Hard Tissues and Materials
Calcium polyphosphate as an additive to zinc-silicate glass ionomer cements
Journal of Biomaterials Applications 2015, Vol. 30(1) 61–70 ! The Author(s) 2015 Reprints and permissions: sagepub.co.uk/journalsPermissions.nav DOI: 10.1177/0885328215568985 jba.sagepub.com
Esther Mae Valliant, David Gagnier, Brett Thomas Dickey, Daniel Boyd and Mark Joseph Filiaggi
Abstract Aluminum-free glass ionomer cements (GICs) are under development for orthopedic applications, but are limited by their insufficient handling properties. Here, the addition of calcium polyphosphate (CPP) was investigated as an additive to an experimental zinc-silicate glass ionomer cement. A 50% maximum increase in working time was observed with CPP addition, though this was not clinically significant due to the short working times of the starting zinc-silicate GIC. Surprisingly, CPP also improved the mechanical properties, especially the tensile strength which increased by 33% after 30 days in TRIS buffer solution upon CPP addition up to 37.5 wt%. This strengthening may have been due to the formation of ionic crosslinks between the polyphosphate chains and polyacrylic acid. Thus, CPP is a potential additive to future GIC compositions as it has been shown to improve handling and mechanical properties. In addition, CPP may stimulate new bone growth and provide the ability for drug delivery, which are desirable modifications for an orthopedic cement. Keywords Calcium polyphosphate, glass ionomer cement, bone, minimally invasive, composite
Introduction Vertebral body stabilization can be achieved through a minimally invasive procedure, vertebroplasty or kyphoplasty, where an injectable bone cement is used to stabilize a weakened vertebral body.1 Osteoporotic compression fractures are very common, with a higher incidence in women.2–4 In Canada, 45% of women and 36% of men over the age of 80 have a vertebral deformity.5 The risk of vertebral fracture increases with age; worldwide 15–27% of women aged 70–75 have had a fracture which increases to 26–51% at age 80–85.4 To stabilize these fractures through a minimally invasive procedure, cement is either directly injected into the vertebra (vertebroplasty), or into a cavity that has been formed by a balloon (kyphoplasty) under radioscopic control.6,7 There are many requirements for the ideal bone cement in these applications, including: it must be injectable, be radio-opaque, have similar mechanical properties to the host bone, have good handling properties (working time 6–10 min, setting time 15 min), bond to existing bone (osteoconductive), encourage new bone growth (osteoinductive), and resorb at a rate compatible with new bone growth.8–10
Acrylic bone cements composed of polymethylmethacrylate (PMMA) are the most widely used in orthopedic procedures.6–8 However, some concerns have been raised in the literature with these cements; namely, they do not interact and bond with host bone, they have an exothermic setting reaction and are formed from toxic monomers. The first issue, bonding with host bone, is desirable to create a stable interface with bone over time and to prevent aseptic loosening.8 It has been suggested that high temperatures produced by the exothermic setting reaction, and the toxic monomers of PMMA, may cause necrosis of the surrounding tissue.8,9 Glass ionomer cements (GICs), commonly used in dental applications, have been suggested as a possible alternative to PMMA.11,12 Dental GICs contain aluminum, making them unsuitable for orthopedic
Department of Applied Oral Sciences, Dalhousie University, 5981 University Avenue, Halifax, Nova Scotia, B3H 4R2, Canada Corresponding author: Esther Mae Valliant, Department of Applied Oral Sciences, Dalhousie University, 5981 University Avenue, Halifax, NS Nova Scotia, B3H 4R2, Canada. Email: [email protected]
62 applications as Al3þ has been linked with neurological disease.13–16 Aluminum containing GICs have also been contraindicated for orthopedic applications.17 A new class of Al-free GICs is under development using calcium zinc-silicate glass,18,19 where zinc replaces aluminum in the glass network. A cement is formed when the zinc-silicate glass powder is combined with an aqueous acidic polymer, in this case polyacrylic acid (PAA), without causing an increase in temperature. The acidbase setting reaction occurs when acid attacks the surface of the glass particles through a process that does not produce heat. Ions are released from the glass and divalent cations are chelated to the PAA chains, crosslinking the polymer. The resulting cement contains partially reacted glass particles within a hydrated polysalt matrix.16,20 This cement network is strengthened with increased PAA molecular weight and concentration,18,21 a property that has also been observed with conventional GICs.11 The zinc-silicate glass cements were modified to incorporate strontium, which can inhibit bone resorption and stimulate bone formation.21–24 The inherently radio-opaque cements were found to have therapeutic release of Zn2þ and Sr2þ, as well as enhanced cell viability in vitro.25 Thus, cements with many desirable traits for orthopedic applications were achieved, but were not clinically relevant due to their poor handling properties. Working times of 6–10 min are required, but the zinc-silicate GICs have short working times of 16–218 s.18,21–23 One technique known to improve handling properties of GICs is to use an additive. These additives can extend the working time while causing the setting to occur more sharply.11,13 In this case, the workability agent, trisodium citrate (TSC), was added to the experimental Alfree GIC. The addition of up to 15 wt% of TSC into a zinc-silicate glass cement extended the working time, by approximately 4.5 times, and also improved compressive strength.22 Unfortunately, cements containing TSC lost all adhesive strength and delaminated from the HA substrate upon incubation in distilled water.26 Delamination may lead to instability of the compression fracture if these cements were to be used in vertebroplasty. A different approach is needed to delay the setting reaction so that these promising zinc-silicate glass cements will fulfill the criteria for orthopedic applications. We propose a new methodology to improve handling properties whereby a metal chelating agent also forms part of the GIC network as it is substituted for the silica-based glass. Calcium polyphosphate (CPP) is a degradable, inorganic polymer27 with calcium ions forming crosslinks between the chains.28 The amorphous structure of CPP leads to properties unlike traditional hydroxyapatite for bone applications, which is dense and nondegradable.8–10,29,30 The capacity of CPP to chelate metal cations may delay the setting reaction of the
Journal of Biomaterials Applications 30(1) zinc-silicate glass cements by chelating some of the metal ions released during the acid erosion of the glass particles.31 Due to the reduction of ions available to form crosslinks with the PAA, a delayed cement network formation and increased working time may be achieved. In addition, the drug delivery ability of CPP has been well studied and has been shown to provide tailorable and controlled release.32–34 CPP is degraded and resorbed in the body, releasing Ca2þ and P ions that encourage new bone formation. However, degradation occurs rapidly as CPP quickly absorbs water, swells, becomes gel-like and undergoes chain scission, causing a decrease in pH.32 This rapid breaking down of the polyphosphate network may negatively affect the mechanical properties of the resulting GIC, if sufficiently substituted. CPP may also speed the dissolution of zinc-silicate glass through acid erosion due to a decrease in pH caused by polyphosphate chain scission, which again may result in a loss of mechanical properties with time. The stability of CPP containing GICs is unknown and must be evaluated to determine if the mechanical properties undermine the other potential benefits of CPP. The aim of this work was to incorporate CPP glass into a calcium zinc-silicate GIC and to characterize the effect of the CPP substitution. It is proposed that CPP may improve handling properties by acting as a calcium sink, thus increasing working time, as well as simulating bone growth and providing potential for drug delivery. Specifically, the handling properties, radio-opacity, mechanical properties, and dissolution behavior of the resulting composite cements will be evaluated and compared to the criteria for orthopedic applications.
Materials and methods Synthesis of zinc-silicate glasses Melt derived zinc-silicate glass was synthesized with a composition of 0.04 SrO: 0.12 CaO: 0.36 ZnO: 0.48 SiO2 (mol fraction).21–23 Zinc oxide, strontium carbonate, silicon dioxide, and calcium carbonate (analytical grade, Sigma Aldrich, Canada) glass precursors were blended for 1 h and dried at 100 C for 1 h. The powders were packed into a platinum crucible (10% Rh, Alfa Aesar, part number 023133-KT), melted at 1520 C (Carbolite RHF1600), and quenched in deionoized water. The glass frit was dried and ground to
Calcium polyphosphate as an additive to zinc-silicate glass ionomer cements
Journal of Biomaterials Applications 2015, Vol. 30(1) 61–70 ! The Author(s) 2015 Reprints and permissions: sagepub.co.uk/journalsPermissions.nav DOI: 10.1177/0885328215568985 jba.sagepub.com
Esther Mae Valliant, David Gagnier, Brett Thomas Dickey, Daniel Boyd and Mark Joseph Filiaggi
Abstract Aluminum-free glass ionomer cements (GICs) are under development for orthopedic applications, but are limited by their insufficient handling properties. Here, the addition of calcium polyphosphate (CPP) was investigated as an additive to an experimental zinc-silicate glass ionomer cement. A 50% maximum increase in working time was observed with CPP addition, though this was not clinically significant due to the short working times of the starting zinc-silicate GIC. Surprisingly, CPP also improved the mechanical properties, especially the tensile strength which increased by 33% after 30 days in TRIS buffer solution upon CPP addition up to 37.5 wt%. This strengthening may have been due to the formation of ionic crosslinks between the polyphosphate chains and polyacrylic acid. Thus, CPP is a potential additive to future GIC compositions as it has been shown to improve handling and mechanical properties. In addition, CPP may stimulate new bone growth and provide the ability for drug delivery, which are desirable modifications for an orthopedic cement. Keywords Calcium polyphosphate, glass ionomer cement, bone, minimally invasive, composite
Introduction Vertebral body stabilization can be achieved through a minimally invasive procedure, vertebroplasty or kyphoplasty, where an injectable bone cement is used to stabilize a weakened vertebral body.1 Osteoporotic compression fractures are very common, with a higher incidence in women.2–4 In Canada, 45% of women and 36% of men over the age of 80 have a vertebral deformity.5 The risk of vertebral fracture increases with age; worldwide 15–27% of women aged 70–75 have had a fracture which increases to 26–51% at age 80–85.4 To stabilize these fractures through a minimally invasive procedure, cement is either directly injected into the vertebra (vertebroplasty), or into a cavity that has been formed by a balloon (kyphoplasty) under radioscopic control.6,7 There are many requirements for the ideal bone cement in these applications, including: it must be injectable, be radio-opaque, have similar mechanical properties to the host bone, have good handling properties (working time 6–10 min, setting time 15 min), bond to existing bone (osteoconductive), encourage new bone growth (osteoinductive), and resorb at a rate compatible with new bone growth.8–10
Acrylic bone cements composed of polymethylmethacrylate (PMMA) are the most widely used in orthopedic procedures.6–8 However, some concerns have been raised in the literature with these cements; namely, they do not interact and bond with host bone, they have an exothermic setting reaction and are formed from toxic monomers. The first issue, bonding with host bone, is desirable to create a stable interface with bone over time and to prevent aseptic loosening.8 It has been suggested that high temperatures produced by the exothermic setting reaction, and the toxic monomers of PMMA, may cause necrosis of the surrounding tissue.8,9 Glass ionomer cements (GICs), commonly used in dental applications, have been suggested as a possible alternative to PMMA.11,12 Dental GICs contain aluminum, making them unsuitable for orthopedic
Department of Applied Oral Sciences, Dalhousie University, 5981 University Avenue, Halifax, Nova Scotia, B3H 4R2, Canada Corresponding author: Esther Mae Valliant, Department of Applied Oral Sciences, Dalhousie University, 5981 University Avenue, Halifax, NS Nova Scotia, B3H 4R2, Canada. Email: [email protected]
62 applications as Al3þ has been linked with neurological disease.13–16 Aluminum containing GICs have also been contraindicated for orthopedic applications.17 A new class of Al-free GICs is under development using calcium zinc-silicate glass,18,19 where zinc replaces aluminum in the glass network. A cement is formed when the zinc-silicate glass powder is combined with an aqueous acidic polymer, in this case polyacrylic acid (PAA), without causing an increase in temperature. The acidbase setting reaction occurs when acid attacks the surface of the glass particles through a process that does not produce heat. Ions are released from the glass and divalent cations are chelated to the PAA chains, crosslinking the polymer. The resulting cement contains partially reacted glass particles within a hydrated polysalt matrix.16,20 This cement network is strengthened with increased PAA molecular weight and concentration,18,21 a property that has also been observed with conventional GICs.11 The zinc-silicate glass cements were modified to incorporate strontium, which can inhibit bone resorption and stimulate bone formation.21–24 The inherently radio-opaque cements were found to have therapeutic release of Zn2þ and Sr2þ, as well as enhanced cell viability in vitro.25 Thus, cements with many desirable traits for orthopedic applications were achieved, but were not clinically relevant due to their poor handling properties. Working times of 6–10 min are required, but the zinc-silicate GICs have short working times of 16–218 s.18,21–23 One technique known to improve handling properties of GICs is to use an additive. These additives can extend the working time while causing the setting to occur more sharply.11,13 In this case, the workability agent, trisodium citrate (TSC), was added to the experimental Alfree GIC. The addition of up to 15 wt% of TSC into a zinc-silicate glass cement extended the working time, by approximately 4.5 times, and also improved compressive strength.22 Unfortunately, cements containing TSC lost all adhesive strength and delaminated from the HA substrate upon incubation in distilled water.26 Delamination may lead to instability of the compression fracture if these cements were to be used in vertebroplasty. A different approach is needed to delay the setting reaction so that these promising zinc-silicate glass cements will fulfill the criteria for orthopedic applications. We propose a new methodology to improve handling properties whereby a metal chelating agent also forms part of the GIC network as it is substituted for the silica-based glass. Calcium polyphosphate (CPP) is a degradable, inorganic polymer27 with calcium ions forming crosslinks between the chains.28 The amorphous structure of CPP leads to properties unlike traditional hydroxyapatite for bone applications, which is dense and nondegradable.8–10,29,30 The capacity of CPP to chelate metal cations may delay the setting reaction of the
Journal of Biomaterials Applications 30(1) zinc-silicate glass cements by chelating some of the metal ions released during the acid erosion of the glass particles.31 Due to the reduction of ions available to form crosslinks with the PAA, a delayed cement network formation and increased working time may be achieved. In addition, the drug delivery ability of CPP has been well studied and has been shown to provide tailorable and controlled release.32–34 CPP is degraded and resorbed in the body, releasing Ca2þ and P ions that encourage new bone formation. However, degradation occurs rapidly as CPP quickly absorbs water, swells, becomes gel-like and undergoes chain scission, causing a decrease in pH.32 This rapid breaking down of the polyphosphate network may negatively affect the mechanical properties of the resulting GIC, if sufficiently substituted. CPP may also speed the dissolution of zinc-silicate glass through acid erosion due to a decrease in pH caused by polyphosphate chain scission, which again may result in a loss of mechanical properties with time. The stability of CPP containing GICs is unknown and must be evaluated to determine if the mechanical properties undermine the other potential benefits of CPP. The aim of this work was to incorporate CPP glass into a calcium zinc-silicate GIC and to characterize the effect of the CPP substitution. It is proposed that CPP may improve handling properties by acting as a calcium sink, thus increasing working time, as well as simulating bone growth and providing potential for drug delivery. Specifically, the handling properties, radio-opacity, mechanical properties, and dissolution behavior of the resulting composite cements will be evaluated and compared to the criteria for orthopedic applications.
Materials and methods Synthesis of zinc-silicate glasses Melt derived zinc-silicate glass was synthesized with a composition of 0.04 SrO: 0.12 CaO: 0.36 ZnO: 0.48 SiO2 (mol fraction).21–23 Zinc oxide, strontium carbonate, silicon dioxide, and calcium carbonate (analytical grade, Sigma Aldrich, Canada) glass precursors were blended for 1 h and dried at 100 C for 1 h. The powders were packed into a platinum crucible (10% Rh, Alfa Aesar, part number 023133-KT), melted at 1520 C (Carbolite RHF1600), and quenched in deionoized water. The glass frit was dried and ground to
