Hydrogels are hydrophilic, highly water swellable polymer networks capable of converting chemical energy into mechanical energy and vice versa. They can be tailored regarding their chemical nature ...and physical structure, sensitiveness to external stimuli and biocompatibility; they can be formed in various structures and integrated into (micro-)systems. Accordingly, over the last decade, these materials have gained considerable recognition as valuable tool for sensors and in diagnostics. This article reviews the use of hydrogels in sensor development with focus on recent efforts in the application of stimuli responsive hydrogels as sensors, hydrogels as suitable matrices in which the sensing (bio-)molecules are embedded and hydrogels for modification and protection of sensor surfaces. In the first part of the review, both sensors and hydrogels are defined and a basic theoretical overview of hydrogels and their behavior is given. Subsequent chapters focus on hydrogels in physicochemical and biochemical sensing mechanisms with a primary emphasis on the hydrogels as such and the applied sensing mechanism. Finally, the review is concluded by a summary and discussion including an outlook on future perspectives for hydrogels in sensing applications.
It has been shown before that anisotropically microstructured surfaces exhibit anisotropic wetting phenomena. This study presents a possibility to control the anisotropy of wetting by tailoring the ...surface chemistry. PDMS microchannels were permanently hydrophilized and subsequently functionalized further. Thereby, systematic studies on the effect of the surface modification on the wetting properties of microstructures have been possible. Importantly, we found that the wetting parallel to the groove strongly depended on the chemical modification of the structure although the wetting perpendicular to the groove is almost unaffected. Through immobilization of a monolayer of Si nanoparticles (SiNPs) exclusively on the elevations of the hydrogel-coated microstructured PDMS substrate, the anisotropic wetting could be selectively altered unidirectionally along the pattern direction.
Abstract We present a systematic study of a perfluoropolyether (PFPE)-based elastomer as a new biomaterial. Besides its excellent long-term stability and inertness, PFPE can be decorated with ...topographical surface structures by replica molding. Micrometer-sized pillar structures led to considerably different cell morphology of fibroblasts. Although PFPE is a very hydrophobic material we could show that PFPE substrates allow cell adhesion and spreading of primary human fibroblasts (HDF) very similar to that observed on standard cell culture substrates. Less advanced cell spreading was observed for L929 (murine fibroblast cell line) cells during the first 5 h in culture which was accompanied by retarded recruitment of αv β3 -integrin into focal adhesions (FAs). After 24 h distinct FAs were evident also in L929 cells on PFPE. Furthermore, organization of soluble FN into a fibrillar ECM network was shown for hdF and L929 cells. Based on these results PFPE is believed to be a suitable substrate for several biological applications. On the one hand it is an ideal cell culture substrate for fundamental research of substrate-independent adhesion signaling due to its different characteristics (e.g. wettability, elasticity) compared to glass or TCPS. On the other hand it could be a promising implant material, especially due to its straightforward patternability, which is a tool to direct cell growth and differentiation.
The reliability of implantable blood sensors is often hampered by unspecific adsorption of plasma proteins and blood cells. This not only leads to a loss of sensor signal over time, but can also ...result in undesired host vs. graft reactions. Within this study we evaluated the hemocompatibility of isocyanate conjugated star shaped polytheylene oxide-polypropylene oxide co-polymers NCO-sP(EO-stat-PO) when applied to gold surfaces as an auspicious coating material for gold sputtered blood contacting sensors. Quartz crystal microbalance (QCM) sensors were coated with ultrathin NCO-sP(EO-stat-PO) films and compared with uncoated gold sensors. Protein resistance was assessed by QCM measurements with fibrinogen solution and platelet poor plasma (PPP), followed by quantification of fibrinogen adsorption. Hemocompatibility was tested by incubation with human platelet rich plasma (PRP). Thrombin antithrombin-III complex (TAT), β-thromboglobulin (β-TG) and platelet factor 4 (PF4) were used as coagulation activation markers. Furthermore, scanning electron microscopy (SEM) was used to visualize platelet adhesion to the sensor surfaces. Compared to uncoated gold sensors, NCO-sP(EO-stat-PO) coated sensors revealed significant better resistance against protein adsorption, lower TAT generation and a lower amount of adherent platelets. Moreover, coating with ultrathin NCO-sP(EO-stat-PO) films creates a cell resistant hemocompatible surface on gold that increases the chance of prolonged sensor functionality and can easily be modified with specific receptor molecules.
The multi-level perspective has been criticized for being functionalistic and paying little attention to actor-based perspectives. Nevertheless, for the identification and assessment of potential ...change agents in a sustainability transition, a clear conceptual and methodological approach is necessary. This paper, thus, develops a multi-dimensional typology of niche, regime, and hybrid actors, which is conceptually grounded in transition studies and empirically illustrated by a cluster analysis based on a survey of pig and poultry farmers in Germany, France, and the Netherlands. Animal husbandry is chosen as a case study because a significant share of the environmental impact within the agri-food system is attributed to this sector and there is evidence for resistance to change by mainstream actors. Conceptually, the paper provides a framework of constitutive elements for different kinds of actors and contributes to an extension of the niche–regime dichotomy by adding the group of hybrid actors. The empirical results show that cluster analysis is a suitable approach to identify conceptually meaningful differences among interviewed farmers. Among pig and poultry farmers, the regime actors are by far the largest group. The smaller group of hybrid actors, however, has large potential to act as boundary spanners. A particularly interesting finding is that several larger farms are among the group of niche actors which hints at the possibility that larger farms are not necessarily resistant to change.
The study objective was to evaluate the population pharmacokinetics and pharmacodynamics of extended-infusion piperacillin-tazobactam in children hospitalized in an intensive care unit. Seventy-two ...serum samples were collected at steady state from 12 patients who received piperacillin-tazobactam at 100/12.5 mg/kg of body weight every 8 h infused over 4 h. Population pharmacokinetic analyses were performed using NONMEM, and Monte Carlo simulations were performed to estimate the piperacillin pharmacokinetic profiles for dosing regimens of 80 to 100 mg/kg of the piperacillin component given every 6 to 8 h and infused over 0.5, 3, or 4 h. The probability of target attainment (PTA) for a cumulative percentage of the dosing interval that the drug concentration exceeds the MIC under steady-state pharmacokinetic conditions (TMIC) of ≥50% was calculated at MICs ranging from 0.25 to 64 mg/liter. The mean ± standard deviation (SD) age, weight, and estimated glomerular filtration rate were 5 ± 3 years, 17 ± 6.2 kg, and 118 ± 41 ml/min/1.73 m(2), respectively. A one-compartment model with zero-order input and first-order elimination best fit the pharmacokinetic data for both drugs. Weight was significantly associated with piperacillin clearance, and weight and sex were significantly associated with tazobactam clearance. Pharmacokinetic parameters (mean ± SD) for piperacillin and tazobactam were as follows: clearance, 0.22 ± 0.07 and 0.19 ± 0.07 liter/h/kg, respectively; volume of distribution, 0.43 ± 0.16 and 0.37 ± 0.14 liter/kg, respectively. All extended-infusion regimens achieved PTAs of >90% at MICs of ≤16 mg/liter. Only the 3-h infusion regimens given every 6 h achieved PTAs of >90% at an MIC of 32 mg/liter. For susceptible bacterial pathogens, piperacillin-tazobactam doses of ≥80/10 mg/kg given every 8 h and infused over 4 h achieve adequate pharmacodynamic exposures in critically ill children.
Inhalation of biopersistent fibers like asbestos can cause strong chronic inflammatory effects, often resulting in fibrosis or even cancer. The interplay between fiber shape, fiber size and the ...resulting biological effects is still poorly understood due to the lack of reference materials.
We investigated how length, diameter, aspect ratio, and shape of synthetic silica fibers influence inflammatory effects at doses up to 250 µg cm
. Silica nanofibers were prepared with different diameter and shape. Straight (length ca. 6 to 8 µm, thickness ca. 0.25 to 0.35 µm, aspect ratio ca. 17:1 to 32:1) and curly fibers (length ca. 9 µm, thickness ca. 0.13 µm, radius of curvature ca. 0.5 µm, aspect ratio ca. 70:1) were dispersed in water with no apparent change in the fiber shape during up to 28 days. Upon immersion in aqueous saline (DPBS), the fibers released about 5 wt% silica after 7 days irrespectively of their shape. The uptake of the fibers by macrophages (human THP-1 and rat NR8383) was studied by scanning electron microscopy and confocal laser scanning microscopy. Some fibers were completely taken up whereas others were only partially internalized, leading to visual damage of the cell wall. The biological effects were assessed by determining cell toxicity, particle-induced chemotaxis, and the induction of gene expression of inflammatory mediators.
Straight fibers were only slightly cytotoxic and caused weak cell migration, regardless of their thickness, while the curly fibers were more toxic and caused significantly stronger chemotaxis. Curly fibers also had the strongest effect on the expression of cytokines and chemokines. This may be due to the different aspect ratio or its twisted shape.
The fifth multistakeholder Paediatric Strategy Forum focussed on epigenetic modifier therapies for children and adolescents with cancer. As most mutations in paediatric malignancies influence ...chromatin-associated proteins or transcription and paediatric cancers are driven by developmental gene expression programs, targeting epigenetic mechanisms is predicted to be a very important therapeutic approach in paediatric cancer. The Research to Accelerate Cures and Equity (RACE) for Children Act FDARA amendments to section 505B of the FD&C Act was implemented in August 2020, and as there are many epigenetic targets on the FDA Paediatric Molecular Targets List, clinical evaluation of epigenetic modifiers in paediatric cancers should be considered early in drug development. Companies are also required to submit to the EMA paediatric investigation plans aiming to ensure that the necessary data to support the authorisation of a medicine for children in EU are of high quality and ethically researched. The specific aims of the forum were i) to identify epigenetic targets or mechanisms of action associated with epigenetic modification relevant to paediatric cancers and ii) to define the landscape for paediatric drug development of epigenetic modifier therapies. DNA methyltransferase inhibitors/hypomethylating agents and histone deacetylase inhibitors were largely excluded from discussion as the aim was to discuss those targets for which therapeutic agents are currently in early paediatric and adult development. Epigenetics is an evolving field and could be highly relevant to many paediatric cancers; the biology is multifaceted and new targets are frequently emerging. Targeting epigenetic mechanisms in paediatric malignancy has in most circumstances yet to reach or extend beyond clinical proof of concept, as many targets do not yet have available investigational drugs developed. Eight classes of medicinal products were discussed and prioritised based on the existing level of science to support early evaluation in children: inhibitors of menin, DOT1L, EZH2, EED, BET, PRMT5 and LSD1 and a retinoic acid receptor alpha agonist. Menin inhibitors should be moved rapidly into paediatric development, in view of their biological rationale, strong preclinical activity and ability to fulfil an unmet clinical need. A combination approach is critical for successful utilisation of any epigenetic modifiers (e.g. EZH2 and EED) and exploration of the optimum combination(s) should be supported by preclinical research and, where possible, molecular biomarker validation in advance of clinical translation. A follow-up multistakeholder meeting focussing on BET inhibitors will be held to define how to prioritise the multiple compounds in clinical development that could be evaluated in children with cancer. As epigenetic modifiers are relatively early in development in paediatrics, there is a clear opportunity to shape the landscape of therapies targeting the epigenome in order that efficient and optimum plans for their evaluation in children and adolescents are developed in a timely manner.
Biopersistent pro-inflammatory fibers are suspected human carcinogens. Cytotoxicity and transcription of pro- and anti-inflammatory mediators of different fibers were investigated in functional ...relationship to chemotaxis in vitro as a model for fiber-induced inflammation of the lung. We challenged NR8383 rat macrophages with multi-walled carbon nanotubes (MWCNT) and various asbestos fibers. The resulting cell supernatants were than studied using the Particle-induced Cell Migration Assay (PICMA) and cytotoxicity was determined using the LDH test. Expression of inflammatory mediators was analyzed with qPCR and verified by ELISA. Chrysotile A and the rigid, needle-shaped NM-401 caused the strongest cytotoxic effects and the largest number of migrated cells. In contrast, the MWCNT NM-400, NM-402, and NM403 were apparently non-cytotoxic but induced pronounced cell migration showing a very steep dose response. However, the strength of cell migration and cytotoxicity of the asbestos fibers were correlated. The expression profile of inflammatory mediators was comparable, although cytotoxicity of the MWCNT NM-401 and NM-403 differed strongly. Induction of the corresponding proteins was confirmed for CCL2, CCL3, CXCL1, CXCL3, IL1RA (IL1RN), CSF1, GDF15 and TNFa. Chrysotile A and NM-401 induced much stronger chemotaxis than the non-fibrous particles reported in our previous study. Cytotoxic and chemotactic effects correspond to the induction of inflammatory mediators.
•We describe an in vitro model that allows the investigation of the particle and fiber induced inflammation of the lung.•Strong, dose dependent, and clearly differentiated chemotaxis in response to fibers is shown.•Fiber induced chemotaxis is paralleled by induction of inflammatory mediators and can occur independently from cytotoxicity.
Objective
This cross-sectional study determined whether acute sensory irritative or (sub)chronic inflammatory effects of the eyes, nose or respiratory tract are observed in employees who are exposed ...to naphthalene at the workplace.
Methods
Thirtynine healthy and non-smoking male employees with either moderate (
n
= 22) or high (
n
= 17) exposure to naphthalene were compared to 22 male employees from the same plants with no or only rare exposure to naphthalene. (Sub)clinical endpoint measures included nasal endoscopy, smell sensitivity, self-reported work-related complaints and the intensity of naphthalene odor and irritation. In addition, cellular and soluble mediators in blood, nasal lavage fluid (NALF) and induced sputum (IS) were analysed. All measurements were carried out pre-shift on Monday and post-shift on Thursday. Personal air monitoring revealed naphthalene shift concentrations up to 11.6 mg/m
3
with short-term peak concentrations up to 145.8 mg/m
3
and 1- and 2-naphthol levels (sum) in post-shift urine up to 10.1 mg/L.
Results
Acute sensory irritating effects at the eyes and upper airways were reported to occur when directly handling naphthalene (e.g., sieving pure naphthalene). Generally, naphthalene odor was described as intense and unpleasant. Habituation effects or olfactory fatigue were not observed. Endoscopic examination revealed mild inflammatory effects at the nasal mucosa of exposed employees in terms of reddening and swelling and abnormal mucus production. No consistent pattern of cellular and soluble mediators in blood, NALF or IS was observed which would indicate a chronic or acute inflammatory effect of naphthalene in exposed workers.
Conclusions
The results suggest that exposure to naphthalene induces acute sensory irritative effects in exposed workers. No (sub)chronic inflammatory effects on the nasal epithelium or the respiratory tract could be observed under the study conditions described here.
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