Microglia play a pivotal role in the central nervous system (CNS) homeostasis, acting as housekeepers and defenders of the surrounding environment. These cells can elicit their functions by shifting into two main phenotypes: pro‐inflammatory classical phenotype, M1, and anti‐inflammatory alternative phenotype, M2. Despite their pivotal role in CNS homeostasis, microglia phenotypes can influence the development and progression of several CNS disorders such as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, multiple sclerosis, ischemic stroke, traumatic brain injuries, and even brain cancer. It is thus clear that the possibility of modulating microglia activation has gained attention as a therapeutic tool against many CNS pathologies. Nanomaterials are an unprecedented tool for manipulating microglia responses, in particular, to specifically target microglia and elicit an in situ immunomodulation activity. This review focuses the discussion on two main aspects: analyzing the possibility of using nanomaterials to stimulate a pro‐inflammatory response of microglia against brain cancer and introducing nanostructures able to foster an anti‐inflammatory response for treating neurodegenerative disorders. The final aim is to stimulate the analysis of the development of new microglia nano‐immunomodulators, paving the way for innovative and effective therapeutic approaches for the treatment of CNS disorders.

In the past decades, bone tissue engineering developed and exploited many typologies of bioreactors, which, besides providing proper culture conditions, aimed at integrating those bio‐physical stimulations that cells experience in vivo, to promote osteogenic differentiation. Nevertheless, the highly challenging combination and deployment of many stimulation systems into a single bioreactor led to the generation of several unimodal bioreactors, investigating one or at mostly two of the required biophysical stimuli. These systems miss the physiological mimicry of bone cells environment, and often produced contrasting results, thus making the knowledge of bone mechanotransduction fragmented and often inconsistent. To overcome this issue, in this study we developed a perfusion and electroactive‐vibrational reconfigurable stimulation bioreactor to investigate the differentiation of SaOS‐2 bone‐derived cells, hosting a piezoelectric nanocomposite membrane as cell culture substrate. This multimodal perfusion bioreactor is designed based on a numerical (finite element) model aimed at assessing the possibility to induce membrane nano‐scaled vibrations (with ~12 nm amplitude at a frequency of 939 kHz) during perfusion (featuring 1.46 dyn cm⁻² wall shear stress), large enough for inducing a physiologically‐relevant electric output (in the order of 10 mV on average) on the membrane surface. This study explored the effects of different stimuli individually, enabling to switch on one stimulation at a time, and then to combine them to induce a faster bone matrix deposition rate. Biological results demonstrate that the multimodal configuration is the most effective in inducing SaOS‐2 cell differentiation, leading to 20‐fold higher collagen deposition compared to static cultures, and to 1.6‐ and 1.2‐fold higher deposition than the perfused‐ or vibrated‐only cultures. These promising results can provide tissue engineering scientists with a comprehensive and biomimetic stimulation platform for a better understanding of mechanotransduction phenomena beyond cells differentiation.

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.

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 (α_c) 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 T_a. 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.

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.

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 d ₃₃ 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.