Novel Superparamagnetic Microdevices Based on Magnetized PLGA/PLA Microparticles Obtained by Supercritical Fluid Emulsion and Coating by Carboxybetaine-Functionalized Chitosan Allowing the Tuneable Release of Therapeutics.

When superparamagnetic nanoparticles (MAG) are loaded within microcarriers of thermosensitive and injectable biopolymers, "smart" microdevices are obtained: they respond to an external magnetic field through the release of any co-encapsulated molecules with a remote on-off control. Creating reliable and effective fabrication technologies for the production of these smart nano/microdevices remains a challenge. In this work, supercritical emulsion extraction technology is proposed for the fabrication of microcapsules with a core of poly-lactic-co-glycolic acid (PLGA) or polylactic acid (PLA) covered by carboxybetaine-functionalized chitosan (f-chi) and loaded with MAG (mean size of 6.5 ± 3.0 nm) and water-soluble fluorescein (Fluo). Fluo is co-encapsulated as a fluorescent marker for the release study. Microcarriers showed a mean size of 800 ± 60 nm with an encapsulation efficiency of up to 90%. The inversion of surface charge, after the f-chi coating, suggested the presence of a uniform functionalized surface available for further chemical linkage. The external chitosan layer had a thickness of 200 ± 50 nm. An excellent MAG dispersion was confirmed within the biopolymer matrix that was shown to be responsive to external magnetic field; indeed, Fluo was released over 3 or 5 days from PLGA or f-chi-PLGA microdevices into phosphate-buffered saline medium at 37°C, whereas remote on-off controlled release was achieved when an alternating magnetic field was applied.

Injectable PLGA/Hydroxyapatite/Chitosan Microcapsules Produced by Supercritical Emulsion Extraction Technology: An In Vitro Study on Teriparatide/Gentamicin Controlled Release.

Supercritical emulsion extraction (SEE) is proposed as a green and effective strategy for the fabrication of chitosan-covered poly-lactic-co-glycolic acid (chi-PLGA) injectable microcapsules for the controlled release of teriparatide (THA) and teriparatide/gentamicin sulfate (THA/Gen). These formulations can be used for locally bone pathologies treatment or in complex fracture healing of aged patients. Several oil-water (o-w) and water-oil-water (w-o-w) emulsions were processed by SEE to produce multifunctional microcapsules containing hydroxyapatite (HA) within a poly-lactic-co-glycolic acid (PLGA) matrix (up to 24 mg/g) and with both THA (0.45 mg/g) and Gen (up to 9 mg/g). Chitosan coating was also successfully added, as external layer (0.4 µm). SEE-fabricated microcapsules showed good encapsulation efficiency (up to 90%) for all the drugs tested and a mean size ranging between 1.4 (±0.4) µm and 2.2 (±0.5) µm. Different drug amounts loaded and microcapsules compositions assured a controlled drug release over a wide range of times and concentrations, as in vitro monitored in PBS medium at 37°C for 15/20 days. HA embedded into the biopolymer structure delayed the THA release profile; chitosan coating strongly reduced the initial drug "burst" release. In addition, the coencapsulation of both THA and Gen, which have very different water solubility, accelerated the release profile of the less water-soluble drug. No drugs degradation was also monitored after the SEE manufacturing. Apparent drug diffusivities (D) were calculated by fitting of the release profiles. In the case of Gen, D ranged between 2.9 × 10(-8) and 1.6 × 10(-9) cm(2)s(-1) if the drug was entrapped in simple PLGA or in the chitosan-coated microcapsules, respectively. In the case of THA, the calculated values ranged between 8.1 × 10(-9) and 7.4 × 10(-10) cm(2)s(-1) when the drug was entrapped in PLGA/HA microcapsules or in the chitosan-coated ones, respectively. These mass transfer values are consistent with the different release behaviors observed and confirmed the possibility of multicomponent microcapsules fabrication by SEE.