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Stem cell derived in vivo-like human cardiac bodies in a microfluidic device for toxicity testing by beating frequency imaging
Linköping University, Department of Physics, Chemistry and Biology, Biotechnology. Linköping University, The Institute of Technology.
Linköping University, Department of Physics, Chemistry and Biology, Biotechnology. Linköping University, Faculty of Science & Engineering.
Hannover Medical School, Leibniz Research Laboratories for Biotechnology and Artificial Organs -LEBAO-, Hannover, Germany.
Hannover Medical School, Leibniz Research Laboratories for Biotechnology and Artificial Organs -LEBAO-, Hannover, Germany.
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2015 (English)In: Lab on a Chip, ISSN 1473-0197, E-ISSN 1473-0189, Vol. 15, no 15, p. 3242-3249Article 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. Vol. 15, no 15, p. 3242-3249
National Category
Biological Sciences Physical Sciences
Identifiers
URN: urn:nbn:se:liu:diva-118294DOI: 10.1039/c5lc00449gISI: 000358022900017OAI: oai:DiVA.org:liu-118294DiVA, id: diva2:814066
Available from: 2015-05-26 Created: 2015-05-26 Last updated: 2018-02-21Bibliographically approved
In thesis
1. Microfluidic biosensor systems for cardiotoxicity assaying
Open this publication in new window or tab >>Microfluidic biosensor systems for cardiotoxicity assaying
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. p. 49
Series
Linköping Studies in Science and Technology. Dissertations, ISSN 0345-7524 ; 1678
National Category
Biological Sciences Physical Sciences
Identifiers
urn:nbn:se:liu:diva-118295 (URN)978-91-7519-046-4 (ISBN)
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
2. Organs-on-chips for the pharmaceutical development process: design perspectives and implementations
Open this publication in new window or tab >>Organs-on-chips for the pharmaceutical development process: design perspectives and implementations
2018 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Organs-on-chips are dynamic cell culture devices created with the intention to mimic organ function in vitro. Their purpose is to assess the toxicity and efficacy of drugs and, as early as possible in the pharmaceutical development process, predict the outcome of clinical trials. The aim of this thesis is to explain and discuss these cell culture devices from a design perspective and to experimentally exemplify some of the specific functions that characterize organs-on-chips.

The cells in our body reside in complex environments with chemical and mechanical cues that affect their function and purpose. Such a complex environment is difficult to recreate in the laboratory and has therefore been overlooked in favor of more simple models, i.e. static twodimensional (2D) cell cultures. Numerous recent reports have shown cell culture systems that can resemble the cell’s natural habitat and enhance cell functionality and thereby potentially provide results that better reflects animal and human trials. The way these organs-on-chips improve in vitro cell culture assays is to include e.g. a three-dimensional cell architecture (3D), mechanical stimuli, gradients of oxygen or nutrients, or by combining several relevant cell types that affect each other in close proximity.

The research conducted for this thesis shows how cells in 3D spheroids or in 3D hydrogels can be cultured in perfused microbioreactors. Furthermore, a pump based on electroosmosis, and a method for an objective conceptual design process, is introduced to the field of organs-on-chips.

Place, publisher, year, edition, pages
Linköping: Linköping University Electronic Press, 2018. p. 78
Series
Linköping Studies in Science and Technology. Dissertations, ISSN 0345-7524 ; 1907
Keywords
Organs-on-chips, cell culture models, pharmaceutical development, microfluidics
National Category
Cell and Molecular Biology
Identifiers
urn:nbn:se:liu:diva-145300 (URN)10.3384/diss.diva-145300 (DOI)9789176853597 (ISBN)
Public defence
2018-03-23, Planck, Fysikhuset, Campus Valla, Linköping, 13:30 (English)
Opponent
Supervisors
Note

I den tryckta versionen är det ena serienamnet felaktigt. I den elektroniska versionen är detta ändrat till korrekt "Linköping Studies in Science and Technology. Dissertations"

Available from: 2018-02-21 Created: 2018-02-21 Last updated: 2018-04-24Bibliographically approved

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Bergström, GunnarChristoffersson, JonasMandenius, Carl-Fredrik

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