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The brain exhibits extraordinary information processing capabilities thanks to neural networks that can operate in parallel with minimal energy consumption. Memory and learning require the creation of new neural networks through the long-term modification of the structure of the synapses, a phenomenon called long-term plasticity. Here, we use an organic electrochemical transistor to simulate long-term potentiation and depotentiation processes. Similarly to what happens in a synapse, the polymerization of the 3,4-ethylenedioxythiophene (EDOT) on the gate electrode modifies the structure of the device and boosts the ability of the gate potential to modify the conductivity of the channel. Operando AFM measurements were carried out to demonstrate the correlation between neuromorphic behavior and modification of the gate electrode. Long-term enhancement depends on both the number of pulses used and the gate potential, which generates long-term potentiation when a threshold of +0.7 V is overcome. Long-term depotentiation occurs by applying a +3.0 V potential and exploits the overoxidation of the deposited PEDOT:PSS. The induced states are stable for at least 2 months. The developed device shows very interesting characteristics in the field of neuromorphic electronics.

Understanding the dynamics of ion migration and volume change is crucial to studying the functionality and long-term stability of soft polymeric materials operating at liquid interfaces, but the subsurface characterization of swelling processes in these systems remains elusive. In this work, we address the issue using modulated electrochemical atomic force microscopy as a depth-sensitive technique to study electroswelling effects in the high-performance actuator material polypyrrole doped with dodecylbenzenesulfonate (Ppy:DBS). We perform multidimensional measurements combining local electroswelling and electrochemical impedance spectroscopies on microstructured Ppy:DBS actuators. We interpret charge accumulation in the polymeric matrix with a quantitative model, giving access to both the spatiotemporal dynamics of ion migration and the distribution of electroswelling in the electroactive polymer layer. The findings demonstrate a nonuniform distribution of the effective ionic volume in the Ppy:DBS layer depending on the film morphology and redox state. Our findings indicate that the highly efficient actuation performance of Ppy:DBS is caused by rearrangements of the polymer microstructure induced by charge accumulation in the soft polymeric matrix, increasing the effective ionic volume in the bulk of the electroactive film for up to two times the value measured in free water.

Electrode arrays that interface with peripheral nerves are used in the diagnosis and treatment of neurological disorders; however, they require complex placement surgeries that carry a high risk of nerve injury. Here we leverage recent advances in soft robotic actuators and flexible electronics to develop highly conformable nerve cuffs that combine electrochemically driven conducting-polymer-based soft actuators with low-impedance microelectrodes. Driven with applied voltages as small as a few hundreds of millivolts, these cuffs allow active grasping or wrapping around delicate nerves. We validate this technology using in vivo rat models, showing that the cuffs form and maintain a self-closing and reliable bioelectronic interface with the sciatic nerve of rats without the use of surgical sutures or glues. This seamless integration of soft electrochemical actuators with neurotechnology offers a path towards minimally invasive intraoperative monitoring of nerve activity and high-quality bioelectronic interfaces., (© 2024. The Author(s).)

The conversion of electrochemical processes into mechanical deformation in organic mixed ionic-electronic conductors (OMIECs) enables artificial muscle-like actuators but is also critical for degradation processes affecting OMIEC-based devices. To provide a microscopic understanding of electroactuation, the modulated electrochemical atomic force microscopy (mEC-AFM) is introduced here as a novel in-operando characterization method for electroactive materials. The technique enables multidimensional spectroscopic investigations of local electroactuation and charge uptake giving access to the electroactuation transfer function. For poly(3,4-ethylenedioxythiophene) polystyrene sulfonate (PEDOT:PSS) based microelectrodes, the spectroscopic measurements are combined with multichannel mEC-AFM imaging, providing maps of local electroactuation amplitude and phase as well as surface morphology. The results demonstrate that the amplitude and timescales of electroactuation are governed by the drift motion of hydrated ions. Accordingly, slower water diffusion processes are not limiting, and the results illustrate how OMIEC microactuators can operate at sub-millisecond timescales., (© 2024 The Authors. Advanced Science published by Wiley‐VCH GmbH.)

Research on electrolyte-gated and organic electrochemical transistor (OECT) architectures is motivated by the prospect of a highly biocompatible interface capable of amplifying bioelectronic signals at the site of detection. Despite many demonstrations in these directions, a quantitative model for OECTs as impedance biosensors is still lacking. We overcome this issue by introducing a model experiment where we simulate the detection of a single cell by the impedance sensing of a dielectric microparticle. The highly reproducible experiment allows us to study the impact of transistor geometry and operation conditions on device sensitivity. With the data we rationalize a mathematical model that provides clear guidelines for the optimization of OECTs as single cell sensors, and we verify the quantitative predictions in an in-vitro experiment. In the optimized geometry, the OECT-based impedance sensor allows to record single cell adhesion and detachment transients, showing a maximum gain of 20.2±0.9 dB with respect to a single electrode-based impedance sensor., (© 2022. The Author(s).)

Oxygen depletion in confined spaces represents one of the most serious and underestimated dangers for workers. Despite the existence of several commercially available and widely used gas oxygen sensors, injuries and deaths from reduced oxygen levels are still more common than for other hazardous gases. Here, we present hydrogel-based organic electrochemical transistors (OECTs) made with the conducting polymer poly(3,4-ethylenedioxythiophene): poly(styrene sulfonate) (PEDOT:PSS) as wearable and real-time oxygen gas sensors. After comparing OECT performances using liquid and hydrogel electrolytes, we identified the best PEDOT:PSS active layer and hydrogel coating (30 µm) combination for sensing oxygen in the concentration range of 13−21% (v/v), critical for work safety applications. The fast O2 solubilization in the hydrogel allowed for gaseous oxygen transduction in an electrical signal thanks to the electrocatalytic activity of PEDOT:PSS, while OECT architecture amplified the response (gain ~ 104). OECTs proved to have comparable sensitivities if fabricated on glass and thin plastic substrates, (−12.2 ± 0.6) and (−15.4 ± 0.4) µA/dec, respectively, with low power consumption (<40 µW). Sample bending does not influence the device response, demonstrating that our real-time conformable and lightweight sensor could be implemented as a wearable, noninvasive safety tool for operators working in potentially hazardous confined spaces.

Purpose: The aim of this study was to evaluate the effects exerted over chondrogenic commitment of human adipose-derived mesenchymal stem cells (ADSCs) by a very low oxygen tension (<1% pO 2 )., Materials/methods: Cell morphology, mRNA levels of chondrocyte-specific marker genes and the involvement of p38 MAPK signalling were monitored in human ADSCs under a very low oxygen tension., Results: Cell morphology was significantly changed after two days of hypoxic preconditioning when they featured as elongated spindle-shaped cells. SRY-box containing gene 9, aggrecan and collagen type II mRNA levels were enhanced under severe hypoxic culture conditions. Moreover, the inhibition of p38 MAPK resulted in a substantial reduction in transcription of the above-mentioned specific genes, proving the pivotal role of this pathway in the transcriptional regulation of chondrogenesis., Conclusions: Here, we propose a protocol showing the early commitment of stem cells towards the chondrogenic phenotype in only 2 days of culture via a very low hypoxic environment, in the absence of growth factors added in the culture medium., Competing Interests: Declaration of competing interest The authors declare no conflict of interest., (Copyright © 2020 Medical University of Bialystok. Published by Elsevier B.V. All rights reserved.)

Background: α-Mangostin (αMG) is a natural substance that exerts a wide range of antitumor effects. Recently, we described that free αMG was able to dissociate multicellular tumour spheroids (MCTSs) generated from breast carcinoma cells and to reduce their cellular viability and motility. Here, αMG was encapsulated into lipidic nanoparticles (NPs), conjugated or not to a CD44 thioaptamer, and the anticancer action evaluated against MCF-7 breast MCTSs. Methods: NPs containing αMG were formulated with a core of polylactic-co-glycolyc acid. Some of them were decorated with a CD44 thioaptamer using as catalysts 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide and N-hydroxysuccinimide. Both size and density of MCF-7-derived MCTSs were monitored during 72 h of treatment with NPs carrying 0.1, 0.5 and 1.0 μg/ml final concentrations of αMG. MCTSs were cultured on Matrigel or gelatine to better simulate the extracellular environment. Results: The NPs without thioaptamer and conveying 0.1 μg/ml αMG caused a significant dissociation of the MCTSs grown in gelatine after 24 h of treatment (p < 0.01). The most significant disaggregation of MCTSs was obtained using NPs carrying 0.5 μg/ml αMG (p < 0.01). A similar dissociating effect was observed when MCTSs were cultured in Matrigel under the same conditions for 48 - 72 h. By contrast, only concentrations over 1.0 μg/ml of free αMG were able to provoke a damage to MCTSs, consisting in a substantial reduction in their size (p < 0.05). Since the MCTS dissociation induced by αMG-loaded NPs occurred only in the presence of Matrigel or gelatine, an impairment of cell contacts to collagen fibres was likely responsible of this effect. Finally, the treatment of MCTSs with αMG-loaded NPs that were conjugated to the CD44 thioaptamer caused a similar decrease in density but a lower expansion of the spheroid, suggesting that a significant number of cells were died or arrested in cycle. Conclusion: Very low concentrations of αMG delivered by lipidic NPs are sufficient to provoke a substantial disaggregation of MCF-7 MCTSs that involves cell-to-collagen contacts. Similarly, the treatment of MCTSs with NPs conjugated to a CD44 thioaptamer leads to MCTS dissociation but through a more damaging action that causes also a reduction in cell number., Competing Interests: Competing Interests: The authors have declared that no competing interest exists.

Background: α-Mangostin (αMG) is extracted from Garcinia mangostana Linn and exerts antiproliferative activities. Although several researches on αMG were performed using cell monolayers, the in vitro pharmacological effects on 3D cancer models have never been investigated. Aim of the present study was to find new anticancer properties of αMG by evaluating the changes that this compound provokes in multicellular tumour spheroids (MCTSs). Methods: MCTSs were generated from MDA-MB-231 and MCF-7 breast tumour cell lines and then treated with 0.1÷30 μg/ml αMG for 24 and 48 h. MCTS size, density, and cell migration were determined by software elaboration of phase contrast images captured by a digital camera. Cell viability was evaluated by resazurin and acid phosphatase assays, while cell apoptosis was assessed by a fluorescent assay of caspase activity. The distribution of living cells inside MCTSs was shown by live/dead fluorescence staining. Results: A dose-dependent decrease in cell viability was obtained by treating MDA-MB-231 spheroids with αMG for 48 h (IC 50 = 0.70-1.25 μg/ml). A significant reduction in spheroid volume, paralleled by its increased compactness, was observed only at concentration of 30 μg/ml, but not with lower doses of αMG. By contrast, αMG in the range of 5-15 μg/ml increased the size of MCTSs due to a parallel reduction in cell aggregation. The same window of concentrations was also able to stimulate cell apoptosis in a dose-dependent manner. Bimodal volumetric effects were also obtained by treating the spheroids generated from the MCF-7 cells with 0.1÷30 μg/ml αMG for 48 h. Finally, doses higher than 5 μg/ml caused a progressive impairment in cell migration from the edge of MDA-MB-231 MCTSs. Conclusion: After exposure at doses of αMG just above IC 50 , MDA-MB-231 spheroids showed a significant reduction in cell adhesion that did not stimulate cell migration but, on the contrary, blunted cell motility. These findings suggest a novel anticancer feature of αMG that could be taken into consideration to improve conventional drug penetration into the tumour bulk., Competing Interests: Competing Interests: The authors have declared that no competing interest exists.

At present, injuries or rupture of tendons are treated by surgical repair or conservative approaches with unpredictable clinical outcome. Alternative strategies to repair tendon defects without the undesirable side effects associated with the current options are needed. With this in mind, a tissue engineering approach has gained considerable attention as a promising strategy. Here we investigated a synthetic three-dimensional (3D) microenvironment able to interact with stem cells and inducing, via coupled biochemical and physical signals, their early commitment toward the tenogenic lineage. This multiphase 3D construct consisted of a braided hyaluronate elastic band merged with human bone marrow mesenchymal stem cells (hBMSCs) and poly-lactic-co-glycolic acid microcarriers loaded with human growth differentiation factor 5 (hGDF-5) by means of fibrin hydrogel. The multiphase structure allowed hBMSC culture under cyclic strain within a microenvironment where a controlled amount of hGDF-5 was regularly delivered. The cooperative biochemical and physical stimuli induced significantly increased expression of tenogenic markers, such as collagen type I and III, decorin, scleraxis, and tenascin-C, within only 3 days of dynamic hBMSC culture. This approach opens exciting perspectives for future development of engineered tendon tissue substitutes.

For tissue-engineering studies of the infarcted heart it is essential to identify a source of cells that may provide cardiomyocyte progenitors, which is easy to amplify, accessible in adults, and allowing autologous grafts. Preclinical studies have shown that human adipose-derived stem cells (ADSCs) can differentiate into cardiomyocyte-like cells and improve heart function in myocardial infarction. We have developed pharmacologically active microcarriers (PAMs) which are biodegradable and biocompatible polymeric microspheres conveying cells on their biomimetic surface, therefore providing an adequate three-dimensional (3D) microenvironment. Moreover, they can release a growth factor in a prolonged manner. In order to implement ADSCs and PAMs for cardiac tissue engineering we first defined the biomimetic surface by studying the influence of matrix molecules laminin (LM) and fibronectin (FN), in combination with growth factors present in the cardiogenic niche, to further enhance the in vitro cardiac differentiation of ADSCs. We demonstrated that LM increased the expression of cardiac markers (Nkx2.5, GATA4, MEF2C) by ADSCs after 2 weeks in vitro. Interestingly, our results suggest that the 3D support provided by PAMs with a LM biomimetic surface (LM-PAMs) further enhanced the expression of cardiac markers and induced the expression of a more mature contractile protein, cardiac troponin I, compared with the 2D differentiating conditions after only 1 week in culture. The enrichment of the growth-factor cocktail with TGF-β1 potentiated the cardiomyogenic differentiation. These results suggest that PAMs offering a LM biomimetic surface may be efficiently used for applications combining adult stem cells in tissue-engineering strategies of the ischemic heart., (© 2014 Wiley Periodicals, Inc.)

Nitric oxide is an endogenous gas which exerts autocrine/paracrine actions by different signaling pathways and/or direct interactions with intracellular compounds and structures. Several processes are regulated by nitric oxide in stem cells including self-renewal, viability, migration, proliferation, and differentiation. The modulation of cell functions depends on its concentrations because opposite effects can be observed when low and high levels of nitric oxide are compared. Here, the responses to nitric oxide of adult stem/progenitor cells which are often used in regenerative medicine, including mesenchymal stem cells, hematopoietic stem cells, neural stem cells, endothelial progenitor cells, satellite cells, and fibro-adipogenic precursor cells, are reviewed. Therapeutic strategies which employ drugs releasing nitric oxide or modulating nitric oxide intracellular pathways are suggested to perform new ex vivo preconditioning or in vivo treatments suitable for stem/progenitor cell therapy and tissue engineering applications.

Putative cancer stem cells (CSCs) reside in a hypoxic microenvironment where mesenchymal stem cells (MSCs) are also present. In this niche MSCs seem to promote the generation of CSCs and sustain tumor progression. Therefore, it may assume clinical relevance to produce a drug which kills not only CSCs but also MSCs. We hypothesized that bifunctional nanoparticles, loaded with a HIF-1α inhibitor and conjugated with an aptamer targeting a common receptor of CSCs and MSCs, may fulfill this strategy. The nanoparticle should ensure that: (1) the conveyed drug is less susceptible to degradation, (2) the common receptor of CSCs and MSCs is recognized by a superselective aptamer, and (3) receptor-mediated internalization is the main process to enter target cells. Small RNA or DNA aptamers represent an advantage over antibodies because do not cause immune reactions, are better internalized into the target cell, are more resistant to degradation, their cost of production are lower, and the purity of the oligonucleotide ligand is extremely elevated. Concerning the drugs to be delivered, we suggest to employ those exerting an anti-HIF-1α activity because they should be harmful for hypoxic CSCs and MCSs in their tumor niche but provide very limited toxicity, or even none, to well-oxygenated normal cells. Corresponding experimental approaches to perform pre-clinical studies and verify this hypothesis are also addressed., (Copyright © 2015 Elsevier Ltd. All rights reserved.)