uu.seUppsala University Publications
Change search
CiteExportLink to record
Permanent link

Direct link
Cite
Citation style
  • apa
  • ieee
  • modern-language-association
  • vancouver
  • Other style
More styles
Language
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Other locale
More languages
Output format
  • html
  • text
  • asciidoc
  • rtf
Self-Healing Silk Fibroin-Based Hydrogel for Bone Regeneration: Dynamic Metal-Ligand Self-Assembly Approach
Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - Ångström, Polymer Chemistry. Uppsala University, Science for Life Laboratory, SciLifeLab.
Experimental Trauma Surgery, University Medical Center Schleswig Holstein UKSH, Kiel, Germany.
Department of Big Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China.
Institute of Applied Bioresources Research, College of Animal Science, Zhejiang University, Hangzhou, China.
Show others and affiliations
2017 (English)In: Advanced Functional Materials, article id 1700591Article in journal (Refereed) 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.

Place, publisher, year, edition, pages
2017. article id 1700591
Keywords [en]
bone regeneration, hydrogels, self-assembly, self-healing, silk fibroin
National Category
Polymer Chemistry
Identifiers
URN: urn:nbn:se:uu:diva-327126DOI: 10.1002/adfm.201700591ISI: 000412324200012OAI: oai:DiVA.org:uu-327126DiVA, id: diva2:1129580
Funder
EU, FP7, Seventh Framework ProgrammeAvailable from: 2017-08-04 Created: 2017-08-04 Last updated: 2018-06-27Bibliographically 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

Open Access in DiVA

No full text in DiVA

Other links

Publisher's full text

Authority records BETA

Shi, LiyangHilborn, JönsOssipov, Dmitri A.

Search in DiVA

By author/editor
Shi, LiyangHilborn, JönsOssipov, Dmitri A.
By organisation
Polymer ChemistryScience for Life Laboratory, SciLifeLab
Polymer Chemistry

Search outside of DiVA

GoogleGoogle Scholar

doi
urn-nbn

Altmetric score

doi
urn-nbn
Total: 460 hits
CiteExportLink to record
Permanent link

Direct link
Cite
Citation style
  • apa
  • ieee
  • modern-language-association
  • vancouver
  • Other style
More styles
Language
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Other locale
More languages
Output format
  • html
  • text
  • asciidoc
  • rtf