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Peripheral intravenous catheters are administered for various purposes, such as blood sampling or the infusion of contrast agents and drugs. Extravasation happens when the catheter is unintentionally directed outside of the vein due to movement of the intravascular catheter, enhanced vascular permeability, or occlusion of the upstream vein. In this article, extravasation and its mechanism are discussed. Subsequently, the sensorized devices (e.g., single sensor and multimodal detection) to identify the extravasation phenomena are highlighted. In this review article, we have shed light on both physiological and engineering points of view of extravasation and its detection approaches. This review provides an overview on the most recent and relevant technologies that can help in the early detection of extravasation.

The blood-brain barrier (BBB) acts as a physical/biochemical barrier that protects brain parenchyma from potential hazards exerted by different xenobiotics found in the systemic circulation. This barrier is created by "a lipophilic gate" as well as a series of highly organized influx/efflux mechanisms. The BBB bottleneck adversely affects the efficacy of chemotherapeutic agents in treating different CNS malignancies such as glioblastoma, an aggressive type of cancer affecting the brain. In the present study, mesoporous silica nanoparticles (MSNs) were conjugated with the transactivator of transcription (TAT) peptide, a cell-penetrating peptide, to produce MSN-NH-TAT with the aim of improving methotrexate (MTX) penetration into the brain. The TAT-modified nanosystem was characterized by Fourier transform infrared spectrometry (FTIR), field emission scanning electron microscopy (FE-SEM), transmission electron microscopy (TEM), atomic force microscopy (AFM), dynamic light scattering (DLS), and N 2 adsorption-desorption analysis. In vitro hemolysis and cell viability studies confirmed the biocompatibility of the MSN-based nanocarriers. In addition, in vivo studies showed that the MTX-loaded MSN-NH-TAT improved brain-to-plasma concentration ratio, brain uptake clearance, and the drug's blood terminal half-life, compared with the use of free MTX. Taken together, the results of the present study indicate that MSN functionalization with TAT is crucial for delivery of MTX into the brain. The present nanosystem represents a promising alternative drug carrier to deliver MTX into the brain via overcoming the BBB.

In this study, we present a thermoplasmonic transparent ink based on a colloidal dispersion of indium tin oxide (ITO) nanoparticles, which can offer several advantages as anti-counterfeiting technology. The custom ink could be directly printed on several substrates, and it is transparent under visible light but is able to generate heat by absorption of NIR radiation. Dynamic temperature mapping of the printed motifs was performed by using a thermal camera while irradiating the samples with an IR lamp. The printed samples presented fine features (in the order of 75 μm) and high thermal resolution (of about 250 μm). The findings are supported by thermal finite-element simulations, which also allow us to explore the effect of different substrate characteristics on the thermal readout. Finally, we built a demonstrator comprising a QR Code invisible to the naked eye, which became visible in thermal images under NIR radiation. The high transparency of the printed ink and the high speed of the thermal reading (figures appear/disappear in less than 1 s) offer an extremely promising strategy toward low-cost, scalable production of photothermally active invisible labels.

Unwanted icing has major safety and economic repercussions on human activities, affecting means of transportation, infrastructures, and consumer goods. Compared to the common deicing methods in use today, intrinsically icephobic surfaces can decrease ice accumulation and formation without any active intervention from humans or machines. However, such systems often require complex fabrication methods and can be costly, which limits their applicability. In this study, we report the preparation and characterization of several slippery lubricant-infused porous surfaces (SLIPSs) realized by impregnating with silicone oil a candle soot layer deposited on double-sided adhesive tape. Despite the use of common household items, these SLIPSs showed anti-icing performance comparable to other systems described in the literature (ice adhesion < 20 kPa) and a good resistance to mechanical and environmental damages in laboratory conditions. The use of a flexible and functional substrate as tape allowed these devices to be stretchable without suffering significant degradation and highlights how these systems can be easily prepared and applied anywhere needed. In addition, the possibility of deforming the substrate can "allow" the application of SLIPS technology in mechanical ice removal methodologies, drastically incrementing their performance.

Mild heat stimulation of muscle cells within the physiological range represents an intriguing approach for the modulation of their functions. In this work, photothermal conversion was exploited to remotely stimulate striated muscle cells by using gold nanoshells (NSs) in combination with near-infrared (NIR) radiation. Temperature increments of approximately 5 °C were recorded by using an intracellular fluorescent molecular thermometer and were demonstrated to efficiently induce myotube contraction. The mechanism at the base of this phenomenon was thoroughly investigated and was observed to be a Ca 2+ -independent event directly involving actin-myosin interactions. Finally, chronic remote photothermal stimulations significantly increased the mRNA transcription of genes encoding heat shock proteins and sirtuin 1, a protein which in turn can induce mitochondrial biogenesis. Overall, we provide evidence that remote NIR + NS muscle excitation represents an effective wireless stimulation technique with great potential in the fields of muscle tissue engineering, regenerative medicine, and bionics.

Stimuli-responsive photonic crystals (PCs) represent an intriguing class of smart materials very promising for sensing applications. Here, selective ionic strength responsive polymeric PCs are reported. They are easily fabricated by partial sulfonation of polystyrene opals, without using toxic or expensive monomers and etching steps. The color of the resulting hydrogel-like ordered structures can be continuously shifted over the entire visible range (405-760 nm) by changing the content of ions over an extremely wide range of concentration (from about 70 μM to 4 M). The optical response is completely independent from pH and temperature, and the initial color can be fully recovered by washing the sulfonated opals with pure water. These new smart photonic materials could find important applications as ionic strength sensors for environmental monitoring as well as for healthcare screening.

Three-dimensionally micropatterned surfaces are attracting increasing interest in soft robotics owing to the potential of mimicking natural morphologies at the micro/nanoscale. We employ direct laser lithography to fabricate molds with complex three-dimensional (3D) micrometric features, in a positive photoresist on flexible substrates, to pattern curved macroscopic soft surfaces with shapes not achievable with standard methods (e.g., reentrant angles). We present several 3D intricate microstructures in poly(dimethylsiloxane) (PDMS) and show a soft cylinder patterned with 3D microstructures with one molding process. Finally, we deform PDMS-based 3D architectures and show soft microgripping capability, indicating the potentiality of this approach for future application in soft robotics.

Biomimetic functional surfaces are attracting increasing attention for their relevant technological applications. Despite these efforts, inherent limitations of microfabrication techniques prevent the replication of complex hierarchical microstructures. Using a 3D laser lithography technique, we fabricated a 3D patterned surface bioinspired to Salvinia molesta leaves. The artificial hairs, with crownlike heads, were reproduced by scaling down (ca. 100 times smaller) the dimensions of natural features, so that microscale hairs with submicrometric resolution were attained. The micropatterned surface, in analogy with the natural model, shows interesting properties in terms of hydrophobicity and air retention when submerged by water, even if realized with a hydrophilic material. Furthermore, we successfully demonstrated the capability to promote localized condensation of water droplets from moisture in the atmosphere.

In this letter, we report on the fabrication, the characterization, and the in vitro testing of structures suitable for cell culturing, prepared through two-photon polymerization of a nanocomposite resist. More in details, commercially available Ormocomp has been doped with piezoelectric barium titanate nanoparticles, and bioinspired 3D structures resembling trabeculae of sponge bone have been fabricated. After an extensive characterization, preliminary in vitro testing demonstrated that both the topographical and the piezoelectric cues of these scaffolds are able to enhance the differentiation process of human SaOS-2 cells.

Tetragonal barium titanate nanoparticles (BTNPs) have been exploited as nanotransducers owing to their piezoelectric properties, in order to provide indirect electrical stimulation to SH-SY5Y neuron-like cells. Following application of ultrasounds to cells treated with BTNPs, fluorescence imaging of ion dynamics revealed that the synergic stimulation is able to elicit a significant cellular response in terms of calcium and sodium fluxes; moreover, tests with appropriate blockers demonstrated that voltage-gated membrane channels are activated. The hypothesis of piezoelectric stimulation of neuron-like cells was supported by lack of cellular response in the presence of cubic nonpiezoelectric BTNPs, and further corroborated by a simple electroelastic model of a BTNP subjected to ultrasounds, according to which the generated voltage is compatible with the values required for the activation of voltage-sensitive channels.

A thermally shrinkable and conductive nanocomposite material is prepared by supersonic cluster beam implantation (SCBI) of neutral Au nanoparticles (Au NPs) into a commercially available thermo-retractable polystyrene (PS) sheet. Micronanowrinkling is obtained during shrinking, which is studied by means of SEM, TEM and AFM imaging. Characteristic periodicity is determined and correlated with nanoparticle implantation dose, which permits us to tune the topographic pattern. Remarkable differences emerged with respect to the well-known case of wrinkling of bilayer metal-polymer. Wrinkled composite surfaces are characterized by a peculiar multiscale structuring that promises potential technological applications in the field of catalytic surfaces, sensors, biointerfaces, and optics, among others.

Nondeterministic phenomena are at the base of plenty of biological processes that comprise physiological signaling, cellular communications, and biological architectures. Among them, natural surface topographies are often characterized by "chaotic" features that are not trivial to be recreated in vitro. Recently, some methods have been proposed to resemble the hierarchical organization of the extracellular microenvironment, through the chemical preparation of randomly rough and self-affine fractal surfaces. Notwithstanding, this approach does not allow the fractal dimension to be modulated at a desired value, being moreover the self-affinity maintained just for one decade of spatial frequencies. Here, we propose the replication of in silico generated Brownian surfaces through a two-photon polymerization technique. As a result of the direct laser writing of the desired patterns, we were able to obtain highly reproducible self-affine (in a range of two spatial frequency decades) structures characterized by the desired predetermined Hurst exponents. Rat mesenchymal stem cells were moreover cultured on the obtained substrates, highlighting interesting phenomena concerning cell adhesion, cytoskeleton conformation, and actin polymerization, strictly depending on the fractal dimension of the surfaces.

We report on the fabrication and characterization of a freestanding ultrathin, mucoadhesive gold nanoshell/polysaccharide multilayer nanocomposite (thermonanofilm, TNF), that can be used for controlled photothermal ablation of tissues through irradiation with near-infrared radiation (NIR) laser. The aim of this work is to provide a new strategy to precisely control particle concentration during photothermalization of cancerous lesions, since unpredictable and aspecific biodistributions still remains the central issue of inorganic nanoparticle-assisted photothermal ablation. Gold nanoshell encapsulation in polysaccharide matrix is achieved by drop casting deposition method combined with spin-assisted layer-by-layer (LbL) assembly. Submicrometric thickness of films ensures tissue adhesion. Basic laser-induced heating functionality has been demonstrated by in vitro TNF-mediated thermal ablation of human neuroblastoma cancer cells, evidenced by irreversible damage to cell membranes and nuclei. Ex vivo localized vaporization and carbonization of animal muscular tissue is also demonstrated by applying TNF onto tissue surface. Thermal distribution in the tissue reaches a steady state in a few seconds, with significant increases in temperature (ΔT > 50) occurring across an 1 mm span, ensuring control of local photothermalization and providing more safety and predictability with respect to traditional laser surgery. A steady-state model of tissue thermalization mediated by TNFs is also introduced, predicting the temperature distribution being known the absorbance of TNFs, the laser power, and the tissue thermal conductivity, thus providing useful guidelines in the development of TNFs. Thermonanofilms can find applications for local photothermal treatment of cancerous lesions and wherever high precision and control of heat treatment is required.

Direct Laser Writing (DLW) is an innovative tool that allows the photofabrication of high resolution 3D structures, which can be successfully exploited for the study of the physical interactions between cells and substrates. In this work, we focused our attention on the topographical effects of submicrometric patterned surfaces fabricated via DLW on neuronal cell behavior. In particular, we designed, prepared, and characterized substrates based on aligned ridges for the promotion of axonal outgrowth and guidance. We demonstrated that both rat PC12 neuron-like cells and human SH-SY5Y derived neurons differentiate on parallel 2.5 μm spaced submicrometric ridges, being characterized by strongly aligned and significantly longer neurites with respect to those differentiated on flat control substrates, or on more spaced (5 and 10 μm) ridges. Furthermore, we detected an increased molecular differentiation toward neurons of the SH-SY5Y cells when grown on the submicrometric patterned substrates. Finally, we observed that the axons can exert forces able of bending the ridges, and we indirectly estimated the order of magnitude of these forces thanks to scanning probe techniques. Collectively, we showed as submicrometric structures fabricated by DLW can be used as a useful tool for the study of the axon mechanobiology.

A novel drug delivery vector, a free-standing polymeric ultrathin film (nanofilm) composed of PMMA and a polysaccharides multilayer, is presented. Chitosan and sodium alginate are alternatively deposited by spin-assisted LbL assembly onto a plasma-treated PMMA thin film. Hydrophobic anti-inflammatory drugs, an adenosine deaminase inhibitor (APP) and its fluorescent dansyl derivate (APP-Dns), are encapsulated inside the LbL multilayer using a simple casting deposition procedure. The resulting drug loaded nanofilm can be suspended in water upon dissolution of a PVA sacrificial layer. Morphological characterization of the nanofilm shows that PMMA/LbL nanofilms possess nanometric thickness (<200 nm) and very low surface roughness (1-2 nm for drug loaded nanofilms and <1 nm for blank nanofilm). Drug loaded films exhibit a diffusion controlled release mechanism following the Korsmayer-Peppas release model, confirmed by the fit of release data with a characteristic power law. Drug release is impaired through the PMMA layer, which acts effectively as a barrier for drug transport. This ultrathin polymer film can find application as a nanopatch for targeted inflammatory drug delivery to treat localized pathologies as inflammatory bowel disease.

A process is presented for the fabrication of patterned ultrathin free-standing conductive nanofilms based on an all-polymer bilayer structure composed of poly(3,4-ethylenedioxythiophene)/poly(styrene sulfonate) and poly(lactic acid) (PEDOT:PSS/PLA). Based on the strategy recently introduced by our group for producing large area free-standing nanofilms of conductive polymers with ultrahigh conformability, here an inkjet subtractive patterning technique was used, with localized overoxidation of PEDOT:PSS that caused the local irreversible loss of electrical conductivity. Different pattern geometries (e.g., interdigitated electrodes with various spacing, etc.) were tested for validating the proposed process. The fabrication of individually addressable microelectrodes and simple circuits on nanofilm having thickness ∼250 nm has been demonstrated. Using this strategy, mechanically robust, conformable ultrathin polymer films could be produced that can be released in water as free-standing nanofilms and/or collected on surfaces with arbitrary shapes, topography and compliance, including human skin. The patterned bilayer nanofilms were characterized as regards their morphology, thickness, topography, conductivity, and electrochemical behavior. In addition, the electrochemical switching of surface properties has been evaluated by means of contact angle measurements. These novel conductive materials can find use as ultrathin, conformable electronic devices and in many bioelectrical applications. Moreover, by exploiting the electrochemical properties of conducting polymers, they can act as responsive smart biointerfaces and in the field of conformable bioelectronics, for example, as electrodes on tissues or smart conductive substrates for cell culturing and stimulation.

In this study, a new simple, fast, and inexpensive technique for the preparation of free-standing nanocomposite ultrathin films based on the conductive polymer poly(3,4-ethylenedioxythiophene):polystyrene sulfonate (PEDOT:PSS) and embedding iron oxide nanoparticles (NPs) is presented. These nanofilms were fabricated by a single step of spin-coated assisted deposition in conjunction with a release technique ("supporting layer technique") to detach them from the substrate. Free-standing nanofilms can be easily transferred onto several substrates due to their high conformability, preserving their functionalities. The effect of the addition of iron oxide nanoparticles on the structural and functional properties of the PEDOT:PSS nanofilms is investigated through topography, thickness, magnetic, magneto-optical activity, and conductivity characterizations. PEDOT:PSS and PEDOT:PSS/iron oxide NP nanofilms were tested as resistive humidity sensors. Their sensitivity to humidity was found to increase with increasing nanoparticle concentration. On the basis of these results, it is expected that these composites may furnish inexpensive and reliable means for relative humidity detection.

Surfaces with controlled micro and nanoscale topographical cues are useful as smart scaffolds and biointerfaces for cell culture. Recently, use of thin-film and surface wrinkling is emerging as a rapid unconventional method for preparing topographically patterned surfaces, especially suited for the production of smart patterns over large area surfaces. On the other hand, there is an increasing interest in employing conducting polymers as soft, biocompatible, conductive biointerfaces or as parts of bioelectronic devices. A novel convenient and versatile method is presented for producing anisotropic topographical cues at the micro- and nanoscale on conducting polymer surfaces. Micro and nanowrinkles were formed during the heat-shrinking process of a thermo-retractable polystyrene substrate. Surface wrinkling was due to the mismatch between the mechanical properties of a conducting polymer ultrathin film and the substrate. Various geometries of wrinkled structures were prepared, demonstrating the tunability of topography depending on the thickness of the conductive film. A method for patterning the conductive properties of the wrinkled substrates was also presented. Such surfaces acted as smart scaffolds for the functional alignment of cells, envisioning their electrical stimulation. Cell adhesion and proliferation were evaluated, comparing different topographies, and a preferential anisotropic alignment of C2C12 murine skeletal muscle cells along wrinkles was demonstrated. The observed trends were also confirmed concerning the formation of aligned myotubes in C2C12 differentiation stage. Furthermore, improved results in terms of aligned and mature myotube formation were obtained by co-culturing C2C12 cells with a fibroblasts feeder layer. The combination of living cells and tunable conductive nanowrinkles will represent a unique tool for the development of innovative biomedical devices.

Investigation of the interactions between cells and material surfaces is important not only for the understanding of cell biology but also for the development of smart biomaterials. In this study, we investigated the substrate-related effects on the interaction between cell and polymeric ultrathin film (nanosheet) by modulating the mechanical properties of the nanosheet with a metal substrate or mesh. A freestanding polymeric nanosheet with tens-of-nanometers thickness composed of poly(L-lactic acid) (PLLA nanosheet) was fabricated by combination of a spin-coating technique and a water-soluble sacrificial layer. The freestanding PLLA nanosheet was collected on a stainless steel mesh (PLLA-mesh) and subsequently used for cell adhesion studies, comparing the results to the ones on a control SiO(2) substrate coated with an ultrathin layer of PLLA (PLLA-substrate). The adhesion of rat cardiomyocytes (H9c2) was evaluated on both samples after 24 h of culture. The PLLA-mesh with the tens-of-nanometers thick nanosheets induced an anisotropic adhesion of H9c2, while H9c2 on the PLLA-substrate showed an isotropic adhesion independent from the nanosheet thickness. Interestingly, an increment in the nanosheet thickness in the PLLA-mesh samples reduced the cellular anisotropy and led to a similar morphology to the PLLA-substrate. Considering the huge discrepancy of Young's modulus between PLLA nanosheet (3.5-4.2 GPa) and metal substrate (hundreds of GPa), cell adhesion was mechanically regulated by the Young's modulus of the underlying substrate when the thickness of the PLLA nanosheet was tens of nanometers. Modulation of the stiffness of the polymeric nanosheet by utilizing a rigid underlying material will allow the constitution of a unique cell culture environment.

Freely suspended nanocomposite thin films based on soft polymers and functional nanostructures have been widely investigated for their potential application as active elements in microdevices. However, most studies are focused on the preparation of nanofilms composed of polyelectrolytes and charged colloidal particles. Here, a new technique for the preparation of poly(l-lactic acid) free-standing nanofilms embeddidng superparamagnetic iron oxide nanoparticles is presented. The fabrication process, based on a spin-coating deposition approach, is described, and the influence of each production parameter on the morphology and magnetic properties of the final structure is investigated. Superparamagnetic free-standing nanofilms were obtained, as evidenced by a magnetization hysteresis measurement performed with a superconducting quantum interference device (SQUID). Nanofilm surface morphology and thickness were evaluated by atomic force microscopy (AFM), and the nanoparticle dispersion inside the composites was investigated by transmission electron microscopy (TEM). These nanofilms, composed of a biodegradable polyester and remotely controllable by external magnetic fields, are promising candidates for many potential applications in the biomedical field.

In this paper, we propose an absolutely innovative technique for the electrical stimulation of cells, based on piezoelectric nanoparticles. Ultrasounds are used to impart mechanical stress to boron nitride nanotubes incubated with neuronal-like PC12 cells. By virtue of their piezoelectric properties, these nanotubes can polarize and convey electrical stimuli to the cells. PC12 stimulated with the present method exhibit neurite sprout 30% greater than the control cultures after 9 days of treatment.