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Christoffersson, J., Aronsson, C., Jury, M., Selegård, R., Aili, D. & Mandenius, C.-F. (2019). Fabrication of modular hyaluronan-PEG hydrogels to support 3D cultures of hepatocytes in a perfused liver-on-a-chip device. Biofabrication, 11(1), Article ID 015013.
Open this publication in new window or tab >>Fabrication of modular hyaluronan-PEG hydrogels to support 3D cultures of hepatocytes in a perfused liver-on-a-chip device
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2019 (English)In: Biofabrication, ISSN 1758-5082, E-ISSN 1758-5090, Vol. 11, no 1, article id 015013Article in journal (Refereed) Published
Abstract [en]

Liver cell culture models are attractive in both tissue engineering and for development of assays for drug toxicology research. To retain liver specific cell functions, the use of adequate cell types and culture conditions, such as a 3Dorientation of the cells and a proper supply of nutrients and oxygen, are critical. In this article, we show how extracellular matrix mimetic hydrogels can support hepatocyte viability and functionality in a perfused liver-on-a-chip device. A modular hydrogel system based on hyaluronan and poly(ethylene glycol) (HA-PEG), modified with cyclooctyne moieties for bioorthogonal strain-promoted alkyne-azide 1, 3-dipolar cycloaddition (SPAAC), was developed, characterized, and compared for cell compatibility to hydrogels based on agarose and alginate. Hepatoma cells (HepG2) formed spheroids with viable cells in all hydrogels with the highest expression of albumin and urea in alginate hydrogels. By including an excess of cyclooctyne in theHA backbone, azide-modified cell adhesion motifs (linear and cyclicRGDpeptides) could be introduced in order to enhance viability and functionality of human induced pluripotent stem cell derived hepatocytes (hiPS-HEPs). In the HA-PEG hydrogels modified with cyclicRGDpeptides hiPS-HEPs migrated and grew in 3D and showed an increased viability and higher albumin production compared to when cultured in the other hydrogels. This flexible SPAAC crosslinked hydrogel system enabled fabrication of perfused 3D cell culture of hiPS-HEPs and is a promising material for further development and optimization of liver-on-a-chip devices.

Place, publisher, year, edition, pages
Institute of Physics Publishing (IOPP), 2019
Keywords
Organ-on-a-chip; biofabrication; bioorthogonal crosslinking; cell-binding motif; microfluidics
National Category
Cell and Molecular Biology
Identifiers
urn:nbn:se:liu:diva-153971 (URN)10.1088/1758-5090/aaf657 (DOI)000454550900002 ()30523863 (PubMedID)2-s2.0-85059228017 (Scopus ID)
Note

Funding Agencies|EU Innovative Medicines Initiative Joint Undertaking [115439]; European Union; Swedish Research Council (VR) [B0431901]; Swedish Foundation for Strategic Research (SFF) [FFL15-0026]; Carl Trygger Foundation [CTS15:79]; Knut and Alice Wallenberg Foundation [KAW 2016.0231]; Swedish Government Strategic Research Area in Materials Science on Functional Materials at Linkoping University (Faculty Grant SFO-Mat-LiU) [2009-00971]

Available from: 2019-01-22 Created: 2019-01-22 Last updated: 2019-02-01Bibliographically approved
Christoffersson, J., Aronsson, C., Jury, M., Selegård, R., Aili, D. & Mandenius, C.-F. (2018). Fabrication of modular hyaluronan-PEG hydrogels to support 3D cultures of hepatocytes in a perfused liver-on-a-chip device. Biofabrication, 11(1), 1-13, Article ID 015013.
Open this publication in new window or tab >>Fabrication of modular hyaluronan-PEG hydrogels to support 3D cultures of hepatocytes in a perfused liver-on-a-chip device
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2018 (English)In: Biofabrication, ISSN 1758-5082, E-ISSN 1758-5090, Vol. 11, no 1, p. 1-13, article id 015013Article in journal (Refereed) Published
Abstract [en]

Liver cell culture models are attractive in both tissue engineering and for development of assays for drug toxicology research. To retain liver specific cell functions, the use of adequate cell types and culture conditions, such as a 3D orientation of the cells and a proper supply of nutrients and oxygen, are critical. In this article, we show how extracellular matrix mimetic hydrogels can support hepatocyte viability and functionality in a perfused liver-on-a-chip device. A modular hydrogel system based on hyaluronan and poly(ethylene glycol) (HA-PEG), modified with cyclooctyne moieties for bioorthogonal strain-promoted alkyne-azide 1, 3-dipolar cycloaddition (SPAAC), was developed, characterized, and compared for cell compatibility to hydrogels based on agarose and alginate. Hepatoma cells (HepG2) formed spheroids with viable cells in all hydrogels with the highest expression of albumin and urea in alginate hydrogels. By including an excess of cyclooctyne in the HA backbone, azide-modified cell adhesion motifs (linear and cyclic RGD peptides) could be introduced in order to enhance viability and functionality of human induced pluripotent stem cell derived hepatocytes (hiPS-HEPs). In the HA-PEG hydrogels modified with cyclic RGD peptides hiPS-HEPs migrated and grew in 3D and showed an increased viability and higher albumin production compared to when cultured in the other hydrogels. This flexible SPAAC crosslinked hydrogel system enabled fabrication of perfused 3D cell culture of hiPS-HEPs and is a promising material for further development and optimization of liver-on-a-chip devices.

Place, publisher, year, edition, pages
Institute of Physics (IOP), 2018
National Category
Cell and Molecular Biology Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy) Cell Biology
Identifiers
urn:nbn:se:liu:diva-154008 (URN)10.1088/1758-5090/aaf657 (DOI)
Available from: 2019-01-22 Created: 2019-01-22 Last updated: 2019-01-22Bibliographically approved
Chen, H., Chen, P., Huang, J., Selegård, R., Platt, M., Palaniappan, A., . . . Liedberg, B. (2016). Detection of Matrilysin Activity Using Polypeptide Functionalized Reduced Graphene Oxide Field-Effect Transistor Sensor. Analytical Chemistry, 88(6), 2994-2998
Open this publication in new window or tab >>Detection of Matrilysin Activity Using Polypeptide Functionalized Reduced Graphene Oxide Field-Effect Transistor Sensor
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2016 (English)In: Analytical Chemistry, ISSN 0003-2700, E-ISSN 1520-6882, Vol. 88, no 6, p. 2994-2998Article in journal (Refereed) Published
Abstract [en]

A novel approach for rapid and sensitive detection of matrilysin (MMP-7, a biomarker involved in the degradation of various macromolecules) based on a polypeptide (JR2EC) functionalized reduced graphene oxide (rGO) field effect transistor (FET) is reported. MMP-7 specifically digests negatively charged JR2EC immobilized on rGO, thereby modulating the conductance of rGO-FET. The proposed assay enabled detection of MMP-7 at clinically relevant concentrations with a limit of detection (LOD) of 10 ng/mL (400 pM), attributed to the significant reduction of the net charge of JR2EC upon digestion by MMP-7. Quantitative detection of MMP-7 in human plasma was further demonstrated with a LOD of 40 ng/mL, illustrating the potential for the proposed methodology for tumor detection and carcinoma diagnostic (e.g., lung cancer and salivary gland cancer). Additionally, excellent specificity of the proposed assay was demonstrated using matrix metallopeptidase 1 (MMP-1), a protease of the same family. With appropriate selection and modification of polypeptides, the proposed assay could be extended for detection of other enzymes with polypeptide digestion capability.

Place, publisher, year, edition, pages
AMER CHEMICAL SOC, 2016
National Category
Physical Sciences
Identifiers
urn:nbn:se:liu:diva-127272 (URN)10.1021/acs.analchem.5b04663 (DOI)000372391500003 ()26887256 (PubMedID)
Note

Funding Agencies|Institute for Sports Research, Nanyang Technological University; MOE-Tier 1 [2014-T1-001-133-01]

Available from: 2016-04-20 Created: 2016-04-19 Last updated: 2019-01-22
Koon Lim, S., Sandén, C., Selegård, R., Liedberg, B. & Aili, D. (2016). Tuning Liposome Membrane Permeability by Competitive Peptide Dimerization and Partitioning-Folding Interactions Regulated by Proteolytic Activity. Scientific Reports, 6(21123), 1-9
Open this publication in new window or tab >>Tuning Liposome Membrane Permeability by Competitive Peptide Dimerization and Partitioning-Folding Interactions Regulated by Proteolytic Activity
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2016 (English)In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 6, no 21123, p. 1-9Article in journal (Refereed) Published
Abstract [en]

Membrane active peptides are of large interest for development of drug delivery vehicles and therapeutics for treatment of multiple drug resistant infections. Lack of specificity can be detrimental and finding routes to tune specificity and activity of membrane active peptides is vital for improving their therapeutic efficacy and minimize harmful side effects. We describe a de novo designed membrane active peptide that partition into lipid membranes only when specifically and covalently anchored to the membrane, resulting in pore-formation. Dimerization with a complementary peptide efficiently inhibits formation of pores. The effect can be regulated by proteolytic digestion of the inhibitory peptide by the matrix metalloproteinase MMP-7, an enzyme upregulated in many malignant tumors. This system thus provides a precise and specific route for tuning the permeability of lipid membranes and a novel strategy for development of recognition based membrane active peptides and indirect enzymatically controlled release of liposomal cargo.

Place, publisher, year, edition, pages
NATURE PUBLISHING GROUP, 2016
National Category
Physical Sciences Biochemistry and Molecular Biology
Identifiers
urn:nbn:se:liu:diva-126131 (URN)10.1038/srep21123 (DOI)000370532500002 ()26892926 (PubMedID)
Note

Funding Agencies|Linkoping University; Swedish Research Council (VR); Swedish Foundation for Strategic Research (SSF); Knut and Alice Wallenberg Foundation (KAW); Centre in Nanoscience and Technology (CeNano); Provost Office, NTU

Available from: 2016-03-15 Created: 2016-03-15 Last updated: 2019-01-22
Selegård, R., Enander, K. & Aili, D. (2014). Generic Phosphatase Activity Detection using Zinc Mediated Aggregation Modulation of Polypeptide-Modified Gold Nanoparticles. Nanoscale, 6(23), 14204-14212
Open this publication in new window or tab >>Generic Phosphatase Activity Detection using Zinc Mediated Aggregation Modulation of Polypeptide-Modified Gold Nanoparticles
2014 (English)In: Nanoscale, ISSN 2040-3364, E-ISSN 2040-3372, Vol. 6, no 23, p. 14204-14212Article in journal (Refereed) Published
Abstract [en]

A challenge in the design of plasmonic nanoparticle-based colorimetric assays is that the change in colloidal stability, which generates the colorimetric response, is often directly linked to the biomolecular recognition event. New assay strategies are hence required for every type of substrate and enzyme of interest. Here, a generic strategy for monitoring of phosphatase activity is presented where substrate recognition is completely decoupled from the nanoparticle stability modulation mechanism, which enables detection of a wide range of enzymes using different natural substrates with a single simple detection scheme. Phosphatase activity generates inorganic phosphate that forms an insoluble complex with Zn2+. In a sample containing a preset concentration of Zn2+, phosphatase activity will markedly reduce the concentration of dissolved Zn2+ from the original value, which in turn affects the aggregation of gold nanoparticles functionalized with a designed Zn2+ responsive polypeptide. The change in nanoparticle stability thus provides a rapid and sensitive readout of the phosphatase activity. The assay is not limited to a particular enzyme or enzyme substrate, which is demonstrated using three completely different phosphatases and five different substrates, and thus constitutes a highly interesting system for drug screening and diagnostics.

Place, publisher, year, edition, pages
Royal Society of Chemistry, 2014
Keywords
Phosphatase, gold nanoparticle, assay, chelation, polypeptide, zinc
National Category
Chemical Sciences
Identifiers
urn:nbn:se:liu:diva-106718 (URN)10.1039/c4nr02791d (DOI)000344997600018 ()
Available from: 2014-05-19 Created: 2014-05-19 Last updated: 2019-01-22Bibliographically approved
Mak, W. C., Selegård, R., Garbrecht, M. & Aili, D. (2014). Probing Zinc-Protein-Chelant Interactions using Gold Nanoparticles Functionalized with Zinc-Responsive Polypeptides. Particle & particle systems characterization, 31(11), 1127-1133
Open this publication in new window or tab >>Probing Zinc-Protein-Chelant Interactions using Gold Nanoparticles Functionalized with Zinc-Responsive Polypeptides
2014 (English)In: Particle & particle systems characterization, ISSN 0934-0866, E-ISSN 1521-4117, Vol. 31, no 11, p. 1127-1133Article in journal (Refereed) Published
Abstract [en]

The coordination of zinc by proteins and various other organic molecules is essential for numerous biological processes, such as in enzymatic catalysis, metabolism and signal transduction. Presence of small molecular chelants can have a profound effect on the bioavailability of zinc and affect critical Zn2+-protein interactions. Zn2+ chelators are also emerging therapeutics for Alzheimer’s diseases because of their preventive effect on zinc promoted amyloid formation. Despite the importance of zinc-protein-chelant interactions in biology and medicine, probing such interactions is  challenging. Here, we introduce an innovative approach for real-time characterization of zinc-protein-chelant interactions using gold nanoparticles (AuNPs) functionalized with a zinc-responsive protein mimetic polypeptide. The peptide functionalized AuNPs aggregate extensively in the presence of Zn2+, triggered by specific Zn2+-mediated polypeptide dimerization and folding, causing a massive red shift of the plasmon band. Chelants affects the Zn2+- polypeptide interaction and thus the aggregation differently depending on their concentrations, zincbinding affinities and coordination numbers, which affect the position of the plasmon band. This system is a simple and powerful tool that provides extensive information about the interactions of chelants in the formation of Zn2+ coordination complexes and is an interesting platform for development of bioanalytical techniques and characterization of chelation-based therapeutics.

Place, publisher, year, edition, pages
Wiley-VCH Verlagsgesellschaft, 2014
Keywords
Gold nanoparticles, zinc, peptide, chelation
National Category
Chemical Sciences
Identifiers
urn:nbn:se:liu:diva-106717 (URN)10.1002/ppsc.201400082 (DOI)000344681700003 ()
Available from: 2014-05-19 Created: 2014-05-19 Last updated: 2019-01-22Bibliographically approved
Chen, P., Selegård, R., Aili, D. & Liedberg, B. (2013). Peptide functionalized gold nanoparticles for colorimetric detection of matrilysin (MMP-7) activity. Nanoscale, 5(19), 8973-8976
Open this publication in new window or tab >>Peptide functionalized gold nanoparticles for colorimetric detection of matrilysin (MMP-7) activity
2013 (English)In: Nanoscale, ISSN 2040-3364, E-ISSN 2040-3372, Vol. 5, no 19, p. 8973-8976Article in journal (Refereed) Published
Abstract [en]

A peptide with two cleavage sites for MMP-7 has been synthesized and immobilized on gold nanoparticles (AuNPs) through a cysteine residue. Digestion of the peptide by MMP-7 decreases its size and net charge, which leads to the aggregation of the AuNPs. The color shift caused by aggregation enables a direct and quantitative measurement of the concentration and activity of MMP-7 with an estimated limit of detection of 5 nM (0.1 μg mL−1).

Place, publisher, year, edition, pages
Royal Society of Chemistry, 2013
National Category
Engineering and Technology
Identifiers
urn:nbn:se:liu:diva-99413 (URN)10.1039/c3nr03006g (DOI)000324500900027 ()
Note

Funding Agencies|School of Materials Science and Engineering, Nanyang Technological University, Singapore||Provost Office, Nanyang Technological University, Singapore||Swedish Foundation for Strategic Research (SSF)||Knut and Alice Wallenberg Foundation (KAW), CeNano||Swedish Research Council (VR)||

Available from: 2013-10-17 Created: 2013-10-17 Last updated: 2019-01-22
Wang, Y., Aili, D., Selegård, R., Tay, Y., Baltzer, L., Zhang, H. & Liedberg, B. (2012). Specific functionalization of CTAB stabilized anisotropic gold nanoparticles with polypeptides for folding-mediated self-assembly. Journal of Materials Chemistry, 22(38), 20368-20373
Open this publication in new window or tab >>Specific functionalization of CTAB stabilized anisotropic gold nanoparticles with polypeptides for folding-mediated self-assembly
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2012 (English)In: Journal of Materials Chemistry, ISSN 0959-9428, E-ISSN 1364-5501, Vol. 22, no 38, p. 20368-20373Article in journal (Refereed) Published
Abstract [en]

Anisotropic nanoparticles stabilized by cetyltrimethylammonium bromide (CTAB) are notoriously difficult to homogenously functionalize using conventional gold-thiol chemistry. Using surface assisted laser desorption time of flight mass spectroscopy and scanning transmission electron microscopy-energy dispersive X-ray spectroscopy, we demonstrate that silver species adsorbed on the particle surface prevent effective surface functionalization. When covered by a thin gold film, particle functionalization was drastically improved. A thiol-containing polypeptide was immobilized on arrowhead gold nanorods (NRs) and was subsequently able to selectively heteroassociate with a complementary polypeptide resulting in a folding-mediated bridging aggregation of the NRs. Despite using arrowhead NRs with a pronounced difference in surface arrangement on the {111} facets on the arrowheads compared to the {100} facets at the particle sides, the polypeptides were efficiently and homogeneously immobilized on the particles after gold film overgrowth.

Place, publisher, year, edition, pages
Royal Society of Chemistry, 2012
National Category
Engineering and Technology
Identifiers
urn:nbn:se:liu:diva-84914 (URN)10.1039/c2jm31176c (DOI)000308658600039 ()
Note

Funding Agencies|Knut and Alice Wallenberg Foundation (KAW)||Swedish Research Council (VR)||Swedish Foundation for Strategic Research (SSF)||

Available from: 2012-10-26 Created: 2012-10-26 Last updated: 2019-01-22
Aili, D., Selegård, R., Baltzer, L., Enander, K. & Liedberg, B. (2009). Colorimetric Protein Sensing by Controlled Assembly of Gold Nanoparticles Functionalized with Synthetic Receptors. Small, 5(21), 2445-2452
Open this publication in new window or tab >>Colorimetric Protein Sensing by Controlled Assembly of Gold Nanoparticles Functionalized with Synthetic Receptors
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2009 (English)In: Small, ISSN 1613-6810, Vol. 5, no 21, p. 2445-2452Article in journal (Refereed) Published
Abstract [en]

A strategy for colorimetric sensing of proteins, based on the induced assembly of polypeptide-functionalized gold nanoparticles, is described. Recognition was accomplished using a polypeptide sensor scaffold designed to specifically bind the model analyte, human carbonic anhydrase II (HCAII). The extent of particle aggregation, induced by the Zn2+-triggered dimerization and folding of a second polypeptide also present on the surface of the gold nanoparticle, gave a readily detectable colorimetric shift that was dependent on the concentration of the target protein. In the absence of HCAII, particle aggregation resulted in a major redshift of the plasmon peak whereas analyte binding prevented formation of dense aggregates, significantly reducing the magnitude of the redshift. The limit of detection of HCAII was estimated to be around 15 nM. The versatility of the technique was demonstrated using a second model system based on the recognition of a peptide sequence from the tobacco mosaic virus coat protein (TMVP by a recombinant antibody fragment. This strategy is proposed as a generic platform for robust and specific protein analysis that can be further developed for monitoring a wide range of target proteins.

Keywords
Not available.
National Category
Chemical Sciences
Identifiers
urn:nbn:se:liu:diva-15122 (URN)10.1002/smll.200900530 (DOI)
Available from: 2008-10-16 Created: 2008-10-16 Last updated: 2019-01-22Bibliographically approved
Aili, D., Selegård, R., Baltzer, L., Enander, K. & Liedberg, B. (2009). Colorimetric sensing: Small 21/2009. Small, 5(21)
Open this publication in new window or tab >>Colorimetric sensing: Small 21/2009
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2009 (English)In: Small, ISSN 1613-6810, E-ISSN 1613-6829, Vol. 5, no 21Article in journal, Editorial material (Other academic) Published
Abstract [en]

The cover picture illustrates a novel concept for colorimetric protein sensing based on the controllable assembly of polypeptide-functionalized gold nanoparticles. Recognition of the analyte is accomplished by polypeptide-based synthetic receptors immobilized on gold nanoparticles. Also present on the particle surface is a de novo-designed helix-loop-helix polypeptide that homodimerizes and folds into four-helix bundles in the presence of Zn2+, resulting in particle aggregation. Analyte binding interferes with the folding-induced aggregation, giving rise to a clearly detectable colorimetric response.

Place, publisher, year, edition, pages
John Wiley & Sons, 2009
National Category
Natural Sciences
Identifiers
urn:nbn:se:liu:diva-53089 (URN)10.1002/smll.200990103 (DOI)19866478 (PubMedID)
Available from: 2010-01-15 Created: 2010-01-15 Last updated: 2019-01-22Bibliographically approved
Organisations
Identifiers
ORCID iD: ORCID iD iconorcid.org/0000-0002-1781-1489

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