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Injectable Biomaterials for Spinal Applications
Uppsala University, Disciplinary Domain of Science and Technology, Technology, Department of Engineering Sciences.
2014 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

The use of injectable biomaterials is growing as the demands for minimally invasive procedures, and more easily applicable implants become higher, but their availability is still limited due to the difficulties associated to their design.

Each year, more than 700,000 vertebral compression fractures (VCF’s) are reported in the US and 500,000 VCF’s in Europe due to primary osteoporosis only. VCF’s can compromise the delicacy of the spinal canal and also cause back pain, which affects the patient’s quality of life. Vertebroplasty was developed in the 80’s, and has proven to be a safe minimally invasive procedure that can, quickly and sustainably, relieve the pain in patients experiencing VCF’s. However, biomaterials for vertebroplasty still have limitations. For instance, ceramic bone cements are difficult to distinguish from the bone using X-ray techniques. On the other hand, acrylic bone cements may cause adjacent vertebral fractures (AVF’s). Large clinical studies have indicated that 12 to 20% vertebroplasty recipients developed subsequent vertebral fractures, and that 41 to 67% of these, were AVF’s. This may be attributed to the load shifting and increased pressure on the adjacent endplates reached after vertebroplasty with stiff cements.

The primary aim of this thesis was to develop better injectable biomaterials for spinal applications, particularly, bone cements for vertebroplasty. Water-soluble radiopacifiers were first investigated to enhance the radiopacity of resorbable ceramic cements. Additionally, different strategies to produce materials that mechanically comply with the surrounding tissues (low-modulus bone cements) were investigated. When a suitable low-modulus cement was produced, its performance was evaluated in both bovine bone, and human vertebra ex vivo models.

In summary, strontium halides showed potential as water-soluble radiocontrast agents and could be used in resorbable calcium phosphates and other types of resorbable biomaterials. Conversely, linoleic acid-modified (low-modulus) cements appeared to be a promising alternative to currently available high-modulus cements. It was also shown that the influence of the cement properties on the strength and stiffness of a single vertebra depend upon the initial bone volume fraction, and that at low bone volume fractions, the initial mechanical properties of the vertebroplasty cement become more relevant. Finally, it was shown that vertebroplasty with low-modulus cements is biomechanically safe, and could become a recommended minimally invasive therapy in selected cases, especially for patients suffering from vertebral compression fractures due to osteoporosis.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2014. , 66 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Science and Technology, ISSN 1651-6214 ; 1114
Keyword [en]
injectable, biomaterials, bone cement, vertebral compression fractures, spine, radiopacity, minimally invasive treatment, low-modulus cement, oligomer, PMMA, calcium phosphate, vertebroplasty, bone
National Category
Biomaterials Science
Research subject
Engineering Science with specialization in Materials Science
Identifiers
URN: urn:nbn:se:uu:diva-215606ISBN: 978-91-554-8854-3 (print)OAI: oai:DiVA.org:uu-215606DiVA: diva2:687988
Public defence
2014-02-28, Polhemssalen, Ångströmlaboratoriet, Lägerhyddsvägen 1, Uppsala, 13:00 (English)
Opponent
Supervisors
Available from: 2014-02-05 Created: 2014-01-15 Last updated: 2014-02-10
List of papers
1. 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
2. Comparative characterization of oligomeric precursors intended for injectable implants
Open this publication in new window or tab >>Comparative characterization of oligomeric precursors intended for injectable implants
2013 (English)In: Polymers for Advanced Technologies, ISSN 1042-7147, E-ISSN 1099-1581, Vol. 24, no 1, 15-21 p.Article in journal (Refereed) Published
Abstract [en]

The use of injectable materials is a simple approach for drug delivery and tissue repair, in, e.g. minimally invasive surgery applications. If these materials are used past their glass transition temperature and have a low viscosity, they will be able to flow while delivered in situ. Whether these materials are to be used as low viscosity drug carriers or further crosslinked for tissue repair, there is a need for a better understanding of their handling properties. In this study, oligo(trimethylene carbonate) (oTMC) and oligo[D,L-lactide-co-(«-caprolactone)] (oDLLA-co-CL) of various molecular weights within a relevant injectability range were synthesized via ring-opening polymerization. The materials were comparatively characterized by 1H NMR spectroscopy, differential scanning calorimetry, gel permeation chromatography, and rheological measurements. After comparing the viscosities and molecular weights of the materials, it was concluded that oDLLA-co-CLs were, gener- ally, better suited as an injectable in situ crosslinking network, whereas oTMCs were found to be better candidates as injectable drug carriers. This study provides useful data and guidelines on the use of these and other similar oligomers intended for injectable implants.

Place, publisher, year, edition, pages
John Wiley & Sons, 2013
Keyword
oligomer(s), polyester(s), polycarbonate(s), rheology, injectable implant(s)
National Category
Medical Materials Polymer Chemistry
Research subject
Engineering Science with specialization in Materials Science; Chemistry with specialization in Polymer Chemistry
Identifiers
urn:nbn:se:uu:diva-174546 (URN)10.1002/pat.3042 (DOI)000312887500005 ()
Available from: 2012-05-25 Created: 2012-05-22 Last updated: 2017-12-07Bibliographically approved
3. Polyhedral oligomeric silsesquioxane (POSS)–poly(ethylene glycol) (PEG) hybrids as injectable biomaterials
Open this publication in new window or tab >>Polyhedral oligomeric silsesquioxane (POSS)–poly(ethylene glycol) (PEG) hybrids as injectable biomaterials
2012 (English)In: Biomedical Materials, ISSN 1748-6041, E-ISSN 1748-605X, Vol. 7, no 3, 035013- p.Article in journal (Refereed) Published
Abstract [en]

One of the major issues with the currently available injectable biomaterials for hard tissue replacement is the mismatch between their mechanical properties and those of the surrounding bone. Hybrid bone cements that combine the benefits of tough polymeric and bioactive ceramic materials could become a good alternative. In this work, polyhedral oligomeric silsesquioxane (POSS) was copolymerized with poly(ethylene glycol) (PEG) to form injectable in situ cross-linkable hybrid cements. The hybrids were characterized in terms of their mechanical, rheological, handling and in vitro bioactive properties. The results indicated that hybridization improves the mechanical and bioactive properties of POSS and PEG. The Young moduli of the hybrids were lower than those of commercial cements and more similar to those of cancellous bone. Furthermore, the strength of the hybrids was similar to that of commercial cements. Calcium deficient hydroxyapatite grew on the surface of the hybrids after 28 days in PBS, indicating bioactivity. The study showed that PEG–POSS-based hybrid materials are a promising alternative to commercial bone cements.

National Category
Bio Materials Engineering and Technology
Research subject
Engineering Science with specialization in Materials Science
Identifiers
urn:nbn:se:uu:diva-172865 (URN)10.1088/1748-6041/7/3/035013 (DOI)000303667600013 ()
Available from: 2012-04-16 Created: 2012-04-16 Last updated: 2017-12-07Bibliographically approved
4. Direct and interactive effects of three variables on properties of PMMA bone cement for vertebral body augmentation
Open this publication in new window or tab >>Direct and interactive effects of three variables on properties of PMMA bone cement for vertebral body augmentation
2011 (English)In: Journal of materials science. Materials in medicine, ISSN 0957-4530, E-ISSN 1573-4838, Vol. 22, no 6, 1599-1606 p.Article in journal (Refereed) Published
Abstract [en]

PMMA bone cements are widely used for vertebral body augmentation procedures vertebroplasty and balloon kyphoplasty. Although there are studies in the literature on the direct effects of relevant variables on the properties of these cements, there are none on the interactive effects. In the present work, such a study was performed on both types of effects, with the variables being the concentration of initiator (benzoyl peroxide), the concentration of crosslinker (ethylene glycol dimethacrylate), and the liquid-to-powder ratio used in preparing the cement; and the properties being the compressive strength, the compressive modulus, the doughing time, the setting time, and the maximum polymerization temperature. Two additional properties obtained from the viscosity-versustime curves, namely the time at the onset of curing, and the critical curing rate were also studied. Significant interactive effects between the amount of crosslinker and the amount of radical initiator were found to affect the doughing time and the critical curing rate. These effects were explained in terms of the reaction kinetics. It was concluded that interactive effects may exist and should be taken into account when designing bone cement formulations.

National Category
Biomaterials Science Engineering and Technology
Research subject
Engineering Science with specialization in Materials Science
Identifiers
urn:nbn:se:uu:diva-155927 (URN)10.1007/s10856-011-4322-7 (DOI)000291702500023 ()
Available from: 2011-07-04 Created: 2011-07-04 Last updated: 2017-12-11Bibliographically approved
5. Low-modulus PMMA bone cement modified with castor oil
Open this publication in new window or tab >>Low-modulus PMMA bone cement modified with castor oil
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2011 (English)In: Bio-medical materials and engineering, ISSN 0959-2989, E-ISSN 1878-3619, Vol. 21, no 5-6, 323-332 p.Article in journal (Refereed) Published
Abstract [en]

Some of the current clinical and biomechanical data suggest that vertebroplasty causes the development of adjacent vertebral fractures shortly after augmentation. These findings have been attributed to high injection volumes as well as high Young’s moduli of PMMA bone cements compared to that of the osteoporotic cancellous bone. The aim of this study was to evaluate the use of castor oil as a plasticizer for PMMA bone cements. The Young’s modulus, yield strength, maximum polymerization temperature, doughing time, setting time and the complex viscosity curves during curing, were determined. The cytotoxicity of the materials extracts was assessed on cells of an osteoblast-like cell line. The addition of up to 12 wt% castor oil decreased yield strength from 88 to 15 MPa, Young’s modulus from 1500 to 446 MPa and maximum polymerization temperature from 41.3 to 25.6◦C, without affecting the setting time. However, castor oil seemed to interfere with the polymerization reaction, giving a negative effect on cell viability in a worst-case scenario.

Place, publisher, year, edition, pages
IOS Press, 2011
Keyword
bone cement, PMMA, low-modulus, castor oil, cytotoxicity
National Category
Medical Materials
Research subject
Engineering Science with specialization in Materials Science
Identifiers
urn:nbn:se:uu:diva-174544 (URN)10.3233/BME-2012-0679 (DOI)000303669200005 ()
Available from: 2012-05-25 Created: 2012-05-22 Last updated: 2017-12-07Bibliographically approved
6. Compressive mechanical properties and cytocompatibility of bone-compliant, linoleic acid-modified bone cement in a bovine model
Open this publication in new window or tab >>Compressive mechanical properties and cytocompatibility of bone-compliant, linoleic acid-modified bone cement in a bovine model
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2014 (English)In: Journal of The Mechanical Behavior of Biomedical Materials, ISSN 1751-6161, E-ISSN 1878-0180, Vol. 32, 245-256 p.Article in journal (Refereed) Published
Abstract [en]

Adjacent vertebral fractures are a common complication experienced by osteoporosis patients shortly after vertebroplasty. Whether these fractures are due to the bone cement properties, the cement filling characteristics or to the natural course of the disease is still unclear. However, some data suggests that such fractures might occur because of an imbalance in the load distribution due to a mismatch between the elastic modulus (E) of the bone-cement composite, and that of the vertebral cancellous bone. In this study, the properties of bone-compliant linoleic acid-modified bone cements were assessed using a bovine vertebroplasty model. Two groups of specimens (cement-only and bone-cement composites), and four subgroups comprising bone cements with elastic moduli in the range of 870-3500 MPa were tested to failure in uniaxial compression. In addition, monomer release as well as time and concentration-dependent cytocompatibility was assessed through the cement extracts using a Saos-2 cell model. Composites augmented with bone-compliant cements exhibited a reduction in E despite their relatively high bone volume fraction (BVF). Moreover, a significant positive correlation between the BVF and the E for the composites augmented with 870 MPa modulus cements was found. This was attributed to the increased relative contribution of the bone to the mechanical properties of the composites with a decrease in E of the bone cement. The use of linoleic acid reduced monomer conversion resulting in six times more monomer released after 24 h. However, the cytocompatibility of the bone-compliant cements was comparable to that of the unmodified cements after the extracts were diluted four times. This study represents an important step towards introducing viable bone-compliant bone cements into vertebroplasty practice.

Keyword
adjacent vertebral fracture(s), low-modulus bone cement(s), vertebroplasty, linoleic acid, bone-cement composite(s)
National Category
Biomaterials Science Engineering and Technology
Research subject
Engineering Science with specialization in Materials Science
Identifiers
urn:nbn:se:uu:diva-213224 (URN)10.1016/j.jmbbm.2014.01.002 (DOI)000333488300024 ()
Available from: 2013-12-19 Created: 2013-12-19 Last updated: 2017-12-06Bibliographically approved
7. Biomechanics of low-modulus and standard acrylic bone cements in simulated vertebroplasty: A human ex vivo study
Open this publication in new window or tab >>Biomechanics of low-modulus and standard acrylic bone cements in simulated vertebroplasty: A human ex vivo study
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2015 (English)In: Journal of Biomechanics, ISSN 0021-9290, E-ISSN 1873-2380, Vol. 48, no 12, 3258-3266 p.Article in journal (Refereed) Published
Abstract [en]

The high stiffness of bone cements used in vertebroplasty has been hypothesised to contribute to the propensity of adjacent vertebral fractures after treatment. Therefore, new low-modulus cements have been developed; however, there are currently no studies assessing the biomechanical aspects of vertebroplasty with these cements in an ex vivo non-prophylactic model. In this study, we induced wedge fractures through eccentric uniaxial compression to single whole-vertebrae, before and after augmentation with either standard or low-modulus cement. Compressive strength and stiffness of individual vertebrae were measured, on 19 samples from metastatic spines and 20 samples from elderly, osteopenic spines. While both cement types increased the strength of both the metastatic (+34% and +63% for standard and low-modulus cement, respectively) and the elderly vertebrae (+303% and +113%, respectively), none of them restored the initial stiffness of metastatic specimens (−51% and −46%, respectively). Furthermore, low-modulus cement gave a lower total stiffness (−13%) of elderly specimens whereas standard cement increased it above initial levels (+17%). Results show that vertebroplasty with low-modulus cement could provide restoration of the initial stiffness while increasing the strength of fractured elderly vertebrae and hence represent a treatment modality which is closer to pre-augmented behaviour. Also, this study indicates that stiffness-modified cement needs to be optimised for patient/pathology specific treatment.

Keyword
vertebroplasty, PMMA, low-modulus cement(s), adjacent vertebral fracture(s), osteoporosis, metastasis, wedge compression fracture(s)
National Category
Biomaterials Science Engineering and Technology
Research subject
Engineering Science with specialization in Materials Science
Identifiers
urn:nbn:se:uu:diva-213226 (URN)10.1016/j.jbiomech.2015.06.026 (DOI)000363069900045 ()
Funder
EU, FP7, Seventh Framework ProgrammeVINNOVA, VINNMER 2010-02073
Available from: 2013-12-19 Created: 2013-12-19 Last updated: 2017-12-06Bibliographically approved

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