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Dynamic Coordination Chemistry Enables Free Directional Printing of Biopolymer Hydrogel
Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - Ångström, Polymer Chemistry.
Uppsala University, Disciplinary Domain of Science and Technology, Physics, Department of Physics and Astronomy, Materials Physics.
Institute of Materials Science and Technology, Technische Universität Wien.
Institute of Materials Science and Technology, Technische Universität Wien.
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2017 (English)In: Chemistry of Materials, ISSN 0897-4756, E-ISSN 1520-5002, Vol. 29, p. 5816-5823Article in journal (Refereed) Published
Abstract [en]

Three-dimensional (3D) printing is a promising technology to develop customized biomaterials in regenerative medicine. However, for the majority of printable biomaterials (bioinks) there is always a compromise between excellent printability of fluids and good mechanical properties of solids. 3D printing of soft materials based on the transition from a fluid to gel state is challenging because of the difficulties to control such transition as well as to maintain uniform conditions three-dimensionally. To solve these challenges, a facile chemical strategy for the development of a novel hydrogel bioink with shear-thinning and self-healing properties based on dynamic metal-ligand coordination bonds is presented. The non-covalent cross-linking allows easy extrusion of the bioink from a reservoir without changing of its bulk mechanical properties. The soft hydrogel can avoid deformation and collapse using omnidirectional embedding of the printable hydrogel into a support gel bath sharing the same cross-linking chemistry. After combination with photo-initiated covalent cross-linking, it enables manufacturing of hydrogel structures with complex shapes and precise location of chemically attached ligands. Living cells can be entrapped in the new printable hydrogel and survive the following in situ photocross-linking. The presented printable hydrogel mate-rial expands the existing tool-box of bioinks for generation of in vitro 3D tissue-like structures and direct in vivo 3D printing.

Place, publisher, year, edition, pages
American Chemical Society (ACS), 2017. Vol. 29, p. 5816-5823
National Category
Polymer Chemistry
Identifiers
URN: urn:nbn:se:uu:diva-324796DOI: 10.1021/acs.chemmater.7b00128ISI: 000406573200011OAI: oai:DiVA.org:uu-324796DiVA, id: diva2:1111592
Funder
EU, European Research Council, 307701Available from: 2017-06-19 Created: 2017-06-19 Last updated: 2018-09-03Bibliographically approved
In thesis
1. Injectable Composite Hydrogels Based on Metal-Ligand Assembly for Biomedical Applications
Open this publication in new window or tab >>Injectable Composite Hydrogels Based on Metal-Ligand Assembly for Biomedical Applications
2018 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

This thesis presents new strategies to construct injectable hydrogels and their various biomedical applications, such as 3D printing, regenerative medicine and drug delivery. These hydrogels cross-linked by dynamic metal-ligand coordination bonds exhibit shear-thinning and self-healing properties, resulting in the unlimited time window for injection. Compared with non-dynamic networks based on chemically reactive liquid polymer precursors that forms covalent bond during and/or post-injection, our injectable hydrogels with dynamic cross-linkages can be injected from an already cross-linked hydrogel state. 

Hyaluronic acid (HA) has been selected as the polymer due to its high biocompatibility and biodegradability. HA has been modified by attaching the bisphosphonates (BP) functionality as ligands for chelation of the metal ions or metal salts to form coordination cross-linkages. In the first part of this thesis, I presented the different chemical approaches to synthesize BP-modified HA (HA-BP) derivatives as well as HA derivatives dually modified with BP and acrylamide (Am) groups (Am-HA-BP). The structures of HA-BP derivatives were confirmed by NMR characterizations, e.g. by the peak at 2.18 ppm for methylene protons adjacent to the bridging carbon of BP in 1H-NMR spectrum and phosphorus peak at 18.27 ppm in 31P-NMR spectrum, respectively. In the next part, the hydrogels were constructed by simple mixing of HA-BP or Am-HA-BP solution with Ca2+ ions (Paper I), Ag+ ions (Paper II),  calcium phosphonate coated silk microfibers (CaP@mSF) (Paper III), and magnesium silicate (MgSiO3) nanoparticles (Paper IV). The presented hydrogels exhibited dynamic features determined by reversible nature of coordination networks formed between of BP moieties of HA-BP or Am-HA-BP and metal ions or metal salts on the surface of the inorganic particles. Dynamic properties were characterized by rheological strain sweep experiments and strain-alternating time sweep experiments. Additionally, reversible coordination hydrogels were demonstrated to be further covalently cross-linked by UV light to form a secondary cross-linkage, allowing an increase of the strength and modulus of the hydrogels. In the last part of this thesis, biomedical applications of these hydrogels were presented. Am-HA-BP•Ca2+ hydrogel was extruded, using home-made 3D printer, then fixed by UV irradiation to fabricate multi-layered 3D tube-like construct (Paper I). In full-thickness skin defects of rat model, HA-BP•Ag+ hydrogel accelerated the wound healing process and increased thickness of newly-regenerated epidermal layer (Paper II). In the rat cranial critical defect model, double cross-linked Am-HA-BP•CaP@mSF hydrogel induced new bone formation without addition of biological factors and cells (Paper III). The anti-cancer drug loaded hydrogel was also prepared by mixing of the drug loaded MgSiO3 nanoparticles with HA-BP solution. The released particles from the hydrogel were shown to be taken up by cancer cells to induce a toxic response (Paper IV).

In summary, this thesis presents metal-ligand coordination chemical strategies to build injectable hydrogels with dynamic cross-linking resulting in time-independent injection behavior. These hydrogels open new possibilities for use in biomedical areas.

Place, publisher, year, edition, pages
Acta Universitatis Upsaliensis, 2018. p. 55
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Science and Technology, ISSN 1651-6214 ; 1690
Keywords
injectable, hydrogel, shear-thinning, self-healing, coordination chemistry, biomedical applications
National Category
Polymer Chemistry
Identifiers
urn:nbn:se:uu:diva-355252 (URN)978-91-513-0379-6 (ISBN)
Public defence
2018-09-14, Häggsalen, Ångströmlaboratoriet, Lägerhyddsvägen 1, Uppsala, 13:15 (English)
Opponent
Supervisors
Available from: 2018-08-21 Created: 2018-06-27 Last updated: 2018-08-28

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Shi, LiyangCarstensen, HaukeLi, HaoHilborn, JönsOssipov, Dmitri A.

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