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  • 1.
    Aronsson, Christopher
    et al.
    Laboratory of Molecular Materials, Division of Biophysics and Bioengineering, Department of Physics, Chemistry and Biology, Linköping University, Sweden.
    Jury, Michael
    Laboratory of Molecular Materials, Division of Biophysics and Bioengineering, Department of Physics, Chemistry and Biology, Linköping University, Sweden.
    Naeimipour, Sajjad
    Laboratory of Molecular Materials, Division of Biophysics and Bioengineering, Department of Physics, Chemistry and Biology, Linköping University, Sweden.
    Boroojeni, Fatemeh Rasti
    Laboratory of Molecular Materials, Division of Biophysics and Bioengineering, Department of Physics, Chemistry and Biology, Linköping University, Sweden.
    Christoffersson, Jonas
    University of Skövde, School of Bioscience. University of Skövde, Systems Biology Research Environment. Division of Biotechnology, Department of Physics, Chemistry and Biology, Linköping University, Sweden.
    Lifwergren, Philip
    Laboratory of Molecular Materials, Division of Biophysics and Bioengineering, Department of Physics, Chemistry and Biology, Linköping University, Sweden.
    Mandenius, Carl-Fredrik
    Division of Biotechnology, Department of Physics, Chemistry and Biology, Linköping University, Sweden.
    Selegård, Robert
    Laboratory of Molecular Materials, Division of Biophysics and Bioengineering, Department of Physics, Chemistry and Biology, Linköping University, Sweden.
    Aili, Daniel
    Laboratory of Molecular Materials, Division of Biophysics and Bioengineering, Department of Physics, Chemistry and Biology, Linköping University, Sweden.
    Dynamic peptide-folding mediated biofunctionalization and modulation of hydrogels for 4D bioprinting2020In: Biofabrication, ISSN 1758-5082, E-ISSN 1758-5090, Vol. 12, no 3, article id 035031Article in journal (Refereed)
    Abstract [en]

    Hydrogels are used in a wide range of biomedical applications, including three-dimensional (3D) cell culture, cell therapy and bioprinting. To enable processing using advanced additive fabrication techniques and to mimic the dynamic nature of the extracellular matrix (ECM), the properties of the hydrogels must be possible to tailor and change over time with high precision. The design of hydrogels that are both structurally and functionally dynamic, while providing necessary mechanical support is challenging using conventional synthesis techniques. Here, we show a modular and 3D printable hydrogel system that combines a robust but tunable covalent bioorthogonal cross-linking strategy with specific peptide-folding mediated interactions for dynamic modulation of cross-linking and functionalization. The hyaluronan-based hydrogels were covalently cross-linked by strain-promoted alkyne-azide cycloaddition using multi-arm poly(ethylene glycol). In addition, a de novo designed helix-loop-helix peptide was conjugated to the hyaluronan backbone to enable specific peptide-folding modulation of cross-linking density and kinetics, and hydrogel functionality. An array of complementary peptides with different functionalities was developed and used as a toolbox for supramolecular tuning of cell-hydrogel interactions and for controlling enzyme-mediated biomineralization processes. The modular peptide system enabled dynamic modifications of the properties of 3D printed structures, demonstrating a novel route for design of more sophisticated bioinks for four-dimensional bioprinting. © 2020 The Author(s). Published by IOP Publishing Ltd.

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  • 2.
    Nawaz, Muhammad
    et al.
    Department of Rheumatology and Inflammation Research, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Sweden.
    Heydarkhan-Hagvall, Sepideh
    University of Skövde, School of Bioscience. University of Skövde, Systems Biology Research Environment. BioPharmaceuticals R&D, Early Cardiovascular, Renal and Metabolism (CVRM), Bioscience Cardiovascular, AstraZeneca, Gothenburg, Mölndal, Sweden.
    Tangruksa, Benyapa
    University of Skövde, School of Bioscience. University of Skövde, Systems Biology Research Environment. Department of Rheumatology and Inflammation Research, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Sweden.
    González-King Garibotti, Hernán
    BioPharmaceuticals R&D, Early Cardiovascular, Renal and Metabolism (CVRM), Bioscience Cardiovascular, AstraZeneca, Gothenburg, Mölndal, Sweden.
    Jing, Yujia
    Advanced Drug Delivery, Pharmaceutical Sciences, BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Mölndal, Sweden.
    Maugeri, Marco
    Department of Rheumatology and Inflammation Research, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Sweden ; Safety Innovations, Clinical Pharmacology and Safety Sciences, R&D AstraZeneca, Gothenburg, Mölndal, Sweden.
    Kohl, Franziska
    BioPharmaceuticals R&D, Discovery Sciences, Translational Genomics, AstraZeneca, Gothenburg, Mölndal, Sweden ; Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Solna, Sweden.
    Hultin, Leif
    BioPharmaceuticals R&D, Clinical Pharmacology and Safety Science, Imaging and Data Analytics, AstraZeneca, Gothenburg, Mölndal, Sweden.
    Reyahi, Azadeh
    Department of Rheumatology and Inflammation Research, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Sweden.
    Camponeschi, Alessandro
    Department of Rheumatology and Inflammation Research, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Sweden.
    Kull, Bengt
    BioPharmaceuticals R&D, Early Cardiovascular, Renal and Metabolism (CVRM), Bioscience Cardiovascular, AstraZeneca, Gothenburg, Mölndal, Sweden.
    Christoffersson, Jonas
    University of Skövde, School of Bioscience. University of Skövde, Systems Biology Research Environment. BioPharmaceuticals R&D, Early Cardiovascular, Renal and Metabolism (CVRM), Bioscience Cardiovascular, AstraZeneca, Gothenburg, Mölndal, Sweden.
    Grimsholm, Ola
    Department of Rheumatology and Inflammation Research, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Sweden ; Institute of Pathophysiology and Allergy Research, Medical University of Vienna, Austria.
    Jennbacken, Karin
    BioPharmaceuticals R&D, Early Cardiovascular, Renal and Metabolism (CVRM), Bioscience Cardiovascular, AstraZeneca, Gothenburg, Mölndal, Sweden.
    Sundqvist, Martina
    Department of Rheumatology and Inflammation Research, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Sweden.
    Wiseman, John
    BioPharmaceuticals R&D, Discovery Sciences, Translational Genomics, AstraZeneca, Gothenburg, Mölndal, Sweden.
    Bidar, Abdel Wahad
    BioPharmaceuticals R&D, Discovery Sciences, Translational Genomics, AstraZeneca, Gothenburg, Mölndal, Sweden.
    Lindfors, Lennart
    Advanced Drug Delivery, Pharmaceutical Sciences, BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Mölndal, Sweden.
    Synnergren, Jane
    University of Skövde, School of Bioscience. University of Skövde, Systems Biology Research Environment. Department of Molecular and Clinical Medicine, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Sweden.
    Valadi, Hadi
    Department of Rheumatology and Inflammation Research, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Sweden.
    Lipid Nanoparticles Deliver the Therapeutic VEGFA mRNA In Vitro and In Vivo and Transform Extracellular Vesicles for Their Functional Extensions2023In: Advanced Science, E-ISSN 2198-3844, Vol. 10, no 12, article id 2206187Article in journal (Refereed)
    Abstract [en]

    Lipid nanoparticles (LNPs) are currently used to transport functional mRNAs, such as COVID-19 mRNA vaccines. The delivery of angiogenic molecules, such as therapeutic VEGF-A mRNA, to ischemic tissues for producing new blood vessels is an emerging strategy for the treatment of cardiovascular diseases. Here, the authors deliver VEGF-A mRNA via LNPs and study stoichiometric quantification of their uptake kinetics and how the transport of exogenous LNP-mRNAs between cells is functionally extended by cells’ own vehicles called extracellular vesicles (EVs). The results show that cellular uptake of LNPs and their mRNA molecules occurs quickly, and that the translation of exogenously delivered mRNA begins immediately. Following the VEGF-A mRNA delivery to cells via LNPs, a fraction of internalized VEGF-A mRNA is secreted via EVs. The overexpressed VEGF-A mRNA is detected in EVs secreted from three different cell types. Additionally, RNA-Seq analysis reveals that as cells’ response to LNP-VEGF-A mRNA treatment, several overexpressed proangiogenic transcripts are packaged into EVs. EVs are further deployed to deliver VEGF-A mRNA in vitro and in vivo. Upon equal amount of VEGF-A mRNA delivery via three EV types or LNPs in vitro, EVs from cardiac progenitor cells are the most efficient in promoting angiogenesis per amount of VEGF-A protein produced. Intravenous administration of luciferase mRNA shows that EVs could distribute translatable mRNA to different organs with the highest amounts of luciferase detected in the liver. Direct injections of VEGF-A mRNA (via EVs or LNPs) into mice heart result in locally produced VEGF-A protein without spillover to liver and circulation. In addition, EVs from cardiac progenitor cells cause minimal production of inflammatory cytokines in cardiac tissue compared with all other treatment types. Collectively, the data demonstrate that LNPs transform EVs as functional extensions to distribute therapeutic mRNA between cells, where EVs deliver this mRNA differently than LNPs. 

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