Sharon Kehoe

Hydrogel/bioactive glass composites for bone regeneration applications: Synthesis and characterisation

Due to the deficiencies of current commercially available biological bone grafts, alternative bone graft substitutes have come to the forefront of tissue engineering in recent times. The main challenge for scientists in manufacturing bone graft substitutes is to obtain a scaffold that has sufficient mechanical strength and bioactive properties to promote formation of new tissue. The ability to synthesise hydrogel based composite scaffolds using photopolymerisation has been demonstrated in this study. The prepared hydrogel based composites were characterised using techniques including Fourier Transform Infrared Spectroscopy (FTIR), X-ray diffraction (XRD), scanning electron microscopy (SEM), Energy-dispersive X-ray spectrometry (EDX), rheological studies and compression testing. In addition, gel fraction, differential scanning calorimetry (DSC), thermogravimetric analysis (TGA), porosity and swelling studies of the composites were carried out. It was found that these novel hydrogel bioglass composite formulations did not display the inherent brittleness that is typically associated with bioactive glass based bone graft materials and exhibited enhanced biomechanical properties compared to the polyethylene glycol hydrogel scaffolds along. Together, the combination of enhanced mechanical properties and the deposition of apatite on the surface of these hydrogel based composites make them an ideal candidate as bone graft substitutes in cancellous bone defects or low load bearing applications.

Novel adaptations to zinc–silicate glass polyalkenoate cements: The unexpected influences of germanium based glasses on handling characteristics and mechanical properties

Aluminum-free glass polyalkenoate cements (GPC) have been hindered for use as injectable bone cements by their inability to balance handling characteristics with mechanical integrity. Currently, zinc-based, aluminum-free GPCs demonstrate compression strengths in excess of 60MPa, but set in c. 1-2 min. Previous efforts to extend the setting reaction have remained clinically insufficient and are typically accompanied by a significant drop in strength. This work synthesized novel glasses based on a zinc silicate composition with the inclusion of GeO2, ZrO2, and Na2O, and evaluated the setting reaction and mechanical properties of the resultant GPCs. Germanium based GPCs were found to have working times between 5 and 10 min, setting times between 14 and 36 min, and compression strengths in excess of 30 MPa for the first 30 days. The results of this investigation have shown that the inclusion of GeO2, ZrO2, and Na2O into the glass network have produced, for the first time, an aluminum-free GPC that is clinically viable as injectable bone cements with regards to handling characteristics and mechanical properties.

Mixture designs to assess composition–structure–property relationships in SiO2–CaO–ZnO–La2O3–TiO2–MgO–SrO–Na2O glasses: Potential materials for embolization

Embolization with micron-sized particulates is widely applied to treat uterine fibroids. The objective of this work was to develop mixture designs to predict materials composition–structure–property relationships for the SiO2–CaO–ZnO–La2O3–TiO2–MgO–SrO–Na2O glass system and compare its fundamental materials properties (density and cytocompatibility), against a state-of-the-art embolic agent (contour polyvinyl alcohol) to assess the potential of these materials for embolization therapies. The glass structures were evaluated using 29Si MAS NMR to identify chemical shift and line width; the particulate densities were determined using helium pycnometry and the cell viabilities were assessed via MTT assay. 29Si MAS NMR results indicated peak maxima for each glass in the range of −82.3 ppm to −89.9 ppm; associated with Q2 to Q3 units in silicate glasses. All experimental embolic compositions showed enhanced in vitro compatibility in comparison to Contour PVA with the exceptions of ORP9 and ORP11 (containing no TiO2). In this study, optimal compositions for cell viability were obtained for the following compositional ranges: 0.095–0.188 mole fraction ZnO; 0.068–0.159 mole fraction La2O3; 0.545–0.562 mole fraction SiO2 and 0.042–0.050 mole fraction TiO2. To ensure ease of producibility in obtaining good melts, a maximum loading of 0.068 mole fraction La2O3 is required. This is confirmed by the desirability approach, for which the only experimental composition (ORP5) of the materials evaluated was presented as an optimum composition; combining high cell viability with ease of production (0.188 mole fraction ZnO; 0.068 mole fraction La2O3; 0.562 mole fraction SiO2 and 0.042 mole fraction TiO2).

Experimental composite guidance conduits for peripheral nerve repair: An evaluation of ion release

Poly (lactide-co-glycolide) (PLGA) - Pluronic F127 - glass composites have demonstrated excellent potential, from the perspective of controlled mechanical properties and cytocompatibility, for peripheral nerve regeneration. In addition to controlling the mechanical properties and cytotoxicity for such composite devices, the glass component may mediate specific responses upon implantation via degradation in the physiological environment and release of constituent elements. However, research focused on quantifying the release levels of such therapeutic ions from these experimental medical devices has been limited. To redress the balance, this paper explores the ion release profiles for Si(4+), Ca(2+), Na(+), Zn(2+), and Ce(4+) from experimental composite nerve guidance conduits (CNGC) comprising PLGA (at 12.5, and 20 wt.%), F127 (at 0, 2.5 and 5 wt.%) and various loadings of Si-Ca-Na-Zn-Ce glass (at 20 and 40 wt.%) for incubation periods of up to 28 days. The concentration of each ion, at various time points, was determined using Inductively Coupled Plasma-Atomic Emission Spectrometry (Perkin Elmer Optima 3000). It was observed that the Si(4+), Na(+), Ca(2+), Zn(2+) release from CNGCs in this study ranged from 0.22 to 6.477 ppm, 2.307 to 3.277 ppm, 40 to 119 ppm, and 45 to 51 ppm, respectively. The Ce(4+) concentrations were under the minimum detection limits for the ICP instrument utilized. The results indicate that the ion release levels may be appropriate to mediate therapeutic effects with respect to peripheral nerve regeneration. The data generated in this paper provides requisite evidence to optimize composition for pre-clinical evaluation of the experimental composite.

Temporal analysis of dissolution by-products and genotoxic potential of spherical zinc–silicate bioglass: “Imageable beads” for transarterial embolization

Embolization of vascular tumors is an important tool in minimally invasive surgical intervention. Radiopaque, non-degradable, and non-deformable spherical zinc–silicate glass particles were produced in a range of 45–500 μm. Three size ranges (45–150, 150–300, and 300–500 μm) were used in the current study. The glass microspheres were eluted in polar (saline solution) and non-polar (dimethyl sulfoxide) medium, and ion release profiles were recorded using inductively coupled plasma atomic emission spectroscopy. Approximately 80% of Gaussian distribution was achieved by simple sieving. The ions released from the microspheres were dependent upon surface area to volume ratio as well as the nature of elution media. Greater ions were released from smaller particles (45–150 μm) having largest surface area in polar medium. For the genotoxicity bacterial mutation Ames assay, the concentrations of all the ions were well below their therapeutic concentration reported in the literature. No mutagenic effect was observed in the bacterial mutation Ames test. Hence, it can be concluded that the glass microspheres produced herein are non-mutagenic further supporting the materials potential as a suitable embolic agent.

Composition-property relationships for radiopaque composite materials: pre-loaded drug-eluting beads for transarterial chemoembolization

The purpose of this study was to synthesize and optimize intrinsically radiopaque composite embolic microspheres for sustained release of doxorubicin in drug-eluting bead transarterial chemoembolization. Using a design of experiments approach, 12 radiopaque composites composed of polylactic-co-glycolic acid and a radiopaque glass (ORP5) were screened over a range of compositions and examined for radiopacity (computed tomography) and density. In vitro cell viability was determined using an extract assay derived from each composition against the human hepatocellular carcinoma cell line, HepG2. Mathematical models based on a D-Optimal response surface methodology were used to determine the preferred radiopaque composite. The resulting radiopaque composite was validated and subsequently loaded with doxorubicin between 0 and 1.4% (wt% of polylactic-co-glycolic acid) to yield radiopaque composite drug-eluting beads. Thereafter, the radiopaque composite drug-eluting beads were subjected to an elution study (up to 168 h) to determine doxorubicin release profiles (UV-Vis spectroscopy) and in vitro cell viability. Radiopaque composites evaluated for screening purposes had densities between 1.28 and 1.67 g.cm−3, radiopacity ranged between 211 and 1450HU and cell viabilities between 91 and 106% were observed. The optimized radiopaque composite comprised 23 wt% polylactic-co-glycolic acid and 60 wt% ORP5 with a corresponding density of 1.63 ± 0.001 g.cm−3, radiopacity at 1930 ± 44HU and cell viability of 89 ± 7.6%. Radiopaque composite drug-eluting beads provided sustained doxorubicin release over 168 h. In conclusion, the mathematical models allowed for the identification and synthesis of a unique radiopaque composite. The optimized radiopaque composite had similar density and cell viability to commercially available embolic microspheres. It was possible to preload doxorubicin into radiopaque composite drug-eluting beads, such that sustained release was possible under simulated physiological conditions.

Preliminary Investigation of the Dissolution Behavior, Cytocompatibility, Effects of Fibrinogen Conformation and Platelet Adhesion for Radiopaque Embolic Particles

Experimental embolic particles based on a novel zinc-silicate glass system have been biologically evaluated for potential consideration in transcatheter arterial embolization procedures. In addition to controlling the cytotoxicity and haemocompatibility for such embolic particles, its glass structure may mediate specific responses via dissolution in the physiological environment. In a 120 h in-vitro dissolution study, ion release levels for silicon (Si4+), sodium (Na+), calcium (Ca2+), zinc (Zn2+), titanium (Ti4+), lanthanum (La3+), strontium (Sr2+), and magnesium (Mg2+), were found to range from 0.04 to 5.41 ppm, 0.27–2.28 ppm, 2.32–8.47 ppm, 0.16–0.20 ppm, 0.12–2.15 ppm, 0.16–0.49 ppm and 0.01–0.12 ppm, respectively for the series of glass compositions evaluated. Initial release of Zn2+ (1.93–10.40 ppm) was only evident after 120 h. All compositions showed levels of cell viabilities ranging from 61.31 ± 4.33% to 153.7 ± 1.25% at 25%–100% serial extract dilutions. The conformational state of fibrinogen, known to induce thrombi, indicated that no changes were induced with respect of the materials dissolution by-products. Furthermore, the best-in-class experimental composition showed equivalency to contour PVA in terms of inducing platelet adhesion. The data generated here provides requisite evidence to continue to in-vivo pre-clinical evaluation using the best-in-class experimental composition evaluated.

Imageable Zinc-Silicate Glass Microspheres For Transarterial Embolization: A Renal Artery Embolization Study.

Abstract Intrinsically radiopaque (imageable) microspheres for transarterial embolization (TAE) are required to enable real-time intraprocedural feedback and definition of spatial distribution patterns of embolic materials in target tissues. This pilot study evaluates acute and sub-chronic safety and efficacy of imageable zinc-silicate (Zn-Si) glass microspheres in a swine renal artery embolization (RAE) model. Eight swine were divided into two cohorts. Clinical determinants of embolization effectiveness, including imageability, deliverability and temporal/ spatial distribution of microspheres in target tissues were assessed. Subsequently, cohort I and II were used to evaluate the acute and subchronic host response against the Zn-Si microspheres versus a clinical control. The developed microspheres provide for direct intraprocedural feedback using standard diagnostic imaging techniques. Fluoroscopy correlated with ex-vivo high-resolution radiography, CT and micro-CT, demonstrating high imageability, excellent spatial distribution and packing of the Zn- Si microspheres. At follow-up, infarction of the embolized kidneys was noted without any major adverse tissue reaction. Mild recanalization was observed microscopically for both experimental and control microspheres. Zn-Si microspheres permit the definition of spatial distribution in a target tissue, consequently permitting the optimization, personalization and improvement of TAE techniques.

Regulatory aspects of bioactive glasses: A basic primer on “design control” for academic researchers

Translating new bioactive glass concepts into clinical products requires adherence to the principles of design control. This chapter provides structured information, which can assist academic researchers in understanding the importance of, and principles underpinning, design control. This chapter is designed to be a starting point, which may assist academic researchers in the structured innovation of, and/or the commercialization and clinical deployment of, new bioactive glasses.

Advances in Degradable Embolic Microspheres: A State of the Art Review

Considerable efforts have been placed on the development of degradable microspheres for use in transarterial embolization indications. Using the guidance of the U.S. Food and Drug Administration (FDA) special controls document for the preclinical evaluation of vascular embolization devices, this review consolidates all relevant data pertaining to novel degradable microsphere technologies for bland embolization into a single reference. This review emphasizes intended use, chemical composition, degradative mechanisms, and pre-clinical safety, efficacy, and performance, while summarizing the key advantages and disadvantages for each degradable technology that is currently under development for transarterial embolization. This review is intended to provide an inclusive reference for clinicians that may facilitate an understanding of clinical and technical concepts related to this field of interventional radiology. For materials scientists, this review highlights innovative devices and current evaluation methodologies (i.e., preclinical models), and is designed to be instructive in the development of innovative/new technologies and evaluation methodologies.