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Injectable In Situ Forming Hybrid Iron Oxide-Hyaluronic Acid Hydrogel for Magnetic Resonance Imaging and Drug Delivery
Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - Ångström, Polymer Chemistry. Uppsala University, Science for Life Laboratory, SciLifeLab.
Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - Ångström, Polymer Chemistry. Uppsala University, Science for Life Laboratory, SciLifeLab.
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2014 (English)In: Macromolecular Bioscience, ISSN 1616-5187, E-ISSN 1616-5195, Vol. 14, no 9, 1249-1259 p.Article in journal (Refereed) Published
Abstract [en]

The development of multimodal in situ cross-linkable hyaluronic acid nanogels hybridized with iron oxide nanoparticles is reported. Utilizing a chemoselective hydrazone coupling reaction, the nanogels are converted to a macroscopic hybrid hydrogel without any additional reagent. Hydrophobic cargos remain encapsulated in the hydrophobic domains of the hybrid hydrogel without leakage. However, hydrogel degradation with hyaluronidase liberates iron oxide nanoparticles. This allows the utilization of imaging agents as tracers of the hydrogel degradation. UV-vis spectrometry and MRI studies reveal that the degradability of the hydrogels correlates with their structure. The hydrogels presented here are very promising theranostic tools for hyaluronidase-mediated delivery of hydrophobic drugs, as well as imaging of hydrogel degradation and tracking of degradation products in vivo.

Place, publisher, year, edition, pages
2014. Vol. 14, no 9, 1249-1259 p.
Keyword [en]
hybrid organic-inorganic nanogels, hyaluronan hydrogels, in situ cross-linking, iron oxide nanoparticles, magnetic resonance imaging
National Category
Polymer Chemistry Biochemistry and Molecular Biology
URN: urn:nbn:se:uu:diva-236090DOI: 10.1002/mabi.201400117ISI: 000342921900005OAI: oai:DiVA.org:uu-236090DiVA: diva2:763693
Available from: 2014-11-17 Created: 2014-11-12 Last updated: 2016-09-02Bibliographically approved
In thesis
1. Hyaluronan Based Biomaterials with Imaging Capacity for Tissue Engineering
Open this publication in new window or tab >>Hyaluronan Based Biomaterials with Imaging Capacity for Tissue Engineering
2016 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

This thesis presents the preparation of hyaluronan-based biomaterials with imaging capability and their application as scaffolds in tissue engineering. First, we have synthesized HA derivatives functionalized with different chemoselective groups. Then, functional ligands with capacities for hydrophobic drug loading, imaging, and metal ion coordination were chemically conjugated to HA by chemoselective reactions with these groups. An injectable in situ forming HA hydrogel was prepared by hydrazone cross-linking between hybrid iron-oxide nanogel and HA-aldehyde (paper-I). The degradation of this hydrogel could be monitored by MRI and UV-vis spectroscopy since it contained iron oxide as a contrast agent and pyrene as a fluorescent probe. Additionally, this hydrogel has a potential for a delivery of hydrophobic drugs due to its pyrene hydrophobic domains. The degradation study showed that degradability of the hydrogel was correlated with its structure. Based on the obtained results, disulfide cross-linked and fluorescently labeled hydrogels with different HA concentration were established as a model to study the relationship between the structure of the hydrogel and its degradability (paper-II). We demonstrated that disulfide cross-linked HA hydrogel could be tracked non-invasively by fluorescence imaging. It was proved that the in vivo degradation behavior of the hydrogel is predictable basing on its in vitro degradation study. In paper-III, we developed a disulfide cross-linked HA hydrogel for three-dimensional (3D) cell culture. In order to improve cell viability and adhesion to the matrix, HA derivatives were cross-linked in the presence of fibrinogen undergoing polymerization upon the action of thrombin. It led to the formation of an interpenetrating double network (IPN) of HA and fibrin. The results of 3D cell culture experiments revealed that the IPN hydrogel provides the cells with a more stable environment for proliferation. The results of the cellular studies were also supported by in vitro degradation of IPN monitored by fluorescence measurements of the degraded products. In paper-IV, the effect of biomineralization on hydrogel degradation was evaluated in a non-invasive manner in vitro. For this purpose, two types of fluorescently labeled hydrogels with the different ability for biomineralization were prepared. Fluorescence spectroscopy was applied to monitor degradation of the hydrogels in vitro under two different conditions in longitudinal studies. Under the supply of Ca2+ ions, the BP-modified hydrogel showed the tendency to bio-mineralization and reduction of the rate of degradation. Altogether, the performed studies showed the importance of imaging of hydrogel biomaterials in the design of optimized scaffolds for tissue engineering.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2016. 60 p.
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Science and Technology, ISSN 1651-6214 ; 1402
hyaluronan, hydrogel, scaffold, tissue engineering, imaging, interpenetrating network, MRI, fluorescence imaging, scaffold degradation
National Category
Materials Chemistry Polymer Chemistry
urn:nbn:se:uu:diva-300799 (URN)978-91-554-9649-4 (ISBN)
External cooperation:
Public defence
2016-09-29, 80101, Lägerhyddsvägen 1, Uppsala, 09:00 (English)
Available from: 2016-09-06 Created: 2016-08-14 Last updated: 2016-09-13

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Zhang, YuHilborn, JönsOssipov, Dmitri A.
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