A Gallium-Doped Cement for the Treatment of Bone Cancers. the Effect of ZnO ↔ Ga2O3substitution of an Ionomeric Glass Series on the Rheological, Mechanical, PH and Ion-Eluting Properties of their Corresponding Glass Polyalkenoate Cements

The primary treatment for patients suffering from bone cancers is resection of the tumor followed by reconstruction of the damaged bone. Despite the administration of post-operative chemotherapy, tumor recurrence continues to present itself as a severe complication leading to re-operation. Attempts to incorporate chemotherapeutic drugs into bone cements elicits local toxic effects on healthy bone, which could compromise implant fixation. Alternatively, the local administration of gallium (Ga) may prove to be more effective. This report considers the development of a Ga ionomeric glass series (0.48SiO2-0.355ZnO-0.06CaO-0.08SrO-0.02P2O5-0.005Ta2O5, with 0.01-0.05 mol% substitution for ZnO). X-ray Diffraction (XRD) confirmed the amorphous glass structure and Energy Dispersive x-ray Fluorescence (EDXRF) verified the successful addition of Ga into the glass series at the expense of Zinc (Zn). A Ga-GPC series was then formulated by mixing the glass particles with aqueous poly(acrylic) acid (PAA) and trisodium citrate (TSC). Fourier transform infrared (FTIR) spectroscopy demonstrated no structural changes to the GPC matrix with the incorporation of Ga. Measurements of the rheological properties demonstrated an exponential increase in setting time with increasing Ga content. Furthermore, the addition of ≥ 3 mol% Ga demonstrated deleterious effects on the GPC\u27s mechanical properties and an analysis of pH confirmed that it decreased with increasing Ga content, suggesting a reduction in glass reactivity and PAA cross-linking. Finally, inductively coupled plasma - optical emission spectrometry (ICP-OES) demonstrated the controlled release of Ga across the GPC series, which will prove beneficial to future in vitro studies

The Impact of Gallium Content on Degradation, Bioactivity, and Antibacterial Potency of Zinc Borate Bioactive Glass

Zinc borate glasses with increasing gallium content (0, 2.5, 5, 10, and 15 Wt % Ga) were synthesized and their degradation, bioactivity in simulated body fluid (SBF), and antibacterial properties were investigated. ICP measurements showed that increased gallium content in the glass resulted in increased gallium ion release and decreased release of other ions. Degradability declined with the addition of gallium, indicating the formation of more symmetric BO3 units with three bridging oxygens and asymmetric BO3 units with two bridging oxygens in the glass network as the gallium content in the series increased. The formation of amorphous Ca-P on the glass surface after 24 h of incubation in SBF was confirmed by SEM, XRD, and FTIR analyses. Finally, antibacterial evaluation of the glasses using the agar disc-diffusion method demonstrated that the addition of gallium increased the antibacterial potency of the glasses against P. aeruginosa (Gram-negative) while decreasing it against S. epidermidis (Gram-positive); considering the ion release trends, this indicates that the gallium ion is responsible for the glasses\u27 antibacterial behavior against P. aeruginosa while the zinc ion controls the antibacterial activity against S. epidermidis. The statistical significance of the observed trends in the measurements were confirmed by applying the Kruskal-Wallis H Test. © 2017 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 106B: 367–376, 2018

In Vitro Osteogenic Performance of Two Novel Strontium and Zinc-Containing Glass Polyalkenoate Cements

Glass polyalkenoate cements (GPCs) are under investigation as potential bone adhesives, as they may provide an alternative to polymethylmethacrylate-based cements. GPCs containing strontium (Sr) and zinc (Zn) in place of aluminum (Al) are of particular interest because these ions are known stimulators of osteoprogenitor differentiation. GPCs have been manufactured from a novel bioactive glass (SiO2:0.48, ZnO:0.36, CaO:0.12, SrO:0.04) in the past, but, while such materials have been assessed for their influence on viability, their influence on osteogenic function has not been investigated until now. For this study, two GPCs were formulated from the same glass precursor evaluated in previous studies. These GPCs were named GPC A and GPC B, and they differed in glass particle size, polyacrylic acid molecular weight, and their powder: liquid ratios. The effect of these two GPCs on osteogenic differentiation of primary rat osteoblasts were evaluated using three culture systems: culture with dissolution extracts, indirect contact with trans well-inserts and direct contact. Additionally, the degradation characteristics of GPCs were assessed, including their interfacial pH and surrounding pH. The experimental outcomes revealed that collagen deposition, alkaline phosphatase expression, and mineralization were largely dependent on GPC composition as well as the mode of interaction with cells. These markers were found to be significantly elevated in response to GPC A\u27s dissolution products. However, osteogenic differentiation was inhibited when osteoblasts were cultured indirectly and directly with GPCs, with, overall, GPC B significantly outperforming GPC A. These results suggest that GPC degradation products effect osteogenic differentiation in a dose-dependent manner

A Review of the Latest Insights into the Mechanism of Action of Strontium in Bone

Interest in strontium (Sr) has persisted over the last three decades due to its unique mechanism of action: it simultaneously promotes osteoblast function and inhibits osteoclast function. While this mechanism of action is strongly supported by in vitro studies and small animal trials, recent large-scale clinical trials have demonstrated that orally administered strontium ranelate (SrRan) may have no anabolic effect on bone formation in humans. Yet, there is a strong correlation between Sr accumulation in bone and reduced fracture risk in post-menopausal women, suggesting Sr acts via a purely physiochemical mechanism to enhance bone strength. Conversely, the local administration of Sr with the use of modified biomaterials has been shown to enhance bone growth, osseointegration and bone healing at the bone-implant interface, to a greater degree than Sr-free materials. This review summarizes current knowledge of the main cellular and physiochemical mechanisms that underly Sr\u27s effect in bone, which center around Sr\u27s similarity to calcium (Ca). We will also summarize the main controversies in Sr research which cast doubt on the \u27dual-acting mechanism\u27. Lastly, we will explore the effects of Sr-modified bone-implant materials both in vitro and in vivo, examining whether Sr may act via an alternate mechanism when administered locally

Bone Cement as a Local Chemotherapeutic Drug Delivery Carrier in Orthopedic Oncology: A Review

Metastatic bone lesions are common among patients with advanced cancers. While chemotherapy and radiotherapy may be prescribed immediately after diagnosis, the majority of severe metastatic bone lesions are treated by reconstructive surgery, which, in some cases, is followed by postoperative radiotherapy or chemotherapy. However, despite recent advancements in orthopedic surgery, patients undergoing reconstruction still have the risk of developing severe complications such as tumor recurrence and reconstruction failure. This has led to the introduction and evaluation of poly (methyl methacrylate) and inorganic bone cements as local carriers for chemotherapeutic drugs (usually, antineoplastic drugs (ANPDs)). The present work is a critical review of the literature on the potential use of these cements in orthopedic oncology. While several studies have demonstrated the benefits of providing high local drug concentrations while minimizing systemic side effects, only six studies have been conducted to assess the local toxic effect of these drug-loaded cements and they all reported negative effects on healthy bone structure. These findings do not close the door on chemotherapeutic bone cements; rather, they should assist in materials selection when designing future materials for the treatment of metastatic bone disease

Development of a Novel Bioactive Glass Suitable for Osteosarcoma-Related Bone Grafts

In this study, zinc borate-based glasses with increasing gallium content (0, 2.5, 5, 10, and 15 wt % Ga) were synthesized and their effect on the viability and proliferation of preosteoblasts and osteosarcoma cancer cells were investigated. Methyl thiazolyl tetrazolium (MTT) cell viability assays using glass degradation extracts revealed that the extracts from glasses with lower Ga contents could enhance the viability of preosteoblasts, while extracts from the glass composition with 15 wt % Ga caused statistically significant reduction of their viability. MTT cell viability assays using the extracts and osteosarcoma cells showed that only extracts from the glass composition with 5 wt % Ga (G3) did not cause a statistically significant increase in the viability of cancer cells for all degradation periods (1 day, 7 days, and 28 days). G3 was selected as the most suitable composition for the osteosarcoma-related graft operations as it could improve the viability of preosteoblasts without increasing the viability of cancer cells. The viability of preosteoblasts and osteosarcoma cells in contact with the glass powders were also investigated using MTT assays. The results showed that the G3 powders could enhance the viability of preosteoblasts while decreasing the viability of osteosarcoma cells. Finally, live/dead assays revealed that suppression of proliferation appeared to be the mechanism causing the observed reductions in the viability of osteosarcoma cells exposed to G3 powders. © 2017 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 106B: 1186–1193, 2018

Raman Spectroscopy as a Predictive Tool for Monitoring Osteoporosis Therapy in a Rat Model of Postmenopausal Osteoporosis

Pharmacological therapy of osteoporosis reduces bone loss and risk of fracture in patients. Modulation of bone mineral density cannot explain all effects. Other aspects of bone quality affecting fragility and ways to monitor them need to be better understood. Keratinous tissue acts as surrogate marker for bone protein deterioration caused by oestrogen deficiency in rats. Ovariectomised rats were treated with alendronate (ALN), parathyroid hormone (PTH) or estrogen (E2). MicroCT assessed macro structural changes. Raman spectroscopy assessed biochemical changes. Micro CT confirmed that all treatments prevented ovariectomy-induced macro structural bone loss in rats. PTH induced macro structural changes unrelated to ovariectomy. Raman analysis revealed ALN and PTH partially protect against molecular level changes to bone collagen (80% protection) and mineral (50% protection) phases. E2 failed to prevent biochemical change. The treatments induced alterations unassociated with the ovariectomy; increased beta sheet with E2, globular alpha helices with PTH and fibrous alpha helices with both ALN and PTH. ALN is closest to maintaining physiological status of the animals, while PTH (comparable protective effect) induces side effects. E2 is unable to prevent molecular level changes associated with ovariectomy. Raman spectroscopy can act as predictive tool for monitoring pharmacological therapy of osteoporosis in rodents. Keratinous tissue is a useful surrogate marker for the protein related impact of these therapies. The results demonstrate utility of surrogates where a clear systemic causation connects the surrogate to the target tissue. It demonstrates the need to assess broader biomolecular impact of interventions to examine side effects. [Figure not available: see full text.]

The Effect of the Addition of Gallium on the Structure of Zinc Borate Glass with Controlled Gallium Ion Release

Gallium ion released from bioactive glasses can perform therapeutic functions depending on its concentration. In this study, zinc borate based glasses with increasing gallium content (0, 2.5, 5, 10, and 15wt.% Ga) were synthesized and their structural properties and gallium ion release capabilities were investigated in order to understand how the substitution of gallium for boron affects the glass network. X-ray diffraction verified the amorphous state of the synthesized glasses. Thermal and spectroscopic analyses recorded a steady decline in both glass transition and crystallization temperatures of the glasses alongside small shifts in the position of borate triangles\u27 peaks, indicating short-range order rearrangements, and a rise in the number of pentaborate and loose BO3 units by the addition of gallium. 11B Magic Angle Spinning Nuclear Magnetic Resonance (MAS NMR) analysis showed incremental addition of gallium reduces the BO4/BO3 ratio which indicates an increase in the non-bridging oxygens in the glasses with higher gallium content, and 31P MAS NMR analysis revealed the presence of orthophosphate units with one and two bridging oxygens and that the introduction of gallium overall lowers the fraction of units with two bridging oxygens. The released gallium ion was considerably more in glasses with higher gallium content

The impact of gallium content on degradation, bioactivity, and antibacterial potency of zinc borate bioactive glass

Zinc borate glasses with increasing gallium content (0, 2.5, 5, 10, and 15 Wt % Ga) were synthesized and their degradation, bioactivity in simulated body fluid (SBF), and antibacterial properties were investigated. ICP measurements showed that increased gallium content in the glass resulted in increased gallium ion release and decreased release of other ions. Degradability declined with the addition of gallium, indicating the formation of more symmetric BO3 units with three bridging oxygens and asymmetric BO3 units with two bridging oxygens in the glass network as the gallium content in the series increased. The formation of amorphous CaP on the glass surface after 24 h of incubation in SBF was confirmed by SEM, XRD, and FTIR analyses. Finally, antibacterial evaluation of the glasses using the agar disc-diffusion method demonstrated that the addition of gallium increased the antibacterial potency of the glasses against P. aeruginosa (Gram-negative) while decreasing it against S. epidermidis (Gram-positive); considering the ion release trends, this indicates that the gallium ion is responsible for the glasses’ antibacterial behavior against P. aeruginosa while the zinc ion controls the antibacterial activity against S. epidermidis. The statistical significance of the observed trends in the measurements were confirmed by applying the Kruskal-Wallis H Test