Robust and Environmentally Friendly MXene-Based Electronic Skin Enabling the Three Essential Functions of Natural Skin: Perception, Protection, and Thermoregulation.

The development of electronic skin (e-skin) emulating the human skin's three essential functions (perception, protection, and thermoregulation) has great potential for human-machine interfaces and intelligent robotics. However, existing studies mainly focus on perception. This study presents a novel, eco-friendly, mechanically robust e-skin replicating human skin's three essential functions. The e-skin is composed of Ti3C2Tx MXene, polypyrrole, and bacterial cellulose nanofibers, where the MXene nanoflakes form the matrix, the bacterial cellulose nanofibers act as the filler, and the polypyrrole serves as a conductive "cross-linker". This design allows customization of the electrical conductivity, microarchitecture, and mechanical properties, integrating sensing (perception), EMI shielding (protection), and thermal management (thermoregulation). The optimal e-skin can effectively sense various motions (including minuscule artery pulses), achieve an EMI shielding efficiency of 63.32 dB at 78 µm thickness, and regulate temperature up to 129 °C in 30 s at 2.4 V, demonstrating its potential for smart robotics in complex scenarios.

Polyvinyl Alcohol/Graphene Oxide Conductive Hydrogels via the Synergy of Freezing and Salting Out for Strain Sensors.

Hydrogels of flexibility, strength, and conductivity have demonstrated broad applications in wearable electronics and soft robotics. However, it is still a challenge to fabricate conductive hydrogels with high strength massively and economically. Herein, a simple strategy is proposed to design a strong ionically conductive hydrogel. This ion-conducting hydrogel was obtained under the synergistic action by salting out the frozen mixture of polyvinyl alcohol (PVA) and graphene oxide (GO) using a high concentration of sodium chloride solution. The developed hydrogel containing only 5 wt% PVA manifests good tensile stress (65 kPa) and elongation (180%). Meanwhile, the PVA matrix doped with a small amount of GO formed uniformly porous ion channels after salting out, endowed the PVA/GO hydrogel with excellent ionic conductivity (up to 3.38 S m-1). Therefore, the fabricated PVA/GO hydrogel, anticipated for a strain sensor, exhibits good sensitivity (Gauge factor = 2.05 at 100% strain), satisfying working stability (stably cycled for 10 min), and excellent recognition ability. This facile method to prepare conductive hydrogels displays translational potential in flexible electronics for engineering applications.

Strategies to Achieve a Ferrocene-Based Polymer with Reversible Redox Activity for Chiral Electroanalysis of Nonelectroactive Amino Acids.

In the past, various chiral isomers accompanied by electroactive units have been distinguished using electrochemical techniques, which can produce electrochemical signals by themselves. However, it is still difficult to use an electrochemical technique to detect nonelectroactive samples. To address this bottleneck, an electroactive chiral polymer (S,S)-p-CVB-Fc that contains one redox-active ferrocene unit was designed and synthesized in this study. The electroactive polymer can give electrochemical signals as an alternative to the tested chiral samples, regardless of whether the isomers have electroactive units. Then, it was fixed on the surface of a glassy carbon electrode as an electrochemical chiral sensor. When nonelectroactive amino acids including proline, threonine, and alanine were examined by the sensor, clear discrimination in the response of peak current could be observed toward l- and d-isomers at pH 6.5. The peak current ratios (IL/ID) for proline and alanine were 1.47 and 1.48, respectively. In contrast, for threonine, the d-isomer exhibited a higher peak current than the l -isomer with a ratio of 2.59. In summary, the results ensure that the current work can enlarge the testing scope of chiral samples in the field of chiral electroanalysis using an electroactive sensor.

2-Monoacylglycerol Mimetic Liposomes to Promote Intestinal Lymphatic Transport for Improving Oral Bioavailability of Dihydroartemisinin.

Purpose: Reducing the first-pass hepatic effect via intestinal lymphatic transport is an effective way to increase the oral absorption of drugs. 2-Monoacylglycerol (2-MAG) as a primary digestive product of dietary lipids triglyceride, can be assembled in chylomicrons and then transported from the intestine into the lymphatic system. Herein, we propose a biomimetic strategy and report a 2-MAG mimetic nanocarrier to target the intestinal lymphatic system via the lipid absorption pathway and improve oral bioavailability. Methods: The 2-MAG mimetic liposomes were designed by covalently bonding serinol (SER) on the surface of liposomes named SER-LPs to simulate the structure of 2-MAG. Dihydroartemisinin (DHA) was chosen as the model drug because of its disadvantages such as poor solubility and high first-pass effect. The endocytosis and exocytosis mechanisms were investigated in Caco-2 cells and Caco-2 cell monolayers. The capacity of intestinal lymphatic transport was evaluated by ex vivo biodistribution and in vivo pharmacokinetic experiments. Results: DHA loaded SER-LPs (SER-LPs-DHA) had a particle size of 70 nm and a desirable entrapment efficiency of 93%. SER-LPs showed sustained release for DHA in the simulated gastrointestinal environment. In vitro cell studies demonstrated that the cellular uptake of SER-LPs primarily relied on the caveolae- rather than clathrin-mediated endocytosis pathway and preferred to integrate into the chylomicron assembly process through the endoplasmic reticulum/Golgi apparatus route. After oral administration, SER-LPs efficiently promoted drug accumulation in mesenteric lymphatic nodes. The oral bioavailability of DHA from SER-LPs was 10.40-fold and 1.17-fold larger than that of free DHA and unmodified liposomes at the same dose, respectively. Conclusion: SER-LPs improved oral bioavailability through efficient intestinal lymphatic transport. These findings of the current study provide a good alternative strategy for oral delivery of drugs with high first-pass hepatic metabolism.

Co-delivery of doxorubicin-dihydroartemisinin prodrug/TEPP-46 nano-liposomes for improving antitumor and decreasing cardiotoxicity in B16-F10 tumor-bearing mice.

In order to reduce the cardiotoxicity of doxorubicin (DOX) and improve its antitumor effect, dihydroartemisinin (DHA) and DOX prodrug (DOX-S-DHA) synthesized via a single sulfur bond was used with TEPP-46 to prepare nano-liposomes (DOX-S-DHA@TEPP-46 Lips). In which, TEPP-46 was expected to exert p53 bidirectional regulation to promote the synergistic antitumor effect of DOX and DHA while reducing cardiotoxicity. DOX-S-DHA@TEPP-46 Lips exhibited uniform particle size, good stability, and excellent redox-responsive activity. DOX-S-DHA@TEPP-46 Lips could significantly inhibit the proliferation of tumor cells, but had less cytotoxicity on normal cells. The presence of TEPP-46 increased the content of p53 protein, which further induced tumor cell apoptosis. DOX-S-DHA@TEPP-46 Lips had satisfactory long circulation to enhance the antitumor efficacy and reversed the cardiotoxicity of DOX in B16-F10 tumor-bearing mice. In conclusion, DOX-S-DHA@TEPP-46 Lips provides a new insight on creating sophisticated redox-sensitive nano-liposomes for cancer therapy as well as the decreased cardiotoxicity of DOX.

Controlled assembly and release of retinoic acid based on the layer-by-layer method.

All-trans retinoic acid (RA) has been proved to play important roles in regulating cell growth in various types of cells. Yet most experiments were performed by adding RA in solution previously. In this Article, we focus on the incorporation of RA, as a negatively charged moiety, into layered polyelectrolyte films on surfaces by means of layer-by-layer (LbL) deposition, followed by adding of capping layers to regulate the release of RA from the films. The incorporated RA was designed to release over 5 days in buffer solution. The assembly and release of RA were verified by UV and QCM results. The controlled release of RA from multilayer films can serve as a model system to study the influence of small molecules on cell growth.

Effects of Gene Delivery Approaches on Differentiation Potential and Gene Function of Mesenchymal Stem Cells.

Introduction of a gene to mesenchymal stem cells (MSCs) is a well-known strategy to purposely manipulate the cell fate and further enhance therapeutic performance in cell-based therapy. Viral and chemical approaches for gene delivery interfere with differentiation potential. Although microinjection as a physical delivery method is commonly used for transfection, its influence on MSC cell fate is not fully understood. The current study aimed to evaluate the effects of four nonviral gene delivery methods on stem cell multi-potency. The four delivery methods are robotic microinjection, polyethylenimine (PEI), cationic liposome (cLipo), and calcium phosphate nanoparticles (CaP). Among the four methods, microinjection has exhibited the highest transfection efficiency of ∼60%, while the three others showed lower efficiency of 10-25%. Robotic microinjection preserved fibroblast-like cell morphology, stress fibre intactness, and mature focal adhesion complex, while PEI caused severe cytotoxicity. No marked differentiation bias was observed after microinjection and cLipo treatment. By contrast, CaP-treated MSCs exhibited excessive osteogenesis, while PEI-treated MSCs showed excessive adipogenesis. Robotic microinjection system was used to inject the CRISPR/Cas9-encoding plasmid to knock out PPARγ gene in MSCs, and the robotic microinjection did not interfere with PPARγ function in differentiation commitment. Meanwhile, the bias in osteo-adipogenic differentiation exhibited in CaP and PEI-treated MSCs after PPARγ knockout via chemical carriers. Our results indicate that gene delivery vehicles variously disturb MSCs differentiation and interfere with exogenous gene function. Our findings further suggest that robotic microinjection offers a promise of generating genetically modified MSCs without disrupting stem cell multi-potency and therapeutic gene function.

Advanced antifouling and antibacterial hydrogels enabled by controlled thermo-responses of a biocompatible polymer composite.

To optimally apply antibiotics and antimicrobials, smart wound dressing conferring controlled drug release and preventing adhesions of biological objects is advantageous. Poly(N-isopropylacrylamide) (PNIPAAm), a conventional thermo-responsive polymer, and poly(2-methacryloyloxyethyl phosphorylcholine) (PMPC), a typical antifouling polymer, have therefore potential to be fabricated as copolymers to achieve dual functions of thermo-responsiveness and antifouling. Herein, a hydrogel made of PNIPAM-co-PMPC was designed and loaded with octenidine, a widely applied antimicrobial agent for wound treatment, to achieve both antifouling and triggered drug release. The thermo-switch of the fabricated hydrogel allowed 25-fold more octenidine release at 37 °C (infected wound temperature) than at 30 °C (normal skin temperature) after 120 minutes, which led to at least a 3 lg reduction of the viable bacteria at 37 °C on artificially infected wounds. Furthermore, we pioneeringly assessed the antifouling property of the material in PBS buffer using single molecule/cell/bacterial force spectroscopy, and revealed that the fabricated hydrogel displayed distinctive antifouling properties against proteins, mammalian cells, and bacteria. This work demonstrated a promising design of a hydrogel applicable for preventing and treating wound infections. The concept of dual-functional materials can be envisaged for other clinical applications related to the prevention of biofilm-associated infections, such as urinary catheters, stents, and dental implants.

Uncoupling bacterial attachment on and detachment from polydimethylsiloxane surfaces through empirical and simulation studies.

Bacterial infections related to medical devices can cause severe problems, whose solution requires in-depth understanding of the interactions between bacteria and surfaces. This work investigates the influence of surface physicochemistry on bacterial attachment and detachment under flow through both empirical and simulation studies. We employed polydimethylsiloxane (PDMS) substrates having different degrees of crosslinking as the model material and the extended Derjaguin - Landau - Verwey - Overbeek model as the simulation method. Experimentally, the different PDMS materials led to similar numbers of attached bacteria, which can be rationalized by the identical energy barriers simulated between bacteria and the different materials. However, different numbers of residual bacteria after detachment were observed, which was suggested by simulation that the detachment process is determined by the interfacial physicochemistry rather than the mechanical property of a material. This finding is further supported by analyzing the bacteria detachment from PDMS substrates from which non-crosslinked polymer chains had been removed: similar numbers of residual bacteria were found on the extracted PDMS substrates. The knowledge gained in this work can facilitate the projection of bacterial colonization on a given surface.

Bioresponsive Hybrid Nanofibers Enable Controlled Drug Delivery through Glass Transition Switching at Physiological Temperature.

To avoid excessive usage of antibiotics and antimicrobial agents, smart wound dressings permitting controlled drug release for treatment of bacterial infections are highly desired. In search of a sensitive stimulus to activate drug release under physiological conditions, we found that the glass transition temperature (Tg) of a polymer or polymer blend can be an ideal parameter because a thermal stimulus can regulate drug release at the physiological temperature of 37 °C. A well-tuned Tg for a controlled drug release from fibers at 37 °C was achieved by varying the blending ratio of Eudragit® RS 100 and poly(methyl methacrylate). Octenidine, an antimicrobial agent often used in wound treatment, was encapsulated into the polymer blend during the electrospinning process and evaluated for its controlled release based on modulation of temperature. The thermal switch of the nanofibrous membranes can be turned "on" at physiological temperature (37 °C) and "off" at room temperature (25 °C), conferring a controlled release of octenidine. It was found that octenidine can be released in an amount at least 8.5 times higher (25 mg·L-1) during the "on" stage compared to the "off" stage after 24 h, which was regulated by the wet Tg (34.8-36.5 °C). The "on"/"off" switch for controlled drug release can moreover be repeated at least 5 times. Furthermore, the fabricated nanofibrous membranes displayed a distinctive antibacterial activity, causing a log3 reduction of the viable cells for both Gram negative and positive pathogens at 37 °C, when the thermal switch was "on". This study forms the groundwork for a treatment concept where no external stimulus is needed for the release of antimicrobials at physiological conditions, and will help reduce the overuse of antibiotics by allowing controlled drug release.

Preparation and characterization of solvent-free fluids reinforced and plasticized polylactic acid fibrous membrane.

In this paper, the electronspun Polylactic acid (PLA)/TiO2 nanofluids (nfs) fibrous membrane with good toughness, hydrophilicity and antibacterial activities are fabricated by taking full advantages of solvent-free TiO2 nfs with amphiphilicity and ionic conductivity. The resulting PLA/TiO2 nfs fibrous membrane exhibits excellent mechanical performance with a tensile strength and elongation at break of 3.68 MPa and 97.32 MPa at 5 wt% loading, respectively, which is 4 and 8 times higher than that of pure PLA, respectively. Additionally, TiO2 nfs can migrate onto the surface of PLA fibers during electrospun process, which significantly enhanced hydrophilicity, antistatic property, moisture sorption capacity and wicking properties of PLA fabrics. Meanwhile, the membrane also showed ultrafast water filtration of 3500 L m-2 h-1 driven by gravity force, which is 10-12 times higher than that of commercial ultrafiltration membrane. After ion-exchange reaction with salt solution, excellent antibacterial activity (against E. coli and S. aureus was 95% and 99.9%, respectively) and separation efficiency (above 90% on E. coli) of the obtained fabrics are also achieved. Overall, organic nfs are an idea candidate for fabricating hydrophilic PLA based biodegradable fabric that can be applied in contaminated water treatment, antibacterial textiles and biodegradable absorption materials.

Mitochondria-targeting near-infrared light-triggered thermosensitive liposomes for localized photothermal and photodynamic ablation of tumors combined with chemotherapy.

Lonidamine, an anticancer drug that acts on mitochondria, has poor water solubility. Mitochondria are the primary source of cellular reactive oxygen species (ROS), which are necessary for photodynamic therapy. Hence, a mitochondria-targeting drug delivery system loaded with Lonidamine and a ROS-produced photosensitizer could improve the bioavailability of Lonidamine and maximize photodynamic therapeutic efficiency. Here we report, for the first time, new IR-780 and Lonidamine encapsulated mitochondria-targeting thermosensitive liposomes (IL-TTSL). DSPE-PEG2000-NH2 was coupled with triphenylphosphine to form DSPE-PEG2K-TPP. The liposomes (IL-TTSL) were self-assembled from DPPC, DSPC, DSPE-PEG2K-TPP, cholesterol, IR-780 and Lonidamine. Coupled linker modified triphenylphosphine (TPP) is cationic and can selectively accumulate several hundred-fold within mitochondria. Once the liposomes are located inside mitochondria, 808 nm laser irradiation could trigger photosensitizer IR-780 to elevate the local temperature, which could be utilized in photothermal therapy and induce the release of Lonidamine from the thermosensitive liposomes. Meanwhile, IR-780 could release ROS for photodynamic therapy in mitochondria and increase photodynamic therapeutic efficiency. Our results showed that the surface modification of the liposomes with triphenylphosphine cations had good mitochondria-targeting ability. The liposomes exhibited good biocompatibility and all components of the empty liposomes were safe to be used in humans. Few reports were related to IR-780 being used in photodynamic therapy and we proved this function of IR-780. Overall, the stealth liposomes provide a promising new strategy to realize mitochondria-targeting thermosensitive chemo-, photodynamic and photothermal combination therapy with a single light source for lung cancer.

pH-Sensitive self-assembling nanoparticles for tumor near-infrared fluorescence imaging and chemo-photodynamic combination therapy.

The development of visual tumor theranostic nanoparticles has become a great challenge. In this study, d-α-tocopheryl polyethylene glycol 1000 succinate (TPGS) was conjugated to acid-sensitive cis-aconitic anhydride-modified doxorubicin (CAD) to obtain pH-sensitive anti-tumor prodrug nanoparticles (TCAD NPs) via self-assembling. Subsequently, the photosensitizer chlorin e6 (Ce6) was loaded into the resulting prodrug nanoparticles to prepare a novel tumor near-infrared fluorescence imaging and chemo-photodynamic combination therapy system (TCAD@Ce6 NPs). An accelerated release of doxorubicin (DOX) and chlorin e6 (Ce6) from the TCAD@Ce6 NPs could be achieved due to the hydrolysis of the acid-sensitive amide linker under mild acidic conditions (pH = 5.5). An in vitro experiment showed that A549 lung cancer cells exhibited a significantly higher uptake of DOX and Ce6 by using our delivery system than the free form of DOX and Ce6. An in vivo experiment showed that TCAD@Ce6 NPs displayed better tumor targeting gathering through the enhanced permeability and retention (EPR) effect than free Ce6, thus improving fluorescence imaging. Moreover, the chemo-photodynamic combination therapy of TCAD@Ce6 NPs combined with near-infrared laser irradiation was confirmed to be capable of inducing high apoptosis and necrosis of tumor cells (A549) in vitro and to display a significantly higher tumor growth suppression in the A549 lung cancer-bearing mice model. Furthermore, compared with exclusive chemotreatment (DOX) or photodynamic treatment (Ce6), our system showed enhanced therapeutic effects both in vitro and in vivo. In conclusion, the high performance TCAD@Ce6 NPs can be used as a promising NIR fluorescence imaging and highly effective chemo-photodynamic system for theranostics of lung cancer, etc. in the near future.