Highly Stretchable, Self-Healing, and Sensitive E-Skins at -78 °C for Polar Exploration.

Ultralow temperature-tolerant electronic skins (e-skins) can endow polar robots with tactile feedback for exploring in extremely cold polar environments. However, it remains a challenge to develop e-skins that enable sensitive touch sensation and self-healing at ultralow temperatures. Herein, we describe the development of a sensitive robotic hand e-skin that can stretch, self-heal, and sense at temperatures as low as -78 °C. The elastomeric substrate of this e-skin is based on poly(dimethylsiloxane) supramolecular polymers and multistrength dynamic H-bonds, in particular with quadruple H-bonding motifs (UPy). The structure-performance relationship of the elastomer at ultralow temperatures is investigated. The results show that elastomers with side-chain UPy units exhibit higher stretchability (∼3257%) and self-healing efficiency compared to those with main-chain UPy units. This is attributed to the lower binding energy variation and lower potential well. Based on the elastomer with side-chain UPy and man-made electric ink, a sensitive robotic hand e-skin for usage at -78 °C is constructed to precisely sense the shape of objects and specific symbols, and its sensation can completely self-recover after being damaged. The findings of this study contribute to the concept of using robotic hands with e-skins in polar environments that make human involvement limited, dangerous, or impossible.

Advantages with prophylactic PEG-rhG-CSF versus rhG-CSF in breast cancer patients receiving multiple cycles of myelosuppressive chemotherapy: an open-label, randomized, multicenter phase III study.

BACKGROUND: PEG-rhG-CSF reduces neutropenia and improves chemotherapy safety. In China's registration trial (CFDA: 2006L01305), we assessed its efficacy and safety against rhG-CSF, and prospectively explored its value over multiple cycles of chemotherapy. METHODS: In this open-label, randomized, multicenter phase 3 study, breast cancer patients (n = 569) were randomized to receive PEG-rhG-CSF 100 µg/kg, PEG-rhG-CSF 6 mg, or rhG-CSF 5 µg/kg/d after chemotherapy. The primary endpoints were the incidence and duration of grade 3/4 neutropenia during cycle 1. Secondary endpoints included the incidence and duration of grade 3/4 neutropenia during cycles 2-4, the incidence of febrile neutropenia, and the safety. RESULTS: A once-per-cycle PEG-rhG-CSF at either 100 µg/kg or 6 mg was not different from daily injections of rhG-CSF for either incidence or duration of grade 3/4 neutropenia. Interestingly, a substantial difference was noted during cycle 2, and the difference became bigger over cycles 3-4, reaching a statistical significance at cycle 4 in either incidence (P = 0.0309) or duration (P = 0.0289) favoring PEG-rhG-CSF. A significant trend toward a lower incidence of all-grade adverse events was noted at 129 (68.98%), 142 (75.53%), and 160 (82.47%) in the PEG-rhG-CSF 100 µg/kg and 6 mg and rhG-CSF groups, respectively (P = 0.0085). The corresponding incidence of grade 3/4 drug-related adverse events was 2/187 (1.07%), 1/188 (0.53%), and 8/194 (4.12%), respectively (P = 0.0477). Additionally, PFS in metastatic patients preferred PEG-rhG-CSF to rhG-CSF despite no significance observed by Kaplan-Meier analysis (n = 49, P = 0.153). CONCLUSIONS: PEG-rhG-CSF is a more convenient and safe formulation and a more effective prophylactic measure in breast cancer patients receiving multiple cycles of chemotherapy.

Using a silver-enhanced microarray sandwich structure to improve SERS sensitivity for protein detection.

A simple and sensitive method, based on surface-enhanced Raman scattering (SERS), for immunoassay and label-free protein detection is reported. A series of bowl-shaped silver cavity arrays were fabricated by electrodeposition using a self-assembled polystyrene spheres template. The reflection spectra of these cavity arrays were recorded as a function of film thickness, and then correlated with SERS enhancement using sodium thiophenolate as the probe molecule. The results reveal that SERS enhancement can be maximized when the frequency of both the incident laser and the Raman scattering approach the frequency of the localized surface plasmon resonance. The optimized array was then used as the bottom layer of a silver nanoparticle-protein-bowl-shaped silver cavity array sandwich. The second layer of silver was introduced by the interactions between the proteins in the middle layer of the sandwich architecture and silver nanoparticles. Human IgG bound to the surface of this microcavity array can retain its recognition function. With the Raman reporter molecules labeled on the antibody, a detection limit down to 0.1 ng mL(-1) for human IgG is easily achieved. Furthermore, the SERS spectra of label-free proteins (catalase, cytochrome C, avidin and lysozyme) from the assembled sandwich have excellent reproducibility and high quality. The results reveal that the proposed approach has potential for use in qualitative and quantitative detection of biomolecules.

Malleable, Ultrastrong Antibacterial Thermosets Enabled by Guanidine Urea Structure.

Dynamic covalent polymers (DCPs) that strike a balance between high performance and rapid reconfiguration have been a challenging task. For this purpose, a solution is proposed in the form of a new dynamic covalent supramolecular motif-guanidine urea structure (GUAs). GUAs contain complex and diverse chemical structures as well as unique bonding characteristics, allowing guanidine urea supramolecular polymers to demonstrate advanced physical properties. Noncovalent interaction aggregates (NIAs) have been confirmed to form in GUA-DCPs through multistage H-bonding and π-π stacking, resulting in an extremely high Young's modulus of 14 GPa, suggesting remarkable mechanical strength. Additionally, guanamine urea linkages in GUAs, a new type of dynamic covalent bond, provide resins with excellent malleability and reprocessability. Guanamine urea metathesis is validated using small molecule model compounds, and the temperature dependent infrared and rheological behavior of GUA-DCPs following the dissociative exchange mechanism. Moreover, the inherent photodynamic antibacterial properties are extensively verified by antibacterial experiments. Even after undergoing three reprocessing cycles, the antibacterial rate of GUA-DCPs remains above 99% after 24 h, highlighting their long-lasting antibacterial effectiveness. GUA-DCPs with dynamic nature, tuneable composition, and unique combination of properties make them promising candidates for various technological advancements.

Ligustilide-loaded liposome ameliorates mitochondrial impairments and improves cognitive function via the PKA/AKAP1 signaling pathway in a mouse model of Alzheimer's disease.

BACKGROUND: Oxidative stress is an early event in the development of Alzheimer's disease (AD) and maybe a pivotal point of interaction governing AD pathogenesis; oxidative stress contributes to metabolism imbalance, protein misfolding, neuroinflammation and apoptosis. Excess reactive oxygen species (ROS) are a major contributor to oxidative stress. As vital sources of ROS, mitochondria are also the primary targets of ROS attack. Seeking effective avenues to reduce oxidative stress has attracted increasing attention for AD intervention. METHODS: We developed liposome-packaged Ligustilide (LIG) and investigated its effects on mitochondrial function and AD-like pathology in the APPswe/PS1dE9 (APP/PS1) mouse model of AD, and analyzed possible mechanisms. RESULTS: We observed that LIG-loaded liposome (LIG-LPs) treatment reduced oxidative stress and ß-amyloid (Aß) deposition and mitigated cognitive impairment in APP/PS1 mice. LIG management alleviated the destruction of the inner structure in the hippocampal mitochondria and ameliorated the imbalance between mitochondrial fission and fusion in the APP/PS1 mouse brain. We showed that the decline in cAMP-dependent protein kinase A (PKA) and A-kinase anchor protein 1 for PKA (AKAP1) was associated with oxidative stress and AD-like pathology. We confirmed that LIG-mediated antioxidant properties and neuroprotection were involved in upregulating the PKA/AKAP1 signaling in APPswe cells in vitro. CONCLUSION: Liposome packaging for LIG is relatively biosafe and can overcome the instability of LIG. LIG alleviates mitochondrial dysfunctions and cognitive impairment via the PKA/AKAP1 signaling pathway. Our results provide experimental evidence that LIG-LPs may be a promising agent for AD therapy.

Rational design of a DNA-launched live attenuated vaccine against human enterovirus 71.

Human Enterovirus 71 (EV71) has emerged as one of the predominant causative agents of hand, foot and mouth disease (HFMD) with global impact. Despite the inactivated vaccine being licensed, other vaccine candidates based on advanced technology platforms are under development. In this report, we rationally designed and constructed two DNA-launched live attenuated vaccine candidates (pDL-EV71) under the control of specific promoters. In vitro and in vivo transfection with pDL-EV71 driven by the CMV promoter successfully yielded fully infectious EV71. More importantly, the administration of pDL-EV71 did not cause clinical symptoms following intracranial or intramuscular inoculation in neonatal and IFNα/ßR-/- mice, demonstrating its safety profile. Moreover, a single-dose or two-dose immunization with pDL-EV71 elicited robust neutralizing antibodies against EV71 as well as an antigen-specific cellular response in mice. A single-dose immunization with 10 µg of pDL-EV71 conferred complete protection against lethal EV71 infection in neonates born to immunized maternal mice. Overall, our present results demonstrate that pDL-EV71 is a safe and effective vaccine candidate against EV71 for further development.

Fabrication of a bowl-shaped silver cavity substrate for SERS-based immunoassay.

In this study, a metal sandwich substrate bridged by an immunocomplex has been created for a surface enhanced Raman scattering (SERS)-based immunoassay. The bottom bowl-shaped silver cavity thin film layer was prepared by electrodeposition using a closely packed monolayer of 700 nm diameter polystyrene spheres as a template. The reflection spectra of the films were recorded as a function of film thickness, and then correlated with SERS enhancement using p-aminothiophenol as the probe molecule. The results demonstrate that SERS enhancement can be maximized when both the frequency of the incident laser and Raman scattering approach the resonance frequency of the localized surface plasmon resonance, providing a guideline for the fabrication and further application of these nanocavity arrays. The second layer of silver was introduced by the interactions between the immunocomplexes in the middle layer of the sandwich architecture and the silver nanoparticles. The proposed structure was used to perform the SERS-based immunoassay. The labeled protein can be detected over a wide concentration range and the detection limit of TRITC and Atto610 labeled proteins were 50 and 5 pg mL(-1), respectively. The results demonstrate that the new SERS substrate is suitable for the quantitative identification of biomolecules.

Zwitterionic microgel preservation platform for circulating tumor cells in whole blood specimen.

The immediate processing of whole blood specimen is required in circulating tumor cell-based liquid biopsy. Reliable blood specimen stabilization towards preserving circulating tumor cells can enable more extensive geographic sharing for precise rare-cell technology, but remains challenging due to the fragility and rarity of circulating tumor cells. Herein, we establish a zwitterionic magnetic microgel platform to stabilize whole blood specimen for long-term hypothermic preservation of model circulating tumor cells. We show in a cohort study of 20 cancer patients that blood samples can be preserved for up to 7 days without compromising circulating tumor cell viability and RNA integrity, thereby doubling the viable preservation duration. We demonstrate that the 7-day microgel-preserved blood specimen is able to reliably detect cancer-specific transcripts, similar to fresh blood specimens, while there are up/down expression regulation of 1243 genes in model circulating tumor cells that are preserved by commercial protectant. Mechanistically, we find that the zwitterionic microgel assembly counters the cold-induced excessive reactive oxygen species and platelet activation, as well as extracellular matrix loss-induced cell anoikis, to prevent circulating tumor cell loss in the whole blood sample. The present work could prove useful for the development of blood-based noninvasive diagnostics.

A zwitterionic cellulose-based skin sensor for the real-time monitoring and antibacterial sensing wound dressing.

Wound infection can induce inflammation and impede wound healing, being a major challenge in wound care management. A household device that can monitor infection in real time, prevent bacterial, and promote wound healing is highly desired but still rarely investigated. In this work, a novel zwitterionic cellulose-based hydrogel that enables continuously real-time monitoring and pro-healing of infected wound is designed. It is based on interpenetrating polymeric networks, including zwitterionic covalent bond network and physical bond network of carboxymethyl cellulose (CMC) with Ag+via metal-coordination interactions. When used as a sensing dressing, it is developed to exhibit pH-responsive and temperature-responsive properties for assessment of wound infection. Moreover, Ag+ can be released from carboxyl groups of CMC in response to the decrease of pH, killing bacteria and promoting wound healing. This zwitterionic carboxymethyl cellulose-based hydrogel sensor opens new avenues for domestic real-time monitoring and pro-healing of infected wound.

Evaluation of a custom-designed human-robot collaboration control system for dental implant robot.

BACKGROUND: The purpose of this study is to develop a methodology to better control a human-robot collaboration for robotic dental implant placement. We have designed a human-robot collaborative implant system (HRCDIS) which is based on a zero-force hand-guiding concept and a operational task management workflow that can achieve highly accurate and stable osteotomy drilling based on a surgeon's decision and robotic arm movements during implant surgery. METHOD: The HRCDIS brings forth the robot arm positions, exact drilling location, direction and performs automatic drilling. The HRCDIS can also avoid complex programing in the robot. The purpose of the study is to evaluate the accuracy of drilling resulting from our developed operational task management method (OTMM). The OTMM can enable the robot to switch, pause, and resume drilling tasks. The force required for hand-guiding in a zero-force control mode of the robot was detected by a 6D force sensor. We compared our force data to those provided by the manufacturer's manual. The study was conducted on a phantom head with a 3D-printed jaw bone to verify the validity of our HRCDIS. We appraised the discrepancies between free-hand drillings and the HRCDIS controlled drillings at apical centre and head centre of the implant and implant angulation to the baseline data from a virtual surgical planning model. RESULTS: The average required force used by hand-guiding to operate the robot with HRCDIS was near 7 Newton which is much less than the manufacturer's specification (30 Newton). The results from our study showed that the average error at implant head was 1.04 ± 0.37 mm, 1.56 ± 0.52 mm at the implant apex, and deviation of implant angle was 3.74 ± 0.67°. CONCLUSIONS: The results from this study validate the merit of the human-robot collaboration control by the HRCDIS. Based on the improved navigation system using HRCDIS, a robotic implant placement can provide seamless drilling with ease, efficiency and accuracy.

Lipid nanoparticle-encapsulated mRNA antibody provides long-term protection against SARS-CoV-2 in mice and hamsters.

Monoclonal antibodies represent important weapons in our arsenal to against the COVID-19 pandemic. However, this potential is severely limited by the time-consuming process of developing effective antibodies and the relative high cost of manufacturing. Herein, we present a rapid and cost-effective lipid nanoparticle (LNP) encapsulated-mRNA platform for in vivo delivery of SARS-CoV-2 neutralization antibodies. Two mRNAs encoding the light and heavy chains of a potent SARS-CoV-2 neutralizing antibody HB27, which is currently being evaluated in clinical trials, were encapsulated into clinical grade LNP formulations (named as mRNA-HB27-LNP). In vivo characterization demonstrated that intravenous administration of mRNA-HB27-LNP in mice resulted in a longer circulating half-life compared with the original HB27 antibody in protein format. More importantly, a single prophylactic administration of mRNA-HB27-LNP provided protection against SARS-CoV-2 challenge in mice at 1, 7 and even 63 days post administration. In a close contact transmission model, prophylactic administration of mRNA-HB27-LNP prevented SARS-CoV-2 infection between hamsters in a dose-dependent manner. Overall, our results demonstrate a superior long-term protection against SARS-CoV-2 conferred by a single administration of this unique mRNA antibody, highlighting the potential of this universal platform for antibody-based disease prevention and therapy against COVID-19 as well as a variety of other infectious diseases.

Universal Intraductal Surface Antifouling Coating Based on an Amphiphilic Copolymer.

Surface modification on the inner wall of medical or industrial polymeric catheters with a high length/diameter ratio is highly desired. Herein, a universal and facile method based on an amphiphilic copolymer was developed to immobilize an intraductal surface antifouling coating for a variety of polymeric catheters. A fouling-repelled thin layer was formed by swelling-driven adsorption via directly perfusing an amphiphilic copolymer [polyvinylpyrrolidone-polydimethylsiloxane-polyvinylpyrrolidone (PVP-PDMS-PVP)] solution into catheters. In this copolymer, hydrophobic PDMS was embedded into a shrinking cross-linked network of catheters; also, PVP segments migrated to the surface under driving water to form a hydrophilic antifouling coating. Moreover, because of the coordination between I2 and pyrrolidone of PVP, the copolymer-modified intraductal surface was then infused with aqueous I2 to form the PVP-I2 complex, endowing this coating with bactericidal activity. Notably, diverse catheters with arbitrary shapes (circular, rectangular, triangular, and hexagonal) and different components (silicone, polyurethane, and polyethylene) were also verified to work using this interfacial interpenetration strategy. The findings in this work provide a new avenue toward facile and universal fabrication of intraductal surface antifouling catheters, creating a superior option for decreasing the consumable costs in industrial production and alleviating the pain of replacing catheters for patients.

A Zwitterionic-Aromatic Motif-Based ionic skin for highly biocompatible and Glucose-Responsive sensor.

Electronic skins that can sense external stimuli have been of great significance in artificial intelligence and smart wearable devices in recent years. However, most of current skin materials are unable to achieve high biocompatibility and anti-bacterial activity, which are particularly critical to wearable sensors for neonatal/premature monitoring or tissue-interfaced biosensors (such as electronic wound dressing and smart contact lens). Herein, a zwitterionic-aromatic motif-based conductive hydrogel with electrostatic and π-π interactions is designed for the development of ionic skin sensors. The hydrogel possesses high biocompatibility, anti-bacterial activity, especially glucose-responsive property which has not been achieved by previous ionic skins. Due to its unique molecular design, the zwitterionic-aromatic skin sensor exhibits excellent mechanical properties (robust elasticity and large stretchability) and high-sensitive pressure detection (including a gentle finger touch, small water droplets, and vocal cord vibration). More importantly, aromatic motives in phenylboronic acid segments endow the skin with glucose-responsive property. This skin sensor not only shows great potential in wearable e-skins, but also possesses a promising property for the tissue-interfaced and implantable continuous-glucose-monitor biosensors such as smart wound dressing with a high demand of biocompatibility.

Accuracy of dental implant surgery with robotic position feedback and registration algorithm: An in-vitro study.

BACKGROUND: The purpose of this study was to develop and validate a positioning method with hand-guiding and contact position feedback of robot based on a human-robot collaborative dental implant system (HRCDIS) for robotic guided dental implant surgery. METHODS: An HRCDIS was developed based on a light-weight cooperative robot arm, UR5. A three-dimensional (3D) virtual partially edentulous mandibular bone was reconstructed using the cone bone computed tomography images. After designing the preoperative virtual implant planning using the computer software, a fixation guide worn on teeth for linking and fixing positioning marker was fabricated by 3D printing. The fixation guide with the positioning marker and a resin model mimicking the oral tissues were assembled on a head phantom. The planned implant positions were derived by the coordinate information of the positioning marker. The drilling process using the HRCDIS was conducted after mimicking the experimental set-up and planning the drilling trajectory. Deviations between actual and planned implant positions were measured and analyzed. RESULTS: The head phantom experiments results showed that the error value of the central deviation at hex (refers to the center of the platform level of the implant) was 0.79 ± 0.17 mm, central deviation at the apex was 1.26 ± 0.27 mm, horizontal deviation at the hex was 0.61 ± 0.19 mm, horizontal deviation at the apex was 0.91 ± 0.55 mm, vertical deviation at the hex was 0.38 ± 0.17 mm, vertical deviation at the apex was 0.37 ± 0.20 mm, and angular deviation was 3.77 ± 1.57°. CONCLUSIONS: The results from this study preliminarily validate the feasibility of the accurate navigation method of the HRCDIS.

Evaluation of total phenol and flavonoid content and antimicrobial and antibiofilm activities of Trollius chinensis Bunge extracts on Streptococcus mutans.

Dental caries is a chronic disease with multiple bacterial infections, Streptococcus mutans is the main cariogenic bacteria. Trollius chinensis Bunge is a common folk medicine in the Xinjiang area of China. In this study, we investigated the total flavonoid content and total phenol content in four types of T. chinensis Bunge extracts and the inhibitory effects of these extracts on S. mutans. Agar diffusion method was used to measure the inhibition zone diameters, and the minimum inhibitory concentration and minimum bactericidal concentration were determined by the twofold dilution method. Water extracts from T. chinensis Bunge and ethanol (30, 60, and 90%) extracts at different concentrations could significantly inhibit the growth of S. mutans. Among them, 30% ethanol extract exhibited the best antibacterial and antibiofilms effect. Biofilm research (crystal violet staining and CLSM) showed that 30% ethanol extract of T. chinensis Bunge plays an important role in inhibiting S. mutans growth and the number of biofilms. The results indicate that T. chinensis Bunge extract has good antibacterial and anti-biofilm activity on S. mutans. It has the potential to be developed for the treatment of caries in clinical application.

Evaluation of hypocrellin A-loaded lipase sensitive polymer micelles for intervening methicillin-resistant Staphylococcus Aureus antibiotic-resistant bacterial infection.

There is an urgent need for new antibacterial strategies to overcome the emergence of antibiotic resistance. Antibacterial photodynamic therapy (APDT) may be an effective method to deliver photosensitizers for the treatment of methicillin-resistant Staphylococcus aureus (MRSA) infections. Here, we report that the photosensitizer hypocrellin A (HA) loaded into lipase-sensitive methoxy poly (ethylene glycol)-block-poly(ε-caprolactone) (mPEG-PCL) micelles showed high anti-MRSA activity in vitro and in vivo by PDT. Once the micelles come into contact with bacteria that secrete lipase, the PCL is degraded to release HA. Our results showed that the minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) of mPEG-PCL/HA micelles after light irradiation were 0.69 and 1.38 mg/L (HA concentration), respectively. In the dark, the MIC and MBC of the micelles were 250 and 500 mg/L (HA concentration), respectively. The fluorescent stain results further demonstrated the photodynamic antibacterial activity of mPEG-PCL/HA micelles. The survival rate of mice subjected to experimental acute peritonitis increased to 86% after treated with the micelles. The polymeric micelles showed low hemolytic activity and biocompatibility, simultaneously preventing aggregation in vivo and enhancing the water solubility of HA. Thus, the photosensitizer HA loaded micelles could be used as APDT for infections caused by bacteria without antibiotic resistance.

Effect of over-expression of phasin gene from Aeromonas hydrophila on biosynthesis of copolyesters of 3-hydroxybutyrate and 3-hydroxyhexanoate.

The gene phaPAh, encoding the protein phasin that is associated with poly(3-hydroxybutyrate-co-3-hydroxyhexanoate) (PHBHHx) granule of Aeromonas hydrophila 4AK4, was cloned and characterized. Recombinant strains harboring additional copies of the phasin gene (phaPAh) and the polyhydroxyalkanoate (PHA) synthase gene (phaCAh) accumulated PHBHHx copolyesters consisting of 21 mol% 3-hydroxyhexanoate (3HHx) as compared to 14 mol% 3HHx produced by wild type strain. The molecular weight of PHBHHx produced by the above recombinants was lower than that obtained from the wild type strain grown under similar conditions. Over-expression of phaPAh led to the production of more PHA granules but with reduced sizes. SDS-PAGE showed that PhaPAh was the predominant protein present in the PHBHHx granules. The RT-PCR results suggested that phasin PhaPAh, regulated phaCAh gene at the transcription level. Gene PhaPWe from Wautersia eutropha (formerly Ralstonia eutropha; encoding a 20 kDa protein with low amino acid homology to the A. hydrophila 13 kDa protein) cloned into A. hydrophila 4AK4 exhibited similar effects on PHBHHx production and PHBHHx composition. These data suggest that the phasins could represent a protein family possessing similar functions but different structures.