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“Smart” drug loaded nanoparticle delivery from a self-healing hydrogel enabled by dynamic magnesium–biopolymer chemistry
Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för kemi - Ångström, Polymerkemi.
Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Tekniska sektionen, Institutionen för teknikvetenskaper, Tillämpad materialvetenskap.ORCID-id: 0000-0001-7591-2969
Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för kemi - Ångström, Polymerkemi.
Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för kemi - Ångström, Polymerkemi.
2016 (engelsk)Inngår i: Chemical Communications, ISSN 1359-7345, E-ISSN 1364-548X, Vol. 52, nr 74, s. 11151-11154Artikkel i tidsskrift (Fagfellevurdert) Published
Abstract [en]

We report a strategy to generate a self-healing and pH responsive hydrogel network between drug-loaded nanoparticles and natural polysaccharides via magnesium–bisphosphonate ligand interactions. The injectable drug depot disassembles in a tumor-specific environment, providing localized uptake of the nanoparticles, which is highly appreciated in drug delivery applications and manufacturing of drug-loaded biomaterials using a syringe-based deposition technique.

sted, utgiver, år, opplag, sider
2016. Vol. 52, nr 74, s. 11151-11154
HSV kategori
Identifikatorer
URN: urn:nbn:se:uu:diva-301659DOI: 10.1039/C6CC05565FISI: 000384202000027PubMedID: 27550535OAI: oai:DiVA.org:uu-301659DiVA, id: diva2:955006
Tilgjengelig fra: 2016-08-24 Laget: 2016-08-24 Sist oppdatert: 2019-04-24bibliografisk kontrollert
Inngår i avhandling
1. Injectable Composite Hydrogels Based on Metal-Ligand Assembly for Biomedical Applications
Åpne denne publikasjonen i ny fane eller vindu >>Injectable Composite Hydrogels Based on Metal-Ligand Assembly for Biomedical Applications
2018 (engelsk)Doktoravhandling, med artikler (Annet vitenskapelig)
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.

sted, utgiver, år, opplag, sider
Acta Universitatis Upsaliensis, 2018. s. 55
Serie
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Science and Technology, ISSN 1651-6214 ; 1690
Emneord
injectable, hydrogel, shear-thinning, self-healing, coordination chemistry, biomedical applications
HSV kategori
Identifikatorer
urn:nbn:se:uu:diva-355252 (URN)978-91-513-0379-6 (ISBN)
Disputas
2018-09-14, Häggsalen, Ångströmlaboratoriet, Lägerhyddsvägen 1, Uppsala, 13:15 (engelsk)
Opponent
Veileder
Tilgjengelig fra: 2018-08-21 Laget: 2018-06-27 Sist oppdatert: 2018-08-28

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