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Publications (10 of 190) Show all publications
Jones, J. M., Player, D. J., Samanta, S., Rangasami, V. K., Hilborn, J., Lewis, M. P., . . . Mudera, V. (2020). Hyaluronan derived nanoparticle for simvastatin delivery: evaluation of simvastatin induced myotoxicity in tissue engineered skeletal muscle. Paper presented at 29th Annual Conference of the European-Society-for-Biomaterials (ESB), SEP 09-13, 2018, Maastricht, NETHERLANDS. Biomaterials Science, 8(1), 302-312
Open this publication in new window or tab >>Hyaluronan derived nanoparticle for simvastatin delivery: evaluation of simvastatin induced myotoxicity in tissue engineered skeletal muscle
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2020 (English)In: Biomaterials Science, ISSN 2047-4830, E-ISSN 2047-4849, Vol. 8, no 1, p. 302-312Article in journal (Refereed) Published
Abstract [en]

Statins are currently the most prescribed hypercholesterolemia-lowering drugs worldwide, with estimated usage approaching one-sixth of the population. However, statins are known to cause pleiotropic skeletal myopathies in 1.5% to 10% of patients and the mechanisms by which statins induce this response, are not fully understood. In this study, a 3D collagen-based tissue-engineered skeletal muscle construct is utilised as a screening platform to test the efficacy and toxicity of a new delivery system. A hyaluronic acid derived nanoparticle loaded with simvastatin (HA-SIM-NPs) is designed and the effect of free simvastatin and HA-SIM-NPs on cellular, molecular and tissue response is investigated. Morphological ablation of myotubes and lack of de novo myotube formation (regeneration) was evident at the highest concentrations (333.33 mu M), independent of delivery vehicle (SIM or HA-SIM-NP). A dose-dependent disruption of the cytoskeleton, reductions in metabolic activity and tissue engineered (TE) construct tissue relaxation was evident in the free drug condition (SIM, 3.33 mu M and 33.33 nM). However, most of these changes were ameliorated when SIM was delivered via HA-SIM-NPs. Significantly, homogeneous expressions of MMP2, MMP9, and myogenin in HA-SIM-NPs outlined enhanced regenerative responses compared to SIM. Together, these results outline statin delivery via HA-SIM-NP as an effective delivery mechanism to inhibit deleterious myotoxic side-effects.

Place, publisher, year, edition, pages
ROYAL SOC CHEMISTRY, 2020
National Category
Biomaterials Science
Identifiers
urn:nbn:se:uu:diva-405339 (URN)10.1039/c9bm00986h (DOI)000506879900024 ()31701967 (PubMedID)
Conference
29th Annual Conference of the European-Society-for-Biomaterials (ESB), SEP 09-13, 2018, Maastricht, NETHERLANDS
Funder
EU, FP7, Seventh Framework Programme, 262948EU, Horizon 2020, 713645
Available from: 2020-03-04 Created: 2020-03-04 Last updated: 2020-03-04Bibliographically approved
Roshanbinfar, K., Mohammadi, Z., Mesgar, A.-M. S., Dehghan, M. M., Oommen, O. P., Hilborn, J. & Engel, F. B. (2019). Carbon nanotube doped pericardial matrix derived electroconductive biohybrid hydrogel for cardiac tissue engineering. Biomaterials Science, 7(9), 3906-3917
Open this publication in new window or tab >>Carbon nanotube doped pericardial matrix derived electroconductive biohybrid hydrogel for cardiac tissue engineering
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2019 (English)In: Biomaterials Science, ISSN 2047-4830, E-ISSN 2047-4849, Vol. 7, no 9, p. 3906-3917Article in journal (Refereed) Published
Abstract [en]

Cardiovascular diseases represent a major socio-economic burden. In recent years, considerable effort has been invested in optimizing cell delivery strategies to advance cell transplantation therapies to restore heart function for example after an infarct. A particular issue is that the implantation of cells using a non-electroconductive matrix potentially causes arrhythmia. Here, we demonstrate that our hydrazide-functionalized nanotubes-pericardial matrix-derived electroconductive biohybrid hydrogel provides a suitable environment for maturation of human-induced pluripotent stem cell (hiPSC)-derived cardiomyocytes. hiPSC-derived cardiomyocytes exhibited an improved contraction amplitude (>500%) on conductive hydrogels compared to cells cultured on Matrigel (R). This was accompanied by increased cellular alignment, enhanced connexin 43 expression, and improved sarcomere organization suggesting maturation of the hiPSC-derived cardiomyocytes. Sarcomeric length of these cells increased from 1.3 to 1.7 mu m. Moreover, 3D cell-laden engineered tissues exhibited enhanced calcium handling as well as positive response to external electrical and pharmaceutical stimulation. Collectively, our data indicate that our biohybrid hydrogels consisting of solubilized nanostructured pericardial matrix and electroconductive positively charged hydrazide-conjugated carbon nanotubes provide a promising material for stem cell-based cardiac tissue engineering.

Place, publisher, year, edition, pages
ROYAL SOC CHEMISTRY, 2019
National Category
Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy)
Identifiers
urn:nbn:se:uu:diva-394053 (URN)10.1039/c9bm00434c (DOI)000482087100033 ()31322163 (PubMedID)
Available from: 2019-10-03 Created: 2019-10-03 Last updated: 2019-10-03Bibliographically approved
Bermejo-Velasco, D., Kadekar, S., Tavares da Costa, M. V., Oommen, O. P., Gamstedt, E. K., Hilborn, J. & Varghese, O. P. (2019). First Aldol Cross-Linked Hyaluronic Acid Hydrogel: Fast and Hydrolytically Stable Hydrogel with Tissue Adhesive Properties. ACS Applied Materials and Interfaces, 11(41), 38232-38239
Open this publication in new window or tab >>First Aldol Cross-Linked Hyaluronic Acid Hydrogel: Fast and Hydrolytically Stable Hydrogel with Tissue Adhesive Properties
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2019 (English)In: ACS Applied Materials and Interfaces, ISSN 1944-8244, E-ISSN 1944-8252, Vol. 11, no 41, p. 38232-38239Article in journal (Refereed) Published
Abstract [en]

Currently, there are limited approaches to tailor 3D scaffolds cross-linked with a stable covalent C-C bond that does not require any catalysts or initiators. We present here the first hydrogels employing aldol condensation chemistry that exhibit exceptional physicochemical properties. We investigated the aldol-cross-linking chemistry using two types of aldehyde-modified hyaluronic acid (HA) derivatives, namely, an enolizable HA-aldehyde (HA-EaI) and a non-enolizable HA-aldehyde (HA-NaI). Hydrogels formed using HA-EaI demonstrate inferior cross linking efficiency (due to intramolecular loop formation), when compared with hydrogels formed by mixing HA-EaI and HA-NaI leading to a cross-aldol product. The change in mechanical properties as a result of cross-linking at different pH values is determined using rheological measurements and is interpreted in terms of molecular weight between cross-links (Me). The novel HA cross-aldol hydrogel demonstrate excellent hydrolytic stability and favorable mechanical properties but allow hyaluronidase-mediated enzymatic degradation. Interestingly, residual aldehyde functionality within the aldol product rendered the tissue adhesive properties by bonding two bone tissues. The aldehyde functionality also facilitated facile post-synthetic modifications with nucleophilic reagents. Finally, we demonstrate that the novel hydrogel is biocompatible with encapsulated stem cells that show a linear rate of expansion in our 3-6 days of study.

Keywords
hyaluronic acid, hydrogel, aldol chemistry, tissue adhesive, biomaterial
National Category
Polymer Chemistry Materials Chemistry
Identifiers
urn:nbn:se:uu:diva-397131 (URN)10.1021/acsami.9b10239 (DOI)000491219700090 ()31550878 (PubMedID)
Funder
EU, FP7, Seventh Framework Programme, FP7/2007-2013/607868EU, FP7, Seventh Framework Programme, 607868Swedish Foundation for Strategic Research , SBE13-0028Swedish Foundation for Strategic Research , StemTherapy 2009-1035
Available from: 2019-11-28 Created: 2019-11-28 Last updated: 2019-11-28Bibliographically approved
Han, Y., Li, H., Jafri, S. H., Ossipov, D. A., Hilborn, J. & LEIFER, K. (2019). Graphene Based Mechanical Biosensor by Employing Non-covalent Stacking Functionalization.
Open this publication in new window or tab >>Graphene Based Mechanical Biosensor by Employing Non-covalent Stacking Functionalization
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2019 (English)In: Article in journal, News item (Other academic) Submitted
Abstract [en]

Herein we demonstrate a novel methodology to achieve mechanical biosensor by employing the distinguished interaction forces between the atomic force microscope (AFM) probe and sensor surfaces as the response signal. This mechanical biosensor is fabricated by utilizing the non-covalent π-π stacking of pyrene-maltose onto graphene surfaces with Concanavalin A (Con A) as a target protein. The atomic resolution scanning tunneling microscopy (STM) images indicate the successful formation of the self-assembled and densely packed pyrene-maltose layer on the sensor surface, which gives distinct atomic lattice structure as compared to pristine graphene. This mechanical biosensor exhibits detection of Con A with the sensitivity down to nanomolar level. Therefore, this proposed mechanical biosensor has the potential to be employed in a variety of bio-sensing applications.

National Category
Nano Technology Analytical Chemistry
Identifiers
urn:nbn:se:uu:diva-378559 (URN)
Available from: 2019-03-06 Created: 2019-03-06 Last updated: 2020-02-05Bibliographically approved
Paidikondala, M., Wang, S., Hilborn, J., Larsson, S. & Varghese, O. P. (2019). Impact of Hydrogel Cross-Linking Chemistry on the in Vitro and in VivoBioactivity of Recombinant Human Bone Morphogenetic Protein-2. ACS Applied Bio Materials
Open this publication in new window or tab >>Impact of Hydrogel Cross-Linking Chemistry on the in Vitro and in VivoBioactivity of Recombinant Human Bone Morphogenetic Protein-2
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2019 (English)In: ACS Applied Bio Materials, ISSN 2576-6422Article in journal, Editorial material (Refereed) Published
Abstract [en]

Designing strategies to deliver functional proteins at physiologically relevant concentrations using chemically cross-linked biocompatible hydrogels is a major field of research. However, the impact of cross-linking chemistry on the encapsulated protein bioactivity is rarely studied. Here we examine the two well-known cross-linking reactions namely; hydrazone cross-linking chemistry and thiol-Michael addition reaction to form hyaluronic acid (HA) hydrogels. As a therapeutic protein, we employed recombinant human bone morphogenetic protein-2 (rhBMP-2) for this study. Incubation of rhBMP-2 with HA functionalized with a thiol diminished phosphorylation of Smad 1/5/8, a signal transducer for osteogenic differntiation, whereas an aldehyde functionalized HA had no effect. This indicates that thiol functionalized polymers indeed has an impact on protein function. To validate this result in an in vivo setting we performed BMP-2 induced bone formation in a rat ectopic model. These experiments revealed that the hydrazone-cross-linked HA-hydrogel induced significantly higher bone formation (18.90 ± 4.25 mm3) as compared to the HA-thiol-Michael hydrogels (1.25 ± 0.52 mm3) after 8 weeks as determined by micro-computed tomography. The histological examination of the neo-bone indicated that hydrazone-hydrogels promoted a better quality of bone formation with improved mineralization and collagen formation as compared to the thiol-Michael hydrogels. We believe such a direct comparison of two cross-linking chemistries will provide new insight for developing biomaterials for protein delivery for in vivo applications.

Keywords
bone tissue engineering; cross-linking chemistry; drug delivery; hyaluronic acid; regenerative medicine
National Category
Polymer Chemistry
Identifiers
urn:nbn:se:uu:diva-382321 (URN)10.1021/acsabm.9b00060 (DOI)
Available from: 2019-04-24 Created: 2019-04-24 Last updated: 2020-02-17Bibliographically approved
Wang, S., Nawale, G. N., Oommen, O. P., Hilborn, J. & Varghese, O. P. (2019). Influence of ions to modulate hydrazone and oxime reaction kinetics to obtain dynamically cross-linked hyaluronic acid hydrogels. Polymer Chemistry, 10(31), 4322-4327
Open this publication in new window or tab >>Influence of ions to modulate hydrazone and oxime reaction kinetics to obtain dynamically cross-linked hyaluronic acid hydrogels
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2019 (English)In: Polymer Chemistry, ISSN 1759-9954, E-ISSN 1759-9962, Vol. 10, no 31, p. 4322-4327Article in journal (Refereed) Published
Abstract [en]

Dynamic covalent chemistry forming hydrazone and oxime linkages is attractive due to its simplicity, selectivity and compatibility under aqueous conditions. However, the low reaction rate at physiological pH hampers its use in biomedical applications. Herein, we present different monovalent and bivalent aqueous salt solutions as bio-friendly, non-toxic catalysts which can drive the hydrazone and oxime reactions with excellent efficacy at physiological pH. Direct comparison of hydrazone and oxime reactions using a small molecule model, without any salt catalysis, indicated that oxime formation is 6-times faster than hydrazone formation. Addition of different salts (NaCl, NaBr, KCl, LiCl, LiClO4, Na2SO4, MgCl2 and CaCl2) accelerated the pseudo-first-order reaction kinetics by similar to 1.2-4.9-fold for acylhydrazone formation and by similar to 1.5-6.9-fold for oxime formation, in a concentration-dependent manner. We further explored the potential of such catalysts to develop acylhydrazone and oxime cross-linked hyaluronic acid (HA) hydrogels with different physicochemical properties without changing the degree of chemical modification. Analogous to the small molecule model system, the addition of monovalent and divalent salts as catalysts significantly reduced the gelling time. The gelling time for the acylhydrazone cross-linked HA-hydrogel (1.6 wt%) could be reduced from 300 min to 1.2 min by adding 100 mM CaCl2, while that for the oxime cross-linked HA-hydrogel (1.2 wt%) could be reduced from 68 min to 1.1 min by adding 50 mM CaCl2. This difference in the gelling time also resulted in hydrogels with differential swelling properties as measured after 24 h. Our results are the first to demonstrate the use of salts, for catalyzing hydrogel formation under physiologically relevant conditions.

Place, publisher, year, edition, pages
ROYAL SOC CHEMISTRY, 2019
National Category
Polymer Chemistry
Identifiers
urn:nbn:se:uu:diva-393329 (URN)10.1039/c9py00862d (DOI)000478913500010 ()
Funder
Swedish Foundation for Strategic Research , SBE13-0028
Note

De två första författarna delar förstaförfattarskapet.

Available from: 2019-09-27 Created: 2019-09-27 Last updated: 2019-09-27Bibliographically approved
Han, Y., Qiu, Z., Nawale, G. N., Varghese, O. P., Hilborn, J., Tian, B. & Leifer, K. (2019). MicroRNA detection based on duplex-specific nuclease-assisted target recycling and gold nanoparticle/graphene oxide nanocomposite-mediated electrocatalytic amplification. Biosensors & bioelectronics, 127, 188-193
Open this publication in new window or tab >>MicroRNA detection based on duplex-specific nuclease-assisted target recycling and gold nanoparticle/graphene oxide nanocomposite-mediated electrocatalytic amplification
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2019 (English)In: Biosensors & bioelectronics, ISSN 0956-5663, E-ISSN 1873-4235, Vol. 127, p. 188-193Article in journal (Refereed) Published
Abstract [en]

DNA technology based bio-responsive nanomaterials have been widely studied as promising tools for biomedical applications. Gold nanoparticles (AuNPs) and graphene oxide (GO) sheets are representative zero- and two-dimensional nanomaterials that have long been combined with DNA technology for point-of-care diagnostics. Herein, a cascade amplification system based on duplex-specific nuclease (DSN)-assisted target recycling and electrocatalytic water-splitting is demonstrated for the detection of microRNA. Target microRNAs can form DNA: RNA heteroduplexes with DNA probes on the surface of AuNPs, which can be hydrolyzed by DSN. MicroRNAs are preserved during the reaction and released into the suspension for the digestion of multiple DNA probes. After the DSN-based reaction, AuNPs are collected and mixed with GO to form AuNP/GO nanocomposite on an electrode for the following electrocatalytic amplification. The utilization of AuNP/GO nanocomposite offers large surface area, exceptional affinity to water molecules, and facilitated mass diffusion for the water-splitting reaction. For let-7b detection, the proposed biosensor achieved a limit detection of 1.5 fM in 80 min with a linear detection range of approximately four orders of magnitude. Moreover, it has the capability of discriminating non-target microRNAs containing even single-nucleotide mismatches, thus holding considerable potential for clinical diagnostics.

Keywords
Gold nanoparticles, Graphene oxide, MicroRNA detection, Electrocatalytic amplification, Duplex-specific nuclease
National Category
Analytical Chemistry Physical Chemistry
Identifiers
urn:nbn:se:uu:diva-377203 (URN)10.1016/j.bios.2018.12.027 (DOI)000457508800026 ()30611105 (PubMedID)
Funder
Swedish Research Council, 2016-05259Knut and Alice Wallenberg FoundationEU, Horizon 2020, 713683
Available from: 2019-02-25 Created: 2019-02-25 Last updated: 2019-04-24Bibliographically approved
Bermejo-Velasco, D., Azémar, A., Oommen, O. P., Hilborn, J. & Varghese, O. P. (2019). Modulating thiol pKa promotes disulfide formation at physiological pH: An elegant strategy to design disulfide cross-linked hyaluronic acid hydrogels. Biomacromolecules, 20(3), 1412-1420
Open this publication in new window or tab >>Modulating thiol pKa promotes disulfide formation at physiological pH: An elegant strategy to design disulfide cross-linked hyaluronic acid hydrogels
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2019 (English)In: Biomacromolecules, ISSN 1525-7797, E-ISSN 1526-4602, Vol. 20, no 3, p. 1412-1420Article in journal (Refereed) Published
Abstract [en]

The disulfide bond plays a crucial role in protein biology and has been exploited by scientists to develop antibody-drug conjugates, sensors and for the immobilization other biomolecules to materials surfaces. In spite of its versatile use, the disulfide chemistry suffers from some inevitable limitations such as the need for basic conditions (pH > 8.5), strong oxidants and long reaction times. We demonstrate here that thiol-substrates containing electron-withdrawing groups at the β-position influence the deprotonation of the thiol group, which is the key reaction intermediate in the formation of disulfide bonds. Evaluation of reaction kinetics using small molecule substrate such as L-cysteine indicated disulfide formation at a 2.8-fold higher (k1 = 5.04 x 10-4 min-1) reaction rate as compared to the conventional thiol substrate, namely 3-mercaptopropionic acid (k1 = 1.80 x 10-4 min-1) at physiological pH (pH 7.4). Interestingly, the same effect could not be observed when N-acetyl-L-cysteine substrate (k1 = 0.51 x 10-4 min-1) was used. We further grafted such thiol-containing molecules (cysteine, N-acetyl-cysteine, and 3-mercaptopropionic acid) to a biopolymer namely hyaluronic acid (HA) and determined the pKa value of different thiol groups by spectrophotometric analysis. The electron-withdrawing group at the β-position reduced the pKa of the thiol group to 7.0 for HA-cysteine (HA-Cys); 7.4 for N-acetyl cysteine (HA-ActCys) and 8.1 for HA-thiol (HA-SH) derivatives respectively. These experiments further confirmed that the concentration of thiolate (R-S-) ions could be increased with the presence of electron-withdrawing groups, which could facilitate disulfide cross-linked hydrogel formation at physiological pH. Indeed, HA grafted with cysteine or N-acetyl groups formed hydrogels within 3.5 minutes or 10 hours, respectively at pH 7.4. After completion of crosslinking reaction both gels demonstrated a storage modulus G’ ≈3300–3500 Pa, indicating comparable levels of crosslinking. The HA-SH gel, on the other hand, did not form any gel at pH 7.4 even after 24 h. Finally, we demonstrated that the newly prepared hydrogels exhibited excellent hydrolytic stability but can be degraded by cell-directed processes (enzymatic and reductive degradation). We believe our study provides a valuable insight on the factors governing the disulfide formation and our results are useful to develop strategies that would facilitate generation of stable thiol functionalized biomolecules or promote fast thiol oxidation according to the biomedical needs.

National Category
Materials Chemistry
Research subject
Chemistry with specialization in Materials Chemistry
Identifiers
urn:nbn:se:uu:diva-375001 (URN)10.1021/acs.biomac.8b01830 (DOI)000461270500028 ()30726668 (PubMedID)
Funder
Swedish Foundation for Strategic Research , 139400127EU, FP7, Seventh Framework Programme, 607868Swedish Foundation for Strategic Research , 139400126
Available from: 2019-01-24 Created: 2019-01-24 Last updated: 2019-04-11Bibliographically approved
Shi, L., Ding, P., Wang, Y., Zhang, Y., Ossipov, D. & Hilborn, J. (2019). Self-Healing Polymeric Hydrogel Formed by Metal-Ligand Coordination Assembly: Design, Fabrication, and Biomedical Applications. Macromolecular rapid communications, 40(7), Article ID 1800837.
Open this publication in new window or tab >>Self-Healing Polymeric Hydrogel Formed by Metal-Ligand Coordination Assembly: Design, Fabrication, and Biomedical Applications
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2019 (English)In: Macromolecular rapid communications, ISSN 1022-1336, E-ISSN 1521-3927, Vol. 40, no 7, article id 1800837Article in journal (Refereed) Published
Abstract [en]

Self-healing hydrogels based on metal-ligand coordination chemistry provide new and exciting properties that improve injectability, rheological behaviors, and even biological functionalities. The inherent reversibility of coordination bonds improves on the covalent cross-linking employed previously, allowing for the preparation of completely self-healing hydrogels. In this article, recent advances in the development of this class of hydrogels are summarized and their applications in biology and medicine are discussed. Various chelating ligands such as bisphosphonate, catechol, histidine, thiolate, carboxylate, pyridines (including bipyridine and terpyridine), and iminodiacetate conjugated onto polymeric backbones, as well as the chelated metal ions and metal ions containing inorganic particles, which are used to form dynamic networks, are highlighted. This article provides general ideas and methods for the design of self-healing hydrogel biomaterials based on coordination chemistry.

Place, publisher, year, edition, pages
WILEY-V C H VERLAG GMBH, 2019
Keywords
biomaterials, coordination chemistry, hydrogels, self-healing materials
National Category
Polymer Chemistry
Identifiers
urn:nbn:se:uu:diva-385569 (URN)10.1002/marc.201800837 (DOI)000467997700006 ()30672628 (PubMedID)
Funder
Swedish Research Council, 2017-04651
Available from: 2019-06-19 Created: 2019-06-19 Last updated: 2019-06-19Bibliographically approved
Cantoni, F., Hilborn, J., Johansson, S., Pohlit, H., Porras, A. M., Samanta, A. & Tenje, M. (2018). 2D and 3D patterning of biological hydrogels for organ-on-chip applications. In: : . Paper presented at 44th International Conference on Micro and Nano Engineering (MNE 2018), Copenhagen, Denmark, September 24-27 2018..
Open this publication in new window or tab >>2D and 3D patterning of biological hydrogels for organ-on-chip applications
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2018 (English)Conference paper, Oral presentation with published abstract (Other academic)
Keywords
Organs-on-chip, Hydrogels, UV lithography, Microfluidics, TEER
National Category
Engineering and Technology Other Medical Engineering
Research subject
Engineering Science with specialization in Microsystems Technology
Identifiers
urn:nbn:se:uu:diva-369364 (URN)
Conference
44th International Conference on Micro and Nano Engineering (MNE 2018), Copenhagen, Denmark, September 24-27 2018.
Funder
Knut and Alice Wallenberg Foundation, WAF 2016-0112EU, European Research Council
Available from: 2018-12-13 Created: 2018-12-13 Last updated: 2018-12-13Bibliographically approved
Organisations
Identifiers
ORCID iD: ORCID iD iconorcid.org/0000-0001-6947-9601

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