Publikationen

Cytotoxic T lymphocytes (CTLs) are key players to eliminate tumorigenic or pathogen-infected cells using lytic granules (LG) and Fas ligand (FasL) pathways. Depletion of glucose leads to severely impaired cytotoxic function of CTLs. However, the impact of excessive glucose on CTL functions still remains largely unknown. Here we used primary human CD8(+) T cells, which were stimulated by CD3/CD28 beads and cultured in medium either containing high glucose (HG, 25 mM) or normal glucose (NG, 5.6 mM). We found that in HG-CTLs, glucose uptake and glycolysis were enhanced, whereas proliferation remained unaltered. Furthermore, CTLs cultured in HG exhibited an enhanced CTL killing efficiency compared to their counterparts in NG. Unexpectedly, expression of cytotoxic proteins (perforin, granzyme A, granzyme B and FasL), LG release, cytokine/cytotoxic protein release and CTL migration remained unchanged in HG-cultured CTLs. Interestingly, additional extracellular Ca2+ diminished HG-enhanced CTL killing function. Our findings suggest that in an environment with excessive glucose, CTLs could eliminate target cells more efficiently, at least for a certain period of time, in a Ca2+-dependent manner.

he killing efficiency of cytotoxic T lymphocytes (CTLs) is tightly regulated by intracellular Ca2+ concentration. Glucose is the key energy source for CTLs, lack of which significantly impairs CTL activation, proliferation and effector functions. The impact of high glucose on Ca2+ influx in CTLs remains largely elusive. In this work, we stimulated primary human CD8+ T cells in medium containing either 25 mM (high glucose, HG) or 5.6 mM glucose (normal glucose, NG). We found that store‐operated calcium entry (SOCE) induced by thapsigargin (Tg) is elevated in HG‐cultured CTLs compared to their counterparts in NG. Unexpectedly, the Ca2+ influx elicited by recognition of target cells is reduced in HG‐cultured CTLs. Under HG condition, STIM1 and STIM2, the calcium sensors in the endoplasmic reticulum (ER), were down‐regulated; ORAI1, the main structural component of calcium‐release activated channels, remained unchanged, whereas ORAI2 and ORAI3 were up‐regulated. The fraction of necrosis of HG‐cultured CTLs was enhanced after killing without affecting glucose uptake. Thus, our findings reveal that HG has a distinctive impact on Tg‐evoked SOCE and target recognition‐induced Ca2+ influx in CTLs and causes more CTL death after killing, suggesting a novel regulatory role of high glucose on modulating CTL functions.

In the course of evolution nature has arrived at startling materials solutions to ensure survival. Investigations into biological surfaces, ranging from plants, insects and geckos to aquatic animals, have inspired the design of intricate surface patterns to create useful functionalities. This paper reviews the fundamental interaction mechanisms of such micropatterns with liquids, solids, and soft matter such as skin for control of wetting, self-cleaning, anti-fouling, adhesion, skin adherence, and sensing. Compared to conventional chemical strategies, the paradigm of micropatterning enables solutions with superior resource efficiency and sustainability. Associated applications range from water management and robotics to future health monitoring devices. We finally provide an overview of the relevant patterning methods as an appendix.

Bioinspired micropatterned adhesives have attracted extensive research interest in the past two decades. In modeling the performance of these adhesives, the common assumption has been that the adhesive strength of each sub-contact is identical. Recent experiments, however, have shown that interfacial defects of different characters lead to a distribution of the adhesive strength within a fibrillar array. Based on experimental observations of detachment events, a statistical model for the distribution of the local adhesive strength and the resulting performance of a micropatterned adhesive are presented. This approach constitutes a paradigm shift, providing better understanding of micropatterned adhesives under real conditions. Examples presented include the prediction of unstable detachments in compliant systems. Future directions are discussed, including the extension of the statistical approach to non-uniform loading and rate-dependent effects, the contribution of suction to adhesion and aging of contacts over specific time periods, as well as the necessity for a more in-depth understanding of defect formation considering surface roughness and other imperfections in the system.

Crack propagation in viscoelastic materials cannot be understood with the use of classical fracture mechanics, which predicts no dependence on the speed of propagation, unless cohesive models like Barenblatt or Dugdale are introduced, as done by Knauss & Schapery first in the 1970s. However, there is another approach, suggested qualitatively by deGennes in 1996, and quantitatively by Persson and Brener in 2005, which attempts an energy (power) balance by considering viscoelastic dissipation in the bulk of the material. Here, we revisit the main results of the two theories and show that they lead to approximately the same scaling laws not just for the standard material, but also for power law materials (which have a continuous spectrum of relaxation times). Recent findings by Schapery have concluded that the shape of the cohesive law results essentially in a shift in velocity which depends both on cohesive law shape and viscoelastic properties. Therefore, the Persson-Brener cutoff radius in the integral of dissipation can be chosen to fit approximately the cohesive model results to match the shift of the reference velocity.

Crack propagation in viscoelastic materials has been understood with the use of Barenblatt cohesive models by many authors since the 1970’s. In polymers and metal creep, it is customary to assume that the relaxed modulus is zero, so that we have typically a crack speed which depends on some power of the stress intensity factor. Generally, when there is a finite relaxed modulus, it has been shown that the “apparent” toughness in a semi-infinite crack increases between a value at very low speeds at a threshold toughness w0, to a very fast fracture value at w∞, and that the enhancement factor in infinite systems (where the classical singular fracture mechanics field dominates) simply corresponds to the ratio of instantaneous to relaxed elastic moduli. Here, we apply a cohesive model for the case of a bimaterial interface between an elastic and a viscoelastic material, assuming the crack remains at the interface, and neglect the details of bimaterial singularity. For the case of a Maxwell material at low speeds the crack propagates with a speed which depends only on viscosity, and the fourth power of the stress intensity factor, and not on the elastic moduli of either material. For the Schapery type of power law material with no relaxation modulus, there are more general results. For arbitrary viscoelastic materials with nonzero relaxed modulus, we show that the maximum “effective” toughness enhancement will be reduced with respect to that of a classical viscoelastic crack in homogeneous material.

Adhesives based on fibrillar surface microstructures have shown great potential for handling applications requiring strong, reversible, and switchable adhesion. Recently, the importance of the statistical distribution of adhesive strength of individual fibrils in controlling the overall performance was revealed. Strength variations physically correspond to different interfacial defect sizes, which, among other factors, are related to surface roughness. For analysis of the strength distribution, Weibull’s statistical theory of fracture was introduced. In this study, the importance of the statistical properties in controlling the stability of attachment is explored. Considering the compliance of the loading system, we develop a stability criterion based on the Weibull statistical parameters. It is shown that when the distribution in fibril adhesive strength is narrow, the global strength is higher but unstable detachment is more likely. Experimental variation of the loading system compliance for a specimen of differing statistical properties shows a transition to unstable detachment at low system stiffness, in good agreement with the theoretical stability map. This map serves to inform the design of gripper compliance, when coupled with statistical analysis of strength on the target surface of interest. Such a treatment could prevent catastrophic failure by spontaneous detachment of an object from an adhesive gripper.

Inspired by the gecko foot, polymeric microstructures have demonstrated reliable dry adhesion to both stiff objects and sensitive surfaces such as skin. Microstructured silicone patches are here proposed for the treatment of tympanic membrane perforations with the aim of serving as an alternative for current surgical procedures that require anesthesia and ear canal packing. Sylgard 184 PDMS micropillars of 20 µm in diameter and 60 µm in length are topped by a Soft Skin Adhesive (SSA) MG7-1010 terminal layer, of about 25 µm thickness. The adhesion is evaluated by specially designed tack tests against explanted murine eardrums and, for comparison, against a rigid substrate. Functional effects are evaluated using auditory brainstem responses (ABR) and distortion product otoacoustic emissions (DPOAE). The adhesion strength of the microstructure and unstructured controls to explanted murine tympanic membranes is comparable (typically 12 kPa), but the microstructured patches are easier to handle by the surgeon. For the first time, partial recovery of hearing performance is measured immediately after patch application. The novel patches adhere without the need for further fixation, removing the need for ear canal packing. The proposed material design holds great promise for improving clinical treatments of tympanic membrane perforations.

Polymer adhesive films sandwiched between two rigid solids are a common bonding strategy. The mechanics and consequently the adhesion of such geometrically confined films depend mainly on their thickness, Young's modulus, and the Poisson's ratio of the material. In this work, we explore the effect of a micropatterned subsurface embedded into the adhesive layer. We compare experiments with three-dimensional numerical simulations to evaluate the impact of the microstructure on the contact stiffness and effective modulus. The results are used to extend a previously proposed size scaling argument on adhesion from incompressible to slightly compressible films to account for the silicone used in our study with a Poisson's ratio of 0.495. In addition, interfacial stress distributions between the elastic film and the glass disc are obtained from plane strain simulations to evaluate characteristic adhesion failures such as edge cracks and cavitation. Overall, the micropatterned subsurface has a large impact on the contact stiffness, the interfacial stress distribution, and the detachment behavior; however, the adhesion performance is only slightly improved in comparison to a non-patterned subsurface.

Significance: Optoacoustic stimulation offers an alternative stimulation strategy for the hearing organ. To serve as the base for a novel auditory prosthesis, the optoacoustic stimulation must be biocompatible and energy-saving. Aim: Enhancing the efficiency of optoacoustic stimulation while reducing the energy input in a suited animal model. Approach: Optoacoustically induced auditory brainstem responses (oABRs) were recorded after the pulsed laser irradiation of the tympanic membrane (TM) in mice. The results were compared with the ABRs induced through acoustic click stimulation. In addition, self-adhesive absorbing films were applied on the TM before the optoacoustic stimulation to investigate their effect on the resulting ABRs. Results: Using an absorbing film on the TM during optical stimulation led to considerably enhanced oABR wave I amplitude values compared with the stimulation of the bare TM. When using our stimulation strategy, we induced oABR waves in the 50% to 60% range of the acoustical stimulation reached with 80-dB SPL click stimuli. Conclusions: The mouse model can be used for certain developmental work for an optoacoustic auditory prosthesis. Using absorbing films on the TM during optical stimulation considerably enhances oABR wave I amplitude. Optimization of the stimulation strategy could further enhance the efficiency within biocompatibility margins.