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Organs-on-chips for the pharmaceutical development process: design perspectives and implementations
Linköping University, Department of Physics, Chemistry and Biology, Biotechnology. Linköping University, Faculty of Science & Engineering.
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 [en]
Organs-on-chips, cell culture models, pharmaceutical development, microfluidics
National Category
Cell and Molecular Biology
Identifiers
URN: urn:nbn:se:liu:diva-145300DOI: 10.3384/diss.diva-145300ISBN: 9789176853597 (print)OAI: oai:DiVA.org:liu-145300DiVA, id: diva2:1184461
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
List of papers
1. 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, 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
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: 2018-02-21Bibliographically approved
2. A clip-on electroosmotic pump for oscillating flow in microfluidic cell culture devices
Open this publication in new window or tab >>A clip-on electroosmotic pump for oscillating flow in microfluidic cell culture devices
2018 (English)In: Microfluidics and Nanofluidics, ISSN 1613-4982, E-ISSN 1613-4990, Vol. 22, no 3, article id 27Article in journal (Refereed) Published
Abstract [en]

Recent advances in microfluidic devices put a high demand on small, robust and reliable pumps suitable for high-throughput applications. Here we demonstrate a compact, low-cost, directly attachable (clip-on) electroosmotic pump that couples with standard Luer connectors on a microfluidic device. The pump is easy to make and consists of a porous polycarbonate membrane and poly(3,4-ethylenedioxythiophene) polystyrene sulfonate (PEDOT:PSS) electrodes. The soft electrode and membrane materials make it possible to incorporate the pump into a standard syringe filter holder, which in turn can be attached to commercial chips. The pump is less than half the size of the microscope slide used for many commercial lab-on-a-chip devices, meaning that these pumps can be used to control fluid flow in individual reactors in highly parallelized chemistry and biology experiments. Flow rates at various electric current and device dimensions are reported. We demonstrate the feasibility and safety of the pump for biological experiments by exposing endothelial cells to oscillating shear stress (up to 5 dyn/cm2) and by controlling the movement of both micro- and macroparticles, generating steady or oscillatory flow rates up to ± 400 μL/min.

Place, publisher, year, edition, pages
Springer Berlin/Heidelberg, 2018
National Category
Other Medical Biotechnology
Identifiers
urn:nbn:se:liu:diva-145301 (URN)10.1007/s10404-018-2046-4 (DOI)000427527600005 ()
Note

Funding agencies: Swedish Research Council (Vetenskapsradet) [2015-03298]

Available from: 2018-02-21 Created: 2018-02-21 Last updated: 2018-04-12Bibliographically approved
3. Developing organ-on-a-chip concepts using bio-mechatronic design methodology
Open this publication in new window or tab >>Developing organ-on-a-chip concepts using bio-mechatronic design methodology
2017 (English)In: Biofabrication, ISSN 1758-5082, E-ISSN 1758-5090, Vol. 9, no 2, article id 025023Article in journal (Refereed) Published
Abstract [en]

Mechatronic design is an engineering methodology for conceiving, configuring and optimising the design of a technical device or product to the needs and requirements of the final user. In this article, we show how the basic principles of this methodology can be exploited for in vitro cell cultures-often referred to as organ-on-a-chip devices. Due to the key role of the biological cells, we have introduced the term bio-mechatronic design, to highlight the complexity of designing a system that should integrate biology, mechanics and electronics in the same device structure. The strength of the mechatronic design is to match the needs of the potential users to a systematic evaluation of overall functional design alternative. It may be especially attractive for organs-on-chips where biological constituents such as cells and tissues in 3D settings and in a fluidic environment should be compared, screened and selected. Through this approach, design solutions ranked to customer needs are generated according to specified criteria, thereby defining the key constraints of the fabrication. As an example, the bio-mechatronic methodology is applied to a liver-on-a-chip based on information extrapolated from previous theoretical and experimental knowledge. It is concluded that the methodology can generate new fabrication solutions for devices, as well as efficient guidelines for refining the design and fabrication of many of todays organ-on-a-chip devices.

Place, publisher, year, edition, pages
IOP PUBLISHING LTD, 2017
Keywords
conceptual design; design optimisation; organ-on-a-chip; physiological tissue models; microfluidics
National Category
Cell and Molecular Biology
Identifiers
urn:nbn:se:liu:diva-138470 (URN)10.1088/1758-5090/aa71ca (DOI)000402555300006 ()28485301 (PubMedID)
Note

Funding Agencies|Innovative Medicines Initiative Joint Undertaking [115439]; European Unions Seventh Framework Programme; EFPIA

Available from: 2017-06-19 Created: 2017-06-19 Last updated: 2018-02-21

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Christoffersson, Jonas

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