D. Boyd

The effect of composition on ion release from Ca–Sr–Na–Zn–Si glass bone grafts

Controlled delivery of active ions from biomaterials has become critical in bone regeneration. Some silica-based materials, in particular bioactive glasses, have received much attention due to the ability of their dissolution products to promote cell proliferation, cell differentiation and activate gene expression. However, many of these materials offer little therapeutic potential for diseased tissue. Incorporating trace elements, such as zinc and strontium, known to have beneficial and therapeutic effects on bone may provide a more viable bone graft option for those suffering from metabolic bone diseases such as osteoporosis. Rational compositional design may also allow for controlled release of these active ions at desirable dose levels in order to enhance therapeutic efficacy. In this study, six differing compositions of calcium–strontium–sodium–zinc–silicate (Ca–Sr–Na–Zn–Si) glass bone grafts were immersed in pH 7.4 and pH 3 solutions to study the effect of glass composition on zinc and strontium release in a normal and extreme physiological environment. The zinc release levels over 30xa0days for all zinc-containing glasses in the pH 7.4 solution were 3.0–7.65xa0ppm. In the more acidic pH 3 environment, the zinc levels were higher (89–750xa0ppm) than those reported to be beneficial and may produce cytotoxic or negative effects on bone tissue. Strontium levels released from all examined glasses in both pH environments similarly fell within apparent beneficial ranges—7.5–3500xa0ppm. Glass compositions with identical SrO content but lower ZnO:Na2O ratios, showed higher levels of Sr2+ release. Whereas, zinc release from zinc-containing glasses appeared related to ZnO compositional content. Sustainable strontium and zinc release was seen in the pH 7.4 environment up to day 7. These results indicate that the examined Ca–Sr–Na–Zn–Si glass compositions show good potential as therapeutic bone grafts, and that the graft composition can be tailored to allow therapeutic levels of ions to be released.

Comparison of an experimental bone cement with surgical Simplex® P, Spineplex® and Cortoss®

Conventional polymethylmethacrylate (PMMA) cements and more recently Bisphenol-a-glycidyl dimethacrylate (BIS-GMA) composite cements are employed in procedures such as vertebroplasty. Unfortunately, such materials have inherent drawbacks including, a high curing exotherm, the incorporation of toxic components in their formulations, and critically, exhibit a modulus mismatch between cement and bone. The literature suggests that aluminium free, zinc based glass polyalkenoate cements (Zn-GPC) may be suitable alternative materials for consideration in such applications as vertebroplasty. This paper, examines one formulation of Zn-GPC and compares its strengths, modulus, and biocompatibility with three commercially available bone cements, Spineplex®, Simplex® P and Cortoss®. The setting times indicate that the current formulation of Zn-GPC sets in a time unsuitable for clinical deployment. However during setting, the peak exotherm was recorded to be 33°C, the lowest of all cements examined, and well below the threshold level for tissue necrosis to occur. The data obtained from mechanical testing shows the Zn-GPC has strengths of 63xa0MPa in compression and 30xa0MPa in biaxial flexure. Importantly these strengths remain stable with maturation; similar long term stability was exhibited by both Spineplex® and Simplex® P. Conversely, the strengths of Cortoss® were observed to rapidly diminish with time, a cause for clinical concern. In addition to strengths, the modulus of each material was determined. Only the Zn-GPC exhibited a modulus similar to vertebral trabecular bone, with all commercial materials exhibiting excessively high moduli. Such data indicates that the use of Zn-GPC may reduce adjacent fractures. The final investigation used the well established simulated body fluid (SBF) method to examine the ability of each material to bond with bone. The results indicate that the Zn-GPC is capable of producing a bone like apatite layer at its surface within 24xa0h which increased in coverage and density up to 7xa0days. Conversely, Spineplex®, and Simplex® P exhibit no apatite layer formation, while Cortoss® exhibits only minimal formation of an apatite layer after 7xa0days incubation in SBF. This paper shows that Zn-GPC, with optimised setting times, are suitable candidate materials for further development as bone cements.

Preliminary investigation of novel bone graft substitutes based on strontium–calcium–zinc–silicate glasses

Bone graft procedures typically require surgeons to harvest bone from a second site on a given patient (Autograft) before repairing a bone defect. However, this results in increased surgical time, excessive blood loss and a significant increase in pain. In this context a synthetic bone graft with excellent histocompatibility, built in antibacterial efficacy and the ability to regenerate healthy tissue in place of diseased tissue would be a significant step forward relative to current state of the art philosophies. We developed a range of calcium–strontium–zinc–silicate glass based bone grafts and characterised their structure and physical properties, then evaluated their in vitro cytotoxicity and in vivo biocompatibility using standardised models from the literature. A graft (designated BT109) of composition 0.28SrO/0.32ZnO/0.40 SiO2 (mol fraction) was the best performing formulation in vitro shown to induce extremely mild cytopathic effects (cell viability up to 95%) in comparison with the commercially available bone graft Novabone® (cell viability of up to 72%). Supplementary to this, the grafts were examined using the standard rat femur healing model on healthy Wister rats. All grafts were shown to be equally well tolerated in bone tissue and new bone was seen in close apposition to implanted particles with no evidence of an inflammatory response within bone. Complimentary to this BT109 was implanted into the femurs of ovariectomized rats to monitor the response of osteoporotic tissue to the bone grafts. The results from this experiment indicate that the novel grafts perform equally well in osteoporotic tissue as in healthy tissue, which is encouraging given that bone response to implants is usually diminished in ovariectomized rats. In conclusion these materials exhibit significant potential as synthetic bone grafts to warrant further investigation and optimisation.

Comparison of in vitro and in vivo bioactivity of SrO-CaO-ZnO-SiO2 glass grafts.

A range of calcium—strontium—zinc—silicate glass grafts are developed. Following characterization, their ability to form an apatite layer in simulated body fluid (SBF) is evaluated. Concurrently, their in vivo biocompatibility is determined. These glasses are incapable of forming an apatite layer in SBF. However, in vivo, each glass is well tolerated with new bone formation apparent in close apposition to implanted particles and no evidence of an inflammatory response. Such results are contrary to much of the literature and indicate that forecasting a materials ability to bond to bone based on SBF experiments may provide a false negative result.

Comparison of an experimental bone cement with a commercial control, Hydroset™

Glass polyalkenoate cements based on strontium calcium zinc silicate glasses (Zn-GPCs) and high molecular weight polyacrylic acids (PAA) (MW; 52,000–210,000) have been shown to exhibit mechanical properties and in vitro bioactivity suitable for arthroplasty applications. Unfortunately, these formulations exhibit working times and setting times which are too short for invasive surgical applications such as bone void filling and fracture fixation. In this study, Zn-GPCs were formulated using a low molecular weight PAA (MW; 12,700) and a modifying agent, trisodium citrate dihydrate (TSC), with the aim of improving the rheological properties of Zn-GPCs. These novel formulations were then compared with commercial self-setting calcium phosphate cement, Hydroset™, in terms of compressive strength, biaxial flexural strength and Young’s modulus, as well as working time, setting time and injectability. The novel Zn-GPC formulations performed well, with prolonged mechanical strength (39xa0MPa, compression) greater than both vertebral bone (18.4xa0MPa) and the commercial control (14xa0MPa). However, working times (2xa0min) and rheological properties of Zn-GPCs, though improved, require further modifications prior to their use in minimally invasive surgical techniques.

Strontium-based glass polyalkenoate cements for luting applications in the skeleton.

Glass Polyalkenoate Cements (GPCs) based on strontium calcium zinc silicate (Sr-Ca-Zn-SiO2) glasses and high molecular weight poly(acrylic acid) (PAA) have been shown to exhibit suitable mechanical properties for orthopaedic arthroplasty applications, however for vertebroplasty and other medical luting applications these cements have working and setting times which are unsuitable for such applications. In this study GPCs based on Sr-Ca-Zn-SiO 2 glasses and low molecular weight PAA were evaluated for orthopaedic luting applications. GPCs based on four different glasses; BT100 (0.16CaO, 0.36ZnO, 0.48SiO2), BT101 (0.04SrO, 0.12CaO, 0.36ZnO, 0.48SiO 2), BT102 (0.08SrO 0.08CaO, 0.36ZnO, 0.48SiO2) and BT103 (0.12SrO 0.04CaO, 0.36ZnO, 0.48SiO2) and two PAAs (MW; 12,700 and 25,700) were examined. These cement formulations exhibited handling properties potentially suitable for luting applications as well as mechanical strengths which were similar to those of trabecular bone. Upon immersion in simulated body fluid, the GPCs showed sustained growth of a calcium phosphate layer on the surface of the cement indicating that these cements were bioactive in nature.

Evaluation of two novel aluminum-free, zinc-based glass polyalkenoate cements as alternatives to PMMA bone cement for use in vertebroplasty and balloon kyphoplasty

Vertebroplasty (VP) and balloon kyphoplasty (BKP) are now widely used for treating patients in whom the pain due to vertebral compression fractures is severe and has proved to be refractory to conservative treatment. These procedures involve percutaneous delivery of a bolus of an injectable bone cement either directly to the fractured vertebral body, VB (VP) or to a void created in it by an inflatable bone tamp (BKP). Thus, the cement is a vital component of both procedures. In the vast majority of VPs and BKPs, a poly(methyl methacrylate) (PMMA) bone cement is used. This material has many shortcomings, notably lack of bioactivity and very limited resorbability. Thus, there is room for alternative cements. We report here on two variants of a novel, bioactive, Al-free, Zn-based glass polyalkenoate cement (Zn-GPC), and how their properties compare to those of an injectable PMMA bone cement (SIMPL) that is widely used in VP and BKP. The properties determined were injectability, radiopacity, uniaxial compressive strength, and biaxial flexural modulus. In addition, we compared the compression fatigue lives of a validated synthetic osteoporotic VB model (a polyurethane foam cube with an 8xa0mm-diameter through-thickness cylindrical hole), at 0–2300xa0N and 3xa0Hz, when the hole was filled with each of the three cements. A critical review of the results suggests that the performance of each of the Zn-GPCs is comparable to that of SIMPL; thus, the former cements merit further study with a view to being alternatives to an injectable PMMA cement for use in VP and BKP.

Antibacterial coatings for medical devices based on glass polyalkenoate cement chemistry

A biofilm is an accumulation of micro-organisms and their extracellular products forming a structured community on a surface. Biofilm formation on medical devices has severe health consequences as bacteria growing in this lifestyle are tolerant to both host defense mechanisms and antibiotic therapies. However, silver and zinc ions inhibit the attachment and proliferation of immature biofilms. The objective of this study is to evaluate whether it is possible to produce silver and zinc-containing glass polyalkenoate cement (GPC) coatings for medical devices that have antibacterial activity and which may therefore inhibit biofilm formation on a material surface. Two silver and zinc-containing GPC coatings (A and B) were synthesised and coated onto Ti6Al4V discs. Their handling properties were characterised and atomic absorption spectrometery was employed to determine zinc and silver ion release with coating maturation up to 30xa0days. The antibacterial properties of the coatings were also evaluated against Staphylococcus aureus and a clinical isolate of Pseudomonas aeruginosa using an agar diffusion assay method. The majority of the zinc and silver ions were released within the first 24xa0h; both coatings exhibited antibacterial effect against the two bacterial strains, but the effect was more intense for B which contained more silver and less zinc than A. Both coatings produced clear zones of inhibition with each of the two organisms tested. In this assay, Ps. aeruginosa was more sensitive than S. aureus. The diameters of these zones were reduced after the coating had been immersed in water for varying periods due to the resultant effect on ion release.

Antibacterial properties of a tri-sodium citrate modified glass polyalkenoate cement

Primary deep infection following joint replacement surgery accounts for 7% of all revisions. Glass polyalkenoate cements (GPCs) have previously been shown to exhibit antibacterial properties. The present study had two objectives. The first was to determine if addition of tri-sodium citrate (TSC) to the powder phase of an Al-free GPC (0.04 SrO-0.12 CaO-0.36 ZnO-0.48 SiO2, by mole fraction) enhanced the resultant cements antibacterial properties against three strains of bacteria that are commonly found in periprosthetic sites following total joint replacements (TJRs); namely, E. coli, B. fragilis, and S. epidermidis. Four cement sets were prepared, which contained 0 wt% TSC (control), 5 wt% TSC, 10 wt% TSC, and 15 wt% TSC. All the TSC-modified cements were found to exhibit large inhibition zones against all the bacterial strains, especially the cement containing 15 wt% TSC against E. coli. The antibacterial properties of the TSC containing GPCs are attributed to the release of Zn and Na ions from the cements and the presence of the TSC. The second objective was to investigate if, when a modified GPC is embedded in a bovine bone model, ionic transfer occurs. It was found that Zn ions migrated from the cement to the surrounding bone, particularly at the cement-bone interface. This is a desirable outcome as Zn ions are known to play a vital role in both bone metabolism and the regeneration of healthy bone. The present results point to the potential clinical benefits of using TSC-modified GPCs in TJRs.

Comparison of failure mechanisms for cements used in skeletal luting applications

Glass Polyalkenoate Cements (GPCs) based on strontium calcium zinc silicate (Sr–Ca–Zn–SiO2) glasses and low molecular weight poly(acrylic acid) (PAA) have been shown to exhibit suitable compressive strength (65xa0MPa) and flexural strength (14xa0MPa) for orthopaedic luting applications. In this study, two such GPC formulations, alongside two commercial cements (Simplex® P and Hydroset™) were examined. Fracture toughness and tensile bond strength to sintered hydroxyapatite and a biomedical titanium alloy were examined. Fracture toughness of the commercial Poly(methyl methacrylate) cement, Simplex® P, (3.02xa0MPaxa0m1/2) was superior to that of the novel GPC (0.36xa0MPaxa0m1/2) and the commercial calcium phosphate cement, Hydroset™, for which no significant fracture toughness was obtained. However, tensile bond strengths of the novel GPCs (0.38xa0MPa), after a prolonged period (30xa0days), were observed to be superior to commercial controls (Simplex™ P: 0.07xa0MPa, Hydroset™: 0.16xa0MPa).