Introduction: The inability to directly monitor embolic microspheres during transarterial embolization (TAE) “preclude[s] ideal spatial delivery” of the embolic particles by limiting the accurate assessment of their terminal locations within target tissues[1]. A potential advantage associated with ‘imageable’ microspheres in selective internal radiation therapy (SIRT) expands to the provision of accurate dosimetry determinations; a feature that may enhance and optimize clinical outcomes. A primary design requirement for glass microspheres in this indication is that it be durable enough to limit the release of 90Y in vivo. Intersecting with this design requirement is the necessity that the material be imageable. This work seeks to show how such a design requirement may be achieved through a design of mixtures (DOM) experimental approach, and presents data for potential glass microspheres for use in SIRT.
Materials and Methods: Sixteen glass-based compositions (mol. fraction) (0.100-0.170)Y2O3-(0.025-0.050)SrO-(0.100-0.300)Ga2O3-(0.50-0.75)SiO2 were synthesized using conventional melt-quenching techniques (fired at 1530°C, 3 h). Further processing (drying, grinding and sieving) retrieved particulates with a particle size distribution (PSD) of 20-32µm for subsequent evaluation. Quantitative radiopacity measurements of the experimental materials and control (n=5) were determined by taking axial CT scans (1mm slice thickness, pitch=0.5, 70 and 120kVp) through glass vials using a Somatom Definition AS+ scanner (Siemens Healthcare, Erlangen, Germany). Extracts were derived from the experimental materials over time periods of 1, 7 and 14days at an extraction ratio of 0.2g/mL (per ISO10993-12[2]) in polar medium (DI water). Ionic concentrations were analyzed via inductively coupled plasma atomic emission spectroscopy (ICP-AES, Perkin Elmer Optima 7300, MA, USA). Using a DOM experimental design approach (Design–Expert Ver. 8.0, Stat-Ease Inc.) the ordinary linear Scheffé polynomial[3] mixture equations were fitted to Yttrium (Y) release and CT imageability for each composition to determine the variant to impart the highest level of statistical significance on each response.
Results and Discussion: Y release levels from all compositions tested were observed to not exceed 0.255 ±0.076 (SE) ppm over the 14day period. The regression outputs (mathematical models) developed for Y release and CT radiopacity yielded R2 values ranging from 0.7833-0.9485 and 0.9865-0.9950, respectively. In summary, the top 3 significant (positive and negative) main or interaction compositional factors (ranked highest to lowest based on L_Pseudo components) were noted as follows:
Y release at 1day: +Y2O3*SrO > -SrO > +Ga2O3
Y release at 7 and 14days: -SrO > +Y2O3 > +Ga2O3
CT Imageability at 70kVp: -SrO > -Y2O3 > +Ga2O3
CT Imageability at 120kVp: +SrO > +Y2O3 > -Ga2O3
Overall, reduced concentrations of SrO relative to both Y2O3 and Ga2O3 were observed to impart the most signigifacnt effects (main and interaction) on all properties evaluated with the exception of CT imageability at 120kVp. Fig. 1 illustrates this contrasting effect for each element on subsequent CT imageability at 70 and 120kVp, a feature attributable to the K-absorption edge of these elements.
Conclusions: Imageable glass microspheres synthesized and evaluated herein using DOM methodologies could potentially enhance dosimetry determinations to target tissues for SIRT.
Atlantic Canada Opportunity Agency (ACOA) through the Atlantic Innovation Fund (AIF); John Fraser for his technical assistance with the synthesis of glass
References:
[1] Sharma KV, Dreher MR, Tang YQ, et al. Development of "Imageable" Beads for Transcatheter Embolotherapy. J Vasc Interv Radiol. 2010; 21: 865-76.
[2] ISO10993-12. Biological evaluation of medical devices, part 12: Sample preparation and reference materials 2012.
[3] Duee C, Desanglois F, Lebecq I, et al. Mixture Designs applied to Glass Bioactivity Evaluation in the Si-Ca-Na system. J Non-Cryst Solids 2009; 355: 943–950.