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Nanofeatures of Biomaterials and their Impact on the Inflammatory Response
Uppsala University, Disciplinary Domain of Science and Technology, Technology, Department of Engineering Sciences.
2016 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Nanomaterials offer an advantage over traditional biomaterials since cells naturally communicate via nanoscale interactions. The extracellular matrix, for example, modulates adhesion and cellular functions via nanoscale features. Thus incorporating nanofeatures into biomaterials may promote tissue regeneration, however in certain forms and doses nanomaterials can also cause harm. A thorough understanding of cell-nanomaterial interactions is therefore necessary to better design functional biomaterials. This thesis focuses on evaluating the effect of nanofeatures on inflammation using two different models: nanoporous alumina and hydroxyapatite nanoparticles (HANPs).

The inflammatory response caused by in vitro exposure of macrophages to nanoporous alumina, with pore diameters of 20nm and 200nm, was investigated. In addition in vivo studies were performed by implantation of nanoporous membranes in mice. In both cases the 200nm pore diameter elicited a stronger inflammatory response.

Nanoporous alumina with 20, 100 and 200nm pores were loaded with Trolox, a vitamin E analogue, in order to scavenge ROS produced by primary human polymorphonuclear (PMNC) and mononuclear (MNCs) leukocytes. Unloaded alumina membranes stimulated greater ROS production from PMNCs cultured on 20nm versus 100nm pores. This trend reversed when PMNCs were cultured on Trolox loaded membranes since Trolox eluted slower from 20nm than 100nm and 200nm pores. ROS produced from PMNCs was reduced between 8-30% when cultured on Trolox loaded membranes. For MNCs, ROS production was not affected by pore size. However when the alumina was loaded with Trolox ROS production was quenched by 95%.

HANPs with distinct morphologies (long rods, sheets, dots, and fibers) were synthesized via hydrothermal and precipitation methods. The HANPs were then exposed to PMNCs, MNCs, and the human dermal fibroblast (hDF) cell line. Changes in cell viability, ROS, morphology, and apoptotic behavior were evaluated. PMNC and hDF viability decreased following exposure to fibers, while the dot particles reduced MNC viability. Fibers stimulated greater ROS production from PMNCs and MNCs, and caused apoptotic behavior in all cell types. Furthermore, they also stimulated greater capsule thickness in vivo, suggesting that nanoparticle morphology can significantly influence acute inflammation.

The outcome of this thesis, confirms the importance of understanding how nanofeatures influence inflammation.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2016. , 70 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Science and Technology, ISSN 1651-6214 ; 1374
Keyword [en]
Nanofeatures, alumina, hydroxyapatite, inflammation
National Category
Nano Technology Biological Sciences Materials Engineering
Research subject
Engineering Science with specialization in Materials Science
Identifiers
URN: urn:nbn:se:uu:diva-284402ISBN: 978-91-554-9576-3 (print)OAI: oai:DiVA.org:uu-284402DiVA: diva2:920317
Public defence
2016-06-09, Å2001, Lägerhyddsvägen 1, Uppsala, 09:30 (English)
Opponent
Supervisors
Available from: 2016-05-19 Created: 2016-04-18 Last updated: 2016-06-01
List of papers
1. Effects of nanoporous alumina on inflammatory cell response
Open this publication in new window or tab >>Effects of nanoporous alumina on inflammatory cell response
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2014 (English)In: Journal of Biomedical Materials Research. Part A, ISSN 1549-3296, E-ISSN 1552-4965, Vol. 102, no 11, 3773-3780 p.Article in journal (Refereed) Published
Abstract [en]

The present study focuses on the effects of nanoscale porosity on inflammatory response in vitro and in vivo. Nanoporous alumina membranes with different pore sizes, 20 and 200 nm in diameter, were used. We first evaluated cell/alumina interactions in vitro by observing adhesion, proliferation, and activation of a murine fibroblast and a macrophage cell line. To investigate the chronic inflammatory response, the membranes were implanted subcutaneously in mice for 2 weeks. Cell recruitment to the site of implantation was determined by histology and the production of cytokines was measured by protein array analysis. Both in vitro and in vivo studies showed that 200 nm pores induced a stronger inflammatory response as compared to the alumina with 20 nm pores. This was observed by an increase in macrophage activation in vitro as well as higher cell recruitment and generation of proinflammatory cytokines around the alumina with 200 nm pores, in vivo. Our results suggest that nanofeatures can be modulated in order to control the inflammatory response to implants.

Keyword
nanoporous alumina, nanofeatures, inflammation, in vivo
National Category
Biomaterials Science Engineering and Technology
Research subject
Engineering Science with specialization in Materials Science
Identifiers
urn:nbn:se:uu:diva-236525 (URN)10.1002/jbm.a.35048 (DOI)000343010100001 ()24288233 (PubMedID)
Available from: 2014-12-01 Created: 2014-11-19 Last updated: 2017-12-05Bibliographically approved
2. Reduced oxidative stress in primary human cells by antioxidant released from nanoporous alumina
Open this publication in new window or tab >>Reduced oxidative stress in primary human cells by antioxidant released from nanoporous alumina
2016 (English)In: Journal of Biomedical Materials Research. Part B - Applied biomaterials, ISSN 1552-4973, E-ISSN 1552-4981, Vol. 104, no 3, 568-575 p.Article in journal (Refereed) Published
Abstract [en]

Nanoporous alumina elicits different inflammatory responses dependent on pore size, such as increased complement activation and reactive oxygen species (ROS) production, on 200 versus 20 nm pores. In this study, we attempt to further modulate inflammatory cell response by loading nanoporous alumina membranes (20, 100, and 200 nm pores), with an antioxidant, Trolox, for controlled drug release. For mononuclear cells (MNC) no difference in cell response, due to pore size, was seen when cultured on nonloaded membranes. However, when exposed to membranes loaded with Trolox, 100 uM was enough to quench ROS by more than 95% for all pore sizes. Polymorphonuclear cells (PMNC) produced significantly more ROS when exposed to 20 versus 100 nm pores. For Trolox loaded membranes, this trend reversed, due to slower release of antioxidant from the 20 nm pores. Furthermore, Trolox exhibited a unique effect on PMNCs that has not previously been reported: It delayed the production of ROS in a manner distinct from antioxidant activity. The present study confirms that nanoporous alumina is a suitable vehicle for drug delivery, and that Trolox can successfully modulate the inflammatory response of both MNC and PMNCs.

Keyword
nanoporous alumina; Trolox; mononuclear cells; polymorphonuclear cells; reactive oxygen species
National Category
Immunology Biomaterials Science Engineering and Technology
Identifiers
urn:nbn:se:uu:diva-283488 (URN)10.1002/jbm.b.33427 (DOI)000372297100016 ()25952986 (PubMedID)
Funder
The Swedish Foundation for International Cooperation in Research and Higher Education (STINT)
Available from: 2016-04-13 Created: 2016-04-13 Last updated: 2017-11-30Bibliographically approved
3. Highly repeatable synthesis of nHA with high aspect ratio
Open this publication in new window or tab >>Highly repeatable synthesis of nHA with high aspect ratio
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2015 (English)In: Materials letters (General ed.), ISSN 0167-577X, E-ISSN 1873-4979, Vol. 159, 163-167 p.Article in journal (Refereed) Published
National Category
Biomaterials Science Engineering and Technology
Identifiers
urn:nbn:se:uu:diva-265712 (URN)10.1016/j.matlet.2015.06.086 (DOI)000362603000043 ()
Funder
Swedish Research Council, 2013-5419VINNOVA, 2010-01907EU, FP7, Seventh Framework Programme, INFRA-2010-262163
Available from: 2015-11-02 Created: 2015-11-02 Last updated: 2017-12-01
4. In vivo and in vitro evaluation of hydroxyapatite nanoparticle morphology on the acute inflammatory response
Open this publication in new window or tab >>In vivo and in vitro evaluation of hydroxyapatite nanoparticle morphology on the acute inflammatory response
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2016 (English)In: Biomaterials, ISSN 0142-9612, E-ISSN 1878-5905, Vol. 90, 1-11 p.Article in journal (Refereed) Published
Abstract [en]

Biomedical implants have been widely used in bone repair applications. However, nanosized degradation products from these implants could elicit an inflammatory reaction, which may lead to implant failure. It is well known that the size, chemistry, and charge of these nanoparticles can modulate this response, but little is known regarding the role that the particle's morphology plays in inducing inflammation. The present study aims to investigate the effect of hydroxyapatite nanoparticle (HANPs) morphology on inflammation, in-vitro and in-vivo. Four distinct HANP morphologies were fabricated and characterized: long rods, dots, sheets, and fibers. Primary human polymorphonuclear cells (PMNCs), mononuclear cells (MNCs), and human dermal fibroblasts (hDFs) were exposed to HANPs and alterations in cell viability, morphology, apoptotic activity, and reactive oxygen species (ROS) production were evaluated, in vitro. PMNCs and hDFs experienced a 2-fold decrease in viability following exposure to fibers, while MNC viability decreased 5-fold after treatment with the dots. Additionally, the fibers stimulated an elevated ROS response in both PMNCs and MNCs, and the largest apoptotic behavior for all cell types. Furthermore, exposure to fibers and dots resulted in greater capsule thickness when implanted subcutaneously in mice. Collectively, these results suggest that nanoparticle morphology can significantly impact the inflammatory response.

Keyword
Hydroxyapatite nanoparticles; Morphology; Mononuclear cells; Polymorphonuclear cells; Reactive oxygen species; In vivo
National Category
Immunology Biomaterials Science Engineering and Technology
Identifiers
urn:nbn:se:uu:diva-283555 (URN)10.1016/j.biomaterials.2016.02.039 (DOI)000374618100001 ()26974703 (PubMedID)
Funder
VINNOVA, 2010-01907
Available from: 2016-04-13 Created: 2016-04-13 Last updated: 2017-11-30Bibliographically approved

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