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D’Elía, N. L., Rial Silva, R., Sartuqui, J., Ercoli, D., Ruso, J., Messina, P. & Mestres, G. (2020). Development and characterisation of bilayered periosteum-inspired composite membranes based on sodium alginate-hydroxyapatite nanoparticles. Journal of Colloid and Interface Science, 572, 408-420
Open this publication in new window or tab >>Development and characterisation of bilayered periosteum-inspired composite membranes based on sodium alginate-hydroxyapatite nanoparticles
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2020 (English)In: Journal of Colloid and Interface Science, ISSN 0021-9797, E-ISSN 1095-7103, Vol. 572, p. 408-420Article in journal (Refereed) Published
Abstract [en]

Background and aim: Membranes for guided bone regeneration should have a mechanical structure and a chemical composition suitable for mimicking biological structures. In this work, we pursue the develop- ment of periosteum-inspired bilayered membranes obtained by crosslinking alginate with different amounts of nanohydroxyapatite.

Experiments: Alginate-nanohydroxyapatite interaction was studied by rheology and infrared spectroscopy measurements. The membranes were characterized regarding their tensile strength, degrada- tion and surface morphology. Finally, cell cultures were performed on each side of the membranes.

Findings: The ionic bonding between alginate polysaccharide networks and nanohydroxyapatite was proven, and had a clear effect in the strength and microstructure of the hydrogels. Distinct surface charac- teristics were achieved on each side of the membranes, resulting in a highly porous fibrous side and a mineral-rich side with higher roughness and lower porosity. Moreover, the effect of amount of nanohydroxyapatite was reflected in a decrease of the membranes’ plasticity and an increment of degradation rate. Finally, it was proved that osteoblast-like cells proliferated and differentiated on the mineral-rich side, specially when a higher amount of nanohydroxyapatite was used, whereas fibroblasts-like cells were able to proliferate on the fibrous side. These periosteum-inspired membranes are promising biomaterials for guided tissue regeneration applications.

Keywords
Alginate, Bilayer, Cell culture, Fibroblasts, Guided bone regeneration, Membrane
National Category
Engineering and Technology
Research subject
Engineering Science with specialization in Materials Science
Identifiers
urn:nbn:se:uu:diva-408303 (URN)10.1016/j.jcis.2020.03.086 (DOI)
Available from: 2020-04-07 Created: 2020-04-07 Last updated: 2020-04-14Bibliographically approved
Carter, S.-S., Atif, A. R., Kadekar, S., Lanekoff, I., Engqvist, H., Varghese, O. P., . . . Mestres, G. (2020). PDMS leaching and its implications for on-chip studies focusing on boneregeneration applications. Organs-on-a-Chip, 2(100004)
Open this publication in new window or tab >>PDMS leaching and its implications for on-chip studies focusing on boneregeneration applications
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2020 (English)In: Organs-on-a-Chip, ISSN 2666-1020, Vol. 2, no 100004Article in journal (Refereed) Published
Abstract [en]

Polydimethylsiloxane (PDMS) is among the most widely used materials for organ-on-chip systems. Despite itsmultiple beneficial characteristics from an engineering point of view, there is a concern about the effect of PDMSon the cells cultured in such devices. The aim of this study was to enhance the understanding of the effect of PDMSon cellular behavior in a context relevant for on-chip studies. The focus was put on an indirect effect of PDMS,namely leaching of uncrosslinked oligomers, particularly for bone regeneration applications. PDMS-based chipswere prepared and analyzed for the potential release of PDMS oligomers within the microfluidic channel whenkept at different flow rates. Leaching of uncrosslinked oligomers from PDMS was quantified as silicon concen-tration by inductively coupled plasma - optical emission spectrometry and further confirmed by mass spec-trometry. Subsequently, PDMS-leached media, with a silicon concentration matching the on-chip experiment,were prepared to study cell proliferation and osteogenic differentiation of MC3T3-E1 pre-osteoblasts and humanmesenchymal stem cells. The silicon concentration initially detected in the media was inversely proportional tothe tested flow rates and decreased to control levels within 52 h. In addition, by curing the material overnightinstead of 2 h, regardless of the curing temperature (65 and 80 C), a large reduction in silicon concentration wasfound, indicating the importance of the PDMS curing parameters. Furthermore, it was shown that PDMS oligo-mers enhanced the differentiation of MC3T3-E1 pre-osteoblasts, this being a cell type dependent effect as nochanges in cell differentiation were observed for human mesenchymal stem cells. Overall, this study illustrates theimportance of optimization steps when using PDMS devices for biological studies, in particular PDMS curingconditions and extensive washing steps prior to an experiment.

Place, publisher, year, edition, pages
Elsevier, 2020
Keywords
PDMS, Organs-on-chip, Human mesenchymal stem cells, Osteoblasts, Silicon
National Category
Engineering and Technology
Research subject
Engineering Science with specialization in Microsystems Technology
Identifiers
urn:nbn:se:uu:diva-410262 (URN)10.1016/j.ooc.2020.100004 (DOI)
Funder
Swedish Research Council Formas, 2016-00781Swedish Research Council, 2017-05051Göran Gustafsson Foundation for Research in Natural Sciences and Medicine, 1841Knut and Alice Wallenberg Foundation, 2016-0112
Available from: 2020-05-13 Created: 2020-05-13 Last updated: 2020-05-15Bibliographically approved
Mestres, G., Perez, R. A., d'Elía, N. & Barbe, L. (2019). Advantages of microfluidic systems for studying cell-biomaterial interactions: focus on bone regeneration applications. Biomedical Physics & Engineering Express, 5(3), Article ID 032001.
Open this publication in new window or tab >>Advantages of microfluidic systems for studying cell-biomaterial interactions: focus on bone regeneration applications
2019 (English)In: Biomedical Physics & Engineering Express, ISSN 2057-1976, Vol. 5, no 3, article id 032001Article, review/survey (Refereed) Published
Abstract [en]

The poor correlation between in vitro and in vivo studies emphasises the lack of a reliable methodology for testing the biological properties of biomaterials in the bone tissue regeneration field. Moreover, the success of clinical trials is not guaranteed even with promising results in vivo. Therefore, there is a need for a more physiologically relevant in vitro model to test the biological properties of biomaterials. Microfluidics, which is a field concerning the manipulation and control of liquids at the submillimetre scale, can use channel geometry, cell confinement and fluid flow to recreate a physiological-like environment. This technology has already proven to be a powerful tool in studying the biological response of cells in defined environments, since chemical and mechanical inputs as well as cross-talk between cells can be finely controlled. Moving a step further in complexity, biomaterials can be integrated into microfluidic systems to evaluate biomaterial-cell interactions. The biomaterial- microfluidics combination has the potential to produce more physiologically relevant models to better screen the biological interactions established between biomaterials and cells. This review is divided into two main sections. First, several possible cell-based assays for bone regeneration studies in microfluidic systems are discussed. Second, and the ultimate goal of the review, is to discuss how the gap between in vitro and in vivo studies can be shortened by bridging the biomaterials and microfluidics fields.

Keywords
bone regeneration, biomaterials, in vitro, microfluidics, microsystems, cell culture
National Category
Materials Engineering
Identifiers
urn:nbn:se:uu:diva-381400 (URN)10.1088/2057-1976/ab1033 (DOI)000463561300001 ()
Funder
Swedish Research Council Formas, 2016-00781Swedish Research Council, 2017-05051Göran Gustafsson Foundation for Research in Natural Sciences and Medicine, 1841The Swedish Foundation for International Cooperation in Research and Higher Education (STINT), IB2017-7362
Available from: 2019-04-09 Created: 2019-04-09 Last updated: 2019-04-25Bibliographically approved
D’Elía, N. L., Rial Silva, R., Sartuqui, J., Ercoli, D., Ruso, J., Messina, P. & Mestres, G. (2019). Alginate - hydroxyapatite composites for guided bone regeneration: rheology and tensile strength. In: : . Paper presented at SAP 2019 (Simposio Argentino de Polimeros), Buenos Aires, Argentina, 9-11 october 2019.
Open this publication in new window or tab >>Alginate - hydroxyapatite composites for guided bone regeneration: rheology and tensile strength
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2019 (English)Conference paper, Poster (with or without abstract) (Other academic)
Keywords
biomaterials, bone regeneration
National Category
Materials Engineering
Identifiers
urn:nbn:se:uu:diva-392967 (URN)
Conference
SAP 2019 (Simposio Argentino de Polimeros), Buenos Aires, Argentina, 9-11 october 2019
Available from: 2019-09-11 Created: 2019-09-11 Last updated: 2019-09-16Bibliographically approved
Blasi Romero, A., Nguyen, H., Barbe, L., Tenje, M. & Mestres, G. (2019). Development and validation of a reusable microfluidic system for the evaluation of biomaterials’ biological properties. In: : . Paper presented at 2nd European Organ-on-Chip Conference (EUROoC 2019), 2-3 July 2019, Graz, Austria.
Open this publication in new window or tab >>Development and validation of a reusable microfluidic system for the evaluation of biomaterials’ biological properties
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2019 (English)Conference paper, Poster (with or without abstract) (Other academic)
Keywords
Biomaterials, biomaterials-on-chip, microfluidics
National Category
Medical Materials
Identifiers
urn:nbn:se:uu:diva-392966 (URN)
Conference
2nd European Organ-on-Chip Conference (EUROoC 2019), 2-3 July 2019, Graz, Austria
Available from: 2019-09-11 Created: 2019-09-11 Last updated: 2019-09-16Bibliographically approved
Atif, A. R., Pujari-Palmer, M., Tenje, M. & Mestres, G. (2019). Evaluation of Ionic Interactions of Bone Cement-on-Chip. In: : . Paper presented at 1st European Organ-on-Chips Society Conference, Graz, July 2-3, 2019.
Open this publication in new window or tab >>Evaluation of Ionic Interactions of Bone Cement-on-Chip
2019 (English)Conference paper, Poster (with or without abstract) (Other academic)
Abstract [en]

INTRODUCTION: Biomaterials are synthetic materials that can be incorporated into the body to replace an impaired physiological function. Apatite calcium phosphate cements (CPCs), used for bone regeneration, give calcium-deficient hydroxyapatite (CDHA) as an end-product after a dissolution-precipitation reaction during fabrication. CDHA has a tendency to uptake calcium and release phosphate into cell culture medium. Potentially, this leads to depletion of calcium ions in solution, which can be detrimental to cell survival. The aim of this work is to embed CDHA in a microfluidic system and evaluate ion exchange at different flow rates.

METHODS: CPC paste was cast into a 0.8mm pocket within a Polydimethylsiloxane (PDMS, cured at 60°C for 2h) mould. CPCs were set in 0.9% w/v NaCl at 37°C for 10 days resulting in CDHA. The PDMS containing the CDHA was then bonded to glass, leaving a 0.5mm channel gap. Minimum Essential Media (MEM, 1ml) was pumped through the channel at low (2µl/min), medium (8µl/min) and high (14µl/min) flow rates. A CDHA disc (ø=15mm, h=2mm) was immersed in MEM (1ml) at static conditions (0µl/min) for 24h. Stock Media was taken as control. Calcium and phosphorus concentrations were analysed using Inductively Coupled Plasma Optical Emission Spectroscopy.

RESULTS & CONCLUSIONS: CDHA was successfully embedded in a microfluidic chip (Fig. 1A). Observed [Ca] and [P] levels were closer to levels in stock MEM at higher flow rates (Fig. 1B). We anticipate that osteoblast viability will improve when grown under flow, as opposed to static conditions, due to continuous replenishment of cell medium.

National Category
Medical Materials
Research subject
Engineering Science with specialization in Microsystems Technology
Identifiers
urn:nbn:se:uu:diva-393088 (URN)
Conference
1st European Organ-on-Chips Society Conference, Graz, July 2-3, 2019
Funder
Swedish Research Council, 2017-05051Swedish Research Council Formas, 2016-00781Knut and Alice Wallenberg Foundation, 2016-0112Göran Gustafsson Foundation for Research in Natural Sciences and Medicine, 1841
Available from: 2019-09-16 Created: 2019-09-16 Last updated: 2019-09-16Bibliographically approved
Mestres, G., Fernandez-Yague, M. A., Pastorino, D., Montufar, E. B., Canal, C., Manzanares-Céspedes, M.-C. & Ginebra, M.-P. (2019). In vivo efficiency of antimicrobial inorganic bone grafts in osteomyelitis Treatments. Materials science & engineering. C, biomimetic materials, sensors and systems, 97, 84-95
Open this publication in new window or tab >>In vivo efficiency of antimicrobial inorganic bone grafts in osteomyelitis Treatments
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2019 (English)In: Materials science & engineering. C, biomimetic materials, sensors and systems, ISSN 0928-4931, E-ISSN 1873-0191, Vol. 97, p. 84-95Article in journal (Refereed) Published
Abstract [en]

The purpose of the present work was to evaluate in vivo different antimicrobial therapies to eradicate osteomyelitis created in the femoral head of New Zealand rabbits. Five phosphate-based cements were evaluated: calcium phosphate cements (CPC) and calcium phosphate foams (CPF), both in their pristine form and loaded with doxycycline hyclate, and an intrinsic antimicrobial magnesium phosphate cement (MPC; not loaded with an antibiotic). The cements were implanted in a bone previously infected with Staphylococcus aureus to discern the effects of the type of antibiotic administration (systemic vs. local), porosity (microporosity, i.e. <5 μm vs. macroporosity, i.e. >5 μm) and type of antimicrobial mechanism (release of antibiotic vs. intrinsic antimicrobial activity) on the improvement of the health state of the infected animals. A new method was developed, with a more comprehensive composite score that integrates 5 parameters of bone infection, 4 parameters of bone structural integrity and 4 parameters of bone regeneration. This method was used to evaluate the health state of the infected animals, both before and after osteomyelitis treatment. The results showed that the composite score allows to discern statistically significant differences between treatments that individual evaluations were not able to identify. Despite none of the therapies completely eradicated the infection, it was observed that macroporous materials (CPF and CPFd, the latter loaded with doxycycline hyclate) and intrinsic antimicrobial MPC allowed a better containment of the osteomyelitis. This study provides novel insights to understand the effect of different antimicrobial therapies in vivo, and a promising comprehensive methodology to evaluate the health state of the animals was developed. We expect that the implementation of such methodology could improve the criteria to select a proper antimicrobial therapy.

Keywords
Osteomyelitis; Calcium phosphate cements; Calcium phosphate foams; Magnesium phosphate cements; Drug delivery; In vivo
National Category
Biomaterials Science
Research subject
Engineering Science with specialization in Materials Science
Identifiers
urn:nbn:se:uu:diva-369961 (URN)10.1016/j.msec.2018.11.064 (DOI)000457952800009 ()30678975 (PubMedID)
Note

De 2 första författarna delar förstaförfattarskapet.

Available from: 2018-12-17 Created: 2018-12-17 Last updated: 2019-03-08Bibliographically approved
Carter, S.-S., Nguyen, H., Moreira, M., Tenje, M. & Mestres, G. (2019). Medical grade titanium on-chip: assessing the biological properties of biomaterials for bone regeneration. In: : . Paper presented at 2nd European Organ-on-Chip Conference, EUROoC 2019, Graz, Austria, July 2-3, 2019.
Open this publication in new window or tab >>Medical grade titanium on-chip: assessing the biological properties of biomaterials for bone regeneration
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2019 (English)Conference paper, Poster (with or without abstract) (Other academic)
Abstract [en]

Medical grade titanium on-chip: assessing the biological properties of biomaterials for bone regeneration

 

Sarah-Sophia D. Carter1, Hugo Nguyen2, Milena Moreira1, Maria Tenje1, and Gemma Mestres1

1Department of Engineering Sciences, Science for Life Laboratory, Uppsala University, Sweden

2Department of Engineering Sciences, Uppsala University, Sweden

 

Introduction

Before entering the clinic, biomaterials need to be thoroughly evaluated, which requires accurate in vitro models. In this work, we have developed a microfluidic device that could be used to assess the biological properties of biomaterials, in a more in vivo-like environment than what is currently possible.

 

Methods

Our device consists of a polydimethylsiloxane (PDMS, Sylgard 184) microfluidic channel (l= 6 mm, w= 2 mm, h= 200 µm) and a titanium disc (Ti6Al4V, at bottom), held together by an additively manufactured fixture (Fig. 1A). PDMS was cured overnight at 65°C on a silicon wafer master. Once the microchannel and titanium disc were positioned, MC3T3-E1 pre-osteoblast-like cells were seeded (50,000 cells/cm2). After 5 hours incubation under standard culture conditions, flow was started (2 μl/min). As a control, MC3T3-E1 cells were seeded onto plain titanium discs off-chip. Cell viability and morphology were assessed after 20 hours by calcein-AM/propidium iodide (PI), staining live and dead cells respectively.

 

Results and discussion

Figure 1B and 1C show calcein-AM/PI stained MC3T3-E1 cells cultured on-chip and figure 1D shows the control, MC3T3-E1 cells cultured off-chip. The potential to culture cells in our chip was confirmed by the presence of a majority of viable cells (green) with a similar morphology as the control sample. The reason for the increased amount of dead cells (red) on-chip compared to the control needs to be further examined, which requires longer-term experiments.

Conclusion

We have set the first steps towards a microfluidic tool for the assessment of biological properties of biomaterials.

Keywords
Organ-on-chip, biomaterials, microfluidics
National Category
Engineering and Technology
Research subject
Engineering Science with specialization in Microsystems Technology
Identifiers
urn:nbn:se:uu:diva-393277 (URN)
Conference
2nd European Organ-on-Chip Conference, EUROoC 2019, Graz, Austria, July 2-3, 2019
Funder
Knut and Alice Wallenberg Foundation, WAF 2016-0112Vattenfall AB, 2017-05051
Available from: 2019-09-18 Created: 2019-09-18 Last updated: 2019-09-20Bibliographically approved
Diez-Escudero, A., Liu, Y., Lançon, V., Widhe, M., Persson, C., Hedhammar, M. & Mestres, G. (2019). Recombinant silk with calcium phosphates as macroporous bone scaffolds. In: : . Paper presented at European Congress and Exhibition on advanced materials and processes (EUROMAT 2019), 1-5 September 2019, Stockholm, Sweden.
Open this publication in new window or tab >>Recombinant silk with calcium phosphates as macroporous bone scaffolds
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2019 (English)Conference paper, Oral presentation only (Refereed)
Keywords
Biomaterials, calcium phosphate cements, porosity
National Category
Materials Engineering
Identifiers
urn:nbn:se:uu:diva-392965 (URN)
Conference
European Congress and Exhibition on advanced materials and processes (EUROMAT 2019), 1-5 September 2019, Stockholm, Sweden
Available from: 2019-09-11 Created: 2019-09-11 Last updated: 2019-09-16Bibliographically approved
Atif, A. R., Carter, S.-S., Pujari-Palmer, M., Tenje, M. & Mestres, G. (2018). Bone Cement Embedded in a Microfluidic Device. In: : . Paper presented at Micronano System Workshop (MSW), May 13-15, 2018, Aalto University, Espoo, Finland.
Open this publication in new window or tab >>Bone Cement Embedded in a Microfluidic Device
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2018 (English)Conference paper, Poster (with or without abstract) (Refereed)
Abstract [en]

Calcium phosphate cements (CPCs) have a great potential in the treatment of bone disorders due to their excellent biocompatibility. Although CPCs are promising when implanted in vivo, there is poor correlation between in vitro and in vivo studies. This could be because most conventional in vitro systems lack a 3D architecture, or dynamic conditions (i.e. a continuous refreshment stream). The aim of this work is to embed CPCs into a microfluidic system and evaluate ion and protein exchange at different flow rates.

Keywords
Calcium Phosphate Cements, Microfluidic Chip, Continuous flow, Biomaterial Evaluation, Bone implants, Cells
National Category
Other Materials Engineering Engineering and Technology
Research subject
Engineering Science with specialization in Microsystems Technology
Identifiers
urn:nbn:se:uu:diva-363447 (URN)
Conference
Micronano System Workshop (MSW), May 13-15, 2018, Aalto University, Espoo, Finland
Funder
Swedish Research Council Formas, 2016-00781Knut and Alice Wallenberg Foundation, WAF 2016-0112Swedish Research Council, 2017-05051
Available from: 2018-10-18 Created: 2018-10-18 Last updated: 2018-12-04Bibliographically approved
Organisations
Identifiers
ORCID iD: ORCID iD iconorcid.org/0000-0001-7462-4236

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