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OSTE Microfluidic Technologies for Cell Encapsulation and Biomolecular Analysis
KTH, School of Electrical Engineering (EES), Micro and Nanosystems. (Microfluidics)ORCID iD: 0000-0002-9418-452X
2017 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

In novel drug delivery system, the encapsulation of therapeutic cells in microparticles has great promises for the treatment of a range of health con- ditions. Therefore, the encapsulation material and technology are of great importance to the validity and efficiency of the advanced medical therapy. Several unsolved challenges in regards to versatile microparticle synthesis ma- terials and methods form the main obstacle for a translation of novel cell therapy concepts from research to clinical practice.

Thiol-ene based polymer systems have emerged and gained great popular- ity in material development in general and in biomedical applications specif- ically. The thiol-ene platform is broad and therefore of interest for a variety of applications. At the same time, many aspects of this material platform are largely unexplored, for example material and manufacturing technology developments for microfluidic applications .

In this Ph.D. thesis, thiol-ene materials are explored for use in cell encap- sulation. The marriage of these two technology fields breeds the possibility for a novel microfluidic cell encapsulation approach using a novel encapsulation material. To this end, several new manufacturing technologies for thiol-ene and thiol-ene-epoxy droplet microfluidic devices were developed. Moreover, core-shell microparticle synthesis for cell encapsulation based on a novel co- synthesis concept using a thiol-ene based material was developed and inves- tigated. Finally, a thiol-ene-epoxy system was also used for the formation of microwells and microchannels that improve protein analysis on microarrays.

The first part of the thesis presents the background and state-of-the-art technologies in regards to cell therapy, microfluidics, and thiol-ene based ma- terials. In the second part of the thesis, a novel manufacturing approach of thiol-ene-epoxy material as well as core-shell particle co-synthesis in micro- fluidics using thiol-ene based material are presented and characterized. The third part of the thesis presents the cell viability studies of encapsulated cells using the novel encapsulation material and method. In the final part of the thesis, two applications of thiol-ene-epoxy gaskets for protein detection mi- croarrays are presented. 

Abstract [sv]

Inkapsling av levande celler i mikrokapslar för terapeutiska ändamål är mycket lovande för frmatida behandling av många olika sjukdomar. Emeller- tid är en behandlings effektivitet i hög grad beroende av vilka material som används för inkapsling och vilken teknisk lösning som används för att ska- pa mikrokapslarna. För närvarande återstår det många utmaningar för att omvandla grundforskningresultat till klinisk verklighet, vilken kräver mer än- damålsenliga tillvägagångssätt för att tillverka mikrokapslar i material som är kompatibla med användningsområdena.

De senaste åren har tiol-en baserade polymerer har blivit mycket använda för materialutveckling i stort och för biomedicinska tillämpningar i synnerhet. Med tiol-en kemi kan en mycket stor mängd helt olika syntetiska material framställas, vilket gör tiol-ener intressanta för en mängd applikationer. För närvarande är dock mycket inom denna materialklass outforskat, t.ex. inom material och tillverkningmetodik för mikrofluidiktillämpningar.

I denna avhandling används tiol-ener för cellinkapsling. Sammanslagning av dessa teknologier möjliggör en ny typ av cellinkapsling med nya materi- alegenskaper. En mängd olika tillverkningssätt där tiol-en eller tiol-en-epoxi används för droplet-mikrofluidiksystem utvecklades. Core-shell mikrokapsel- syntes för cell-inkapsling baserat på en ny metod för samtidig syntes av både core och shell utvecklades och karaktäriserades. Slutligen utvecklades ett tiol- en-epoxi system för enkel integrering med proteinmikroarrayer på objektsglas.

I avhandlingens första del presenteras bakgrund och dagens bästa teknolo- gier för terapeutisk cellinkapsling, mikrofluidik och tiol-en baserade material. I avhandlingens andra del presenteras en ny tillverkningsmetod för mikro- strukturerade tiol-en-epoxi artiklar och samtidig syntes av core och shell för mikrokapslar med användande av mikrofluidik. I den tredje delen presenteras cellöverlevandsstudier för de celler som inkapslats med de nya materialen och de nyutvecklade metoderna. I den avslutande delen beskrivs två specifika fall där tiol-en-epoxi komponenter används för proteindetektion och mikroarrayer. 

Place, publisher, year, edition, pages
Stockholm: KTH Royal Institute of Technology, 2017. , p. 137
Series
TRITA-EES ; 2017:171
Keyword [en]
Microfluidics, microfabrication, cell encapsulation, core-shell particle, microparticle synthesis, off-stoichiometry-thiol-ene, OSTE, OSTE+, lab-on-a-chip, surface modification, core-shell particle co-synthesis, microar- ray, micromixer, bonding, surface modification, droplet microfluidics, protein screening.
Keyword [sv]
Mikrofluidik, mikrofabrikation, cellinkapsling, cores-shell kap- sel, mikrokapselsyntes, lab-on-chip, ickestökiometrisk tiol-en, OSTE, OSTE+, ytmodifiering, samtidig syntes av core-shellkapslar, mikroarray, mikromixer, sammanfogning, dropletmikrofluidik, proteindetektion.
National Category
Engineering and Technology
Research subject
Applied Medical Technology
Identifiers
URN: urn:nbn:se:kth:diva-217995ISBN: 978-91-7729-623-2 (print)OAI: oai:DiVA.org:kth-217995DiVA, id: diva2:1158538
Public defence
2017-12-15, M2, Brinellvägen 64, Stockholm, 09:00 (English)
Opponent
Supervisors
Funder
Swedish Childhood Cancer Foundation, 66673
Note

QC 20171122

Available from: 2017-11-22 Created: 2017-11-20 Last updated: 2017-11-22Bibliographically approved
List of papers
1. Ultrarapid synthesis of microbeads with tuneable surface probe density
Open this publication in new window or tab >>Ultrarapid synthesis of microbeads with tuneable surface probe density
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2016 (English)In: Ultrarapid synthesis of microbeads with tuneable surface probe density, Shanghai, China: IEEE conference proceedings, 2016, Vol. 2016, p. 731-734Conference paper, Published paper (Refereed)
Abstract [en]

We present, for the first time, a simplified and ultrarapid (~ 1s) approach for synthesis of microbeads with thiol- functionalized surfaces as potential binding sites, whose density can be tuned according to the ratio of two components in the prepolymer. We verify the successful generation of microbeads and their tuneable surface density resulted from different prepolymer off-stoichiometric ratio. This novel approach can be used for bioassays that require rapid surface capture probe binding and customized probe density for suitable bioreactions.

Place, publisher, year, edition, pages
Shanghai, China: IEEE conference proceedings, 2016
Series
Proceedings of the IEEE International Conference on Micro Electro Mechanical Systems (MEMS), ISSN 1084-6999 ; 2016
Keyword
microbeads, microfluidics, off-stoichiometry thiol-ene, OSTE
National Category
Medical and Health Sciences
Research subject
Materials Science and Engineering
Identifiers
urn:nbn:se:kth:diva-181779 (URN)10.1109/MEMSYS.2016.7421732 (DOI)000381797300192 ()2-s2.0-84970996576 (Scopus ID)978-150901973-1 (ISBN)
Conference
29th IEEE International Conference on Micro Electro Mechanical Systems, MEMS 2016, Shanghai, China, 24 January 2016 through 28 January 2016
Projects
Theracage
Funder
Stockholm County Council, 66673Swedish Childhood Cancer Foundation, 66673
Note

QC 20161018

Available from: 2016-02-03 Created: 2016-02-03 Last updated: 2017-11-22Bibliographically approved
2. Room-temperature bonding and debonding of stiff and robust microfluidic structures to biofunctionalized surfaces
Open this publication in new window or tab >>Room-temperature bonding and debonding of stiff and robust microfluidic structures to biofunctionalized surfaces
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(English)Manuscript (preprint) (Other academic)
National Category
Engineering and Technology
Identifiers
urn:nbn:se:kth:diva-217986 (URN)
Note

QC 20171121

Available from: 2017-11-20 Created: 2017-11-20 Last updated: 2017-11-22Bibliographically approved
3. Thiol–ene–epoxy thermoset for low-temperature bonding to biofunctionalized microarray surfaces
Open this publication in new window or tab >>Thiol–ene–epoxy thermoset for low-temperature bonding to biofunctionalized microarray surfaces
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2017 (English)In: Lab on a Chip, ISSN 1473-0197, E-ISSN 1473-0189, Vol. 17, no 21, p. 3672-3681Article in journal (Refereed) Published
Abstract [en]

One way to improve the sensitivity and throughput of miniaturized biomolecular assays is to integrate microfluidics to enhance the transport efficiency of biomolecules to the reaction sites. Such microfluidic integration requires bonding of a prefabricated microfluidic gasket to an assay surface without destroying its biological activity. In this paper we address the largely unmet challenge to accomplish a proper seal between a microfluidic gasket and a protein surface, with maintained biological activity and without contaminating the surface or blocking the microfluidic channels. We introduce a novel dual cure polymer resin for the formation of microfluidic gaskets that can be room-temperature bonded to a range of substrates using only UVA light. This polymer is the first polymer that features over a month of shelf life between the structure formation and the bonding, moreover the fully cured polymer gaskets feature the following set of properties suitable for microfluidics: high stiffness, which prevents microfluidic channel collapse during handling; very limited absorption of biomolecules; and no significant leaching of uncured monomers. We describe the novel polymer resin and its characteristics, study through FT-IR, and demonstrate its use as microfluidic well-arrays bonded onto protein array slides at room temperature followed by multiplexed immunoassays. The results confirm maintained biological activity and show high repeatability between protein arrays. This new approach for integrating microfluidic gaskets to biofunctionalised surfaces has the potential to improve sample throughput and decrease manufacturing costs for miniaturized biomolecular systems.

Place, publisher, year, edition, pages
Royal Society of Chemistry, 2017
National Category
Engineering and Technology
Identifiers
urn:nbn:se:kth:diva-217985 (URN)10.1039/C7LC00652G (DOI)000413868700012 ()28975170 (PubMedID)2-s2.0-85032439147 (Scopus ID)
Funder
EU, FP7, Seventh Framework ProgrammeEU, FP7, Seventh Framework Programme
Note

QC 20171121

Available from: 2017-11-20 Created: 2017-11-20 Last updated: 2017-11-22Bibliographically approved
4. ONE-STEP INJECTION MOLDING OF OSTE+ MICROFLUIDIC DEVICES WITH SCREW THREADED PORTS
Open this publication in new window or tab >>ONE-STEP INJECTION MOLDING OF OSTE+ MICROFLUIDIC DEVICES WITH SCREW THREADED PORTS
2014 (English)Conference paper, Poster (with or without abstract) (Refereed)
Abstract [en]

We present a simplified method for molding internally threaded fluidic ports in microfluidic devices using a deformable mold and dual-cure OSTE+ polymer. We demonstrate a lab-on-a-chip device where monolithically integrated chip-to-world threaded interfaces, vias and microchannels are reaction injection molded in one single step. 

Place, publisher, year, edition, pages
Chemical and Biological Microsystems Society, 2014
Keyword
reaction injection molding, OSTE+, microfluidics, lab-on-a-chip, threaded ports, microfluidic interfacing, chip-to-world interface
National Category
Engineering and Technology Other Engineering and Technologies
Identifiers
urn:nbn:se:kth:diva-151258 (URN)2-s2.0-84941619242 (Scopus ID)978-097980647-6 (ISBN)
Conference
The 18th International Conference on Miniaturized Systems for Chemistry and Life Sciences,October 26-30, 2014, Texas, USA
Note

QC 20140922

Available from: 2014-09-16 Created: 2014-09-16 Last updated: 2017-11-22Bibliographically approved
5. Human Cell Encapsulation in Gel Microbeads with Cosynthesized Concentric Nanoporous Solid Shells
Open this publication in new window or tab >>Human Cell Encapsulation in Gel Microbeads with Cosynthesized Concentric Nanoporous Solid Shells
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2017 (English)Manuscript (preprint) (Other academic)
Abstract [en]

Encapsulation of therapeutic cells in core–shell microparticles has great promise for the treatment of a range of health conditions. Unresolved challenges related to control of the particle morphology, mechanical stability, and immunogenicity hinder dissemination of this promising approach. Here, a novel polymer material for cell encapsulation and a combined novel, easy to control, synthesis method are introduced. Core–shell cell encapsulation is demonstrated with a concentric core–shell morphology formed during a single UV exposure, resulting in particles that consist of a synthetic hydrogel core of polyethylene glycol diacrylate and a solid, but porous, shell of off‐stoichiometric thiol‐ene. The encapsulated human cells in 100 µm diameter particles have >90% viability. The average shell thickness is controlled between 7 and 13 µm by varying the UV exposure, and the shell is measured to be permeable to low molecular weight species (<180 Da) but impermeable to higher molecular weight species (>480 Da). The unique material properties and the orthogonal control of the microparticle core size, shell thickness, shell permeability, and shell surface properties address the key unresolved challenges in the field, and are expected to enable faster translation of novel cell therapy concepts from research to clinical practice.

Keyword
Nanotechnology, Micro and Nanosystems, Cancer, Cell therapy, Cell encapsulation, Biomedicine, MEMS, Soft Matter
National Category
Engineering and Technology
Research subject
Medical Technology
Identifiers
urn:nbn:se:kth:diva-217987 (URN)
Funder
Swedish Childhood Cancer Foundation
Note

QC 20171121

Available from: 2017-11-20 Created: 2017-11-20 Last updated: 2018-05-22Bibliographically approved
6. OSTE+ microfluidic devices with lithographically defined hydrophobic/ hydrophilic patterns and biocompatible chip sealing: OSTEmer Allows Easy Fabrication of Microfluidic Chips
Open this publication in new window or tab >>OSTE+ microfluidic devices with lithographically defined hydrophobic/ hydrophilic patterns and biocompatible chip sealing: OSTEmer Allows Easy Fabrication of Microfluidic Chips
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2014 (English)In: DIATECH 2014, 2014, p. 26-27Conference paper, Oral presentation with published abstract (Refereed)
Keyword
OSTE+, surface modification, microfabrication, microfluidics, theracage
National Category
Engineering and Technology Medical and Health Sciences
Identifiers
urn:nbn:se:kth:diva-155514 (URN)
Conference
DIATECH 2014, Leuven, Belgium
Projects
Theracage
Note

QC 20150302

Available from: 2014-11-06 Created: 2014-11-06 Last updated: 2017-11-22Bibliographically approved
7. Rapid Fabrication Of OSTE+ Microfluidic Devices With Lithographically Defined Hydrophobic/ Hydrophilic Patterns And Biocompatible Chip Sealing
Open this publication in new window or tab >>Rapid Fabrication Of OSTE+ Microfluidic Devices With Lithographically Defined Hydrophobic/ Hydrophilic Patterns And Biocompatible Chip Sealing
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2013 (English)In: 17th International Conference on Miniaturized Systems for Chemistry and Life Sciences, MicroTAS 2013, Freiburg, Germany: NO , 2013, p. 134-136Conference paper, Published paper (Refereed)
Abstract [en]

Here we present an uncomplicated and robust method for rapid prototyping of microfluidic devices featuring: 1) lithographically defined, permanently surface modified hydrophilic and hydrophobic regions with contact angles varying from 18o to 118o, in which all four channel walls are surface modified in a single step using polymer chain grafting; 2) polymer chains grafted from open surfaces before bonding, making this method suitable for batch fabrication; 3) biomolecule-compatible, room temperature, dry, homogeneous chip-sealing, in which native as well as hydrophobic/hydrophilic modified OSTE+ surfaces allow for epoxy-epoxy and thiol-epoxy covalent bonding, hence greatly simplifying alignment and dramatically increasing device yields. We demonstrate the method with a functional microfluidic device. This represents a complete, simplified and robust method for batch-manufacturing compatible prototyping of microfluidic devices with tunable mechanical and surface properties. 

Place, publisher, year, edition, pages
Freiburg, Germany: NO, 2013
Keyword
Theracage, OSTE+, surface modification, lithography
National Category
Engineering and Technology
Identifiers
urn:nbn:se:kth:diva-124640 (URN)2-s2.0-84905743758 (Scopus ID)978-0-9798064-6-9 (ISBN)
Conference
The 17th International Conference on Miniaturized Systems for Chemistry and Life Sciences (MicroTAS), 27-31 October 2013, Freiburg, Germany
Projects
Theracage
Note

QC 20171122

Available from: 2013-07-23 Created: 2013-07-23 Last updated: 2017-11-22Bibliographically approved
8. ROBUST MICRODEVICE MANUFACTURING BY DIRECT LITHOGRAPHY AND ADHESIVE-FREE BONDING OF OFF-STOICHIOMETRY THIOL-ENE-EPOXY (OSTE+) POLYMER
Open this publication in new window or tab >>ROBUST MICRODEVICE MANUFACTURING BY DIRECT LITHOGRAPHY AND ADHESIVE-FREE BONDING OF OFF-STOICHIOMETRY THIOL-ENE-EPOXY (OSTE+) POLYMER
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2013 (English)In: 17th IEEE International Conference on Solid-State Sensors, Actuators and Microsystems & EUROSENSORS XXVII (IEEE TRANSDUCERS 2013), IEEE conference proceedings, 2013, p. 408-411Conference paper, Published paper (Refereed)
Abstract [en]

We here demonstrate, for the first time, the use of direct lithography in off-stoichiometry thiol-ene-epoxy (OSTE+) to fabricate a microdevice. First, the photolithographic property of OSTE+ is shown by using a photomask to create micropillars with an aspect-ratio of 1:10 in a 2 mm thick layer. Secondly, a three-layer OSTE+ microdevice containing in-/outlet holes, channels, and pillars is fabricated by using a combination of direct lithography and adhesive-free dry bonding. The resulting microdevice shows desirable properties, such as leak-free filling and hydrophilic surfaces. This fabrication method enhances the microstructurability of OSTE+ beyond that of conventional soft lithography replica molding of other polymers, such as PDMS.

Place, publisher, year, edition, pages
IEEE conference proceedings, 2013
Keyword
Bonding, epoxy, microdevice fabrication, Microfluidics, OSTE+, photolithography, soft lithography, thiol, thiol-ene
National Category
Polymer Technologies Nano Technology
Identifiers
urn:nbn:se:kth:diva-124782 (URN)10.1109/Transducers.2013.6626789 (DOI)2-s2.0-84891691276 (Scopus ID)978-146735981-8 (ISBN)
Conference
17th IEEE International Conference on Solid-State Sensors, Actuators and Microsystems & EUROSENSORS XXVII (IEEE TRANSDUCERS 2013), Barcelona, Spain, 16-20 Jun, 2013
Projects
RoutineRappidXMEMS
Note

QC 20140212

Available from: 2013-07-31 Created: 2013-07-31 Last updated: 2017-11-22Bibliographically approved
9. Core-Shell Microparticle Synthesis In Droplet Microfluidics Using A Single Step Polymerization
Open this publication in new window or tab >>Core-Shell Microparticle Synthesis In Droplet Microfluidics Using A Single Step Polymerization
Show others...
2015 (English)In: Micro Electro Mechanical Systems (MEMS), 2015 28th IEEE International Conference on, IEEE conference proceedings, 2015, p. 472-475Conference paper, Published paper (Refereed)
Abstract [en]

We present, for the first time, a method for the synthesis of core-shell microparticles in a single polymerization step using two-phase droplet microfluidics. We verify the successful generation of core-shell microparticles using the novel synthesis approach. 

Place, publisher, year, edition, pages
IEEE conference proceedings, 2015
Keyword
core-shell, microfluidics, polymer, OSTE+, theracage
National Category
Medical and Health Sciences Chemical Engineering
Research subject
Fibre and Polymer Science; Chemical Engineering
Identifiers
urn:nbn:se:kth:diva-155525 (URN)10.1109/MEMSYS.2015.7050994 (DOI)000370382900125 ()2-s2.0-84931034246 (Scopus ID)978-1-4799-7955-4 (ISBN)
Conference
IEEE MEMS 2015, Estoril, Portugal,18-22 Jan. 2015
Projects
Theracage
Note

QC 20150302

Available from: 2014-11-06 Created: 2014-11-06 Last updated: 2017-11-22Bibliographically approved

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