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Key Points Miniaturization from conventional to small size results in several advantages, such as reduced sample consumption and shortened transport times of mass and heat. A key feature in microfluidic systems is the integration of different functional units for reaction, separation and detection in a channel network. Therefore, serial processing and analysis could be easily performed in the flowing systems. Furthermore, because space is used sparingly, massive parallelization can be accomplished. In microfluidic chips, chemical syntheses can be performed. Concentration of reagents and temperature can be regulated precisely. Operating under continuous flow conditions will also allow the combination of multiple reaction steps and on-line analysis on one single chip. Serial and parallel solution-phase synthesis is demonstrated in microchips. Microfluidic screening and sorting devices have been developed that offer the benefits of a continuous operation, including reaction steps preceding as well as succeeding the sorting process. In combination with appropriate biological assays and high-sensitivity detection techniques, such systems allows the identification and isolation of individual cells or molecules. Microfluidic chips facilitate the generation and handling of nano- and picolitre liquid volumes. By injecting the aqueous phase into the stream of the carrier medium at a T-junction or by applying focussing techniques, small reaction chambers ('droplets') are generated. The precisely controllable supply of reagents, handling of small liquid volumes devoid of fast evaporation as well as the high-speed formation of droplets with a homogeneous diameter of a few μm makes this approach a valuable tool for screening experiments that rely on high reproducibility. By generating technologies with nanoscale dimensions, reaction volumes are being achieved similar to those typically found in biological systems such as living cells. Recent studies show the possibility of using microfluidic platforms for cell culturing and observation and being able to manipulate living cells individually. Using microfluidics, cells could be locally stimulated, for example, to study the effect of drug levels on chemotaxis of living cells in vitro . In key issues of drug discovery, such as chemical synthesis, screening of compounds and preclinical testing of drugs on living cells, microfluidic tools can meet the demands for high throughput, and can improve or might eventually replace existing technologies. Advances in microfluidics could prove invaluable both by enhancing existing biological assays and for the design of sophisticated new screens. Dittrich and Manz review current and future applications of scaled-down science and look at the impact of lab-on-a-chip technology on drug discovery. Miniaturization can expand the capability of existing bioassays, separation technologies and chemical synthesis techniques. Although a reduction in size to the micrometre scale will usually not change the nature of molecular reactions, laws of scale for surface per volume, molecular diffusion and heat transport enable dramatic increases in throughput. Besides the many microwell-plate- or bead-based methods, microfluidic chips have been widely used to provide small volumes and fluid connections and could eventually outperform conventionally used robotic fluid handling. Moreover, completely novel applications without a macroscopic equivalent have recently been developed. This article reviews current and future applications of microfluidics and highlights the potential of 'lab-on-a-chip' technology for drug discovery.

Microfluidic-based synthesis of one-dimensional (1D) nanostructures offers tremendous advantages over bulk approaches e.g., the laminar flow, reduced sample consumption and control of self-assembly of nanostructures. In addition to the synthesis, the integration of 1D nanomaterials into microfluidic chips can enable the development of diverse functional microdevices. 1D nanomaterials have been used in applications such as catalysts, electronic instrumentation and sensors for physical parameters or chemical compounds and biomolecules and hence, can be considered as building blocks. Here, we outline and critically discuss promising strategies for microfluidic-assisted synthesis, alignment and various chemical and biochemical applications of 1D nanostructures. In particular, the use of 1D nanostructures for sensing chemical/biological compounds are reviewed.

Membranolytic anticancer peptides represent a potential strategy in the fight against cancer. However, our understanding of the underlying structure-activity relationships and the mechanisms driving their cell selectivity is still limited. We developed a computational approach as a step towards the rational design of potent and selective anticancer peptides. This machine learning model distinguishes between peptides with and without anticancer activity. This classifier was experimentally validated by synthesizing and testing a selection of 12 computationally generated peptides. In total, 83% of these predictions were correct. We then utilized an evolutionary molecular design algorithm to improve the peptide selectivity for cancer cells. This simulated molecular evolution process led to a five-fold selectivity increase with regard to human dermal microvascular endothelial cells and more than ten-fold improvement towards human erythrocytes. The results of the present study advocate for the applicability of machine learning models and evolutionary algorithms to design and optimize novel synthetic anticancer peptides with reduced hemolytic liability and increased cell-type selectivity.

Ultrasound (US) guidance is increasingly used in invasive cardiac electrophysiology (EP) procedures for femoral vascular access. In this study, we assessed the occurrence of vascular access-related complications in EP procedures which were performed with the routine use of anatomical landmark (LM) versus US-guided vascular access. A total of 1119 consecutive EP procedures in 1012 patients performed in a two-year period from September 10, 2020 to September 10, 2022 were included. The endpoint of the present study consisted of any vascular access-related complication, classified as hematoma, aneurysm, or AV-fistula. Different risk factors for increased bleeding risk were analyzed. During the evaluation period, 777 procedures were performed using LM-guiding and 342 procedures using US-guided access. Overall, 19 (1.7%) relevant vascular complications occurred including: 15 (1.3%) hematoma, 2 (0.18%) aneurysm and 2 (0.18%) AV-fistula. 17 (2.2%) complications occurred in the LM-guided group and 2 (0.6%) in the US-guided group. A significant reduction of femoral complications by 89% was observed with introduction of routine US-guided access. 3.8% in the LM-group vs. 0.4% in the US-group (OR 0.1, 95% CI 0.0135–0.8515, p  = 0.034). Intraprocedural ACT and the HASBLED score [range 0–4; mean = 1.47; maximum = 4) were shown to be independent predictors for vascular complications (OR 2.826, 95% CI 1.631–4.895, p  < 0.001). The use of US-guided vascular access significantly decreased the access-related complication rate in EP procedures. Higher procedural ACT and HASBLED score independently predicted a higher risk of vascular access complications.

Cancer cells can be released from a cancerous lesion and migrate into the circulatory system, from whereon they may form metastases at distant sites. Today, it is possible to infer cancer progression and treatment efficacy by determining the number of circulating tumor cells (CTCs) in the patient's blood at multiple time points; further valuable information about CTC phenotypes remains inaccessible. In this article, a microfluidic method for integrated capture, isolation, and analysis of membrane markers as well as quantification of proteins secreted by single CTCs and CTC clusters is introduced. CTCs are isolated from whole blood with extraordinary efficiencies above 95% using dedicated trapping structures that allow co‐capture of functionalized magnetic beads to assess protein secretion. The patform is tested with multiple breast cancer cell lines spiked into human blood and mouse‐model‐derived CTCs. In addition to immunostaining, the secretion level of granulocyte growth stimulating factor (G‐CSF), which is shown to be involved in neutrophil recruitment, is quantified The bead‐based assay provides a limit of detection of 1.5 ng mL−1 or less than 3700 molecules per cell. Employing barcoded magnetic beads, this platform can be adapted for multiplexed analysis and can enable comprehensive functional CTC profiling in the future. Circulating tumor cells (CTCs) isolated from liquid biopsies carry valuable functional information about the tumor phenotype. Here, a uniquely integrated microfluidic device for efficient isolation of CTCs from whole blood and subsequent determination of the protein expression as well as secretion of G‐CSF, a key factor involved in the recruitment of myeloid cells, is presented.

During the COVID-19 pandemic, a significant number of healthcare workers have been infected with SARS-CoV-2. However, there remains little knowledge regarding large droplet dissemination during airway management procedures in real life settings. 12 different airway management procedures were investigated during routine clinical care. A high-speed video camera (1000 frames/second) was for imaging. Quantitative droplet characteristics as size, distance traveled, and velocity were computed. Droplets were detected in 8/12 procedures. The droplet trajectories could be divided into two distinctive patterns (type 1/2). Type 1 represented a ballistic trajectory with higher speed large droplets whereas type 2 represented a random trajectory of slower particles that persisted longer in air. The use of tracheal cannula filters reduced the amount of droplets. Respiratory droplet patterns generated during airway management procedures follow two distinctive trajectories based on the influence of aerodynamic forces. Speaking and coughing produce more droplets than non-invasive ventilation therapy confirming these behaviors as exposure risks. Even large droplets may exhibit patterns resembling the fluid dynamics smaller airborne aerosols that follow the airflow convectively and may place the healthcare provider at risk.

Background The transition from metabolic dysfunction-associated steatotic liver disease (MASLD) to steatohepatitis (MASH) is characterized by a chronic low-grade inflammation, involving activation of resident macrophages (Kupffer cells; KC) and recruitment of infiltrating macrophages. Macrophages produce cytokines and, after induction of Cyclooxygenase 2 (COX-2), the key enzyme of prostanoid synthesis, prostaglandin E 2 (PGE 2 ). PGE 2 modulates cytokine production in an autocrine and paracrine manner, therefore playing a pivotal role in regulating inflammatory processes. Changes in the hepatic macrophage pool during MASLD progression to MASH could influence PGE 2 - and cytokine-mediated signaling processes. The aim of this study was to characterize these changes in mice with diet-induced MASH and further elucidate the role of COX-2-dependently formed PGE 2 on the inflammatory response in different macrophage populations of mice with a macrophage-specific COX-2-deletion. Methods Male, 6-7-week-old wildtype mice were fed either a Standard or high-fat, high-cholesterol MASH-inducing diet for 4, 12 and 20 weeks. Liver macrophages were isolated and analyzed by flow cytometry. For in vitro experiments primary KC, peritoneal macrophages (PM) and Bone-marrow-derived macrophages (BMDM) were isolated from macrophage-specific COX-2-deficient and wildtype mice and treated with lipopolysaccharide (LPS) and/or PGE 2 . Results During MASH-development, the proportion of KC (Clec4F + Tim4 + ) decreased, while the proportion of monocyte-derived macrophages (Clec4F − Tim4 − ) and monocyte-derived cells exhibiting a phenotype similar to KC (Clec4F + Tim4 − ) significantly increased over time. In vitro experiments showed that exogenous PGE 2 completely abrogated the LPS-induced mRNA expression and secretion of tumor necrosis factor-alpha (TNF-α) in primary KC, PM and BMDM from wildtype mice. PM and BMDM, as in vitro models for infiltrating macrophages, were more sensitive to PGE 2 compared to KC. Deletion of COX-2 in all macrophage populations led to an impaired PGE 2 -dependent feedback inhibition of TNF-α production. LPSinduced TNF-α mRNA expression was higher compared to the respective wildtype macrophage population. Conclusion The current study, using a murine MASH model, indicates that PGE 2 may have a protective, anti-inflammatory effect, especially by inhibiting the expression of pro-inflammatory cytokines such as TNFα in infiltrating monocyte-derived macrophages. An inhibition of endogenous PGE 2 synthesis in macrophages by pharmacological inhibition of COX-2 could potentially increase inflammation and promote the progression of MASH.

Multiplexed point-of-care testing (xPOCT), which is simultaneous on-site detection of different analytes from a single specimen, has recently gained increasing importance for clinical diagnostics, with emerging applications in resource-limited settings (such as in the developing world, in doctors’ offices, or directly at home). Nevertheless, only single-analyte approaches are typically considered as the major paradigm in many reviews of point-of-care testing. Here, we comprehensively review the present diagnostic systems and techniques for xPOCT applications. Different multiplexing technologies (e.g., bead- or array-based systems) are considered along with their detection methods (e.g., electrochemical or optical). We also address the unmet needs and challenges of xPOCT. Finally, we critically summarize the in-field applicability and the future perspectives of the presented approaches. Simultaneous on-site measurement of different substances from a single sample, called multiplexed point-of-care testing, has recently become more and more important for in vitro diagnostics. The major aim for the development of xPOCT systems is the smart combination of a high-performing device with a low system complexity. Thus, the on-site tests are realized in a short time by non-experts and ensure comparable results with clinical and central laboratory findings. A multiplexing capability of up to 10 analytes has been sufficient for many recent xPOCT applications. The future of xPOCT devices will be driven by novel biotechnologies (e.g., aptamers) or targets (e.g., circulating RNAs or tumor cells, exosomes, and miRNAs), as well as applications like personalized medicine, homecare monitoring, and wearables.

PtPd catalysts are state-of-the-art for automotive diesel exhaust gas treatment. Although wet-chemical preparation of PtPd nanoparticles below 3 nm and kg-scale synthesis of supported PtPd/Al2O3 are already established, the partial segregation of the bimetallic nanoparticles remains an issue that adversely affects catalytic performance. As a promising alternative, laser-based catalyst preparation allows the continuous synthesis of surfactant-free, solid-solution alloy nanoparticles at the g/h-scale. However, the required productivity of the catalytically relevant size fraction <10 nm has yet to be met. In this work, by optimization of ablation and fragmentation conditions, the continuous flow synthesis of nanoparticles with a productivity of the catalytically relevant size fraction <10 nm of >1 g/h is presented via an in-process size tuning strategy. After the laser-based preparation of hectoliters of colloid and more than 2 kg of PtPd/Al2O3 wash coat, the laser-generated catalysts were benchmarked against an industry-relevant reference catalyst. The conversion of CO by laser-generated catalysts was found to be equivalent to the reference, while improved activity during NO oxidation was achieved. Finally, the present study validates that laser-generated catalysts meet the size and productivity requirements for industrial standard operating procedures. Hence, laser-based catalyst synthesis appears to be a promising alternative to chemical-based preparation of alloy nanoparticles for developing industrial catalysts, such as those needed in the treatment of exhaust gases.