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Sherrell, P., Cieślar-Pobuda, A., Silverå Ejneby, M., Sammalisto, L., Gelmi, A., de Muinck, E., . . . Rafat, M. (2017). Rational Design of a Conductive Collagen Heart Patch. Macromolecular Bioscience, 17(7), Article ID 1600446.
Open this publication in new window or tab >>Rational Design of a Conductive Collagen Heart Patch
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2017 (English)In: Macromolecular Bioscience, ISSN 1616-5187, E-ISSN 1616-5195, Vol. 17, no 7, article id 1600446Article in journal (Refereed) Published
Abstract [en]

Cardiovascular diseases, including myocardial infarction, are the cause of significant morbidity and mortality globally. Tissue engineering is a key emerging treatment method for supporting and repairing the cardiac scar tissue caused by myocardial infarction. Creating cell supportive scaffolds that can be directly implanted on a myocardial infarct is an attractive solution. Hydrogels made of collagen are highly biocompatible materials that can be molded into a range of shapes suitable for cardiac patch applications. The addition of mechanically reinforcing materials, carbon nanotubes, at subtoxic levels allows for the collagen hydrogels to be strengthened, up to a toughness of 30 J m-1 and a two to threefold improvement in Youngs' modulus, thus improving their viability as cardiac patch materials. The addition of carbon nanotubes is shown to be both nontoxic to stem cells, and when using single-walled carbon nanotubes, supportive of live, beating cardiac cells, providing a pathway for the further development of a cardiac patch.

Place, publisher, year, edition, pages
Wiley-VCH Verlagsgesellschaft, 2017
Keywords
Carbon nanotube, Collagen, Hydrogel, Myocardial infarction, Stem cell
National Category
Medical Engineering
Identifiers
urn:nbn:se:liu:diva-136817 (URN)10.1002/mabi.201600446 (DOI)000405566300004 ()28322510 (PubMedID)2-s2.0-85016390421 (Scopus ID)
Note

Funding agencies: Linkoping Initiative in Life Science Technologies (LIST); Central ALF Matching Grant from Landstinget i Ostergotland [LIO-344071]; European Research Agency [304209]; GeCONiI [POIG.02.03.01-24-099/13]

Available from: 2017-04-27 Created: 2017-04-27 Last updated: 2018-04-09Bibliographically approved
Rafat, M., Xeroudaki, M., Koulikovska, M., Sherrell, P., Groth, F., Fagerholm, P. & Lagali, N. (2016). Composite core-and-skirt collagen hydrogels with differential degradation for corneal therapeutic applications. Biomaterials, 83, 142-155
Open this publication in new window or tab >>Composite core-and-skirt collagen hydrogels with differential degradation for corneal therapeutic applications
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2016 (English)In: Biomaterials, ISSN 0142-9612, E-ISSN 1878-5905, Vol. 83, p. 142-155Article in journal (Refereed) Published
Abstract [en]

Scarcity of donor tissue to treat corneal blindness and the need to deliver stem cells or pharmacologic agents to ensure corneal graft survival are major challenges. Here, new composite collagen-based hydrogels are developed as implants to restore corneal transparency while serving as a possible reservoir for cells and drugs. The composite hydrogels have a centrally transparent core and embedded peripheral skirt of adjustable transparency and degradability, with the skirt exhibiting faster degradation in vitro. Both core and skirt supported human epithelial cell populations in vitro and the skirt merged homogeneously with the core material to smoothly distribute a mechanical load in vitro. After in vivo transplantation in rabbit corneas over three months, composites maintained overall corneal shape and integrity, while skirt degradation could be tracked in vivo and non-invasively due to partial opacity. Skirt degradation was associated with partial collagen breakdown, thinning, and migration of host stromal cells and macrophages, while the central core maintained integrity and transparency as host cells migrated and nerves regenerated.

IMPACT:

This study indicates the feasibility of a collagen-based composite hydrogel to maintain corneal stability and transparency while providing a degradable peripheral reservoir for cell or substance release.

Keywords
Composite; Cornea; Degradation; Femtosecond laser; Keratoplasty; Porcine collagen
National Category
Cell and Molecular Biology
Identifiers
urn:nbn:se:liu:diva-125229 (URN)10.1016/j.biomaterials.2016.01.004 (DOI)000371651700012 ()26773670 (PubMedID)
Note

Funding agencies:  Abbott Medical Optics Inc, Solna, Sweden

Available from: 2016-02-16 Created: 2016-02-16 Last updated: 2018-01-22
Gelmi, A., Cieslar-Pobuda, A., de Muinck, E., Los, M. J., Rafat, M. & Jager, E. (2016). Direct Mechanical Stimulation of Stem Cells: A Beating Electromechanically Active Scaffold for Cardiac Tissue Engineering. Advanced Healthcare Materials, 5(12), 1471-1480
Open this publication in new window or tab >>Direct Mechanical Stimulation of Stem Cells: A Beating Electromechanically Active Scaffold for Cardiac Tissue Engineering
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2016 (English)In: Advanced Healthcare Materials, ISSN 2192-2640, E-ISSN 2192-2659, Vol. 5, no 12, p. 1471-1480Article in journal (Refereed) Published
Abstract [en]

The combination of stem cell therapy with a supportive scaffold is a promising approach to improving cardiac tissue engineering. Stem cell therapy can be used to repair nonfunctioning heart tissue and achieve myocardial regeneration, and scaffold materials can be utilized in order to successfully deliver and support stem cells in vivo. Current research describes passive scaffold materials; here an electroactive scaffold that provides electrical, mechanical, and topographical cues to induced human pluripotent stem cells (iPS) is presented. The poly(lactic-co-glycolic acid) fiber scaffold coated with conductive polymer polypyrrole (PPy) is capable of delivering direct electrical and mechanical stimulation to the iPS. The electroactive scaffolds demonstrate no cytotoxic effects on the iPS as well as an increased expression of cardiac markers for both stimulated and unstimulated protocols. This study demonstrates the first application of PPy as a supportive electroactive material for iPS and the first development of a fiber scaffold capable of dynamic mechanical actuation.

Place, publisher, year, edition, pages
Wiley-Blackwell Publishing Inc., 2016
Keywords
actuators; conductive polymers; scaffolds; stem cells; tissue engineering
National Category
Biophysics
Identifiers
urn:nbn:se:liu:diva-130427 (URN)10.1002/adhm.201600307 (DOI)000379550400010 ()27126086 (PubMedID)
Note

Funding Agencies|Linkoping University, Integrative Regenerative Medicine (IGEN) Center; Swedish Research Council [VR-2014-3079]; COST-Action [MP1003]; Knut och Alice Wallenberg Commemorative Fund; GeCONiI [POIG.02.03.01-24-099/13]; European Research Agency

Available from: 2016-08-07 Created: 2016-08-05 Last updated: 2018-10-11Bibliographically approved
Mikhailova, A., Ilmarinen, T., Ratnayake, A., Petrovski, G., Uusitalo, H., Skottman, H. & Rafat, M. (2016). Human pluripotent stem cell-derived limbal epithelial stem cells on bioengineered matrices for corneal reconstruction. Experimental Eye Research, 146, 26-34
Open this publication in new window or tab >>Human pluripotent stem cell-derived limbal epithelial stem cells on bioengineered matrices for corneal reconstruction
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2016 (English)In: Experimental Eye Research, ISSN 0014-4835, Vol. 146, p. 26-34Article in journal (Refereed) Published
Abstract [en]

Corneal epithelium is renewed by limbal epithelial stem cells (LESCs), a type of tissue-specific stem cells located in the limbal palisades of Vogt at the corneo-scleral junction. Acute trauma or inflammatory disorders of the ocular surface can destroy these stem cells, leading to limbal stem cell deficiency (LSCD) – a painful and vision-threatening condition. Treating these disorders is often challenging and complex, especially in bilateral cases with extensive damage. Human pluripotent stem cells (hPSCs) provide new opportunities for corneal reconstruction using cell-based therapy. Here, we investigated the use of hPSC-derived LESC-like cells on bioengineered collagen matrices in serum-free conditions, aiming for clinical applications to reconstruct the corneal epithelium and partially replace the damaged stroma. Differentiation of hPSCs towards LESC-like cells was directed using small-molecule induction followed by maturation in corneal epithelium culture medium. After four to five weeks of culture, differentiated cells were seeded onto bioengineered matrices fabricated as transparent membranes of uniform thickness, using medical-grade porcine collagen type I and a hybrid cross-linking technology. The bioengineered matrices were fully transparent, with high water content and swelling capacity, and parallel lamellar microstructure. Cell proliferation of hPSC-LESCs was significantly higher on bioengineered matrices than on collagen-coated control wells after two weeks of culture, and LESC markers p63 and cytokeratin 15, along with proliferation marker Ki67 were expressed even after 30 days in culture. Overall, hPSC-LESCs retained their capacity to self-renew and proliferate, but were also able to terminally differentiate upon stimulation, as suggested by protein expression of cytokeratins 3 and 12. We propose the use of bioengineered collagen matrices as carriers for the clinically-relevant hPSC-derived LESC-like cells, as a novel tissue engineering approach for corneal reconstruction.

Place, publisher, year, edition, pages
Academic Press, 2016
Keywords
Corneal epithelium;Limbal epithelial stem cells;Human pluripotent stem cells;Serum-free culture conditions;Tissue engineering;Regenerative medicine
National Category
Cell and Molecular Biology
Identifiers
urn:nbn:se:liu:diva-125224 (URN)10.1016/j.exer.2015.11.021 (DOI)000376332400005 ()
Note

Funding agencies:  LinkoCare Life Sciences AB; Academy of Finland [218050, 133879]; Finnish Funding Agency for Technology and Innovation (TEKES); Doctoral Programme in Biomedicine and Biotechnology; Eye and Tissue Bank Foundation; Emil Aaltonen Foundation; Foundation Suppor

Available from: 2016-02-16 Created: 2016-02-16 Last updated: 2018-01-10
Puckert, C., Gelmi, A., Kozak Ljunggren, M., Rafat, M. & Jager, E. (2016). Optimisation of conductive polymer biomaterials for cardiac progenitor cells. RSC Advances, 6(67), 62270-62277
Open this publication in new window or tab >>Optimisation of conductive polymer biomaterials for cardiac progenitor cells
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2016 (English)In: RSC Advances, ISSN 2046-2069, E-ISSN 2046-2069, Vol. 6, no 67, p. 62270-62277Article in journal (Refereed) Published
Abstract [en]

The characterisation of biomaterials for cardiac tissue engineering applications is vital for the development of effective treatments for the repair of cardiac function. New smart materials developed from conductive polymers can provide dynamic benefits in supporting and stimulating stem cells via controlled surface properties, electrical and electromechanical stimulation. In this study we investigate the control of surface properties of conductive polymers through a systematic approach to variable synthesis parameters, and how the resulting surface properties influence the viability of cardiac progenitor cells. A thorough analysis investigating the effect of electropolymerisation parameters, such as current density and growth, and reagent variation on physical properties provides a fundamental understanding of how to optimise conductive polymer biomaterials for cardiac progenitor cells.

Place, publisher, year, edition, pages
ROYAL SOC CHEMISTRY, 2016
National Category
Polymer Chemistry
Identifiers
urn:nbn:se:liu:diva-130451 (URN)10.1039/c6ra11682e (DOI)000379678200028 ()
Note

Funding Agencies|Linkoping University; IGEN (post-doc grant); COST-Action [MP1003]; Knut och Alice Wallenberg Commemorative Fund; European Research Agency

Available from: 2016-08-06 Created: 2016-08-05 Last updated: 2018-10-11
Gelmi, A., Zhang, J., Cieslar-Pobuda, A., Ljunggren, M., Los, M., Rafat, M. & Jager, E. (2015). Electroactive polymer scaffolds for cardiac tissue engineering. In: Bar-Cohen (Ed.), Proc. SPIE 9430, Electroactive Polymer Actuators and Devices (EAPAD) 2015: . Paper presented at Electroactive Polymer Actuators and Devices (EAPAD) 2015 (pp. 94301T-1-94301T-7). SPIE - International Society for Optical Engineering, 9430
Open this publication in new window or tab >>Electroactive polymer scaffolds for cardiac tissue engineering
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2015 (English)In: Proc. SPIE 9430, Electroactive Polymer Actuators and Devices (EAPAD) 2015 / [ed] Bar-Cohen, SPIE - International Society for Optical Engineering, 2015, Vol. 9430, p. 94301T-1-94301T-7Conference paper, Published paper (Refereed)
Abstract [en]

By-pass surgery and heart transplantation are traditionally used to restore the heart’s functionality after a myocardial Infarction (MI or heart attack) that results in scar tissue formation and impaired cardiac function. However, both procedures are associated with serious post-surgical complications. Therefore, new strategies to help re-establish heart functionality are necessary. Tissue engineering and stem cell therapy are the promising approaches that are being explored for the treatment of MI. The stem cell niche is extremely important for the proliferation and differentiation of stem cells and tissue regeneration. For the introduction of stem cells into the host tissue an artificial carrier such as a scaffold is preferred as direct injection of stem cells has resulted in fast stem cell death. Such scaffold will provide the proper microenvironment that can be altered electronically to provide temporal stimulation to the cells. We have developed an electroactive polymer (EAP) scaffold for cardiac tissue engineering. The EAP scaffold mimics the extracellular matrix and provides a 3D microenvironment that can be easily tuned during fabrication, such as controllable fibre dimensions, alignment, and coating. In addition, the scaffold can provide electrical and electromechanical stimulation to the stem cells which are important external stimuli to stem cell differentiation. We tested the initial biocompatibility of these scaffolds using cardiac progenitor cells (CPCs), and continued onto more sensitive induced pluripotent stem cells (iPS). We present the fabrication and characterisation of these electroactive fibres as well as the response of increasingly sensitive cell types to the scaffolds.

Place, publisher, year, edition, pages
SPIE - International Society for Optical Engineering, 2015
Series
Proceedings of SPIE, ISSN 0277-786X ; 9430
National Category
Medical Materials
Identifiers
urn:nbn:se:liu:diva-118260 (URN)10.1117/12.2084165 (DOI)000355580900052 ()
Conference
Electroactive Polymer Actuators and Devices (EAPAD) 2015
Available from: 2015-05-22 Created: 2015-05-22 Last updated: 2018-10-11Bibliographically approved
Koulikovska, M., Rafat, M., Petrovski, G., Veréb, Z., Akhtar, S., Fagerholm, P. & Lagali, N. (2015). Enhanced Regeneration of Corneal Tissue Via a Bioengineered Collagen Construct Implanted by a Nondisruptive Surgical Technique. Tissue Engineering. Part A, 21(5-6), 1116-1130
Open this publication in new window or tab >>Enhanced Regeneration of Corneal Tissue Via a Bioengineered Collagen Construct Implanted by a Nondisruptive Surgical Technique
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2015 (English)In: Tissue Engineering. Part A, ISSN 1937-3341, E-ISSN 1937-335X, Vol. 21, no 5-6, p. 1116-1130Article in journal (Refereed) Published
Abstract [en]

Severe shortage of donor corneas for transplantation, particularly in developing countries, has prompted the advancement of bioengineered tissue alternatives. Bioengineered corneas that can withstand transplantation while maintaining transparency and compatibility with host cells, and that are additionally amenable to standardized low-cost mass production are sought. In this study, a bioengineered porcine construct (BPC) was developed to function as a biodegradable scaffold to promote corneal stromal regeneration by host cells. Using high-purity medical-grade type I collagen, high 18% collagen content and optimized EDC-NHS cross-linker ratio, BPCs were fabricated into hydrogel corneal implants with over 90% transparency and four-fold increase in strength and stiffness compared with previous versions. Remarkably, optical transparency was achieved despite the absence of collagen fibril organization at the nanoscale. In vitro testing indicated that BPC supported confluent human epithelial and stromal-derived mesenchymal stem cell populations. With a novel femtosecond laser-assisted corneal surgical model in rabbits, cell-free BPCs were implanted in vivo in the corneal stroma of 10 rabbits over an 8-week period. In vivo, transparency of implanted corneas was maintained throughout the postoperative period, while healing occurred rapidly without inflammation and without the use of postoperative steroids. BPC implants had a 100% retention rate at 8 weeks, when host stromal cells began to migrate into implants. Direct histochemical evidence of stromal tissue regeneration was observed by means of migrated host cells producing new collagen from within the implants. This study indicates that a cost-effective BPC extracellular matrix equivalent can incorporate cells passively to initiate regenerative healing of the corneal stroma, and is compatible with human stem or organ-specific cells for future therapeutic applications as a stromal replacement for treating blinding disorders of the cornea.

Place, publisher, year, edition, pages
Mary Ann Liebert, 2015
National Category
Biochemistry and Molecular Biology
Identifiers
urn:nbn:se:liu:diva-114699 (URN)10.1089/ten.tea.2014.0562 (DOI)000350549500025 ()25412075 (PubMedID)
Available from: 2015-03-03 Created: 2015-03-03 Last updated: 2018-01-22Bibliographically approved
Islam, M. M., Cėpla, V., He, C., Edin, J., Rakickas, T., Kobuch, K., . . . Griffith, M. (2015). Functional fabrication of recombinant human collagen–phosphorylcholine hydrogels for regenerative medicine applications. Acta Biomaterialia, 12, 70-80
Open this publication in new window or tab >>Functional fabrication of recombinant human collagen–phosphorylcholine hydrogels for regenerative medicine applications
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2015 (English)In: Acta Biomaterialia, ISSN 1742-7061, E-ISSN 1878-7568, Vol. 12, p. 70-80Article in journal (Refereed) Published
Abstract [en]

The implant-host interface is a critical element in guiding tissue or organ regeneration. We previously developed hydrogels comprising interpenetrating networks of recombinant human collagen type III and 2-methacryloyloxyethyl phosphorylcholine (RHCIII-MPC) as substitutes of the corneal extracellular matrix that promote endogenous regeneration of corneal tissue. To render them functional for clinical application, we have now optimized their composition and thereby enhanced their mechanical properties. We have demonstrated that such optimized RHCIII-MPC hydrogels are suitable for precision femtosecond laser cutting to produce complementing implants and host surgical beds for subsequent tissue welding. This avoids the tissue damage and inflammation associated with manual surgical techniques, thereby leading to more efficient healing. Although we previously demonstrated in clinical testing that RHCIII-based implants stimulated cornea regeneration in patients, the rate of epithelial cell coverage of the implants needs improvement, e.g. modification of the implant surface. We now show that our 500 μm thick RHCIII-MPC constructs comprising over 85% water, are suitable for microcontact printing with fibronectin. The resulting fibronectin micropatterns promote cell adhesion, as compared to the bare RHCIII-MPC hydrogel. Interestingly, a pattern of 30 μm wide fibronectin stripes enhanced cell attachment and showed highest mitotic rates, an effect that potentially can be utilized for faster integration of the implant. We have therefore shown that laboratory-produced mimics of naturally occurring collagen and phospholipids can be fabricated into robust hydrogels that can be laser profiled and patterned to enhance their potential function as artificial substitutes of donor human corneas.

Place, publisher, year, edition, pages
Elsevier, 2015
Keywords
Hydrogel, Cornea, Collagen, Fibronectin, Laser ablation, Surface modification
National Category
Basic Medicine Clinical Medicine
Identifiers
urn:nbn:se:liu:diva-111782 (URN)10.1016/j.actbio.2014.10.035 (DOI)000348686100008 ()
Note

We thank Dr. Chyan-Jang Lee for establishing the GFP-HCEC cell line used for this study, and Ms. Kimberley Merrett for assistance in characterization of the hydrogels. We also thank Dr. Sadhana Kulkani and David Priest, University of Ottawa Eye Institue, for assistance with the laser cutting study; and Dr. Joanne M. Hackett (currently at Cambridge University Health Partners) for assistance with preliminary cell culture/biocompatibility studies during optimization of the RHCIII-MPC hydrogels. We thank Johannes Junger and Michael Baumann, MLase AG, for help with the UV crosslinking, and the Medical Devices Bureau, Health Canada, for use of the SEM system. We gratefully acknowledge funding from an NSERC-CIHR Canada Collaborative Health Research Project grant (M.G.) and subsequent funding for an EU Nanomedicine ERAnet project "I-CARE" to M.G., R.V. and MLase AG, through the Swedish Research Council, Research Council of Lithuania and VDI Germany, respectively.

Available from: 2014-11-03 Created: 2014-11-03 Last updated: 2018-01-11Bibliographically approved
Shakeri, R., Hosseinkhani, S., Los, M. J., Davoodi, J., Jain, M. V., Cieslar-Pobuda, A., . . . Kaboudanian Ardestani, S. (2015). Role of the salt bridge between glutamate 546 and arginine 907 in preservation of autoinhibited form of Apaf-1. International Journal of Biological Macromolecules, 81, 370-374
Open this publication in new window or tab >>Role of the salt bridge between glutamate 546 and arginine 907 in preservation of autoinhibited form of Apaf-1
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2015 (English)In: International Journal of Biological Macromolecules, ISSN 0141-8130, E-ISSN 1879-0003, Vol. 81, p. 370-374Article in journal (Refereed) Published
Abstract [en]

Apaf-1, the key element of apoptotic mitochondrial pathway, normally exists in an auto-inhibited form inside the cytosol. WRD-domain of Apaf-1 has a critical role in the preservation of auto-inhibited form; however the underlying mechanism is unclear. It seems the salt bridges between WRD and NOD domains are involved in maintaining the inactive conformation of Apaf-1. At the present study, we have investigated the effect of E546-R907 salt bridge on the maintenance of auto-inhibited form of human Apaf-1. E546 is mutated to glutamine (Q) and arginine (R). Over-expression of wild type Apaf-1 and its E546Q and E546R variants in HEK293T cells does not induce apoptosis unlike - HL-60 cancer cell line. In vitro apoptosome formation assay showed that all variants are cytochrome c and dATP dependent to form apoptosome and activate endogenous procaspase-9 in Apaf-1-knockout MEF cell line. These results suggest that E546 is not a critical residue for preservation of auto-inhibited Apaf-1. Furthermore, the behavior of Apaf-1 variants for in vitro apoptosome formation in HEK293T cell is similar to exogenous wild type Apaf-1. Wild type and its variants can form apoptosome in HEK293T cell with different procaspase-3 processing pattern in the presence and absence of exogenous cytochrome c and dATP. (C) 2015 Elsevier B.V. All rights reserved.

Place, publisher, year, edition, pages
ELSEVIER SCIENCE BV, 2015
Keywords
Apaf-1; Apoptosome; Caspase-9
National Category
Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy)
Identifiers
urn:nbn:se:liu:diva-124522 (URN)10.1016/j.ijbiomac.2015.08.027 (DOI)000367408300045 ()26277751 (PubMedID)
Note

Funding Agencies|Research Council of University of Tehran; Tarbiat Modares University; Linkoping University; Integrative Regenerative Medicine Center (IGEN); Cancerfonden [2013/391]; VR-NanoVision [K2012-99X-22325-01-5]

Available from: 2016-02-02 Created: 2016-02-01 Last updated: 2017-11-30
Gelmi, A., Rafat, M. & Jager, E. (2014). Actuating electroactive scaffolds for cardiac tissue regeneration. In: : . Paper presented at EuroEAP 2014. Fourth international conference on Electromechanically Active Polymer (EAP) transducers and artificial muscles.
Open this publication in new window or tab >>Actuating electroactive scaffolds for cardiac tissue regeneration
2014 (English)Conference paper, Poster (with or without abstract) (Refereed)
National Category
Textile, Rubber and Polymeric Materials
Identifiers
urn:nbn:se:liu:diva-128242 (URN)
Conference
EuroEAP 2014. Fourth international conference on Electromechanically Active Polymer (EAP) transducers and artificial muscles
Available from: 2016-05-23 Created: 2016-05-23 Last updated: 2018-10-11
Organisations
Identifiers
ORCID iD: ORCID iD iconorcid.org/0000-0001-6024-4144

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