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Nanocellulose for Biomedical Applications: Modification, Characterisation and Biocompatibility Studies
Uppsala University, Disciplinary Domain of Science and Technology, Technology, Department of Engineering Sciences, Nanotechnology and Functional Materials.
2015 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

In the past decade there has been increasing interest in exploring the use of nanocellulose in medicine. However, the influence of the physicochemical properties of nanocellulose on the material´s biocompatibility has not been fully investigated. 

In this thesis, thin films of nanocellulose from wood (NFC) and from Cladophora algae (CC) were modified by the addition of charged groups on their surfaces and the influence of these modifications on the material´s physicochemical properties and on cell responses in vitro was studied.

The results indicate that the introduction of charged groups on the surface of NFC and CC results in films with decreased surface area, smaller average pore size and a more compact structure compared with the films of unmodified nanocelluloses. Furthermore, the fibres in the carboxyl-modified CC films were uniquely aggregated and aligned, a state which tended to become more prevalent with increased surface-group density.

The biocompatibility studies showed that NFC films containing hydroxypropyltrime-thylammonium (HPTMA) groups presented a more cytocompatible surface than unmodified NFC and carboxymethylated NFC regarding human dermal fibroblasts. Carboxymethyl groups resulted in NFC films that promoted inflammation, while HPTMA groups had a passivating effect in terms of inflammatory response. 

On the other hand, both modified CC films behaved as inert materials in terms of the inflammatory response of monocytes/macrophages and, under pro-inflammatory stimuli, they suppressed secretion of the pro-inflammatory cytokine TNF-α, with the effects of the carboxylated CC film more pronounced than those of the HPTMA CC material. 

Carboxyl CC films showed good cytocompatibility with fibroblasts and osteoblastic cells. However, it was necessary to reach a threshold value in carboxyl-group density to obtain CC films with cytocompatibility comparable to that of commercial tissue culture material. 

The studies presented here highlight the ability of the nanocellulose films to modulate cell behaviour and provide a foundation for the design of nanocellulose-based materials that trigger specific cell responses. The bioactivity of nanocellulose may be optimized by careful tuning of the surface properties.

The outcomes of this thesis are foreseen to contribute to our fundamental understanding of the biointerface phenomena between cells and nanocellulose as well as to enable engineering of bioinert, bioactive, and bioadaptive materials.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2015. , 80 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Science and Technology, ISSN 1651-6214 ; 1320
Keyword [en]
Nanocellulose, nanofibrillated cellulose, Cladophora cellulose, biocompatibility, inflammation, surface modification, surface group density, surface topography
National Category
Nano Technology
Research subject
Engineering Science with specialization in Nanotechnology and Functional Materials
Identifiers
URN: urn:nbn:se:uu:diva-267301ISBN: 978-91-554-9416-2 (print)OAI: oai:DiVA.org:uu-267301DiVA: diva2:872707
Public defence
2016-01-27, Häggsalen, Ångströmlaboratoriet, Lägerhyddsvägen 1, Uppsala, 09:30 (English)
Opponent
Supervisors
Available from: 2015-12-18 Created: 2015-11-19 Last updated: 2016-01-13
List of papers
1. Translational study between structure and biological response of nanocellulose from wood and green algae
Open this publication in new window or tab >>Translational study between structure and biological response of nanocellulose from wood and green algae
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2014 (English)In: RSC Advances, ISSN 2046-2069, E-ISSN 2046-2069, Vol. 4, no 6, 2892-2903 p.Article in journal (Refereed) Published
Abstract [en]

The influence of nanostructure on the cytocompatibility of cellulose films is analyzed providing insight into how physicochemical properties of surface modified microfibrillated cellulose (MFC) and Cladophora nanocellulose (CC) affect the materials cytocompatibility. CC is modified through TEMPO-mediated oxidation and glycidyltrimethylammonium chloride (EPTMAC) condensation to obtain anionic and cationic nanocellulose samples respectively, while anionic and cationic MFC samples are obtained by carboxymethylation and EPTMAC condensation respectively. Films of unmodified, anionic and cationic MFC and CC are prepared by vacuum filtration and characterized in terms of specific surface area, pore size distribution, degree of crystallinity, surface charge and water content. Human dermal fibroblasts are exposed to culture medium extracts of the films in an indirect contact cytotoxicity test. Moreover, cell adhesion and viability are evaluated in a direct contact assay and the effects of the physicochemical properties on cell behavior are discussed. In the indirect cytotoxicity test no toxic leachables are detected, evidencing that the CC and MFC materials are non-cytotoxic, independently ofthe chemical treatment that they have been subjected to. The direct contact tests show that carboxymethylated-MFC presents a more cytocompatible profile than unmodified and trimethylammonium-MFC. TEMPO-CC promotes fibroblast adhesion and presents cell viability comparable to the results obtained with the tissue culture material Thermanox. We hypothesize that the distinct aligned nanofiber structure present in the TEMPO-CC films is responsible for the improved cell adhesion. Thus, by controlling the surface properties of cellulose nanofibers, such as chemistry, charge, and orientation, cell adhesion properties can be promoted.

Place, publisher, year, edition, pages
Royal Society of Chemistry, 2014
National Category
Nano Technology
Research subject
Engineering Science with specialization in Nanotechnology and Functional Materials
Identifiers
urn:nbn:se:uu:diva-211744 (URN)10.1039/C3RA45553J (DOI)000329037100044 ()
Available from: 2013-11-30 Created: 2013-11-30 Last updated: 2017-12-06Bibliographically approved
2. Surface Chemistry of Nanocellulose Fibers Directs Monocyte/Macrophage Response
Open this publication in new window or tab >>Surface Chemistry of Nanocellulose Fibers Directs Monocyte/Macrophage Response
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2015 (English)In: Biomacromolecules, ISSN 1525-7797, E-ISSN 1526-4602, Vol. 16, no 9, 2787-2795 p.Article in journal (Refereed) Published
Abstract [en]

The effect of surface functionalization of nanofibrillated cellulose (NFC) on monocyte/macrophage (MM) behavior is investigated to understand how the physicochemical properties of nanocelluloses influence the interactions of such materials with biological systems. Films of anionic (a-), cationic (c-), and unmodified (u-) NFC were synthesized and characterized in terms of surface charge. THP-1 monocytes were cultured on the surface of the films for 24 h in the presence and absence of lipopolysaccharide, and the cell response was evaluated in terms of cell adhesion, morphology, and secretion of TNF-α, IL-10, and IL-1ra. The results show that MMs cultured on carboxymethylated-NFC films (a-NFC) are activated toward a proinflammatory phenotype, whereas u-NFC promotes a mild activation of the studied cells. The presence of hydroxypropyltrimethylammonium groups on c-NFC, however, does not promote the activation of MMs, indicating that c-NFC closely behaves as an inert material in terms of MM activation. None of the materials is able to directly activate the MMs toward an anti-inflammatory response. These results may provide a foundation for the design of future NFC-based materials with the ability to control MM activation and may expand the use of NFC in biomedical applications.

National Category
Nano Technology
Research subject
Engineering Science with specialization in Nanotechnology and Functional Materials
Identifiers
urn:nbn:se:uu:diva-264140 (URN)10.1021/acs.biomac.5b00727 (DOI)000361341700025 ()
Funder
Swedish Research Council Formas
Available from: 2015-10-06 Created: 2015-10-06 Last updated: 2017-12-01Bibliographically approved
3. Nanocellulose from green algae modulates the in vitro inflammatory response of monocytes/macrophages
Open this publication in new window or tab >>Nanocellulose from green algae modulates the in vitro inflammatory response of monocytes/macrophages
2015 (English)In: Cellulose (London), ISSN 0969-0239, E-ISSN 1572-882X, Vol. 22, no 6, 3673-3688 p.Article in journal (Refereed) Published
Abstract [en]

The response of monocytes and macrophages to functionalized Cladophora nanocellulose (CC) films was evaluated. Carboxyl-CC and hydroxypropyltrimethylammonium-CC [referred to as anionic-CC (a-CC) and cationic-CC (c-CC), respectively] were synthesized by TEMPO-mediated oxidation and epoxypropyltrimethylammonium chloride condensation of unmodified CC (u-CC). The cell response to u-CC, a-CC and c-CC of untreated and phorbol 12-myristate-13 acetate treated THP-1 cells, i.e. monocytes and macrophages, in the presence and absence of lipopolysaccharide (LPS) was studied. u-CC impairs the viability of THP-1 monocytes and macrophages most probably due to the presence of impurities. In the absence of LPS, the functionalized materials behave as inert materials in terms of the inflammatory response of both monocytes and differentiated macrophages. Under pro-inflammatory stimuli the functionalized CC films suppressed the inflammatory response induced by LPS. The a-CC material with its aggregated, aligned fibre structure caused a more pronounced reduction of TNF-alpha levels compared to the c-CC film that exhibited non-aggregated, randomly oriented fibres. These results push forward the option of using functionalized CC materials in the biomedical field.

Keyword
Cladophora nanocellulose, Biocompatibility, Inflammation, Monocytes/macrophages
National Category
Nano Technology
Research subject
Engineering Science with specialization in Nanotechnology and Functional Materials
Identifiers
urn:nbn:se:uu:diva-264383 (URN)10.1007/s10570-015-0772-2 (DOI)000364513800014 ()
Funder
Swedish Research Council FormasKnut and Alice Wallenberg Foundation
Available from: 2015-10-10 Created: 2015-10-10 Last updated: 2017-12-01Bibliographically approved
4. Transition from bioinert to bioactive material by tailoring the biological cell response to carboxylated nanocellulose
Open this publication in new window or tab >>Transition from bioinert to bioactive material by tailoring the biological cell response to carboxylated nanocellulose
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2016 (English)In: Biomacromolecules, ISSN 1525-7797, E-ISSN 1526-4602, Vol. 17, no 3, 1224-1233 p.Article in journal (Refereed) Published
Abstract [en]

This work presents an insight into the relationship between cell response and physicochemical properties of Cladophora cellulose (CC) by investigating the effect of CC functional group density on the response of model cell lines. CC was carboxylated by electrochemical TEMPO-mediated oxidation. By varying the amount of charge passed through the electrolysis setup, CC materials with different degrees of oxidation were obtained. The effect of carboxyl group density on the material’s physicochemical properties was investigated together with the response of human dermal fibroblasts (hDF) and human osteoblastic cells (Saos-2) to the carboxylated CC films. The introduction of carboxyl groups resulted in CC films with decreased specific surface area and smaller total pore volume compared with the unmodified CC (u-CC). While u-CC films presented a porous network of randomly oriented fibers, a compact and aligned fiber pattern was depicted for the carboxylated-CC films. The decrease in surface area and total pore volume, and the orientation and aggregation of the fibers tended to augment parallel to the increase in the carboxyl group density. hDF and Saos-2 cells presented poor cell adhesion and spreading on u-CC, which gradually increased for the carboxylated CC as the degree of oxidation increased. It was found that a threshold value in carboxyl group density needs be reached to obtain a carboxylated-CC film with cytocompatibility comparable to commercial tissue culture material. Hence, this study demonstrates that a normally bioinert nanomaterial can be rendered bioactive by carefully tuning the density of charged groups on the material surface, a finding that not only may contribute to the fundamental understanding of biointerface phenomena, but also to the development of bioinert/bioactive materials.

National Category
Nano Technology
Research subject
Engineering Science with specialization in Nanotechnology and Functional Materials
Identifiers
urn:nbn:se:uu:diva-267300 (URN)10.1021/acs.biomac.6b00053 (DOI)000372391800056 ()
Funder
Swedish Research Council FormasStiftelsen Olle Engkvist Byggmästare
Available from: 2015-11-19 Created: 2015-11-19 Last updated: 2017-12-01Bibliographically approved

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