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Injectable Composite Hydrogels Based on Metal-Ligand Assembly for Biomedical Applications
Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för kemi - Ångström, Polymerkemi.
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 [en]
injectable, hydrogel, shear-thinning, self-healing, coordination chemistry, biomedical applications
HSV kategori
Identifikatorer
URN: urn:nbn:se:uu:diva-355252ISBN: 978-91-513-0379-6 (tryckt)OAI: oai:DiVA.org:uu-355252DiVA, id: diva2:1228177
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
Delarbeid
1. Dynamic Coordination Chemistry Enables Free Directional Printing of Biopolymer Hydrogel
Åpne denne publikasjonen i ny fane eller vindu >>Dynamic Coordination Chemistry Enables Free Directional Printing of Biopolymer Hydrogel
Vise andre…
2017 (engelsk)Inngår i: Chemistry of Materials, ISSN 0897-4756, E-ISSN 1520-5002, Vol. 29, s. 5816-5823Artikkel i tidsskrift (Fagfellevurdert) 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.

sted, utgiver, år, opplag, sider
American Chemical Society (ACS), 2017
HSV kategori
Identifikatorer
urn:nbn:se:uu:diva-324796 (URN)10.1021/acs.chemmater.7b00128 (DOI)000406573200011 ()
Forskningsfinansiär
EU, European Research Council, 307701
Tilgjengelig fra: 2017-06-19 Laget: 2017-06-19 Sist oppdatert: 2018-09-03bibliografisk kontrollert
2. Moldable Hyaluronan Hydrogel Enabled by Dynamic Metal–Bisphosphonate Coordination Chemistry for Wound Healing
Åpne denne publikasjonen i ny fane eller vindu >>Moldable Hyaluronan Hydrogel Enabled by Dynamic Metal–Bisphosphonate Coordination Chemistry for Wound Healing
Vise andre…
2018 (engelsk)Inngår i: Advanced Healthcare Materials, ISSN 2192-2640, E-ISSN 2192-2659, Vol. 7, nr 5, artikkel-id 1700973Artikkel i tidsskrift (Fagfellevurdert) Published
Abstract [en]

Biomaterial-based regenerative approaches would allow for cost-effective off-the-shelf solution for the treatment of wounds. Hyaluronan (HA)-based hydrogel is one attractive biomaterial candidate because it is involved in natural healing processes, including inflammation, granulation, and reepi-thelialization. Herein, dynamic metal–ligand coordination bonds are used to fabricate moldable supramolecular HA hydrogels with self-healing properties. To achieve reversible crosslinking of HA chains, the biopolymer is modified with pendant bisphosphonate (BP) ligands using carbodiimide coupling and chemoselective “click” reactions. Hydrogel is formed immediately after simple addition of silver (Ag+) ions to the solution of HA containing BP groups (HA-BP). Compared with previous HA-based wound healing hydrogels, the HA-BP·Ag+ hydrogel is highly suitable for clinical use as it can fill irregularly shaped wound defects without the need for premolding. The HA-BP·Ag+ hydrogel shows antimicrobial properties to both Gram-positive and Gram-negative bacterial strains, enabling prevention of infections in wound care. In vivo evaluation using a rat full-thickness skin wound model shows sig-nificantly lower wound remaining rate and a thicker layer of regenerated epidermis as compared with the group left without treatment. The presented moldable and self-healing supramolecular HA hydrogel with “ready-to-use” properties possesses a great potential for regenerative wound treatment.

Emneord
antibacterial, bisphosphonate, hyaluronan, moldable, wound healing
HSV kategori
Identifikatorer
urn:nbn:se:uu:diva-338080 (URN)10.1002/adhm.201700973 (DOI)000426758500016 ()
Tilgjengelig fra: 2018-01-07 Laget: 2018-01-07 Sist oppdatert: 2018-06-27bibliografisk kontrollert
3. Self-Healing Silk Fibroin-Based Hydrogel for Bone Regeneration: Dynamic Metal-Ligand Self-Assembly Approach
Åpne denne publikasjonen i ny fane eller vindu >>Self-Healing Silk Fibroin-Based Hydrogel for Bone Regeneration: Dynamic Metal-Ligand Self-Assembly Approach
Vise andre…
2017 (engelsk)Inngår i: Advanced Functional Materials, artikkel-id 1700591Artikkel i tidsskrift (Fagfellevurdert) Published
Abstract [en]

Despite advances in the development of silk fibroin (SF)-based hydrogels, current methods for SF gelation show significant limitations such as lack of reversible crosslinking, use of nonphysiological conditions, and difficulties in controlling gelation time. In the present study, a strategy based on dynamic metal-ligand coordination chemistry is developed to assemble SF-based hydrogel under physiological conditions between SF microfibers (mSF) and a polysaccharide binder. The presented SF-based hydrogel exhibits shear-thinning and autonomous self-healing properties, thereby enabling the filling of irregularly shaped tissue defects without gel fragmentation. A biomineralization approach is used to generate calcium phosphate-coated mSF, which is chelated by bisphosphonate ligands of the binder to form reversible crosslinkages. Robust dually crosslinked (DC) hydrogel is obtained through photopolymerization of acrylamide groups of the binder. DC SF-based hydrogel supports stem cell proliferation in vitro and accelerates bone regeneration in cranial critical size defects without any additional morphogenes delivered. The developed self-healing and photopolymerizable SF-based hydrogel possesses significant potential for bone regeneration application with the advantages of injectability and fit-to-shape molding.

Emneord
bone regeneration, hydrogels, self-assembly, self-healing, silk fibroin
HSV kategori
Identifikatorer
urn:nbn:se:uu:diva-327126 (URN)10.1002/adfm.201700591 (DOI)000412324200012 ()
Forskningsfinansiär
EU, FP7, Seventh Framework Programme
Tilgjengelig fra: 2017-08-04 Laget: 2017-08-04 Sist oppdatert: 2018-06-27bibliografisk kontrollert
4. “Smart” drug loaded nanoparticle delivery from a self-healing hydrogel enabled by dynamic magnesium–biopolymer chemistry
Åpne denne publikasjonen i ny fane eller vindu >>“Smart” drug loaded nanoparticle delivery from a self-healing hydrogel enabled by dynamic magnesium–biopolymer chemistry
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.

HSV kategori
Identifikatorer
urn:nbn:se:uu:diva-301659 (URN)10.1039/C6CC05565F (DOI)000384202000027 ()27550535 (PubMedID)
Tilgjengelig fra: 2016-08-24 Laget: 2016-08-24 Sist oppdatert: 2019-04-24bibliografisk kontrollert

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