributions are focused on microfluidic Lab-on-a-Chip systems for sepsis diagnosis, autonomous sample-to-answer tests, and dried blood spot sampling.

Sepsis is a serious condition with high mortality and high costs for society and healthcare. To facilitate rapid and effective antibiotic treatment, improved sepsis diagnostics is needed. Diagnosis of sepsis requires the processing of relatively large blood volumes, creating a need for novel and effective techniques for the handling of large volume flows and pressures on chip. Components, materials, and manufacturing methods for pneumatically driven Lab-on-a-Chip systems have therefore been developed in this thesis. Microvalves, an essential component in many Lab-on-a-Chip systems have been the focus on several of the advances: a novel elastomeric material (Rubbery Off-Stoichiometric-Thiol-Ene-Epoxy) with low gas and liquid permeability; the first leak-tight vertical membrane microvalves, allowing large channel cross-sections for high volumetric flow throughput; and novel PDMS manufacturing methods enabling their realization. Additionally, two of the new components developed in this thesis focus on separation of bacteria from blood cells based on differences in particle size, and cell wall composition: inertial microfluidic removal of large particles in multiple parallel microchannels with low aspect ratio; and selective lysis of blood cells while keeping bacteria intact. How these components, materials and methods could be used together to achieve faster sepsis diagnostics is also discussed.

Lab-on-a-Chip tests can not only be used for sepsis, but have implications in many point-of-care tests. Disposable and completely autonomous sampleto- answer tests, like pregnancy tests, are capillary driven. Applying such tests in more demanding applications has traditionally been limited by poor material properties of the paper-based products used. A new porous material, called “Synthetic Microfluidic Paper”, has been developed in this thesis. The Synthetic Microfluidic Paper features well-defined geometries consisting of slanted interlocked micropillars. The material is transparent, has a large surface area, large porous fraction, and results in low variability in capillary flowrates. The fact that Synthetic Microfluidic Paper can be produced with multiple pore sizes in the same sheet enables novel concepts for self-aligned spotting of liquids and well-controlled positioning of functional microbeads.

Diagnostic testing can also be achieved by collecting the sample at the point-of-care while performing the analysis elsewhere. Easy collection of finger-prick blood in paper can be performed by a method called dried blood spots. This thesis investigates how the process of drying affects the homogeneity of dried blood spots, which can explain part of the variability that has been measured in the subsequent analysis. To reduce this variability, a microfluidic sampling chip has been developed in this thesis. The chip, which is capillary driven, autonomously collects a specific volume of plasma from a drop of blood, and dry-stores it in paper. After sampling, the chip can be mailed back to a central lab for analysis.

Place, publisher, year, edition, pages
Stockholm: KTH Royal Institute of Technology, 2016. , xiii, 75 p.
Series
TRITA-EE, ISSN 1653-5146 ; 2016:002
National Category
Other Electrical Engineering, Electronic Engineering, Information Engineering
Research subject
Electrical Engineering
Identifiers
URN: urn:nbn:se:kth:diva-180740ISBN: 978-91-7595-844-6 (print)OAI: oai:DiVA.org:kth-180740DiVA: diva2:896670
Public defence
2016-02-05, F3, Lindstedtsvägen 26, KTH, Stockholm, 09:00 (English)
Opponent
Supervisors
Note

QC 20160122

Available from: 2016-01-22 Created: 2016-01-22 Last updated: 2016-01-22Bibliographically approved
List of papers
1. Inertial microfluidics in parallel channels for high-throughput applications
Open this publication in new window or tab >>Inertial microfluidics in parallel channels for high-throughput applications
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2012 (English)In: Lab on a Chip, ISSN 1473-0197, E-ISSN 1473-0189, Vol. 12, no 22, 4644-4650 p.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 this study, we introduce inertial microfluidics in flows through straight, multiple parallel channels. The scalable, single inlet and two outlet, parallel channel system is enabled by a novel, high-density 3D PDMS microchannel manufacturing technology, mediated via a targeted inhibition of PDMS polymerization. Using single channels, we first demonstrate how randomly distributed particles can be focused into the centre position of the channel in flows through low aspect ratio channels and can be effectively fractionated. As a proof of principle, continuous focusing and filtration of 10 μm particles from a suspension mixture using 4- and 16-parallel-channel devices with a single inlet and two outlets are demonstrated. A filtration efficiency of 95-97% was achieved at throughputs several orders of magnitude higher than previously shown for flows through straight channels. The scalable and low-footprint focusing device requiring neither external force fields nor mechanical parts to operate is readily applicable for high-throughput focusing and filtration applications as a stand-alone device or integrated with lab-on-a-chip systems.

Place, publisher, year, edition, pages
Royal Society of Chemistry, 2012
Keyword
article, filtration, force, fractionation, inertial microfluidics, lab on a chip, microfluidics, priority journal
National Category
Biochemistry and Molecular Biology
Identifiers
urn:nbn:se:kth:diva-95364 (URN)10.1039/c2lc40241f (DOI)000310865200008 ()2-s2.0-84867518462 (Scopus ID)
Funder
Science for Life Laboratory - a national resource center for high-throughput molecular bioscienceEU, European Research Council
Note

QC 20121115. Updated from accepted to published.

Available from: 2012-05-23 Created: 2012-05-23 Last updated: 2017-12-07Bibliographically approved
2. Microfluidic-based isolation of bacteria from whole blood for sepsis diagnostics
Open this publication in new window or tab >>Microfluidic-based isolation of bacteria from whole blood for sepsis diagnostics
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2015 (English)In: Biotechnology letters, ISSN 0141-5492, E-ISSN 1573-6776, Vol. 37, no 4, 825-830 p.Article in journal (Refereed) Published
Abstract [en]

Blood-stream infections (BSI) remain a major health challenge, with an increasing incidence worldwide and a high mortality rate. Early treatment with appropriate antibiotics can reduce BSI-related morbidity and mortality, but success requires rapid identification of the infecting organisms. The rapid, culture-independent diagnosis of BSI could be significantly facilitated by straightforward isolation of highly purified bacteria from whole blood. We present a microfluidic-based, sample-preparation system that rapidly and selectively lyses all blood cells while it extracts intact bacteria for downstream analysis. Whole blood is exposed to a mild detergent, which lyses most blood cells, and then to osmotic shock using deionized water, which eliminates the remaining white blood cells. The recovered bacteria are 100 % viable, which opens up possibilities for performing drug susceptibility tests and for nucleic-acid-based molecular identification.

Keyword
Bacteria; Cells; Cytology; Deionized water; Microfluidics, Bacteria isolation; Blood streams; Cell lysis; Drug susceptibility; Isolation of bacteria; Microfluidic-based; Molecular identification; Rapid identification, Blood
National Category
Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy)
Identifiers
urn:nbn:se:kth:diva-157710 (URN)10.1007/s10529-014-1734-8 (DOI)000351535300010 ()2-s2.0-84925535660 (Scopus ID)
Funder
Science for Life Laboratory - a national resource center for high-throughput molecular bioscience
Note

QC 20141212

Available from: 2014-12-12 Created: 2014-12-12 Last updated: 2017-12-05Bibliographically approved
3. Leak tight vertical membrane microvalves in PDMS
Open this publication in new window or tab >>Leak tight vertical membrane microvalves in PDMS
(English)Manuscript (preprint) (Other academic)
National Category
Engineering and Technology
Identifiers
urn:nbn:se:kth:diva-180736 (URN)
Note

QS 2016

Available from: 2016-01-22 Created: 2016-01-22 Last updated: 2016-01-22Bibliographically approved
4. Fabrication and transfer of fragile 3D PDMS microstructures
Open this publication in new window or tab >>Fabrication and transfer of fragile 3D PDMS microstructures
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2012 (English)In: Journal of Micromechanics and Microengineering, ISSN 0960-1317, E-ISSN 1361-6439, Vol. 22, no 8, 1-9 p.Article in journal (Refereed) Published
Abstract [en]

We present a method for PDMS microfabrication of fragile membranes and 3D fluidic networks, using a surface modified water-dissolvable release material, poly(vinyl alcohol), as a tool for handling, transfer and release of fragile polymer microstructures. The method is well suited for the fabrication of complex multilayer microfluidic devices, here shown for a PDMS device with a thin gas permeable membrane and closely spaced holes for vertical interlayer connections fabricated in a single layer. To the authors knowledge, this constitutes the most advanced PDMS fabrication method for the combination of thin, fragile structures and 3D fluidics networks, and hence a considerable step in the direction of making PDMS fabrication of complex microfluidic devices a routine endeavour.

Keyword
Microfluidic Devices, Layer
National Category
Electrical Engineering, Electronic Engineering, Information Engineering
Identifiers
urn:nbn:se:kth:diva-95357 (URN)10.1088/0960-1317/22/8/085009 (DOI)000306649000009 ()2-s2.0-84864447006 (Scopus ID)
Note

QC 20150624

Available from: 2012-05-23 Created: 2012-05-23 Last updated: 2017-12-07Bibliographically approved
5. Low gas permeable and non-absorbent rubbery OSTE+ for pneumatic microvalves
Open this publication in new window or tab >>Low gas permeable and non-absorbent rubbery OSTE+ for pneumatic microvalves
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2014 (English)In: Proceedings of the 27th IEEE International Conference on Micro Electro Mechanical Systems (MEMS 2014), IEEE conference proceedings, 2014, 987-990 p.Conference paper, Published paper (Refereed)
Abstract [en]

In this paper we introduce a new polymer for use in microfluidic applications, based on the off-stoichiometric thiol–ene-epoxy (OSTE+) polymer system, but with rubbery properties. We characterize and benchmark the new polymer against PDMS. We demonstrate that Rubbery OSTE+: has more than 90% lower permeability to gases compared to PDMS, has little to no absorption of dissolved molecules, can be layer bonded in room temperature without the need for adhesives or plasma treatment, can be structured by standard micro-molding manufacturing, and shows similar performance as PDMS for pneumatic microvalves, albeit allowing handling of larger pressure. 

Place, publisher, year, edition, pages
IEEE conference proceedings, 2014
Keyword
lab-on-chip, microfluidics, microvalve, OSTE+
National Category
Textile, Rubber and Polymeric Materials
Identifiers
urn:nbn:se:kth:diva-141690 (URN)10.1109/MEMSYS.2014.6765809 (DOI)000352217500245 ()2-s2.0-84898951170 (Scopus ID)978-1-4799-3509-3 (ISBN)
Conference
The 27th IEEE International Conference on Micro Electro Mechanical Systems (MEMS 2014), January 26-30, 2014,San Fransisco, CA, USA
Funder
EU, FP7, Seventh Framework Programme
Note

QC 20140221

Available from: 2014-02-20 Created: 2014-02-20 Last updated: 2016-01-22Bibliographically approved
6. Direct Lithography of Rubbery OSTE+ Polymer
Open this publication in new window or tab >>Direct Lithography of Rubbery OSTE+ Polymer
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2014 (English)In: Proceedings 18th International Conference on Miniaturized Systems for Chemistry and Life Sciences (MicroTAS2014), 14CBMS , 2014, 123-125 p.Conference paper, Oral presentation with published abstract (Refereed)
Abstract [en]

We present a Rubbery, Off-Stoichiometric Thiol-Ene-epoxy (OSTE+) polymer for direct lithography manufacturing, demonstrate its use in pneumatic pinch microvalves for lab-on-chip applications, test the lithography process achieving pillars of aspect-ratios (a.r.) 1:8, and characterize it’s surface as hydrophilic.

Place, publisher, year, edition, pages
14CBMS, 2014
Keyword
OSTE+, PDMS, microfluidics, Thiol-ene
National Category
Biomaterials Science
Identifiers
urn:nbn:se:kth:diva-157712 (URN)978-0-9798064-7-6 (ISBN)
Conference
18th International Conference on Miniaturized Systems for Chemistry and Life Sciences (MicroTAS 2014),October 26-30, 2014, San Antonio, Texas, USA
Funder
EU, FP7, Seventh Framework Programme, 66677
Note

QC 20141217

Available from: 2014-12-12 Created: 2014-12-12 Last updated: 2016-01-22Bibliographically approved
7. Synthetic microfluidic paper: high surface area and high porosity polymer micropillar arrays
Open this publication in new window or tab >>Synthetic microfluidic paper: high surface area and high porosity polymer micropillar arrays
2016 (English)In: Lab on a Chip, ISSN 1473-0197, E-ISSN 1473-0189, Vol. 16, no 2, 298-304 p.Article in journal (Refereed) Published
Abstract [en]

We introduce Synthetic Microfluidic Paper, a novel porous material for microfluidic applications that consists of an OSTE polymer that is photostructured in a well-controlled geometry of slanted and interlocked micropillars. We demonstrate the distinct benefits of Synthetic Microfluidic Paper over other porous microfluidic materials, such as nitrocellulose, traditional paper and straight micropillar arrays: in contrast to straight micropillar arrays, the geometry of Synthetic Microfluidic Paper was miniaturized without suffering capillary collapse during manufacturing and fluidic operation, resulting in a six-fold increased internal surface area and a three-fold increased porous fraction. Compared to commercial nitrocellulose materials for capillary assays, Synthetic Microfluidic Paper shows a wider range of capillary pumping speed and four times lower device-to-device variation. Compared to the surfaces of the other porous microfluidic materials that are modified by adsorption, Synthetic Microfluidic Paper contains free thiol groups and has been shown to be suitable for covalent surface chemistry, demonstrated here for increasing the material hydrophilicity. These results illustrate the potential of Synthetic Microfluidic Paper as a porous microfluidic material with improved performance characteristics, especially for bioassay applications such as diagnostic tests.

Place, publisher, year, edition, pages
Royal Society of Chemistry, 2016
Keyword
OSTE, paper microfluidics, microfluidics, porous microfluidics, Lab-on-a-Chip, diagnostics, micropillars
National Category
Paper, Pulp and Fiber Technology Polymer Technologies Biomedical Laboratory Science/Technology
Research subject
Biotechnology
Identifiers
urn:nbn:se:kth:diva-180009 (URN)10.1039/C5LC01318F (DOI)000367953700010 ()2-s2.0-84953410894 (Scopus ID)
Funder
EU, FP7, Seventh Framework Programme
Note

QC 20160115

Available from: 2016-01-05 Created: 2016-01-05 Last updated: 2017-12-01Bibliographically approved
8. Synthetic Microfluidic Paper allows controlled receptor positioning and improvedreadout signal intensity in lateral flow assays
Open this publication in new window or tab >>Synthetic Microfluidic Paper allows controlled receptor positioning and improvedreadout signal intensity in lateral flow assays
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(English)Manuscript (preprint) (Other academic)
National Category
Engineering and Technology
Identifiers
urn:nbn:se:kth:diva-180739 (URN)
Note

QS 2016

Available from: 2016-01-22 Created: 2016-01-22 Last updated: 2016-01-22Bibliographically approved
9. The effect of drying on the homogeneity of DBS
Open this publication in new window or tab >>The effect of drying on the homogeneity of DBS
2015 (English)In: Bioanalysis, ISSN 1757-6180, E-ISSN 1757-6199, Vol. 7, no 16, 1977-1985 p.Article in journal (Refereed) Published
Abstract [en]

Background: Inhomogeneous sample distribution in DBS is a problem for accurate quantitative analysis of DBS, and has often been explained by chromatographic effects. Results: We present a model describing formation of inhomogeneous DBS during drying of the spot caused by higher evaporation rates of water at the edge as compared with the center. Color intensity analysis shows that the relative humidity and DBS card position affect the homogeneity of DBS. Conclusion: The so-called coffee-stain effect' explains the typical distribution pattern of analytes with higher concentrations measured along the edge of DBS as compared with the center. The driving mechanism and potential influencing factors should be considered when addressing the inhomogeneity of DBS in the future.

National Category
Biological Sciences
Identifiers
urn:nbn:se:kth:diva-173995 (URN)10.4155/bio.15.135 (DOI)000360713600005 ()26327179 (PubMedID)2-s2.0-84940752589 (Scopus ID)
Funder
Stockholm County Council, 20130765EU, European Research Council, 267528
Note

QC 20151001

Available from: 2015-10-01 Created: 2015-09-24 Last updated: 2017-12-01Bibliographically approved
10. Capillary driven and volume-metred blood-plasma separation
Open this publication in new window or tab >>Capillary driven and volume-metred blood-plasma separation
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2015 (English)In: Proceedings 18 th IEEE Transducers, IEEE , 2015, no 16, 335-338 p.Conference paper, Published paper (Refereed)
Abstract [en]

Blood plasma samples are widely used in clinical analysis but easy-to-use sampling methods for defined volumes are lacking. We introduce the first capillary driven microfluidic device that separates a specific volume of plasma from a blood sample of unknown volume. The input to the device is a small amount of whole blood in the range of 30-60 μl which results in a 4 μl isolated plasma sample within 3 minutes, available for subsequent processing and/or analysis, as demonstrated by collecting the sample in a paper substrate.

Place, publisher, year, edition, pages
IEEE, 2015
Keyword
Blood plasma separation, Volume metering, Microfluidic, Point-of-care, capillary pump
National Category
Analytical Chemistry
Identifiers
urn:nbn:se:kth:diva-180741 (URN)000380427400042 ()2-s2.0-84955491195 (Scopus ID)978-1-4799-8955-3 (ISBN)
Conference
Transducers 2015, Anchorage, Alaska, USA, June 21-25, 2015
Note

QC 20160122

Available from: 2016-01-22 Created: 2016-01-22 Last updated: 2016-10-05Bibliographically approved

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Citation style
  • apa
  • harvard1
  • ieee
  • modern-language-association-8th-edition
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  • Other style
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