This review focuses on the most recent applications of zinc oxide (ZnO) nanostructures for tissue engineering. ZnO is one of the most investigated metal oxides, thanks to its multifunctional properties coupled with the ease of preparing various morphologies, such as nanowires, nanorods, and nanoparticles. Most ZnO applications are based on its semiconducting, catalytic and piezoelectric properties. However, several works have highlighted that ZnO nanostructures may successfully promote the growth, proliferation and differentiation of several cell lines, in combination with the rise of promising antibacterial activities. In particular, osteogenesis and angiogenesis have been effectively demonstrated in numerous cases. Such peculiarities have been observed both for pure nanostructured ZnO scaffolds as well as for three-dimensional ZnO-based hybrid composite scaffolds, fabricated by additive manufacturing technologies. Therefore, all these findings suggest that ZnO nanostructures represent a powerful tool in promoting the acceleration of diverse biological processes, finally leading to the formation of new living tissue useful for organ repair.

Smart nanoparticles for medical applications have gathered considerable attention due to an improved biocompatibility and multifunctional properties useful in several applications, including advanced drug delivery systems, nanotheranostics and in vivo imaging. Among nanomaterials, zinc oxide nanoparticles (ZnO NPs) were deeply investigated due to their peculiar physical and chemical properties. The large surface to volume ratio, coupled with a reduced size, antimicrobial activity, photocatalytic and semiconducting properties, allowed the use of ZnO NPs as anticancer drugs in new generation physical therapies, nanoantibiotics and osteoinductive agents for bone tissue regeneration. However, ZnO NPs also show a limited stability in biological environments and unpredictable cytotoxic effects thereof. To overcome the abovementioned limitations and further extend the use of ZnO NPs in nanomedicine, doping seems to represent a promising solution. This review covers the main achievements in the use of doped ZnO NPs for nanomedicine applications. Sol-gel, as well as hydrothermal and combustion methods are largely employed to prepare ZnO NPs doped with rare earth and transition metal elements. For both dopant typologies, biomedical applications were demonstrated, such as enhanced antimicrobial activities and contrast imaging properties, along with an improved biocompatibility and stability of the colloidal ZnO NPs in biological media. The obtained results confirm that the doping of ZnO NPs represents a valuable tool to improve the corresponding biomedical properties with respect to the undoped counterpart, and also suggest that a new application of ZnO NPs in nanomedicine can be envisioned.

Herein we report a novel, easy, fast and reliable microwave-assisted synthesis procedure for the preparation of colloidal zinc oxide nanocrystals (ZnO NCs) optimized for biological applications. ZnO NCs are also prepared by a conventional solvo-thermal approach and the properties of the two families of NCs are compared and discussed. All of the NCs are fully characterized in terms of morphological analysis, crystalline structure, chemical composition and optical properties, both as pristine nanomaterials or after amino-propyl group functionalization. Compared to the conventional approach, the novel microwave-derived ZnO NCs demonstrate outstanding colloidal stability in ethanol and water with long shelf-life. Furthermore, together with their more uniform size, shape and chemical surface properties, this long-term colloidal stability also contributes to the highly reproducible data in terms of biocompatibility. Actually, a significantly different biological behavior of the microwave-synthesized ZnO NCs is reported with respect to NCs prepared by the conventional synthesis procedure. In particular, consistent cytotoxicity and highly reproducible cell uptake toward KB cancer cells are measured with the use of microwave-synthesized ZnO NCs, in contrast to the non-reproducible and scattered data obtained with the conventionally-synthesized ones. Thus, we demonstrate how the synthetic route and, as a consequence, the control over all the nanomaterial properties are prominent points to be considered when dealing with the biological world for the achievement of reproducible and reliable results, and how the use of commercially-available and under-characterized nanomaterials should be discouraged in this view.

oxidation methods. In particular, a zinc nanobranched structure is deposited by radio-frequency magnetron sputtering on conductive substrates. Then impregnation of the samples in an antimony acetate solution is performed at different times (2 and 4 h) at room temperature. It has to be noted that longer times produce however an appreciable and even complete dissolution of the zinc material in the Sb acetate solution (at 8 and 16 h, respectively), whereas very short impregnation times (30 min) did not result in a signifi cant doping. Therefore, it resulted that a reasonable impregnation time for inducing a satisfying doping level, without altering the morphological properties of the investigated materials, lies in the range of 2-4 h. The impregnation is then followed by a thermal oxidation at 380 °C, having the dual function to oxidize Zn to ZnO and successfully promote the insertion of Sb in the wurtzite structure, leading to doped ZnO at different ratios depending on the impregnation time. This doping results in a p-type conductive structure and we show that ZnO:Sb nanobranched fi lms can be successfully used as piezoelectric nanogenerators, while the presence of ferro electricity, together with a nonzero spontaneous polarization, is found to give rise to the ferroelectric-photovoltaic effect, [ 11 ] which is here reported for the fi rst time for a ZnObased nanomaterial.The highly nanoporous morphology of the starting Zn layer is shown in Figure S1 (Supporting Information). We take advantage of such a high porous volume and exposed surface area to succeed in the optimal impregnation of the Zn materials with the Sb-precursor solution. Figure 1 a shows the surface morphology of pristine ZnO sample, after calcination of Zn grown on a fl uorine-doped tin oxide (FTO)/glass substrate, and considered the reference sample of this work. The surface is mainly formed by elongated and branched nanostructures, giving rise to a nanoporous network (surface area 14 m 2 g −1 , pore volume 0.095 cm 3 g −1 ). [ 7b ] The presence of a similar highly porous and nanobranched morphology (with a pore volume variation of about ±5% with respect to pristine ZnO fi lm) is also visible in the ZnO:Sb fi lms (Figure 1 b,c) and it is found to be independent from the impregnation time and not signifi cantly altered by doping and thermal processes. Further insight into the morphology of the nanoporous fi lms is given by high-resolution transmission electron microscopy (HRTEM) images (from Figure 1 d-f), showing that the nanobranches are actually constituted by grains smaller than 50 nm for both the pristine and the impregnated samples. Moreover, it can be inferred from HRTEM and fast Fourier transform (FFT) image processing that the grains are single crystals with hexagonal Wurtzite ZnO nanomaterials are widely investigated thanks to the copresence of several unique physical properties like their semiconducting and piezoelectric behaviors. Among all the different morphologies, high-surface area nanostructures are of great interest, such as ZnO n...