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Microfluidic biosensor systems for cardiotoxicity assaying
Linköping University, Department of Physics, Chemistry and Biology, Biotechnology. Linköping University, Faculty of Science & Engineering.
2015 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Toxicity screening is an important part of pharmaceutical development and early detection of toxic side effects provide the opportunity for early redesign or termination of unfeasible projects. Today toxicity testing is relying on experiments on animals. Ethical concerns, high costs and problems with interspecies variability in animal experiments have introduced incentives for cell-based toxicity assays. The recent development of stem cell technology have raised the hope for toxicity testing with higher predictivity that can reduce the amount of animals sacrificed, increase the patient safety and reduce the costs in pharmaceutical development.

Cell development and behavior is to a large extent dependent on the microenvironment. Microfluidic techniques can be used to build small-sized structures that provide the opportunity to introduce a high degree of control of the cell culture environment with features in cell sizes. In this thesis is demonstrated two different methods for infusing cells into microfluidic cell culture devices using either cells clustered in cardiac bodies during differentiation or cells pre-seeded in microporous carriers prior to infusion.

Microfluidic cell culture devices are well suited for optical  evaluation. Demonstrated in this thesis is fluorescent staining in combination with confocal microscopy as well as automated imaging with evaluation of beating frequency of cardiomyocyte cell clusters can be used to assess toxicity of cells cultured in microfluidic devices.

Biosensors use biological recognition elements to measure the presence of a chemical substance, for example low concentrations of biomarkers secreted by cells in a toxicity assay. Especially capacitive biosensors have shown very low limit of detection. In addition, protein G is demonstrated as an affinity ligand to capture IgG antibodies used as recognition element in a biosensor application or used for antibody screening.

Place, publisher, year, edition, pages
Linköping: Linköping University Electronic Press, 2015. , 49 p.
Series
Linköping Studies in Science and Technology. Dissertations, ISSN 0345-7524 ; 1678
National Category
Biological Sciences Physical Sciences
Identifiers
URN: urn:nbn:se:liu:diva-118295ISBN: 978-91-7519-046-4 (print)OAI: oai:DiVA.org:liu-118295DiVA: diva2:814068
Public defence
2015-06-12, Visionen, B-huset, Campus Valla, Linköping, 14:00 (Swedish)
Opponent
Supervisors
Available from: 2015-05-26 Created: 2015-05-26 Last updated: 2015-10-02Bibliographically approved
List of papers
1. Orientation and capturing of antibody affinity ligands: Applications to surface plasmon resonance biochips
Open this publication in new window or tab >>Orientation and capturing of antibody affinity ligands: Applications to surface plasmon resonance biochips
2011 (English)In: Sensors and actuators. B, Chemical, ISSN 0925-4005, Vol. 158, no 1, 265-270 p.Article in journal (Refereed) Published
Abstract [en]

A surface plasmon resonance (SPR) sensor chip with immobilized protein G was used for simultaneously capturing, purifying and orienting antibody ligands. The ligands were further stabilized by chemical cross-linking. This procedure of designing the sensor chip improved efficient use of the ligands and could prolong the analytical use. less thanbrgreater than less thanbrgreater thanThe procedure was evaluated on standard dextran-coated sensor chips onto which commercial semi-purified antibodies towards human serum albumin and human troponin where captured and used for analysing their antigens. less thanbrgreater than less thanbrgreater thanThe procedure demonstrates a general design approach for presenting the biorecognition element on a biosensor surface which enhances sensitivity, stability and selectivity at the same time as an impure ligand is purified.

Place, publisher, year, edition, pages
Elsevier, 2011
Keyword
Biosensor, Affinity interaction, SPR, Biacore, Protein G, Sensor chip
National Category
Engineering and Technology
Identifiers
urn:nbn:se:liu:diva-71770 (URN)10.1016/j.snb.2011.06.017 (DOI)000295500200037 ()
Note

Funding Agencies|European Commission|LSHB-CT-2007-037636|

Available from: 2011-11-04 Created: 2011-11-04 Last updated: 2015-05-28
2. Macroporous microcarriers for introducing cells into a microfluidic chip
Open this publication in new window or tab >>Macroporous microcarriers for introducing cells into a microfluidic chip
2014 (English)In: Lab on a Chip, ISSN 1473-0197, E-ISSN 1473-0189, Vol. 14, no 18, 3502-3504 p.Article in journal (Refereed) Published
Abstract [en]

Macroporous gelatin beads (CultiSpher™ microcarriers) provide a convenient method for rapidly and reliably introducing cells cultured ex situ into a microfluidic device, where the spheres create a 3D environment for continued cell proliferation. We demonstrate the usefulness of this technique with a proof-of-concept viability analysis of cardiac cells after treatment with doxorubicin. © 2014 the Partner Organisations.

Place, publisher, year, edition, pages
Royal Society of Chemistry, 2014
National Category
Biological Sciences Physical Sciences
Identifiers
urn:nbn:se:liu:diva-109971 (URN)10.1039/c4lc00693c (DOI)000340474300008 ()25068539 (PubMedID)2-s2.0-84905837163 (ScopusID)
Funder
Swedish Research Council, 2008-7537 2011-6404
Note

Acknowledgements

The primary embryonic cardiomyocytes were provided byJordi Altimiras, Department of Physics, Chemistry andBiology, Linköping University. The authors thank the SwedishResearch Council (Vetenskapsrådet) for fundingviagrants 2008-7537 and 2011-6404

Available from: 2014-08-29 Created: 2014-08-29 Last updated: 2015-06-01Bibliographically approved
3. Capacitive biosensor for detection of toxicity biomarkers
Open this publication in new window or tab >>Capacitive biosensor for detection of toxicity biomarkers
2015 (English)Manuscript (preprint) (Other academic)
Abstract [en]

Microfluidic devices are rapidly gaining importance for in vitro toxicity testing. Biomarker detection in microfluidic assays are however challenging due to small sample sizes and low analyte concentration. Capacitive electrochemical biosensors have been reported to have high sensitivity and properties that are amenable for implementation into microfluidic devices.

In this work a biosensor application for troponin T (TnT) is presented. The sensor showed linear response to analyte over five orders of magnitude with the lowest detectable signal at 10-13 M. The sensor proved to be able to detect TnT spiked in cell culture media at concentrations relevant for cell cultures.

National Category
Biological Sciences Physical Sciences
Identifiers
urn:nbn:se:liu:diva-118293 (URN)
Available from: 2015-05-26 Created: 2015-05-26 Last updated: 2015-05-26
4. Stem cell derived in vivo-like human cardiac bodies in a microfluidic device for toxicity testing by beating frequency imaging
Open this publication in new window or tab >>Stem cell derived in vivo-like human cardiac bodies in a microfluidic device for toxicity testing by beating frequency imaging
Show others...
2015 (English)In: Lab on a Chip, ISSN 1473-0197, E-ISSN 1473-0189, Vol. 15, no 15, 3242-3249 p.Article in journal (Refereed) Published
Abstract [en]

Beating in vivo-like human cardiac bodies (CBs) were used in a microfluidic device for testing cardiotoxicity. The CBs, cardiomyocyte cell clusters derived from induced pluripotent stem cells, exhibited typical structural and functional properties of the native human myocardium. The CBs were captured in niches along a perfusion channel in the device. Video imaging was utilized for automatic monitoring of the beating frequency of each individual CB. The device allowed assessment of cardiotoxic effects on the 3D clustered cardiomyocytes from the drug substances doxorubicin, verapamil and quinidine. Beating frequency data recorded over a period of 6 hours are presented and compared to literature data. The results indicate that this microfluidic setup with imaging of CB characteristics provides a new opportunity for label-free, non-invasive investigation of toxic effects in a 3D microenvironment.

Place, publisher, year, edition, pages
Royal Society of Chemistry, 2015
National Category
Biological Sciences Physical Sciences
Identifiers
urn:nbn:se:liu:diva-118294 (URN)10.1039/c5lc00449g (DOI)000358022900017 ()
Available from: 2015-05-26 Created: 2015-05-26 Last updated: 2015-08-11Bibliographically approved

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