**4. Conclusions**

In this work, a first attempt toward the design of a hybrid sol-gel formulation able to simultaneously co-release copper ions (exerting pro-angiogenic and anti-bacterial e ffects) and an anti-inflammatory drug (ibuprofen) was successfully achieved. To this aim, Cu-substituted MBG (2% mol) particles were loaded with ibuprofen through an incipient wetness technique, resulting in a high loading capacity, and then embedded within PEU-based thermosensitive gels at the highest possible concentration (20 mg/mL), according to an optimized incorporation protocol. Full characterization of the resulting hybrid systems was performed to highlight the e ffects of particle encapsulation on gelation kinetics as well as on ions/drug release mechanism. The incorporation of MBG particles within the sol-gel systems did not negatively a ffect their capability to undergo a temperature-driven sol-to-gel transition within a few minutes. The progressive release of Cu2+ species was found to play a significant role on the stability of the gels in an aqueous environment and catalyzed the oxidation of the PEU chains. The co-release of copper ions and ibuprofen from hybrid formulations was sustained and prolonged over time for up to more than one week, with a strongly reduced initial burst e ffect compared to MBG particles alone (2%–4% vs. 7%–14% Cu2+ release and 6%–9% vs. 38%–61% ibuprofen release from hybrid MBG-polyurethane formulations and free MBG particles, respectively). However, the release profile of both copper species and ibuprofen was a ffected by the progressive occlusion of mesopores resulting from the dissolution and the re-precipitation of silica-based MBG framework in the form of a silica gel at the pore entrance [40–42].

Taken together the obtained data proved the ability of the proposed hybrid thermosensitive formulation to concentrate and maintain the MBG carriers at the pathological site and to guarantee in situ and prolonged co-release of ions and drugs, thus opening the way to the design of multifunctional platforms for advanced treatment of compromised tissue healing. The high versatility of the proposed approach lies in the possibility to modulate the relative amount of the organic and inorganic components, by changing the initial particle concentration within the hydrogel solution (before gelation), and/or the initial drug loading and the chemical composition of MBGs, in order to design systems able to co-release ions and pharmaceutics with concentrations and kinetics adapted to the targeted applications and not producing cytotoxic e ffects.

The versatility of the herein developed hybrid sol-gel systems could thus pave the way to the treatment of a grea<sup>t</sup> variety of pathological conditions of soft (e.g., non-healing wounds) and hard (e.g., delayed bone healing) tissues.

**Supplementary Materials:** The following are available online at http://www.mdpi.com/1999-4923/11/10/501/s1, Figure S1: TEM image of MBG\_Cu2%\_SD.

**Author Contributions:** Conceptualization, M.B., C.P., S.F. and R.L.; methodology, M.B., C.P. and R.L.; validation, M.B., C.P., S.F. and R.L.; formal analysis, M.B., C.P. and R.L.; investigation, M.B., C.P. and R.L.; resources, M.B., C.P. and R.L.; writing—original draft preparation, M.B., C.P., S.F. and R.L.; writing—review and editing, S.F., G.C. and C.V.-B.; visualization, M.B.; supervision, S.F., G.C. and C.V.-B.; funding acquisition, C.V.-B.

**Funding:** This project has received funding from the European Union's Horizon 2020 research and innovation program under gran<sup>t</sup> agreemen<sup>t</sup> No. 685872-MOZART (www.mozartproject.eu).

**Conflicts of Interest:** The authors declare no competing financial interest.
