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Ion-Crosslinked Nanocellulose Hydrogels for Advanced Wound Care Applications
Uppsala University, Disciplinary Domain of Science and Technology, Technology, Department of Engineering Sciences, Nanotechnology and Functional Materials. (Nanotechnology and Functional Materials)
2018 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

A current trend in the field of wound care is the development of wound healing materials that are designed to address specific types of wounds or underlying pathologies to achieve improved healing. At the same time, there is a societal drive to replace synthetic materials with renewable alternatives. The work presented in this thesis was therefore carried out to investigate the use of wood nanocellulose, produced from the world’s most abundant biopolymer, cellulose, in advanced wound care applications.

Wood-based nanofibrillated cellulose (NFC) was chemically functionalized and crosslinked using calcium to obtain a self-standing hydrogel. The NFC hydrogel was evaluated in terms of its physicochemical properties, biocompatibility, blood interactions, bacterial interactions, in vivo wound healing ability and, finally, as a protein carrier. Parallel with the assessment of the NFC hydrogel, modified versions of the material were tested to investigate the tunability of the above-mentioned characteristics.

The ability of the hydrogel to maintain a moist wound bed was demonstrated. Evaluation of the biocompatibility showed that the material was cytocompatible and did not trigger inflammatory mechanisms. Furthermore, the NFC hydrogel supported cell proliferation, and was shown to possess hemostatic properties. It was also discovered that the material had a slight bacteriostatic effect and the ability to act as a barrier against bacteria. When tested in vivo, the hydrogel was found to significantly improve wound healing.

Modifications through the incorporation of additives to the hydrogel matrix, as well as exchange of the crosslinking ion, were shown to influence the biological response to the material. Moreover, the results presented here demonstrate the possibility of using the NFC hydrogel as a protein carrier; the easily adjustable charge property being identified as a central parameter for manipulation to regulate the release profile.

In conclusion, this work has demonstrated the extensive wound healing ability of the calcium-crosslinked NFC hydrogel, and represents an important milestone in the research on NFC towards advanced wound care applications. It is expected that the easily modifiable nature of the material can be exploited to further develop the NFC hydrogel to suit the treatment needs for a broad range of wound types.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2018. , p. 81
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Science and Technology, ISSN 1651-6214 ; 1731
Keywords [en]
nanofibrillated cellulose, wood nanocellulose, ion crosslinking, hydrogel, wound healing, biocompatibility, blood interactions, bacterial interactions, protein carrier, nanotherapeutic
National Category
Nano Technology
Research subject
Engineering Science with specialization in Nanotechnology and Functional Materials
Identifiers
URN: urn:nbn:se:uu:diva-363087ISBN: 978-91-513-0474-8 (print)OAI: oai:DiVA.org:uu-363087DiVA, id: diva2:1255355
Public defence
2018-11-30, Häggsalen, Ångströmlaboratoriet, Lägerhyddsvägen 1, Uppsala, 09:30 (English)
Opponent
Supervisors
Available from: 2018-11-09 Created: 2018-10-12 Last updated: 2018-11-19
List of papers
1. On the use of ion-crosslinked nanocellulose hydrogels for wound healing solutions: Physicochemical properties and application-oriented biocompatibility studies
Open this publication in new window or tab >>On the use of ion-crosslinked nanocellulose hydrogels for wound healing solutions: Physicochemical properties and application-oriented biocompatibility studies
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2017 (English)In: Carbohydrate Polymers, ISSN 0144-8617, E-ISSN 1879-1344, Vol. 174, p. 299-308Article in journal (Refereed) Published
Abstract [en]

Calcium ion-crosslinked nanofibrillated cellulose (NFC) hydrogels were investigated as potential materials for wound healing dressings. The physicochemical properties of the hydrogels were examined by rheology and water retention tests. Skin cells and monocytes were selected for application-oriented bio-compatibility studies. The NFC hydrogels presented entangled fibrous networks and solid-like behavior. Water retention tests showed the material's potential to maintain a suitable moist environment for different type of wounds. The hydrogels did not affect dermal fibroblasts monolayer cultures upon directcontact, as cell monolayers remained intact after application, incubation and removal of the materials. Inflammatory response studies with blood-derived mononuclear cells revealed the inert nature of the hydrogels in terms of cytokine secretion and reactive oxygen species production. Results highlight the great potential of ion-crosslinked NFC hydrogels for the development of advanced wound dressings, where further functionalization of the material could lead to improved properties towards the healing of specific wound types.

Keywords
Nanofibrillated cellulose, Inflammation, Fibroblasts, Mononuclear cells
National Category
Nano Technology
Research subject
Engineering Science with specialization in Nanotechnology and Functional Materials
Identifiers
urn:nbn:se:uu:diva-332126 (URN)10.1016/j.carbpol.2017.06.073 (DOI)000407696800032 ()28821071 (PubMedID)
Funder
Swedish Research Council Formas
Available from: 2017-10-24 Created: 2017-10-24 Last updated: 2018-10-12Bibliographically approved
2. Hemocompatibility of Ca2+-Crosslinked Nanocellulose Hydrogels: Toward Efficient Management of Hemostasis
Open this publication in new window or tab >>Hemocompatibility of Ca2+-Crosslinked Nanocellulose Hydrogels: Toward Efficient Management of Hemostasis
2017 (English)In: Macromolecular Bioscience, ISSN 1616-5187, E-ISSN 1616-5195, Vol. 17, no 11, article id 1700236Article in journal (Refereed) Published
Abstract [en]

The present work investigates Ca2+-crosslinked nanofibrillated cellulose hydrogels as potential hemostatic wound dressings by studying core interactions between the materials and a central component of wounds and wound healing—the blood. Hydrogels of wood-derived anionic nanofibrillated cellulose (NFC) and NFC hydrogels that incorporate kaolin or collagen are studied in an in vitro whole blood model and with platelet-free plasma assays. The evaluation of thrombin and factor XIIa formation, platelet reduction, and the release of activated complement system proteins, shows that the NFC hydrogel efficiently triggered blood coagulation, with a rapid onset of clot formation, while displaying basal complement system activation. By using the NFC hydrogel as a carrier of kaolin, the onset of hemostasis is further boosted, while the NFC hydrogel containing collagen exhibits blood activating properties comparable to the anionic NFC hydrogel. The herein studied NFC hydrogels demonstrate great potential for being part of advanced wound healing dressings that can be tuned to target certain wounds (e.g., strongly hemorrhaging ones) or specific phases of the wound healing process for optimal wound management.

Keywords
biocompatibility, blood coagulation, complement system, nanofibrillated cellulose, wound dressing
National Category
Nano Technology
Research subject
Engineering Science with specialization in Nanotechnology and Functional Materials
Identifiers
urn:nbn:se:uu:diva-332127 (URN)10.1002/mabi.201700236 (DOI)000415130800015 ()28941135 (PubMedID)
Funder
Swedish Research Council Formas
Available from: 2017-10-24 Created: 2017-10-24 Last updated: 2018-10-12Bibliographically approved
3. Ion-crosslinked wood-derived nanocellulose hydrogels with tunable antibacterial properties: Candidate materials for advanced wound care applications
Open this publication in new window or tab >>Ion-crosslinked wood-derived nanocellulose hydrogels with tunable antibacterial properties: Candidate materials for advanced wound care applications
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2018 (English)In: Carbohydrate Polymers, ISSN 0144-8617, E-ISSN 1879-1344, Vol. 181, p. 345-350Article in journal (Refereed) Published
Abstract [en]

Development of advanced dressings with antimicrobial properties for the treatment of infected wounds is an important approach in the fight against evolution of antibiotic resistant bacterial strains. Herein, the effects of ion-crosslinked nanocellulose hydrogels on bacteria commonly found in infected wounds were investigated in vitro. By using divalent calcium or copper ions as crosslinking agents, different antibacterial properties against the bacterial strains Staphylococcus epidermidis and Pseudomonas aeruginosa were obtained. Calcium crosslinked hydrogels were found to retard S. epidermidis growth (up to 266% increase in lag time, 36% increase in doubling time) and inhibited P. aeruginosa biofilm formation, while copper crosslinked hydrogels prevented S. epidermidis growth and were bacteriostatic towards P. aeruginosa (49% increase in lag time, 78% increase in doubling time). The wound dressing candidates furthermore displayed barrier properties towards both S. epidermidis and P. aeruginosa, hence making them interesting for further development of advanced wound dressings with tunable antibacterial properties.

Keywords
Nanofibrillated cellulose, Biofilm, Wound dressing, Infected wound
National Category
Nano Technology
Research subject
Engineering Science with specialization in Nanotechnology and Functional Materials
Identifiers
urn:nbn:se:uu:diva-333382 (URN)10.1016/j.carbpol.2017.10.085 (DOI)000418661000041 ()29253982 (PubMedID)
Funder
Swedish Research Council Formas
Available from: 2017-11-13 Created: 2017-11-13 Last updated: 2018-10-12Bibliographically approved
4. In vitro and in vivo evaluation of the wound healing properties of nanofibrillated cellulose hydrogels
Open this publication in new window or tab >>In vitro and in vivo evaluation of the wound healing properties of nanofibrillated cellulose hydrogels
(English)In: Article in journal (Refereed) Submitted
National Category
Nano Technology
Research subject
Engineering Science with specialization in Nanotechnology and Functional Materials
Identifiers
urn:nbn:se:uu:diva-362724 (URN)
Available from: 2018-10-09 Created: 2018-10-09 Last updated: 2018-10-12
5. Towards Tunable Protein-Carrier Wound Dressings Based on Nanocellulose Hydrogels Crosslinked with Calcium Ions
Open this publication in new window or tab >>Towards Tunable Protein-Carrier Wound Dressings Based on Nanocellulose Hydrogels Crosslinked with Calcium Ions
2018 (English)In: Nanomaterials, E-ISSN 2079-4991, Vol. 8, no 7, article id 550Article in journal (Refereed) Published
Abstract [en]

A Ca2+-crosslinked wood-based nanofibrillated cellulose (NFC) hydrogel was investigated to build knowledge toward the use of nanocellulose for topical drug delivery applications in a chronic wound healing context. Proteins of varying size and isoelectric point were loaded into the hydrogel in a simple soaking procedure. The release of the proteins from the hydrogel was monitored and kinetics determining parameters of the release processes were assessed. The integrity of the hydrogel and proteins were also studied. The results showed that electrostatic interactions between the proteins and the negatively-charged NFC hydrogel structure played a central role in the loading process. The release of the proteins were governed by Fickian diffusion. An increased protein size, as well as a positive protein charge facilitated a slower and more sustained release process from the hydrogel matrix. At the same time, the positively-charged protein was shown to increase the post-loading hydrogel strength. Released proteins maintained structural stability and activity, thus indicating that the Ca2+-crosslinked NFC hydrogel could function as a carrier of therapeutic proteins without compromising protein function. It is foreseen that, by utilizing tunable charge properties of the NFC hydrogel, release profiles can be tailored to meet very specific treatment needs.

Place, publisher, year, edition, pages
MDPI, 2018
Keywords
nanofibrillated cellulose, ion-crosslinked, drug delivery, wound healing, chronic wounds
National Category
Nano Technology
Research subject
Engineering Science with specialization in Nanotechnology and Functional Materials
Identifiers
urn:nbn:se:uu:diva-362722 (URN)10.3390/nano8070550 (DOI)000442523100101 ()30036970 (PubMedID)
Funder
Swedish Research Council Formas, 942-2015-475
Available from: 2018-10-09 Created: 2018-10-09 Last updated: 2018-10-30Bibliographically approved

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