Hernán E. Romeo

Functionalized Bridged Silsesquioxane-based Nanostructured Microspheres: Performance as Novel Drug-delivery Devices in Bone Tissue-related Applications

Two kinds of functionalized nanostructured hybrid microspheres, based on the bridged silsesquioxane family, were synthesized by employing the sol–gel method via self-assembly of two different organic–inorganic bridged monomers. The architecture reached at molecular level allowed the incorporation of acetylsalicylic acid (ASA) as an anti-inflammatory model drug. The ASA-functionalized microspheres were characterized as delivery devices in simulated body fluid (SBF). The release behaviors of the synthesized microspheres (Fickian or anomalous diffusion mechanisms) were shown to be dependent on the chemical nature of the bridged monomers employed to synthesize the hybrid materials. The functionalized microspheres were proposed as delivery systems into calcium phosphate cements (CPCs), in order to slow down the characteristic drug-delivery kinetics of this kind of bone tissue-related materials. The incorporation of the new functionalized microparticles into the CPCs represented a viable methodology to modify the ASA-release kinetics in comparison to a conventional CPC containing the drug dispersed into the solid phase. The ASA-delivery profiles obtained from the microsphere-loaded CPCs showed that 40–60% of drug can be released after 2 weeks of testing in SBF. The inclusion of the microspheres into the CPC matrices allowed modification of the release profiles through a mechanism that involved two stages: (1) the diffusion of the drug through the organic–inorganic matrix of the microspheres (according to a Fickian or anomalous diffusion, depending on the nanostructuring) and (2) the subsequent diffusion of the drug through the ceramic matrix of the hardened cements. The release behavior of the composite cements was shown to be dependent on the nanostructuring of the hybrid microspheres, which can be selectively tailored by choosing the desired chemical structure of the bridged precursors employed in the sol–gel synthesis. The obtained results demonstrated the ability of this new class of functionalized hybrid microdevices as delivery systems into calcium phosphate materials with potential bone tissue-related drug-delivery applications.

Functionalized bridged silsesquioxane-based nanostructured microspheres: ultrasound-assisted synthesis and in vitro cytotoxicity characterization

Different kinds of polymers have been employed in medicine as biomaterials for different purposes. In recent years, considerable attention has been focused on the development of new drug-delivery systems in order to increase bio-availability, sustain, localize and target drug action in the human body. The versatility of the sol–gel processing to synthesize nanostructured materials and the possibility of incorporating organic molecules into the matrix of the final hybrid material, represent a novel and attractive path to the synthesis of new functionalized hybrid biomaterials with advanced properties. In this work, acetylsalicylic acid (ASA)-functionalized hybrid microspheres based on bridged silsesquioxanes synthesized via ultrasound-assisted sol–gel processing, were characterized. An investigation concerning the cytotoxic response of these new microspheres on CHO-K1 cells was accomplished based on ISO 10993-5 standard (Biological Evaluation of Medical Devices). Microspheres incorporating ASA showed a cytotoxic effect when pure extracts of the microspheres were analyzed, however, they strongly diminished their cytotoxicity as the extracts were diluted. When a 10% concentration extract was employed, hybrid microspheres were shown to be non cytotoxic. These results are promising for considering these novel functionalized organic–inorganic microspheres as potential drug-carriers to be employed in drug delivery-related applications.

TTCP-DCPA Based Calcium Phosphate Cements Containing Hybrid Microparticles as Drug Carriers

In recent years, considerable attention has been focused on the development of new composite materials for application as drug delivery systems. In this field, calcium phosphate cements (CPCs) are often employed as support to delivery of drugs, but their behavior has some drawback related to the so-called burst effect. The aim of this work was to develop new CPCs formulations from synthesized tetracalcium phosphate (TTCP), dicalcium phosphate anhydrous TTCP and drug-containing hybrid microparticles (DCHM). The main function of these DCHM is providing nuclei of high concentration of drugs into the CPCs. The DCHM were synthesized via the sol-gel method from a bridged precursor of the type (H3CO)3 – Bridge – (OCH3)3 and aspirin (AS) as model drug. The inorganic polycondensation reached 89.5 % as calculated by 29Si NMR. The analysis by small angle X-ray scattering (SAXS) reveled a short range structural ordering in the DCHM at molecular level. Effective incorporation of AS inside the microspheres was detected by FTIR spectroscopy. In vitro tests of DCHM according to ISO 10993-5 revealed non-cytotoxic behavior. Four CPCs formulations containing 0, 1, 5 and 10 wt % of DCHM, were evaluated. The presence of DCHM did not modify neither the degree of conversion to low-crystallinity HA nor the measured setting times of the CPCs, however, the amount of incorporated microparticles considerably affected the degree of porosity (macropores of 200 µm) and interconnectivity of the cement matrix.

Unidirectional freezing as a tool for tailoring air permeability in macroporous poly(ethylene glycol)-based cross-linked networks

Unidirectional freezing followed by photopolymerization at subzero temperatures was used to obtain highly air-permeable monoliths with ordered porous structures. Scaffolds were obtained from aqueous solutions of a poly(ethylene glycol)dimethacrylate (PEGDMA) oligomer, a photosensitizer and a reducing agent. Solutions were vertically frozen in liquid nitrogen at a controlled rate to induce the oriented growth of ice crystals and then cryo-photopolymerized under blue-light irradiation. Ice crystals were finally removed under vacuum producing macroporous hydrophilic networks with aligned pores. Porosities ranged between 80 and 95%, depending on the initial concentration of PEGDMA. The influence of processing variables on the final properties of the materials was addressed, concerning particularly the effect of porosity and freezing directionality on air permeability. Compared to porous PEGDMA-based monoliths with non-aligned macropores, gas permeability was two to three times higher for oriented scaffolds at the same porosity level, a fact explained by the easier transport of gas molecules through the aligned structures. However, the role of pore orientation on gas permeability was shown to be less marked as porosity increased. The results demonstrate that the use of unidirectional freezing strongly increases the permeability of monolithic samples up to values usually required, for instance, in tissue engineering applications (higher than 2D). These findings provide new perspectives on pore design principles toward future scaffolding of polymeric cross-linked matrices.