Injectable Thermosensitive Formulation Based on Polyurethane Hydrogel/Mesoporous Glasses for Sustained Co-Delivery of Functional Ions and Drugs

Abstract

Mini-invasively injectable hydrogels are widely attracting interest as smart tools for the co-delivery of therapeutic agents targeting different aspects of tissue/organ healing (e.g., neo-angiogenesis, inflammation). In this work, copper-substituted bioactive mesoporous glasses (Cu-MBGs) were prepared as nano- and micro-particles and successfully loaded with ibuprofen through an incipient wetness method (loaded ibuprofen approx. 10% w/w). Injectable hybrid formulations were then developed by dispersing ibuprofen-loaded Cu-MBGs within thermosensitive hydrogels based on a custom-made amphiphilic polyurethane. This procedure showed almost no effects on the gelation potential (gelation at 37 °C within 3–5 min). Cu2+ and ibuprofen were co-released over time in a sustained manner with a significantly lower burst release compared to MBG particles alone (burst release reduction approx. 85% and 65% for ibuprofen and Cu2+, respectively). Additionally, released Cu2+ species triggered polyurethane chemical degradation, thus enabling a possible tuning of gel residence time at the pathological site. The overall results suggest that hybrid injectable thermosensitive gels could be successfully designed for the simultaneous localized co-delivery of multiple therapeutics.

Plasma Treatment of Polymer Powder as an Effective Tool to Functionalize Polymers: Case Study Application on an Amphiphilic Polyurethane

“…We have previously reported that [15][16][17] aqueous solutions of the here-studied amphiphilic PEU, containing Poloxamer® 407 as building block, undergo temperature driven sol-to-gel transition by micelle self-assembly. In this work, the effect of plasma treatment on PEU thermosensitivity was studied, by estimating the critical micellar temperature of aqueous solutions of the modified polymer.…”

“…The P407-based poly(ether urethane) used in this work was synthesized under nitrogen atmosphere in a two step procedure according to the protocol recently published by Boffito, Pontremoli et al [16]. Briefly, P407 was first dissolved in DCE at 20% w/V concentration and equilibrated at 80 • C; then, HDI was added to P407 solution at 2:1 molar ratio.…”

Hybrid Injectable Sol-Gel Systems Based on Thermo-Sensitive Polyurethane Hydrogels Carrying pH-Sensitive Mesoporous Silica Nanoparticles for the Controlled and Triggered Release of Therapeutic Agents

“…Pontremoli et al (2018) reported the development of hybrid sol-gel systems based on a custom-made poly(ether urethane) (PEU) containing F127 as building block and ion-doped bioactive glasses (MBGs) in the form of nanoparticles or microspheres, demonstrating that the resulting composite formulations allowed a prolonged and sustained release of copper ions over time. Later, the same authors described similar injectable formulations co-releasing copper ions and ibuprofen (Boffito et al, 2019b). Interestingly, they demonstrated that drugs could be released from hybrid formulations with an anomalous mechanism resulting from the existence of a double diffusive barrier (i.e., the hydrogel and the mesoporous framework) the drug molecules must pass through before being released in the surrounding aqueous medium.…”

In Vivo Validation of Spray-Dried Mesoporous Bioactive Glass Microspheres Acting as Prolonged Local Release Systems for BMP-2 to Support Bone Regeneration

“…The administration of the BMP-2 loaded SD-MBG in particulate form enables versatility in dosing, since different clinical applications certainly require adjustable concentrations, and shaping of the blood clot is equally customizable. The SD-MBG can be injected if contained in a liquid dispersion and the embedding moiety can be exchanged based on the specific requirements, e.g., to a thermo-sensitive hydrogel that solidifies at body temperature [ 30 , 71 ]. However, it should be noted that the composite utilized in this study does not provide mechanical or distinct structural support to guide bone formation.…”

“…In the current study, we analyzed mesoporous bioactive glasses, produced in the form of microspheres by aerosol-assisted spray-drying method (SD-MBGs) [ 29 ], as an alternative promising carrier for BMP-2 instead of the currently used ACS. We selected SD-MBGs due to their intrinsic excellent bioactive behavior and related pro-regenerative potential, along with the high exposed surface area and regular nanopores, which allow the storage and the release of active agents, such as drugs [ 30 ] or biomolecules [ 31 ]. Based on previous studies showing the suitability of mesoporous bioactive glass microspheres (MBGs) for sustained drug release [ 32 ], we hypothesized that the SD-MBGs could act as a carrier for BMP-2 that controls and prolongs BMP-2 release without hindering the healing process.…”