Tailoring and application of a multi-responsive cellulose nanofibre-based 3D nanonetwork wound dressing.

The rapid loss of drugs and the weak curative effects due to cyclical urination are the main reasons why wound heal with difficulty after bladder tumour resection. Here, a bioinspired cellulose nanofibre (CNF)-based magnetic 3D nanonetwork wound dressing with excellent tissue adhesion and biocompatibility is designed by the assembly of pH- and near infrared-responsive CNF nanoskeletons, magnetic switching Fe3O4 nanoparticles, and temperature switching Pluronic®F-127. The dressing with high loading capacity for mitomycin and indocyanine green can form a sticky 3D nanonetwork at the wound site and remain for a long time to release drugs through an external magnetic field. Interestingly, the dressing possessed excellent antibacterial activity, bacterial biofilm elimination, T24 tumour cell killing, and wound healing promotion through photothermal, photodynamic, and chemotherapy. Therefore, it has promising application for bladder postoperative infected wound healing to avoid rapid loss of drugs due to cyclical urination.

Design of Near-Infrared-Triggered Cellulose Nanocrystal-Based In Situ Intelligent Wound Dressings for Drug-Resistant Bacteria-Infected Wound Healing.

Postoperative infected wound complications caused by residual tumor cells, bacterial biofilms, and drug-resistant bacteria have become the main challenge in postsurgical skin regeneration. Herein, a bionic cellulose nanocrystal (CNC)-based in situ intelligent wound dressing with near-infrared (NIR)-, temperature-, and pH-responsive functions was designed by using NIR-responsive CNC as the network skeleton, dynamic imine bonds between dialdehyde cellulose nanocrystals and doxorubicin, chitosan oligosaccharide as the pH-responsive switch, and temperature-sensitive poly(N-isopropyl acrylamide) as the temperature-responsive in situ formation switch. The as-prepared wound dressing with the intertwining three-dimensional (3D) network structure possessed high drug loadability of indocyanine green (30 mg/g) and doxorubicin (420 mg/g) simultaneously. The temperature-, NIR-, and pH-responsive switches endowed the wound dressing with controllable on-demand drug release behavior. In particular, the temperature switch endowed the dressing with a shape-adaptable ability on irregularly infected wounds. Interestingly, the wound dressing showed excellent antitumor activity for A375 tumor cells, antibacterial activity against methicillin-resistant Staphylococcus aureus (MRSA) and bacterial biofilm removal ability. Therefore, the developed wound dressing can provide an ideal synergistic treatment strategy combined with chemotherapy and photodynamic and photothermal therapy for postoperative drug-resistant bacteria-infected wound healing.

Dual light-responsive cellulose nanofibril-based in situ hydrogel for drug-resistant bacteria infected wound healing.

In situ hydrogels with rapid hemostasis and antibacterial activity have received considerable attention in the field of wound healing. Herein, a white light and NIR dual light-responsive cellulose nanofibril (CNF)-based in situ hydrogel wound dressing is tailored by using white light-responsive CNF and endogenous antibacterial CNF as the skeleton, Prussian blue nanoparticles, Pluronic® F127 and hydroxypropyl methyl cellulose as the NIR, temperature-responsive switch and binder, respectively. The dressing exhibits rapid hemostasis properties in rat liver injury model with low blood loss of 286.4 mg and short hemostasis time of 63 s. Meanwhile, the antibacterial activity of the dressing with white and NIR irradiation against Escherichia coli, Staphylococcus aureus and methicillin-resistant Staphylococcus aureus (MRSA) is higher than 99.9 %. Interestingly, the dressing with biocompatibility can promote MRSA infection wound healing and can be removed on demand without secondary injury to skin. Therefore, it has promising applications for first-aid hemostasis and wound healing.

Origin of Pressure-Dependent Adhesion in Nanoscale Contacts.

The adhesion between nanoscale components has been shown to increase with applied load, contradicting well-established mechanics models. Here, we use in situ transmission electron microscopy and atomistic simulations to reveal the underlying mechanism for this increase as a change in the mode of separation. Analyzing 135 nanoscale adhesion tests on technologically relevant materials of anatase TiO2, silicon, and diamond, we demonstrate a transition from fracture-controlled to strength-controlled separation. When fracture models are incorrectly applied, they yield a 7-fold increase in apparent work of adhesion; however, we show that the true work of adhesion is unchanged with loading. Instead, the nanoscale adhesion is governed by the product of adhesive strength and contact area; the pressure dependence of adhesion arises because contact area increases with applied load. By revealing the mechanism of separation for loaded nanoscale contacts, these findings provide guidance for tailoring adhesion in applications from nanoprobe-based manufacturing to nanoparticle catalysts.

A bionic cellulose nanofiber-based nanocage wound dressing for NIR-triggered multiple synergistic therapy of tumors and infected wounds.

Tumor recurrence and drug-resistant bacterial infection are the main reasons that wounds heal with difficulty after skin tumor treatment. The near infrared- (NIR-) and pH-responsive, bionic, cellulose nanofiber-based (CNF-based) nanocage wound dressing with biocompatibility, bioviscosity, and shape adaptability is designed for dual NIR-triggered photothermal therapy of tumor and infection-induced wound healing. The wound dressing with the intertwining three dimensional (3D) nanocage network structure is skillfully constructed using NIR-responsive cellulose nanofibers and pH-responsive cellulose nanofibers as the skeleton, which endows the dressing with a high drug-loading capacity of doxorubicin (400 mg·g-1), and indocyanine green (25 mg·g-1). Moreover, the NIR- and pH-responsive bionic "On/Off" switches of the dressing enable a controllable and efficient drug release onto the wound area. The dual NIR-triggered wound dressing with excellent photothermal conversion performance possesses good antibacterial properties against Escherichia coli, Staphylococcus aureus, and drug-resistant Staphylococcus aureus. It could effectively eliminate bacterial biofilms and kill A375 tumor cells. Interestingly, the bionic wound dressing with shape adaptability could adapt and treat irregular postoperative skin tumor wounds and drug-resistant bacterial infection via the synergistic therapy of photothermal, photodynamic, and chemotherapy, which provides an ideal strategy for clinical intervention.

Bioinspired Multifunctional Cellulose Nanofibril-Based In Situ Liquid Wound Dressing for Multiple Synergistic Therapy of the Postoperative Infected Wound.

A smart in situ-formed wound dressing with excellent antibacterial ability against drug-resistance bacterial, antitumor, and biofilm-eliminating activities to promote effective wound closure is highly desirable in therapeutic and clinical applications. Herein, we designed and developed a multifunctional; shape-adaptable; and pH, temperature, and near-infrared radiation (NIR) multiple responsive cellulose nanofibril (CNF)-based in situ liquid wound dressing, using a pH-sensitive CNF grafted with terminated amino hyperbranched polyamines (HBP-NH2) as a substrate, along with poly(N-isopropylacrylamide) and indocyanine green (ICG) loaded as the temperature and NIR on/off switches, respectively. The 3D nanocage network structure of CNF and the nanocavities in the hyperbranched structure of HBP-NH2 endow the dressing with a high loading capacity for active drugs (doxorubicin and ICG) simultaneously. Moreover, the responsiveness of the dressing to multiple stimuli enables controllable and efficient drug release to the wound area. The bioinspired dressing demonstrates excellent antibacterial activity against common bacteria and methicillin-resistant Staphylococcus aureus, antitumor activity against A375 tumor cells, and biofilm-eliminating capability. In addition, the developed dressing synergistically combines multiple therapeutic strategies for effective wound healing, specifically photothermal therapy, photodynamic therapy, and chemotherapy. The design provides an ideal clinical intervention strategy for irregular tumor postoperative infected wounds.

Temperature/pH Smart Nanofibers with Excellent Biocompatibility and Their Dual Interactions Stimulus-Responsive Mechanism.

Novel nanosized biomass-based pH- and temperature-responsive cellulose nanofibers (TOCNF-HPEI-IBAm) were designed and prepared by grafting hyperbranched polyethylenimine (HPEI) modified with isobutyramide (IBAm) groups (HPEI-IBAm) onto carboxylated cellulose nanofibers (TOCNFs). The as-prepared TOCNF-HPEI-IBAm possessed excellent biocompatibility and pH- and temperature-responsive properties. TOCNF-HPEI-IBAm showed a rapid wettability conversion from hydrophilic (WCA = 41.1°, WCA = 70.7°) to hydrophobic (WCA = 147.3°, WCA = 142.2°) in response to changes in pH and temperature from acidic conditions to alkaline conditions and from lower to higher temperatures. In addition, it possesses strong antibacterial activity against Escherichia coli and Listeria (Eb ≥ 97%). The amount of DOX loaded in TOCNF-HPEI-IBAm was 642.52 mg/g, and the maximum amount of DOX released was 39.30% at pH = 3.0 within 9 h. Furthermore, the dual interactions stimulus-responsive mechanism was revealed to be attributed to the expansion and collapse of the molecular chains of TOCNF-HPEI-IBAm in response to temperature and pH through mutual promotion and inhibition.

Quantitative measurement of contact area and electron transport across platinum nanocontacts for scanning probe microscopy and electrical nanodevices.

Conductive modes of atomic force microscopy are widely used to characterize the electronic properties of materials, and in such measurements, contact size is typically determined from current flow. Conversely, in nanodevice applications, the current flow is predicted from the estimated contact size. In both cases, it is very common to relate the contact size and current flow using well-established ballistic electron transport theory. Here we performed 19 electromechanical tests of platinum nanocontacts with in situ transmission electron microscopy to measure contact size and conductance. We also used molecular dynamics simulations of matched nanocontacts to investigate the nature of contact on the atomic scale. Together, these tests show that the ballistic transport equations under-predict the contact size by more than an order of magnitude. The measurements suggest that the low conductance of the contact cannot be explained by the scattering of electrons at defects nor by patchy contact due to surface roughness; instead, the lower-than-expected contact conductance is attributed to approximately a monolayer of insulating surface species on the platinum. Surprisingly, the low conductance persists throughout loading and even after significant sliding of the contact in vacuum. We apply tunneling theory and extract best-fit barrier parameters that describe the properties of this surface layer. The implications of this investigation are that electron transport in device-relevant platinum nanocontacts can be significantly limited by the presence and persistence of surface species, resulting in current flow that is better described by tunneling theory than ballistic electron transport, even for cleaned pure-platinum surfaces and even after loading and sliding in vacuum.

Understanding contact between platinum nanocontacts at low loads: The effect of reversible plasticity.

Metal nanocontacts play a critical role in atomic force microscopy, functional nanostructures, metallic nanoparticles, and nanoscale electromechanical devices. In all cases, knowledge of the area of contact, and its variation with load, is critical for the quantitative prediction of behavior. Often, the contact area is predicted using continuum mechanics models which relate contact size to geometry, material properties, and load. Here we show for platinum nanoprobes that the contact size deviates significantly from these continuum predictions, even at low applied loads and in the absence of irreversible shape change. We use in situ transmission electron microscopy (TEM) with matched molecular dynamics (MD) simulations to investigate the load-dependent size of the contact. Direct measurements of contact radius from MD and TEM exceed the predictions of continuum mechanics by 24%-164%, depending on the model applied. The physical mechanism for this deviation is found to be dislocation activity in the near-surface material, which is fully reversed upon unloading. These findings demonstrate that contact mechanics models are insufficient for predicting contact area in real-world platinum nanostructures, even at ultra-low applied loads.

Simulations of the effect of an oxide on contact area measurements from conductive atomic force microscopy.

Nanoscale contact area in conductive atomic force microscopy can be determined by analyzing current flow using electron transport theories. However, it is recognized that native oxides on the conductive tip will reduce current flow, thus degrading the accuracy of the measured contact area. To quantify the adverse effect of an oxide on contact area measurements, we use molecular dynamics simulations of an oxide-coated platinum tip and a crystalline platinum substrate, where both the contact size and conductance can be inferred from the positions of atoms in the interface. We develop a method to approximate conductance based on the distance between atoms in platinum channels across the contact. Then, the contact area calculated from conductance using ballistic transport and tunneling theories is compared to that obtained using the known positions of atoms in the contact. The difference is small for very thin (<0.1 nm) or very thick (>1.0 nm) oxides, where ballistic transport and tunneling theories work well; however, the difference is significant for oxides between these limits, which is expected to be the case for platinum in many practical applications.

Phase Transitions in Dipalmitoylphosphatidylcholine Monolayers.

A self-assembled phospholipid monolayer at an air-water interface is a well-defined model system for studying surface thermodynamics, membrane biophysics, thin-film materials, and colloidal soft matter. Here we report a study of two-dimensional phase transitions in the dipalmitoylphosphatidylcholine (DPPC) monolayer at the air-water interface using a newly developed methodology called constrained drop surfactometry (CDS). CDS is superior to the classical Langmuir balance in its capacity for rigorous temperature control and leak-proof environments, thus making it an ideal alternative to the Langmuir balance for studying lipid polymorphism. In addition, we have developed a novel Langmuir-Blodgett (LB) transfer technique that allows the direct transfer of lipid monolayers from the droplet surface under well-controlled conditions. This LB transfer technique permits the direct visualization of phase coexistence in the DPPC monolayer. With these technological advances, we found that the two-dimensional phase behavior of the DPPC monolayer is analogous to the three-dimensional phase transition of a pure substance. This study has implications in the fundamental understanding of surface thermodynamics as well as applications such as self-assembled monolayers and pulmonary surfactant biophysics.

Differential susceptibility of transgenic mice expressing human surfactant protein B genetic variants to Pseudomonas aeruginosa induced pneumonia.

Surfactant protein B (SP-B) is essential for lung function. Previous studies have indicated that a SP-B 1580C/T polymorphism (SNP rs1130866) was associated with lung diseases including pneumonia. The SNP causes an altered N-linked glycosylation modification at Asn129 of proSP-B, e.g. the C allele with this glycosylation site but not in the T allele. This study aimed to generate humanized SP-B transgenic mice carrying either SP-B C or T allele without a mouse SP-B background and then examine functional susceptibility to bacterial pneumonia in vivo. A total of 18 transgenic mouse founders were generated by the DNA microinjection method. These founders were back-crossed with SP-B KO mice to eliminate mouse SP-B background. Four founder lines expressing similar SP-B levels to human lung were chosen for further investigation. After intratracheal infection with 50 µl of Pseudomonas aeruginosa solution (1 × 10(6) CFU/mouse) or saline in SP-B-C, SP-B-T mice the mice were sacrificed 24 h post-infection and tissues were harvested. Analysis of surfactant activity revealed differential susceptibility between SP-B-C and SP-B-T mice to bacterial infection, e.g. higher minimum surface tension in infected SP-B-C versus infected SP-B-T mice. These results demonstrate for the first time that human SP-B C allele is more susceptible to bacterial pneumonia than SP-B T allele in vivo.

Long-chain acyl-CoA dehydrogenase deficiency as a cause of pulmonary surfactant dysfunction.

Long-chain acyl-CoA dehydrogenase (LCAD) is a mitochondrial fatty acid oxidation enzyme whose expression in humans is low or absent in organs known to utilize fatty acids for energy such as heart, muscle, and liver. This study demonstrates localization of LCAD to human alveolar type II pneumocytes, which synthesize and secrete pulmonary surfactant. The physiological role of LCAD and the fatty acid oxidation pathway in lung was subsequently studied using LCAD knock-out mice. Lung fatty acid oxidation was reduced in LCAD(-/-) mice. LCAD(-/-) mice demonstrated reduced pulmonary compliance, but histological examination of lung tissue revealed no obvious signs of inflammation or pathology. The changes in lung mechanics were found to be due to pulmonary surfactant dysfunction. Large aggregate surfactant isolated from LCAD(-/-) mouse lavage fluid had significantly reduced phospholipid content as well as alterations in the acyl chain composition of phosphatidylcholine and phosphatidylglycerol. LCAD(-/-) surfactant demonstrated functional abnormalities when subjected to dynamic compression-expansion cycling on a constrained drop surfactometer. Serum albumin, which has been shown to degrade and inactivate pulmonary surfactant, was significantly increased in LCAD(-/-) lavage fluid, suggesting increased epithelial permeability. Finally, we identified two cases of sudden unexplained infant death where no lung LCAD antigen was detectable. Both infants were homozygous for an amino acid changing polymorphism (K333Q). These findings for the first time identify the fatty acid oxidation pathway and LCAD in particular as factors contributing to the pathophysiology of pulmonary disease.