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Additives Increasing the Bone-Forming Potential around Calcium Phosphate Cements: Statin, Strontium and Silicon
Uppsala University, Disciplinary Domain of Science and Technology, Technology, Department of Engineering Sciences, Applied Materials Sciences. (Materials in Medicine)
2015 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

More than one million people worldwide receive some kind of bone graft each year. Grafts are often needed following bone tumour removal or traumatic fractures to fill voids in the bone and to aid in the healing process. The most common method involves bone transplantation, in which bone tissue is taken from one site to fill the defect in another site. The procedure thus involves two surgeries, which leads to an increased risk of complications. New, synthetic graft materials that can be used to fill defects and minimise the complications associated with bone tissue harvesting are therefore necessary. The synthetic materials available today lack the inherent biological factors of bone that stimulate the bone regeneration process. Much of today’s research concerning synthetic bone graft materials aims to solve this issue and researchers have suggested several different strategies.

The purpose of this thesis is to improve the performance of acidic calcium phosphate cements, which are materials used as synthetic bone grafts. By combining these cements with drugs or ion additives, local delivery could be achieved with the potential to stimulate bone formation. Two different combinations were attempted in this thesis: cement in combination with simvastatin, or cement in combination with strontium halide salts. Both simvastatin and strontium are known to positively affect bone formation. The efficacy of the cements with the additives was evaluated using different bone cell cultures. The results regarding simvastatin showed that the cement’s mechanical property was not affected upon drug loading, and that the drug was released by a diffusion-controlled mechanism. Moreover, results showed that simvastatin stimulated the bone-forming cells (osteoblasts) to produce more bone tissue, while it inhibited bone-degrading cells (osteoclasts) from degrading the cement. These findings suggest that simvastatin could aid in the bone regeneration process in the local area surrounding the cement.

The main purpose of the study using strontium halide salts was to increase the cement’s X-ray contrast, which is a property used to monitor cement during injection. In addition, strontium is believed to positively affect bone cells. The X-ray contrast did increase after the addition of 10 wt% strontium bromide or strontium iodide, while the cell study results did not indicate any significant effects on the bone-forming cells.

In the last section of this thesis, zebrafish were used as a model to evaluate bone formation upon treatment with degradation products from synthetic bone grafts. The zebrafish is a small organism with 70 % gene homology to humans; due to its transparency, fast development and ease of handling, it is an interesting model for high-throughput studies. Silicate, which is an ionic degradation product of many different bone substitute materials, was used as a proof-of-concept to visualise bone formation in these fish. The results showed an increased bone formation upon treatment with 0.625 μM silicate ions. The results suggest that this model could be used as a complement to bone cell culture studies in pre-clinical evaluations of the degradation products of bone substitute materials, thus helping researchers to design materials with degradation products that could stimulate bone formation.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2015. , 69 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Science and Technology, ISSN 1651-6214 ; 1232
Keyword [en]
Calcium Phosphate Cements, Osteoblast, Osteoclast, Monetite, Zebrafish, Simvastatin, Strontium, Silicon
National Category
Medical Materials
Research subject
Engineering Science with specialization in Materials Science
Identifiers
URN: urn:nbn:se:uu:diva-246289ISBN: 978-91-554-9183-3 (print)OAI: oai:DiVA.org:uu-246289DiVA: diva2:792716
Public defence
2015-04-22, Häggsalen, Ångströmlaboratoriet, Uppsala, 13:00 (English)
Opponent
Supervisors
Available from: 2015-03-31 Created: 2015-03-04 Last updated: 2015-04-17
List of papers
1. Sustained release of simvastatin from premixed injectable calcium phosphate cement
Open this publication in new window or tab >>Sustained release of simvastatin from premixed injectable calcium phosphate cement
2014 (English)In: Journal of Biomedical Materials Research. Part A, ISSN 1549-3296, E-ISSN 1552-4965, Vol. 102, no 2, 340-347 p.Article in journal (Refereed) Published
Abstract [en]

Locally applied simvastatin is known to promote bone regeneration; however, the lack of suitable delivery systems has restricted its clinical use. In this study we demonstrate for the first time the use ofpremixed acidic calcium phosphate cement (CPC) as a delivery system for water-solubilizedsimvastatin. Freeze-dried simvastatin -hydroxy acid (SVA) was added to the premixed cement paste in four different doses (1, 0.5, 0.25, and 0 mg SVA/g cement). The addition of the drug did not alter thecement setting time (38 min), compression strength (5.54 MPa), or diametral tensile strength (2.62 MPa). In a release study conducted in phosphate buffered saline at 37 degrees C, a diffusion-controlledrelease was observed for over a week. Furthermore, the osteogenic effect of the released SVA was demonstrated in vitro. Cell proliferation, alkaline phosphatase activity, and mineralization were assayed after incubation with cement extracts. The lower doses of SVA (0.5 and 0.25 mg SVA/g cement) showed an approximately fourfold increase in mineralization as compared to the control. In conclusion, our findings suggest that premixed acidic CPC is a good option for local delivery of SVA, due to its ability of slowly releasing the drug, leading to a prolonged stimulation of osteogenesis.

Keyword
simvastatin, calcium phosphate cement, osteogenesis, drug release, Saos-2 cells
National Category
Medical Materials
Research subject
Engineering Science with specialization in Materials Science
Identifiers
urn:nbn:se:uu:diva-210792 (URN)10.1002/jbm.a.34702 (DOI)000328246100005 ()
Available from: 2013-11-14 Created: 2013-11-14 Last updated: 2017-12-06Bibliographically approved
2. Resorption of Monetite Calcium Phosphate Cement by Mouse Bone Marrow derived Osteoclasts
Open this publication in new window or tab >>Resorption of Monetite Calcium Phosphate Cement by Mouse Bone Marrow derived Osteoclasts
Show others...
2015 (English)In: Materials science & engineering. C, biomimetic materials, sensors and systems, ISSN 0928-4931, E-ISSN 1873-0191, Vol. 52, 212-218 p.Article in journal (Refereed) Published
Keyword
Monetite Osteoclast Resorption Calcium Phosphate Cement
National Category
Clinical Medicine Engineering and Technology
Research subject
Engineering Science with specialization in Materials Science
Identifiers
urn:nbn:se:uu:diva-245776 (URN)10.1016/j.msec.2015.03.038 (DOI)000357751100028 ()25953560 (PubMedID)
Available from: 2015-03-04 Created: 2015-02-28 Last updated: 2017-12-04Bibliographically approved
3. Simvastatin-doped pre-mixed calcium phosphate cement inhibits osteoclast differentiation and resorption
Open this publication in new window or tab >>Simvastatin-doped pre-mixed calcium phosphate cement inhibits osteoclast differentiation and resorption
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2016 (English)In: Journal of materials science. Materials in medicine, ISSN 0957-4530, E-ISSN 1573-4838, Vol. 27, no 5, 83Article in journal (Refereed) Published
Abstract [en]

Simvastatin, a cholesterol lowering drug, has been shown to have positive effects on fracture healing and bone regeneration based on its dual effect; bone anabolic and anti-resorptive. In this study the focus has been on the anti-resorptive effect of the drug and its impact on the degradation of acidic calcium phosphate cement. The drug was added to the pre-mixed acidic cement in three different doses (0.1, 0.25 and 0.5 mg/g cement) and the release was measured. Furthermore the effect of the loaded cements on osteoclast differentiation and resorption was evaluated by TRAP activity, number of multinucleated cells, gene expression and calcium ion concentration in vitro using murine bone marrow macrophages. The simvastatin did not affect the cell proliferation while it clearly inhibited osteoclastic differentiation at all three doses as shown by TRAP staining, TRAP activity and gene expression. Consistent with these results, simvastatin also impaired resorption of cements by osteoclasts as indicated by reduced calcium ion concentrations. In conclusion, our findings suggest that simvastatin-doped pre-mixed acidic calcium phosphate cement inhibits the osteoclastic mediated resorption of the cement thus slowing down the degradation rate. In addition with simvastatin's bone anabolic effect it makes the cement-drug combination a promising bone graft material, especially useful for sites with compromised bone formation.

National Category
Clinical Medicine Biomaterials Science Engineering and Technology
Research subject
Engineering Science with specialization in Materials Science
Identifiers
urn:nbn:se:uu:diva-245778 (URN)10.1007/s10856-016-5692-7 (DOI)000372261300002 ()26968758 (PubMedID)
Available from: 2015-03-04 Created: 2015-02-28 Last updated: 2017-12-04Bibliographically approved
4. Calcium phosphate cements with strontium halides as radiopacifiers
Open this publication in new window or tab >>Calcium phosphate cements with strontium halides as radiopacifiers
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2014 (English)In: Journal of Biomedical Materials Research. Part B - Applied biomaterials, ISSN 1552-4973, E-ISSN 1552-4981, Vol. 102, no 2, 250-259 p.Article in journal (Refereed) Published
Abstract [en]

High radiopacity is required to monitor the delivery and positioning of injectable implants. Inorganic nonsoluble radiopacifiers are typically used in nondegradable bone cements; however, their usefulness in resorbable cements is limited due to their low solubility. Strontium halides, except strontium fluoride, are ionic water-soluble compounds that possess potential as radiopacifiers. In this study, we compare the radiopacity, mechanical properties, composition, and cytotoxicity of radiopaque brushite cements prepared with strontium fluoride (SrF2), strontium chloride (SrCl2·6H2O), strontium bromide (SrBr2), or strontium iodide (SrI2). Brushite cements containing 10 wt % SrCl2·6H2O, SrBr2, or SrI2 exhibited equal to or higher radiopacity than commercial radiopaque cements. Furthermore, the brushite crystal lattice in cements that contained the ionic radiopacifiers was larger than in unmodified cements and in cements that contained SrF2, indicating strontium substitution. Despite the fact that the strontium halides increased the solubility of the cements and affected their mechanical properties, calcium phosphate cements containing SrCl2·6H2O, SrBr2, and SrI2 showed no significant differences in Saos-2 cell viability and proliferation with respect to the control. Strontium halides: SrCl2·6H2O, SrBr2, and SrI2 may be potential candidates as radiopacifiers in resorbable biomaterials although their in vivo biocompatibility, when incorporated into injectable implants, is yet to be assessed.

Keyword
water-soluble radiopacifier, strontium halide, brushite, radiopaque bone cement, calcium phosphate
National Category
Biomaterials Science Engineering and Technology
Research subject
Engineering Science with specialization in Materials Science
Identifiers
urn:nbn:se:uu:diva-211052 (URN)10.1002/jbm.b.33002 (DOI)000330639400007 ()
Funder
VinnovaSwedish Research CouncilCarl Tryggers foundation
Available from: 2013-11-19 Created: 2013-11-19 Last updated: 2017-12-06
5. Zebrafish: A possible tool to evaluate bioactive ions
Open this publication in new window or tab >>Zebrafish: A possible tool to evaluate bioactive ions
2015 (English)In: Acta Biomaterialia, ISSN 1742-7061, E-ISSN 1878-7568, Vol. 19, 10-14 p.Article in journal (Refereed) Published
Abstract [en]

Zebrafish is a well-established model organism with a skeletal structure that highly resembles mammalian bone. Yet its use in the research field of biomaterials has been limited. One area that could benefit from this model system is the evaluation of ionic dissolution products from different materials. As a proof of concept we have evaluated the effect of silicate ions on the zebrafish larvae and compared it to a well-known osteblastic cell line, MC3T3-E1 subclone 14. We have shown that sodium metasilicate (125 mu M and 625 mu M) induces more mineralisation in a dose-dependent manner in zebrafish larvae, 9 days post fertilisation as compared to the non-treated group. Moreover the same trends were seen when adding sodium metasilicate to MC3T3-E1 cultures, with more mineralisation and higher ALP levels with higher doses of silicate (25, 125 and 625 mu M). These results indicate the feasibility of zebrafish larvae for ionic dissolution studies. The zebrafish model is superior to isolated cell cultures in the aspect that it includes the whole bone remodelling system, with osteoblasts, osteoclasts and osteocytes. Zebrafish could thus provide a powerful in vivo tool and be a bridge between cell culture systems and mammalian models.

Keyword
Zebrafish, Silicon, MC3T3-E1, Bone mineralisation
National Category
Medical Materials
Identifiers
urn:nbn:se:uu:diva-245779 (URN)10.1016/j.actbio.2015.03.010 (DOI)000354152100002 ()25770927 (PubMedID)
Funder
Swedish Research Council, GA 621-2011-3399
Available from: 2015-03-04 Created: 2015-02-28 Last updated: 2017-12-04Bibliographically approved

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