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Premixed Acidic Calcium Phosphate Cements
Uppsala University, Disciplinary Domain of Science and Technology, Technology, Department of Engineering Sciences, Applied Materials Sciences. (Materials in Medicine)
2012 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Calcium phosphate cements are used in medicine to fill bone defects or give support to screws and plates in fracture fixation. The cements are formed via mixing a powder with water and the mixture harden through a dissolution-precipitation reaction. Today the cement mixing is performed in the operating room and consists of several complicated steps that need to be performed under sterile conditions. This renders the mixing a risk factor, potentially leading to harm for the patient e.g. unsatisfactory healing or infection. To reduce this risk, premixed cements have been developed using glycerol as mixing liquid. The premixed cement sets when it is exposed to body liquids. Therefore, premixed cement can be delivered to the operating room in prefilled syringes ready for use, thus eliminating the mixing step.

The aim of this thesis is to describe differences between premixed and water-mixed cements and their advantages and drawbacks. The differences will be discussed based on results obtained from bench testing of specific cement properties as function of cement formulations as well as in vitro and in vivo studies.

Several cement formulations were evaluated e.g. the influence of powder to liquid ratio (P/L), powder particle size and addition of water on key properties. The results showed that premixed cements have excellent handling properties and have mechanical properties similar to water-based cements. Both P/L and particle size can be used to control these properties. It was shown that small amounts of water improve certain cement properties while dry raw materials were important for long shelf life. To better understand the setting of premixed cements new methods for evaluating working time and setting of premixed cements were developed. In vivo studies showed that the formulations developed in this thesis are biocompatible, resorbable and show good tissue response in bone.

This thesis concludes, that the premixed cements are a promising biomaterial with excellent handling properties and good biological response. The most important challenge for the premixed cements, in order to become commercially successful, is to obtain clinically relevant setting time and shelf life simultaneously. An increasing use of premixed cements in the clinics should shorten operation times and reduce infection rates to the benefit of both patients and medical staff.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2012. , 61 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Science and Technology, ISSN 1651-6214 ; 904
Keyword [en]
monetite, brushite, bone void filler, injecatilbity, in vivo, in vitro
National Category
Biomaterials Science Ceramics
Identifiers
URN: urn:nbn:se:uu:diva-168650ISBN: 978-91-554-8285-5 (print)OAI: oai:DiVA.org:uu-168650DiVA: diva2:501762
Public defence
2012-03-29, Å2001, Ångstrsömslaboratoriet, Lägerhyddsvägen 1, Uppsala, 10:15 (English)
Opponent
Supervisors
Available from: 2012-03-08 Created: 2012-02-14 Last updated: 2013-04-08Bibliographically approved
List of papers
1. Influence of water content on hardening and handling of a premixed calcium phosphate cement
Open this publication in new window or tab >>Influence of water content on hardening and handling of a premixed calcium phosphate cement
2013 (English)In: Materials science & engineering. C, biomimetic materials, sensors and systems, ISSN 0928-4931, E-ISSN 1873-0191, Vol. 33, no 1, 527-531 p.Article in journal (Refereed) Published
Abstract [en]

Handling of calcium phosphate cements is difficult, where problems often arise during mixing, transferring tosyringes, and subsequent injection. Via the use of premixed cements the risk of handling complications is reduced. However, for premixed cements to work in a clinical situation the setting time needs to be improved. The objective of this study is to investigate the influence of the addition of water on the properties of premixed cement. Monetite-forming premixed cements with small amounts of added water (less than 6.8 wt.%) were prepared and the influence on injectability, working time, setting time and mechanical strength was evaluated. The results showed that the addition of small amounts of water had significant influence on the properties of the premixed cement. With the addition of just 1.7 wt.% water, the force needed to extrude the cement from a syringe was reduced from 107 (±15)N to 39 (±9)N, the compression strength was almost doubled, and the setting time decreased from 29 (±4)min to 19 (±2)min, while the working time remained 5 to 6 h. This study demonstrates the importance of controlling the water content in premixed cement pastes and how water can be used to improve the properties of premixed cements.

Keyword
monetite, brushite, injectability, handling, bone void filler
National Category
Ceramics Biomaterials Science
Research subject
Engineering Science with specialization in Materials Science
Identifiers
urn:nbn:se:uu:diva-168648 (URN)10.1016/j.msec.2012.09.026 (DOI)000313155500072 ()
Funder
Swedish Research CouncilEU, FP7, Seventh Framework Programme
Available from: 2012-02-14 Created: 2012-02-14 Last updated: 2017-12-07
2. Influence of particle size on hardening and handling of a premixed calcium phosphate cement
Open this publication in new window or tab >>Influence of particle size on hardening and handling of a premixed calcium phosphate cement
2013 (English)In: Journal of materials science. Materials in medicine, ISSN 0957-4530, E-ISSN 1573-4838, Vol. 24, no 4, 829-835 p.Article in journal (Refereed) Published
Abstract [en]

Premixed calcium phosphate cements (pCPC) have been developed to circumvent problems related to mixing and transfer of cements in the operating room. In addition, by using pCPC the short working times generally associated with conventional water-mixed cements are avoided. In this work, the influence of particle size on handlingand hardening characteristics of a premixed monetite cement has been assessed. The cements were evaluated with respect to their injectability, setting time and compressive strength. It was found that cements with smaller particle sizes were more difficult to inject and had higher compressive strength. Regarding setting time, no clear trend could be discerned. The addition of granules made the cements easier to inject, but setting time was prolonged and lower strengths were obtained. The main findings of this work demonstrate that particle size can be used to control handling and physical properties ofpremixed cements and that previous knowledge from water-based CPC, regarding effects of particle size, is not directly applicable to premixed CPC.

Keyword
monetite, brushite, injectability
National Category
Ceramics Biomaterials Science
Research subject
Engineering Science with specialization in Materials Science
Identifiers
urn:nbn:se:uu:diva-168646 (URN)10.1007/s10856-013-4855-z (DOI)000318509100001 ()
Available from: 2012-02-14 Created: 2012-02-14 Last updated: 2017-12-07
3. Setting mechanisms of an acidic premixed calcium phosphate cement
Open this publication in new window or tab >>Setting mechanisms of an acidic premixed calcium phosphate cement
2013 (English)In: Bioceramics Development and Applications, ISSN 2090-5017, E-ISSN 2090-5025, Vol. 3, no 1, 1000070- p.Article in journal (Refereed) Published
Abstract [en]

Premixed calcium phosphate cements (pCPC), where glycerol is used instead of water as mixing liquid, present better handling characteristics than water-based cements. However, the setting mechanisms of pCPC have not been described thoroughly. The aim of this paper is to increase the understanding of the setting mechanism of pCPC. The investigated cement starts to set when glycerol is exchanged with water via diffusion of glycerol out to the surrounding body fluid and water into the material. To better understand the water-glycerol exchange a method was developed where the setting depth of the cement was measured over time. Thermo gravimetric analysis (TGA) was used to determine the liquid exchange rate during setting. To study the influence of temperature on the crystalline end product, pCPC and water-mixed calcium phosphate cement (wCPC) were set at different temperatures and analyzed with X-ray diffraction (XRD). The setting depth measurements showed that the set layer of the pCPC grew with a speed proportional to t0.51 at 37°C. TGA results furthermore showed that less than 10% of the glycerol remained after 16 hours. Setting of pCPC at different temperatures showed that mainly brushite was formed at 5°C, a mixture of brushite and monetite at 21°C and mainly monetite at 37°C. It furthermore showed that brushite was the main phase after setting of wCPC, but some monetite was present in these cements. The study presents a new method for evaluation of pCPC that increases the understanding of their setting mechanism. Furthermore, the XRD results indicate that storage at 5°C could improve the shelf life of acidic pCPC.

Keyword
Premixed, Calcium phosphate, Cements, Setting, Monetite, Brushite
National Category
Ceramics Biomaterials Science
Research subject
Engineering Science with specialization in Materials Science
Identifiers
urn:nbn:se:uu:diva-168645 (URN)10.4172/2090-5025.1000070 (DOI)
Note

Detta är den omarbetad versionen av artikeln ursprungligen inskickad till "Journal of Biomedical Materials Research. Part B - Applied biomaterials".

Available from: 2012-02-14 Created: 2012-02-14 Last updated: 2017-12-07Bibliographically approved
4. Premixed acidic calcium phosphate cement: characterization of strength and microstructure
Open this publication in new window or tab >>Premixed acidic calcium phosphate cement: characterization of strength and microstructure
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2010 (English)In: Journal of biomedical materials research. Part B, Applied biomaterials, ISSN 1552-4973, Vol. 93B, no 2, 436-441 p.Article in journal (Refereed) Published
Abstract [en]

By using a premixed calcium phosphate cement (CPC), the handling properties of the cement are drastically improved, which is a challenge for traditional injectable CPCs. Previously premixed cements have been based on apatite cements In this article, acidic cement has been developed and evaluated Monocalcium phosphate monohydrate and beta-tricalcium phosphate were mixed with glycerol to form a paste As the paste does not contain water, no setting reaction starts and thus the working time is indefinite Powder/liquid ratios (P/L) of 2 25, 3 5 and 475 were evaluated Setting time (ST) and compressive strength (CS) were measured after 1 day, 1 week and 4 weeks in phosphate buffered saline (PBS) solution, and the corresponding microstructure was evaluated using electron microscopy and X-ray diffraction The ST started when the cements were placed in PBS and ranged from 28 to 75 min, higher P/L gave a lower ST Higher P/L also gave a higher CS, which ranged from 2 to 16 MPa The microstructure mainly consisted of monetite, 1-5 mu m in grain size After 4 weeks in PBS, the strength increased As acidic cements are resorbed faster in vivo, this cement should allow faster bone regeneration than apatitic cements Premixed cements show a great handling benefit when compared with normal CPCs and can be formulated with similar ST and mechanical properties.

National Category
Engineering and Technology
Identifiers
urn:nbn:se:uu:diva-114484 (URN)10.1002/jbm.b.31600 (DOI)000276715800018 ()
Available from: 2010-02-16 Created: 2010-02-16 Last updated: 2016-04-19Bibliographically approved
5. In vitro and in vivo evaluation of an injectable premixed calcium phosphate cement: cell viability and immunological response from rat
Open this publication in new window or tab >>In vitro and in vivo evaluation of an injectable premixed calcium phosphate cement: cell viability and immunological response from rat
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2010 (English)In: International Journal of Nano and Biomaterials, ISSN 1752-8941Article in journal (Refereed) Published
Abstract [en]

By using premixed calcium phosphate cement (CPC) the handling properties of the cement are drastically improved, which is a challenge for traditional injectable CPC. In this article, a premixed acidic CPC has been compared to a conventional water mixed brushite cement to evaluate whether the premixed concept affects the biological response. The cements were evaluated regarding the pH-variation in simulated body fluid (SBF). Further, the biocompatibility of the cement with human mesenchymal stem cells (MSC) was studied in vitro and eventual inflammation properties studied in vivo, after subcutaneous material injections in rats. A larger pH decrease was seen for the conventional cement than the premixed cement in SBF. For both materials, > 90% of the MSC remained alive in vitro. No systemic or macroscopic inflammation was detected, only a mild microscopic inflammation was detected around both materials. In addition to the handling benefit of premixed cements compared to conventional water mixed CPC, the premixed CPC in the present study demonstrated high and in comparison to conventional CPC comparable biocompability, both in vitro and in vivo.

Keyword
premixed, calcium phosphate cement, in vitro, in vivo
National Category
Engineering and Technology
Research subject
Materials Science
Identifiers
urn:nbn:se:uu:diva-138450 (URN)10.1504/IJNBM.2011.042130 (DOI)
Funder
Swedish Research Council
Available from: 2010-12-17 Created: 2010-12-17 Last updated: 2016-04-19Bibliographically approved
6. In vivo evaluation of an injectable premixed radiopaque calcium phosphate cement International Journal of Biomaterials
Open this publication in new window or tab >>In vivo evaluation of an injectable premixed radiopaque calcium phosphate cement International Journal of Biomaterials
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(English)In: International Journal of BiomaterialsArticle in journal (Refereed) Submitted
Keyword
premixed, calcium phosphate cement, in vivo, radiopacity, zirconia
National Category
Engineering and Technology
Research subject
Materials Science
Identifiers
urn:nbn:se:uu:diva-138451 (URN)
Available from: 2010-12-17 Created: 2010-12-17 Last updated: 2012-03-29Bibliographically approved
7. Biocompatibility and resorption of a radiopaque premixed calcium phosphate cement
Open this publication in new window or tab >>Biocompatibility and resorption of a radiopaque premixed calcium phosphate cement
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2012 (English)In: Journal of Biomedical Materials Research. Part A, ISSN 1549-3296, E-ISSN 1552-4965, Vol. 100A, no 5, 1269-1278 p.Article in journal (Refereed) Published
Abstract [en]

Calcium phosphate cements (CPC) are used as bone void filler in various orthopedic indications; however, there are some major drawbacks regarding mixing, transfer, and injection of traditional CPC. By using glycerol as mixing liquid, a premixed calcium phosphate cement (pCPC), some of these difficulties can be overcome. In the treatment of vertebral fractures the handling characteristics need to be excellent including a high radio-opacity for optimal control during injection. The aim of this study is to evaluate a radiopaque pCPC regarding its resorption behavior and biocompatibility in vivo. pCPC and a water-based CPC were injected into a circle divide 4-mm drilled femur defect in rabbits. The rabbits were sacrificed after 2 and 12 weeks. Cross sections of the defects were evaluated using histology, electron microscopy, and immunohistochemical analysis. Signs of inflammation were evaluated both locally and systemically. The results showed a higher bone formation in the pCPC compared to the water-based CPC after 2 weeks by expression of RUNX-2. After 12 weeks most of the cement had been resorbed in both groups. Both materials were considered to have a high biocompatibility since no marked immunological response was induced and extensive bone ingrowth was observed. The conclusion from the study was that pCPC with ZrO2 radiopacifier is a promising alternative regarding bone replacement material and may be suggested for treatment of, for example, vertebral fractures based on its high biocompatibility, fast bone ingrowth, and good handling properties.

Keyword
monetite, brushite, in vivo, bone void filler, immunological response
National Category
Ceramics Biomaterials Science
Research subject
Engineering Science with specialization in Materials Science
Identifiers
urn:nbn:se:uu:diva-168647 (URN)10.1002/jbm.a.34065 (DOI)000302017800020 ()
Available from: 2012-02-14 Created: 2012-02-14 Last updated: 2017-12-07Bibliographically approved

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