Bone is a dynamic, mechanoresponsive tissue with intrinsic mechanoelectrical behavior. Schematic (created with BioRender) illustrates how mechanical stimulation applied to a conductive scaffold enhances osteogenic differentiation.

Chitosan films have attracted interest as flexible and biocompatible materials in health monitoring technologies due to their intrinsic piezoelectricity. This work studies, for the first time, the piezoelectric performances of solution‐cast chitosan films in relation to their fabrication process and crystalline content. We investigate how processing parameters, such as solvent type, NaOH treatment duration, and thermal annealing, affect the crystalline content of chitosan films and its correlation with the overall piezoelectric behavior through comprehensive physico‐chemical characterizations. Special care is devoted to a reliable determination of converse piezoelectricity, using constant‐excitation frequency‐modulation piezoresponse force microscopy (CE‐FM‐PFM), a scanning probe method specifically suited to suppress measurement artifacts that affect conventional PFM in the investigation of soft materials such as semicrystalline polymers. Our findings reveal that a post‐processing strategy combining NaOH treatment and thermal annealing significantly enhances the piezoelectric response of chitosan, with a piezoelectric coefficient d33 reaching 27 pm V−1, nearly twice as high as those previously reported in the literature. These results pave a promising path for the development of eco‐friendly and functional piezoelectric materials for biomedical applications.

Myocardial infarction remains a global health challenge, necessitating advanced therapeutic strategies to address both acute injury and chronic ventricular remodeling. This study presents an innovative tri-layered bioartificial patch engineered to modulate degradation kinetics and drug release for prolonged cardiac regeneration. By integrating a slower-degrading polycaprolactone (PCL) and gelatine-based inner layer into a microstructured polylactic-co-glycolic acid (PLGA) and gelatine architecture, we developed a system with a highly controlled biphasic degradation profile. Hydrolytic degradation tests revealed that while the external PLGA-based layers undergo bulk degradation and complete dissolution by 60 to 90 days, the internal PCL-based membrane successfully retains its structural integrity and biomimetic micropatterning for up to 90 days. This structural stability also enabled a tailored dual-release of bioactive molecules: a rapid 50-70% burst release of the cardioprotective agent adenosine within the first 5 hours to target acute reperfusion injury, paired with a restricted about 6% release of the antifibrotic drug pirfenidone over 7 days, effectively preserving it for the later stages of tissue healing. Furthermore, the incorporation of the Fmoc-FF peptide conferred a stable electrical conductivity of 4.6 µS cm-1 at 1 Hz without compromising the matrix structure. In vitro biological assessments confirmed excellent cytocompatibility across all layers, supporting an H9c2 cardiomyoblast viability of roughly 90% after 72 hours. Human iPSC-CMs cultured on the patch maintained spontaneous and synchronous beating activity. Moreover, the patch loaded with PIR exhibited significant antifibrotic activity, confirming that the released drug remained biologically active. Ultimately, this multi-layered design provides a promising and functionally active platform for counteracting pathological remodeling and restoring myocardial tissue.

Volumetric muscle loss (VML) poses a significant challenge due to the limited regenerative capacity of skeletal muscle. In this context, emerging four-dimensional (4D) regenerative strategies, which couple biomimetic scaffolds with external dynamic stimuli, have gained increasing attention for their potential to enhance repair outcomes. A novel piezoelectric scaffold based on egg white proteins (EWP) integrated with barium titanate (BTO) particles was developed using a rapid and versatile microwave-assisted method. The optimized EWP:BTO 1:1 scaffolds combine favourable porosity, mechanical compliance, and controlled degradation, closely mimicking native muscle tissue. Corona poling imparts permanent polarisation to the BTO phase, enabling localised electromechanical stimulation under ultrasound. C2C12 myoblasts cultured on these scaffolds exhibited enhanced adhesion, proliferation, infiltration and differentiation. Ultrasound stimulation synergized with polarisation to upregulate early mechanosensitive and electroactive genes. These findings highlight the capacity of piezoelectric scaffolds to integrate structural and dynamic cues, an essential feature of 4D scaffold-based approaches, promoting early myogenic signalling. A pilot in vivo study confirmed biocompatibility and structural integrity over 28 days, with no evidence of local or systemic toxicity, supporting the suitability of the scaffold for further evaluation in VML models. Overall, EWP:BTO 1:1 piezoelectric scaffolds constitute a sustainable, biocompatible, and functionally active 4D platform that converts mechanical energy into targeted electrical cues. By coupling biomimetic architecture with ultrasound-driven electromechanical activation, this approach provides a versatile and non-invasive strategy to modulate muscle regeneration and represents a promising platform for future functional muscle regeneration studies in VML.

We produced a microstructured, electroconductive and nano-functionalized drug eluting cardiac patch (MENDEP) designed to attract endogenous precursor cells, favor their differentiation and counteract adverse ventricular remodeling in situ. MENDEP showed mechanical anisotropy and biaxial strength comparable to porcine myocardium, reduced impedance, controlled biodegradability, molecular recognition ability and controlled drug release activity. In vitro, cytocompatibility and cardioinductivity were demonstrated. Migration tests showed the chemoattractive capacity of the patches and conductivity assays showed unaltered cell-cell interactions and cell beating synchronicity. MENDEP was then epicardially implanted in a rat model of ischemia/reperfusion (I/R). Histological, immunofluorescence and biomarker analysis indicated that implantation did not cause damage to the healthy myocardium. After I/R, MENDEP recruited precursor cells into the damaged myocardium and triggered their differentiation towards the vascular lineage. Under the patch, the myocardial tissue appeared well preserved and cardiac gap junctions were correctly distributed at the level of the intercalated discs. The fibrotic area measured in the I/R group was partially reduced in the patch group.Overall, these results demonstrate that MENDEP was fully retained on the epicardial surface of the left ventricle over 4-week implantation period, underwent progressive vascularization, did not perturb the healthy myocardium and showed great potential in repairing the infarcted area.

The intrinsic limitation of myocardial tissue to self-repair after damage underscores the need for innovative approaches in addressing cardiac tissue damage post-myocardial infarction (MI). We aimed to develop an acellular, bioartificial, microstructured and electroconductive patch (PGF) made of poly(lactic-co-glycolic acid) (PLGA), Gelatin, and 9-fluorenylmethoxycarbonyl-diphenylalanine (Fmoc-FF), to foster post-MI endogenous cardiac healing capabilities. The self-assembling semi-conductive peptide Fmoc-FF was introduced to reduce the electrical impedance of the polymer components while maintaining the complete biodegradation of the patch. Unexpectedly, the electroconductive component was found to increase the patch microstructure stability, improve cardiomyoblast elongation, augment stromal cell differentiation and sustain Human induced Pluripotent Stem Cell-derived Cardiomyocytes (hiPSC-CM) beating for at least 30 days. The main outcome was demonstrated in vivo, where epicardial implantation of the PGF patch in a rat model of ischaemia-reperfusion promoted significant cardiac tissue repair: this was evidenced by preservation of the myocardial tissue, reduced fibrosis, and recruitment of endogenous c-Kit+ cells. This newly implemented patch configuration promotes efficient myocardial healing, offering a promising therapeutic approach for infarcted patients.

Chitosan films obtained by solution casting were investigated by broadband dielectric spectroscopy (BDS) to explore both their glass transition and the effects of thermal annealing on molecular dynamics, deriving from residual water content as well as from cold crystallization. Glass transition at low temperatures could be evidenced in as-produced as well as thermally annealed films, where non-Arrhenian dielectric relaxation processes, consistent with a structural (α) relaxation, could be detected. The process detected at low temperatures could reflect the dynamics of residual water slaved by the polymer matrix. Secondary (β) relaxations, along with a slow process ascribed to interfacial polarization at the amorphous/crystalline interfaces, were concurrently detected. In most cases, a further Arrhenian process at intermediate temperatures (αc) was present, also indicative of crystallization. Notably, the α processes, due to the primary relaxation of the polymer matrix plasticized by water, could be discriminated from other processes, present in the same frequency range, thanks to improvements in the dielectric fitting strategy. All relaxation processes showed the expected dependence on Ta. The more accurate exploration of the glass transition for chitosan helps to better rationalize its crystallization behavior, in view of an optimized application of this biopolymer.

Glioblastoma multiforme (GBM) is the most aggressive brain cancer, characterized by a rapid and drug-resistant progression. GBM "builds" around its primary core a genetically heterogeneous tumor-microenvironment (TME), recruiting surrounding healthy brain cells by releasing various intercellular signals. Glioma-associated microglia (GAM) represent the largest population of collaborating cells, which, in the TME, usually exhibit the anti-inflammatory M2 phenotype, thus promoting an immunosuppressing environment that helps tumor growth. Conversely, "classically activated" M1 microglia could provide proinflammatory and antitumorigenic activity, expected to exert a beneficial effect in defeating glioblastoma. In this work, an immunotherapy approach based on proinflammatory modulation of the GAM phenotype is proposed, through a controlled and localized electrical stimulation. The developed strategy relies on the wireless ultrasonic excitation of polymeric piezoelectric nanoparticles coated with GBM cell membrane extracts, to exploit homotypic targeting in antiglioma applications. Such camouflaged nanotransducers locally generate electrical cues on GAM membranes, activating their M1 phenotype and ultimately triggering a promising anticancer activity. Collected findings open new perspectives in the modulation of immune cell activities through "smart" nanomaterials and, more specifically, provide an innovative auspicious tool in glioma immunotherapy.

Many tissues and cells are influenced by mechano-electric stimulation, thus the application of piezoelectric materials has recently received considerable attention in tissue engineering. This report investigated electrospun fiber meshes based on poly(vinylidenefluoride-co-trifluoroethylene) [P(VDF-TrFE)] as instructive biomaterials for osteogenic differentiation of human mesenchymal stromal cells (hMSCs). The influence played by methyl ethyl ketone (MEK), used as a solvent in place of dimethylformamide (DMF)/acetone mixture, and the effect of rotating velocity of the electrospinning collector on fiber morphology, mechanical and piezoelectric properties were studied. The solvent had noticeable effects on morphology and piezoelectric properties of electrospun fibers, with MEK outperforming DMF/acetone. By increasing the collector velocity up to 4000 rpm, the fiber diameter reduced and the mutual alignment of the fibers increased, corresponding to enhanced mechanical properties and piezo-active β-phase content. However, as a consequence of the diverse mechanical properties of random and aligned fibrous architectures, which ultimately affected the piezoelectric properties, randomly-oriented fibers exhibited higher remnant piezoelectric properties (Vout and d31 piezoelectric coefficient) than aligned ones. On these scaffolds, hMSCs showed an excellent capability of early osteogenic differentiation, leading to high calcium production. Fiber surface topology, fiber mesh morphology and remnant piezoelectric properties played a determinant role on hMSC osteogenic commitment.

Nosocomial infections affect implanted medical devices and greatly challenge their functional outcomes, becoming sometimes life threatening for the patients. Therefore, aggressive antibiotic therapies are administered, which often require the use of last-resort drugs, if the infection is caused by multi-drug-resistant bacteria. Reducing the risk of bacterial contamination of medical devices in the hospitals has thus become an emerging issue. Promising routes to control these infections are based on materials provided with intrinsic bactericidal properties (i.e., chemical action) and on the design of surface coatings able to limit bacteria adhesion and fouling phenomena (i.e., physical action), thus preventing bacterial biofilm formation. Here, we report the development and validation of coatings made of layer-by-layer deposition of electrospun poly(vinylidene fluoride-co-trifluoro ethylene) P(VDF-TrFE) fibers with controlled orientations, which ultimately gave rise to antifouling surfaces. The obtained 10-layer surface morphology with 90° orientation fibers was able to efficiently prevent the adhesion of bacteria, by establishing a superhydrophobic-like behavior compatible with the Cassie-Baxter regimen. Moreover, the results highlighted that surface wettability and bacteria adhesion could be controlled using fibers with diameter comparable to bacteria size (i.e., achievable via electrospinning process), by tuning the intra-fiber spacing, with relevant implications in the future design of biomedical surface coatings.

Quantitative converse piezoelectric coefficient (d33) mapping of polymer ultrafine fibers of poly(acrylonitrile) (PAN), as well as of poly(vinylidene fluoride) (PVDF) as a reference material, obtained by rotating electrospinning, was carried out by piezoresponse force microscopy in the constant-excitation frequency-modulation mode (CE-FM-PFM). PFM mapping of single fibers reveals their piezoelectric activity and provides information on its distribution along the fiber length. Uniform behavior is typically observed on a length scale of a few micrometers. In some cases, variations with sinusoidal dependence along the fiber are reported, compatibly with a possible twisting around the fiber axis. The observed features of the piezoelectric yield have motivated numerical simulations of the surface displacement in a piezoelectric ultrafine fiber concerned by the electric field generated by biasing of the PFM probe. Uniform alignment of the piezoelectric axis along the fiber would comply with the uniform but strongly variable values observed, and sinusoidal variations were occasionally found on the fibers laying on the conductive substrate. Furthermore, in the latter case, numerical simulations show that the piezoelectric tensor’s shear terms should be carefully considered in estimations since they may provide a remarkably different contribution to the overall deformation profile.

The regenerative capacity of the central nervous system (CNS) is limited. Understanding and enhancing the mechanisms that induce neural differentiation of neural stem cells (NSCs) is crucial for advancing regenerative medicine; one significant challenge in this effort is the remote delivery of pro-differentiation cues. In this framework, a nanotechnology-based solution able to remotely trigger the differentiation of human NSCs (hNSCs) into neurons is proposed. The approach involves organic piezoelectric nanotransducers, which can be remotely activated by low-intensity ultrasound (US) for local and noninvasive electrical stimulation. Highly biocompatible piezoelectric polymeric nanoparticles, when activated by US, demonstrate the ability to induce calcium influx, exit from the cell cycle, and neuronal differentiation in hNSCs, as evidenced by calcium imaging experiments and the expression analysis of the NeuN post-mitotic neural marker; additionally, an increased outgrowth of the developing axons is observed. Gene expression analysis moreover suggests that the neural differentiation mechanism induced by piezoelectric stimulation acts by upregulating the calcium signaling-sensitive NeuroD1 neural inducer and the Lamb1 marker, independently of the c-Jun/c-Fos pathway. Considering the high biocompatibility and the good piezoelectricity of the polymeric nanotransducers used in this work, it is believed that this "wireless" stimulation approach holds high potential in CNS regenerative medicine.

Bone defects are a significant health problem worldwide. Novel treatment approaches in the tissue engineering field rely on the use of biomaterial scaffolds to stimulate and guide the regeneration of damaged tissue that cannot repair or regrow spontaneously. This work aimed at developing and characterizing new piezoelectric scaffolds to provide electric bio-signals naturally present in bone and vascular tissues. Mixing and extrusion were used to obtain nanocomposites made of polyhydroxybutyrate (PHB) as a matrix and barium titanate (BaTiO3) nanoparticles as a filler, at BaTiO3/PHB compositions of 5/95, 10/90, 15/85 and 20/80 (w/w%). The morphological, thermal, mechanical and piezoelectric properties of the nanocomposites were studied. Scanning electron microscopy analysis showed good nanoparticle dispersion within the polymer matrix. Considerable increases in the Young’s modulus, compressive strength and the piezoelectric coefficient d31 were observed with increasing BaTiO3 content, with d31 = 37 pm/V in 20/80 (w/w%) BaTiO3/PHB. 3D printing was used to produce porous cubic-shaped scaffolds using a 90° lay-down pattern, with pore size ranging in 0.60–0.77 mm and good mechanical stability. Biodegradation tests conducted for 8 weeks in saline solution at 37 °C showed low mass loss (∼4%) for 3D printed scaffolds. The results obtained in terms of piezoelectric, mechanical and chemical properties of the nanocomposite provide a new promising strategy for vascularized bone tissue engineering.

AbstractRecently, in vitro models emerge as valuable tools in biomedical research by enabling the investigation of complex physiological processes in a controlled environment, replicating some traits of interest of the biological tissues. This study focuses on the development of tubular polymeric scaffolds, made of electrospun fibers, aimed to generate three‐dimensional (3D) in vitro intestinal models resembling the lumen of the gut. Polycaprolactone (PCL) and polyacrylonitrile (PAN) are used to produce tightly arranged ultrafine fiber meshes via electrospinning in the form of continuous tubular structures, mimicking the basement membrane on which the epithelial barrier is formed. Morphological, physical, mechanical, and piezoelectric properties of the PCL and PAN tubular scaffolds are investigated. They are cultured with Caco‐2 cells using different biological coatings (i.e., collagen, gelatin, and fibrin) and their capability of promoting a compact epithelial layer is assessed. PCL and PAN scaffolds show 42% and 50% porosity, respectively, with pore diameters and size suitable to impede cell penetration, thus promoting an intestinal epithelial barrier formation. Even if both polymeric structures allow Caco‐2 cell adhesion, PAN fiber meshes best suit many requirements needed by this model, including highest mechanical strength upon expansion, porosity and piezoelectric properties, along with the lowest pore size.

The advent of nanodielectrics, nanocomposite materials based on a polymeric matrix, and materials with physical properties ruled by interfacial effects in general demands techniques to characterize functional properties on a local scale with high spatial resolution. Scanning probe microscopies (SPMs), in their electrical modes, have emerged as indispensable tools to access physical quantities such as dielectric constant, surface potential, and static charge, with nanometer-scale lateral resolution and with surface selectivity, being influenced mainly by the outermost layer of the specimen. In this tribute, the development of various SPM electrical modes is illustrated, focusing on the measurement of dielectric permittivity and its spectroscopic extension to access the local, frequency-dependent dielectric function (local dielectric spectroscopy [LDS]). The application to nanostructured polymers in the form of ultrathin films, nanometer-scale-separated blends, and self-assembled block copolymer structures is described. LDS appears to be a promising technique for characterizing the electric properties of polymers and their composites as well as other glass formers and nanostructured systems.

Core–double-shell-structured nanocomposite films consisting of polyvinylidene fluoride-grafted-barium titanate (PVDF-g-BT) incorporated into a P(VDF-co-hexafluoropropylene (HFP)) copolymer matrix were produced via a solution mixing method for energy storage applications. The resulting films were thoroughly investigated via spectroscopic, thermal, and morphological analyses. Thermogravimetric data provided an enhancement of the thermal stability, while differential scanning calorimetry indicated an increase in the crystallinity of the films after the addition of PVDF-g-BT. Moreover, broadband dielectric spectroscopy revealed three dielectric processes, namely, glass–rubber relaxation (αa), relaxation associated with the polymer crystalline phase (αc), and slower relaxation in the nanocomposites resulting from the accumulation of charge on the interface between the PVDF-g-BT filler and the P(VDF-co-HFP) matrix. The dependence of the dielectric constant from the composition was analyzed, and we found that the highest permittivity enhancement was obtained by the highest concentration filler added to the largest concentration of P(VDF-co-HFP). Mechanical analysis revealed an improvement in Young’s modulus for all nanocomposites versus pristine P(VDF-co-HFP), confirming the uniformity of the distribution of the PVDF-g-BT nanocomposite with a strong interaction with the copolymer matrix, as also evidenced via scanning electron microscopy. The suggested system is promising for use in high-energy-density storage devices as supercapacitors.

Dielectric properties of poly(vinylidene fluoride)-grafted-BaTiO3 (PVDF-g-BT) core-shell structured nanocomposites obtained from Reversible Addition Fragmentation chain Transfer (RAFT) polymerization of VDF were investigated by Broadband Dielectric Spectroscopy (BDS). The dielectric constant increased along with the BT content, about +50% by addition of 15 vol% of BT, which was around 40% more than expected from predictions using the usual dielectric modeling methods for composite materials, to be ascribed to the effect of the interfacial core-shell structure. The known dielectric relaxations for PVDF were observed for the neat polymer as well as for its nanocomposites, not affected by the presence of nanoparticles. A relaxation process at higher temperatures was found, due to interfacial polarization at the amorphous-crystalline interface, due to the high crystallinity of materials produced by RAFT. Isochronal BDS spectra were exploited to detect the primary relaxation of the amorphous fraction. Thermal analysis demonstrated a very broad endotherm at temperatures much lower than the usual melting peaks, possibly due to the ungrafted fraction of the polymer that is more easily removable by repeated washing of the pristine material with acetone.

Effective converse piezoelectric coefficient (d33,eff) mapping of poly(vinylidene fluoride) (PVDF) nanofibers with ceramic BaTiO3 nanoparticle inclusions obtained by electrospinning was carried out by piezoresponse force microscopy (PFM) in a peculiar dynamic mode, namely constant-excitation frequency-modulation (CE-FM), particularly suitable for the analysis of compliant materials. Mapping of single nanocomposite fibers was carried out to demonstrate the ability of CE-FM-PFM to investigate the nanostructure of semicrystalline polymers well above their glass transition temperature, such as PVDF, by revealing the distribution of piezoelectric activity of the nanofiber, as well as of the embedded nanoparticles employed. A decreased piezoelectric activity at the nanoparticle site compared to the polymeric fiber was found. This evidence can be rationalized in terms of a tradeoff between the dielectric constants and piezoelectric coefficients of the component materials, as well as on the mutual orientation of polar axes.

The dynamics of polymer chains in poly(ethylene oxide)/silica (PEO/SiO2) nanoparticle nanohybrids have been investigated via a combined computational and experimental approach involving atomistic molecular dynamics simulations and dielectric relaxation spectroscopy (DRS) measurements. The complementarity of the approaches allows us to study systems with different polymer molecular weights, nanoparticle radii, and compositions across a broad range of temperatures. We study the effects of spatial confinement, which is induced by the nanoparticles, and chain adsorption on the polymer's structure and dynamics. The investigation of the static properties of the nanocomposites via detailed atomistic simulations revealed a heterogeneous polymer density layer at the vicinity of the PEO/SiO2 interface that exhibited an intense maximum close to the inorganic surface, whereas the bulk density was reached for distances ∼1-1.2 nm away from the nanoparticle. For small volume fractions of nanoparticles, the polymer dynamics, probed by the atomistic simulations of low-molecular-weight chains at high temperatures, are consistent with the presence of a thin adsorbed layer that exhibits slow dynamics, with the dynamics far away from the nanoparticle being similar to those in the bulk. However, for high volume fractions of nanoparticles (strong confinement), the dynamics of all polymer chains were predicted slower than that in the bulk. On the other hand, similar dynamics were found experimentally for both the local β-process and the segmental dynamics for high-molecular-weight systems measured at temperatures below the melting temperature of the polymer, which were probed by DRS. These differences can be attributed to various parameters, including systems of different molecular weights and nanoparticle states of dispersion, the different temperature range studied by the different methods, the potential presence of a reduced-mobility PEO/SiO2 interfacial layer that does not contribute to the dielectric spectrum, and the presence of amorphous-crystalline interfaces in the experimental samples that may lead to a different dynamical behaviors of the PEO chains.