Improved design of efficient drug delivery systems (DDS) capable of responding to biological stimuli within an extended time window are a constant pursue in the field of tissue engineering and regenerative medicine (TERM). Polyhydroxybutyrate-co-hydroxyvalerate (PHBV) is a natural and biodegradable polymer with piezoelectric properties, i.e. capable of suffering electric polarization due to mechanical stress, and vice-versa.  Naturally occurring electric currents are an intrinsic property of human skin tissues, likely to act as an integrator of cells organization, development as well tissue regeneration. Under this context, this work reports an injectable piezoelectric DDS system incorporating hydrophilic and hydrophobic bioactive molecules aiming at modulating defined biological functions and tackle tissue regeneration.

Microparticles of PHBV incorporating a model protein, Bovine Serum Albumin (BSA), and glucocorticoid, Dexamethasone (Dex), were produced by a double emulsification-solvent evaporation method with modifications. Variations of the composition of the organic phase during processing allowed tuning surface topography, size distribution and core porosity of the PHBV microparticles. Likewise, the entrapment efficiency of Dex, but not BSA was modulated by varying the processing method.  However, the in vitro release profile studies confirmed an initial burst effect which was followed by a sustained pattern, typical of a first order release kinetics independently of the conditions and the incorporated molecules.

An innovative approach that tackle the reduced residence time of microparticles at the injection site, and takes advantage of its piezoelectric character to release the loaded bioactive molecules was designed. Injectable formulations of Gellan Gum hydrogel, already proposed by us for diverse tissue engineering applications, were considered as carriers. Combined and well integrated systems of PHBV microparticles within GG hydrogel, responsive to electrical stimulation, were successfully achieved. By varying the properties of the hydrogel and the intensity of the provided signal, we were able to design systems with different release profiles, which can then be tuned according to tissue and pathology/injury specific requirements.

In this sense, the development of an injectable piezoelectric drug delivery system, which guarantees a localized delivery and allows the release of biochemical cues with different physicochemical features, as well as its localized deliver, was achieved representing a versatile tool to prepare instructive cell microenvironments towards tissue regeneration in TERM applications.

Microparticles of PHBV incorporating a model protein, Bovine Serum Albumin (BSA), and glucocorticoid, Dexamethasone (Dex), were produced by a double emulsification-solvent evaporation method with modifications. Variations of the composition of the organic phase during processing allowed tuning surface topography, size distribution and core porosity of the PHBV microparticles and, thus, the in vitro release profile of Dex, but not of BSA, which followed typical first order release kinetics independently of the conditions and the incorporated agent. Uncontrollable displacements that greatly affects the concentration of active agents at the target tissues are among a major limitation of the use of microparticulate DDS. Under this context an innovative approach that tackle the reduced residence time of microparticles at the injection site, and takes advantage of its piezoelectric character to release the loaded active agents was designed. A hybrid DDS that combines PHBV microparticles with injectable gellan gum hydrogels, already proposed by us for diverse tissue engineering applications, responsive to electrical stimulation, were successfully achieved. By varying the properties of the hydrogel and the intensity of the provided signal, we were able to design systems with different release profiles, which can then be tuned according to tissue and pathology/injury specific requirements.

In this sense, the development of an in situ gelling piezoelectric drug delivery system, which combines a localized delivery of model active cues with different physicochemical features, was achieved representing a versatile tool to therapeutically induce tissue repair or function restoration.