Publications

The use of bioactive glasses (e.g. silicates, phosphates, borates) has demonstrated to be an effective therapy for the restoration of bone fractures, wound healing and vascularization. Their partial dissolution towards the surrounding tissue has shown to trigger positive bioactive responses, without the necessity of using growth factors or cell therapy, which reduces money-costs, side effects and increases their translation to the clinics. However, bioactive glasses often need from stabilizers (e.g. SiO44−, Ti4+, Co2+, etc.) that are not highly abundant in the body and which metabolization is not fully understood. In this study, we were focused on synthesizing pure calcium phosphate glasses without the presence of such stabilizers. We combined a mixture of ethylphosphate and calcium 2-methoxyethoxide to synthesize nanoparticles with different compositions and degradability. Synthesis was followed by an in-depth nuclear magnetic resonance characterization, complemented with other techniques that helped us to correlate the chemical structure of the glasses with their physiochemical properties and reaction mechanism. After synthesis, the organically modified xerogel (i.e. calcium monoethylphosphate) was treated at 200 or 350 °C and its solubility was maintained and controlled due to the elimination of organics, increase of phosphate-calcium interactions and phosphate polycondensation. To the best of our knowledge, we are reporting the first sol-gel synthesis of binary (P2O5-CaO) calcium phosphate glass nanoparticles in terms of continuous polycondensated phosphate chains structure without the addition of extra ions. The main goal is to straightforward the synthesis, to get a safer metabolization and to modulate the bioactive ion release. Additionally, we shed light on the chemical structure, reaction mechanism and properties of calcium phosphate glasses with high calcium contents, which nowadays are poorly understood. Statement of Significance The use of bioactive inorganic materials (i.e. bioactive ceramics, glass-ceramics and glasses) for biomedical applications is attractive due to their good integration with the host tissue without the necessity of adding exogenous cells or growth factors. In particular, degradable calcium phosphate glasses are completely resorbable, avoiding the retention in the body of the highly stable silica network of silicate glasses, and inducing a more controllable degradability than bioactive ceramics. However, most calcium phosphate glasses include the presence of stabilizers (e.g. Ti4+, Na+, Co2+), which metabolization is not fully understood and complicates their synthesis. The development of binary calcium phosphate glasses with controlled degradability reduces these limitations, offering a simple and completely metabolizable material with higher transfer to the clinics.

JTD Keywords: Calcium phosphate glasses, Sol-gel process, NMR spectroscopy, Ion release, Biomaterials

In bone regeneration, silicon-based calcium phosphate glasses (Bioglasses) have been widely used since the 1970s. However, they dissolve very slowly because of their high amount of Si (SiO2 > 45%). Recently, our group has found that calcium ions released by the degradation of glasses in which the job of silicon is done by just 5% of TiO2 are effective angiogenic promoters, because of their stimulation of a cell-membrane calcium sensing receptor (CaSR). Based on this, other focused tests on angiogenesis have found that Bioglasses also have the potential to be angiogenic promoters even with high contents of silicon (80%); however, their slow degradation is still a problem, as the levels of silicon cannot be decreased any lower than 45%. In this work, we propose a new generation of hybrid organically modified glasses, ormoglasses, that enable the levels of silicon to be reduced, therefore speeding up the degradation process. Using electrospinning as a faithful way to mimic the extracellular matrix (ECM), we successfully produced hybrid fibrous mats with three different contents of Si (40, 52, and 70%), and thus three different calcium ion release rates, using an ormoglass–polycaprolactone blend approach. These mats offered a good platform to evaluate different calcium release rates as osteogenic promoters in an in vivo subcutaneous environment. Complementary data were collected to complement Ca2+ release analysis, such as stiffness evaluation by AFM, ζ-potential, morphology evaluation by FESEM, proliferation and differentiation analysis, as well as in vivo subcutaneous implantations. Material and biological characterization suggested that compositions of organic/inorganic hybrid materials with a Si content equivalent to 40%, which were also those that released more calcium, were osteogenic. They also showed a greater ability to form blood vessels. These results suggest that Si-based ormoglasses can be considered an efficient tool for calcium release modulation, which could play a key role in the angiogenic promoting process.

JTD Keywords: Biological materials, Blood vessels, Calcium, Electrospinning, Glass, Hybrid materials, Silicon oxides, Sol-gel process, Sol-gels, Angiogenesis, Biological characterization, Calcium phosphate glass, Calcium-sensing receptors, Degradation process, Extracellular matrices, Organic/inorganic hybrid materials, ormoglasses, Silicon