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Foil-based Lab-on-Chip technologies for advanced Point-of-Care molecular diagnostics
KTH, School of Biotechnology (BIO), Proteomics and Nanobiotechnology. (Clinical Microfluidics and Nanobiotechnology)
2017 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Infectious diseases pose a serious threat to global health. Molecular diagnostics provide solutions for effective control and prevention of infections, however suffers from expensive laboratory equipment, and infrastructure to be fully implemented at point of care (POC), especially at low-resource settings. Lab-on-a-chip that aims to integrate complex biochemical analyses into automated systems is promising for POC analysis. A major challenge is the integration of a complete molecular diagnostic assay, generally translating into complex microfluidics, with the requirement of low fabrication cost. This thesis explores the use of flexible electronics, plastic foils and roll-to-roll manufacturing to enable low-cost microfluidic systems, for molecular diagnostic assays especially targeted towards infectious diseases. Many biochemical assays rely on heat; hence a first aspect in this thesis is the integration of a microheater into microfluidics. In a first project a system for SNP-genotyping is presented using solid phase melting curve analysis to discriminate mutations at a single base resolution. Starting with a glass based concept (paper I) which is further developed to a foil based system (paper II), detection of the polymorphism in the neuropeptide Y associated with increased risk of type II diabetes is demonstrated as a proof of principle. Further development and optimization of the microheater concept has enabled roll-to-roll manufacturing compatibility and multiplexing of targets (paper III). A bacterial sub-typing and multiresistance detection in clinical Staphylococcus Aureus samples is demonstrated for applications in infectious diseases diagnostics. Finally, the microheater concept is further developed to enable μPCR (paper IV). Detection of genomic HIV-1 is demonstrated and a portable detection setup based on an LED light source and low cost CMOS camera for detection was developed. A second aspect of this thesis is integration of light sources and optical detection (paper V-VI). A multilayer system integrating an electroluminescent light source, reactive sensor dyes and organic semiconductor transistor for detection is demonstrated. The system could be used for amine detection in gases (paper V). System was made further roll-to-roll compatible. The system uses an external LED light source and a photodetector processed in only one screen printing- and one dispensing step (paper VI). As a proof of principle, absorbance based DNA hybridization was detected. Collectively, roll-to-roll manufacturing compatible “lab on foil” systems have the potential to improve our ability to diagnose at POC especially at resource-limited settings.

Place, publisher, year, edition, pages
KTH: KTH Royal Institute of Technology, 2017. , 83 p.
Series
TRITA-BIO-Report, ISSN 1654-2312 ; 2017:12
National Category
Medical Engineering Medical Laboratory and Measurements Technologies
Research subject
Biotechnology; Medical Technology; Materials Science and Engineering
Identifiers
URN: urn:nbn:se:kth:diva-205933ISBN: 978-91-7729-372-9 (print)OAI: oai:DiVA.org:kth-205933DiVA: diva2:1090968
Public defence
2017-05-19, Air and Fire, Scilife lab, Tomtebodav.23A, Stockholm, 13:00 (English)
Opponent
Supervisors
Note

QC 20170426

Available from: 2017-04-26 Created: 2017-04-25 Last updated: 2017-04-28Bibliographically approved
List of papers
1. Genotyping by dynamic heating of monolayered beads on a microheated surface
Open this publication in new window or tab >>Genotyping by dynamic heating of monolayered beads on a microheated surface
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2004 (English)In: Electrophoresis, ISSN 0173-0835, E-ISSN 1522-2683, Vol. 25, no 21-22, 3712-3719 p.Article in journal (Refereed) Published
Abstract [en]

 A miniaturized bead-based dynamic allele-specific hybridization (DASH) approach for sing le-nucleotide polymorphism analysis is presented. Chips with integrated heater and temperature sensors for open-surface DNA analysis were microfabricated. Microcontact printing using a poly(dimethylsiloxane) (PDMS) stamp was employed to create monolayers of immobilized beads on the surface of the chip. This chip allows fast, well-controllable temperature ramping. The temperature distribution was homogeneous over the entire heater area. All three possible variants of an SNP site of a synthesized oligonucleotide were accurately scored using the bead-based DASH approach. Our assay has a nonoptimized temperature ramping rate of 4degreesC-6degreesC/min compared to earlier reported values of 2degreesC-3degreesC/min, thereby reducing the total analysis time by a factor of 2. Reliable DASH measurement data from areas as small as 12 x 13 mum was achieved. Our bead-based DASH approach has enabled a dramatic volume reduction and is a step towards developing a cost-effective high-throughput DASH method on arrays of single beads.

Keyword
beads, dynamic allele-specific hybridization, microcontact printing, microheater, miniaturization, single-nucleotide polymorphism
National Category
Medical Genetics
Identifiers
urn:nbn:se:kth:diva-5011 (URN)10.1002/elps.200406065 (DOI)000225679000021 ()2-s2.0-10944219819 (Scopus ID)
Note

QC 20100916 20110915

Available from: 2005-04-01 Created: 2005-04-01 Last updated: 2017-04-26Bibliographically approved
2. Genotyping of single nucleotide polymorphisms by melting curve analysis using thin film semi-transparent heaters integrated in a lab-on-foil system
Open this publication in new window or tab >>Genotyping of single nucleotide polymorphisms by melting curve analysis using thin film semi-transparent heaters integrated in a lab-on-foil system
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2013 (English)In: Lab on a Chip, ISSN 1473-0197, E-ISSN 1473-0189, Vol. 13, no 11, 2075-2082 p.Article in journal (Refereed) Published
Abstract [en]

The recent technological advances in micro/nanotechnology present new opportunities to combine microfluidics with microarray technology for the development of small, sensitive, single-use, point-of-care molecular diagnostic devices. As such, the integration of microarray and plastic microfluidic systems is an attractive low-cost alternative to glass based microarray systems. This paper presents the integration of a DNA microarray and an all-polymer microfluidic foil system with integrated thin film heaters, which demonstrate DNA analysis based on melting curve analysis (MCA). A novel micro-heater concept using semi-transparent copper heaters manufactured by roll-to-roll and lift-off on polyethylene naphthalate (PEN) foil has been developed. Using a mesh structure, heater surfaces have been realized in only one single metallization step, providing more efficient and homogenous heating characteristics than conventional meander heaters. A robust DNA microarray spotting protocol was adapted on Parylene C coated heater-foils, using co-polymer poly(DMA-NAS-MAPS) to enable covalent immobilization of DNA. The heaters were integrated in a microfluidic channel using lamination foils and MCA of the spotted DNA duplexes showed single based discrimination of mismatched over matched target DNA-probes. Finally, as a proof of principle, we perform MCA on PCR products to detect the Leu7Pro polymorphism of the neutropeptide Y related to increased risk of Type II diabetes, BMI and depression.

Keyword
article, body mass, depression, devices, DNA determination, DNA microarray, film, foil, heating, melting curve analysis, non insulin dependent diabetes mellitus, nucleic acid analysis, polymerase chain reaction, priority journal, single nucleotide polymorphism, thin film heater
National Category
Biochemistry and Molecular Biology
Identifiers
urn:nbn:se:kth:diva-123643 (URN)10.1039/c3lc50171j (DOI)000318514400008 ()2-s2.0-84877682690 (Scopus ID)
Funder
Science for Life Laboratory - a national resource center for high-throughput molecular bioscience
Note

QC 20130614

Available from: 2013-06-14 Created: 2013-06-13 Last updated: 2017-04-27Bibliographically approved
3. Staphylococcus Aureus subtyping and detection of MRSA on a microfluidic lab-on-Foil device
Open this publication in new window or tab >>Staphylococcus Aureus subtyping and detection of MRSA on a microfluidic lab-on-Foil device
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(English)Manuscript (preprint) (Other academic)
National Category
Biomedical Laboratory Science/Technology
Identifiers
urn:nbn:se:kth:diva-205726 (URN)
Funder
Science for Life Laboratory - a national resource center for high-throughput molecular bioscience
Note

QC 20170427

Available from: 2017-04-24 Created: 2017-04-24 Last updated: 2017-05-29Bibliographically approved
4. Lab-on-foil based portable microPCR for point-of-care nucleic acid testing of HIV-1
Open this publication in new window or tab >>Lab-on-foil based portable microPCR for point-of-care nucleic acid testing of HIV-1
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(English)Manuscript (preprint) (Other academic)
National Category
Biomedical Laboratory Science/Technology
Identifiers
urn:nbn:se:kth:diva-205728 (URN)
Funder
Science for Life Laboratory - a national resource center for high-throughput molecular bioscience
Note

QC 20170427

Available from: 2017-04-24 Created: 2017-04-24 Last updated: 2017-05-29Bibliographically approved
5. Polymer opto-chemical-electronic based module as a detection system for volatile analytes on a foil substrate
Open this publication in new window or tab >>Polymer opto-chemical-electronic based module as a detection system for volatile analytes on a foil substrate
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2012 (English)In: Proceedings of SPIE - The International Society for Optical Engineering, SPIE - International Society for Optical Engineering, 2012, Vol. 8479Conference paper, Published paper (Other academic)
Abstract [en]

In this paper, we report on a novel device that addresses the needs for an efficient, field deployable and disposable system in the field of bio-chemical sensors using organic semiconductors. The Fraunhofer Institute has enabled a complete roll-to-roll manufactured polymer-opto-chemical-electronic module on a foil substrate, wherein an electroluminescent light source has been hetero-integrated together with an organic TFT, working as a photo detector. A chemically sensitive, colour changing film is sandwiched in between the two elements to form an optical detection system for volatile analytes such as amines. The setup, henceforth referred to as the “PolyOpto” module, comprises of a dye coated layer that can detect specific chemical reactions by colour change inserted in between the EL light source and the OTFT photo-detector. A hole is laser cut through the system to allow the sensor layer to come in contact with the gases, which then through a chemical reaction, changes colour and initiates a different response in the output of the organic transistor. Hence, this allows for a disposable chemo-analytical system that can be used in various application fields. As compared to conventional systems, the advantage here lies in the direct integration of the different functionalities without any advanced assembly steps, simultaneous use of coatings for both components (transparent electrode and wiring layer) and roll-to-roll compatibility, thus rendering a disposable system. We believe that it aptly demonstrates the capabilities of polytronics in functional integration for low-cost bio-sensor manufacturing

Place, publisher, year, edition, pages
SPIE - International Society for Optical Engineering, 2012
National Category
Polymer Technologies
Identifiers
urn:nbn:se:kth:diva-205724 (URN)10.1117/12.929821 (DOI)000312029300002 ()2-s2.0-84872167248 (Scopus ID)
Conference
Proc. SPIE 8479, Organic Semiconductors in Sensors and Bioelectronics V
Note

QC 20170424

Available from: 2017-04-24 Created: 2017-04-24 Last updated: 2017-05-29Bibliographically approved
6. DNA Analysis on integrated all foil based microdevices
Open this publication in new window or tab >>DNA Analysis on integrated all foil based microdevices
(English)Manuscript (preprint) (Other academic)
National Category
Biomedical Laboratory Science/Technology
Identifiers
urn:nbn:se:kth:diva-205727 (URN)
Note

QC 20170424

Available from: 2017-04-24 Created: 2017-04-24 Last updated: 2017-05-29Bibliographically approved

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