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Golfers must modify their motor patterns when the demands of a putting task change. The objective was to compare joint angles and putter kinematics during putting at two distances and inclines. Recreational golfers (n = 14) completed putts over four conditions: 3-foot putts on flat and incline surfaces, and 7-foot putts on flat and incline surfaces. A Vicon motion capture system measured kinematic data. Joint angles, putter angles, and spatiotemporal variables were calculated. Analysis of variance compared spatiotemporal variables, and statistical parametric mapping compared angles between putts. There were faster putter head and ball velocities during longer and incline putts. The amplitude and time of backswing increased with longer putts. Longer putts resulted in increased trunk axial rotation during backswing, downswing, and follow-through, while incline putts only resulted in greater rotation during follow-through. There were minimal differences in shoulder angle. There was greater head rotation toward the hole during all putting phases for longer putts and during follow-through for incline putts. The trunk is the primary mechanism to increase putter head amplitude, and thereby velocity, when putting from longer distances. A similar strategy could be used when putting uphill. Additional work should confirm these results in highly skilled golfers.

Abstract Volcano-shaped microelectrodes have demonstrated superior performance in measuring attenuated intracellular action potentials from cardiomyocyte cultures. However, their application to neuronal cultures has not yet yielded reliable intracellular access. This common pitfall supports a growing consensus in the field that nanostructures need to be pitched to the cell of interest to enable intracellular access. Accordingly, we present a new methodology that enables us to resolve the cell/probe interface noninvasively through impedance spectroscopy. This method measures changes in the seal resistance of single cells in a scalable manner to predict the quality of electrophysiological recordings. In particular, the impact of chemical functionalization and variation of the probe’s geometry can be quantitatively measured. We demonstrate this approach on human embryonic kidney cells and primary rodent neurons. Through systematic optimization, the seal resistance can be increased by as much as 20-fold with chemical functionalization, while different probe geometries demonstrated a lower impact. The method presented is therefore well suited to the study of cell coupling to probes designed for electrophysiology, and it is poised to contribute to elucidate the nature and mechanism of plasma membrane disruption by micro/nanostructures.

The controlled contact between two micro-sized objects, such as beads and cells, and the assessment of their adhesion status is demonstrated in this research. The controlled contact is carried out in a microfluidic channel under flow conditions and makes use of a combination of hydrodynamic traps, flow drag force and dielectrophoretic (DEP) force to maintain the two objects in contact for the desired duration in a first step. Then, the pair objects are separated in the second step in order to explore their adhesion status. Adhesion events are mediated by the bond formed between a receptor and its ligand, and their binding kinetic parameters can be extracted from the measurements using the proposed device.

Single-cell isolation is a truly transformative tool for the understanding of biological systems. It allows single-cell molecular analyses and considers the heterogeneity of cell populations, which is of particular relevance for the diagnosis and treatment of evolving diseases and for personalized medicine. Single-cell isolation is also a key process in cell line development, where it is used to obtain stable and high producing clonally-derived cell lines, thus contributing to the efficiency, safety and reproducible quality of the drug produced. High producing clonally-derived cell lines are however rare events and their identification is a time-consuming process that requires the screening of thousands of clones. Therefore, there is an unmet need for a device that would allow the fast and efficient isolation of single cells, while preserving their integrity and providing an insurance of their clonality.We proposed earlier an impedance based pipetting technology for isolation of single cells (Bonzon et al., 2020), with initial validations for state-of-the-art stem cell in-vitro and in-vivo assays (Muller et al., 2020). Here, we present the transition from this pioneering technology developed in an academic setting into an automated instrument, called DispenCell-S1, allowing for traceable isolation of single cells.We developed and validated models predicting the performances for 96-well plates single-cell isolation. This resulted in a time of dispense down to 3 min and a plate filling rate up to 96%. Finally, we obtained an impedance signal reliability for proof of single particle isolation of 99% with beads and ranging from 93 to 95% with CHO cells.

N-arylated bicyclic alkaloid skeletons are attractive scaffolds for medicinal chemistry, but aren’t conveniently accessible via the classical Robinson tropane synthesis. Here, a mild and simple visible-light catalyzed radical [3 + 3]-annulation process is designed, affording N-arylated 8-azabicyclo[3.2.1]octane and 9-azabicyclo[3.3.1]nonane derivatives with good yields and high diastereoselectivity from readily available starting materials.

We present a microfluidic dielectrophoretic-actuated system designed to trap chosen single-cell and form controlled cell aggregates. A novel method is proposed to characterize the efficiency of the dielectrophoretic trapping, considering the flow speed but also the heat generated by the traps as limiting criteria in cell-safe manipulation. Two original designs with different manufacturing processes are experimentally compared. The most efficient design is selected and the cell membrane integrity is monitored by fluorescence imaging to guarantee a safe-cell trapping. Design rules are suggested to adapt the traps to multiple-cells trapping and are experimentally validated as we formed aggregates of controlled size and composition with two different types of cells. We provide hereby a simple manufactured tool allowing the controlled manipulation of particles for the composition of multicellular assemblies.

Myocardium consists of cardiac cells that interact with their environment through physical, biochemical, and electrical stimulations. The physiology, function, and metabolism of cardiac tissue are affected by this dynamic structure. Within the myocardium, cardiomyocytes’ orientations are parallel, creating a dominant orientation. Additionally, local alignments of fibers, along with a helical organization, become evident at the macroscopic level. For the successful development of a reliable in vitro cardiac model, evaluation of cardiac cells’ behavior in a dynamic microenvironment, as well as their spatial architecture, is mandatory. In this study, we hypothesize that complex interactions between long-term contraction boundary conditions and cyclic mechanical stimulation may provide a physiological mechanism to generate off-axis alignments in the preferred mechanical stretch direction. This off-axis alignment can be engineered in vitro and, most importantly, mirrors the helical arrangements observed in vivo. For this purpose, uniaxial mechanical stretching of dECM-fibrin hydrogels was performed on pre-aligned 3D cultures of cardiac cells. In view of the potential development of helical structures similar to those in native hearts, the possibility of generating oblique alignments ranging between 0° and 90° was explored. Indeed, our investigations of cell alignment in 3D, employing both mechanical stimulation and groove constraint, provide a reliable mechanism for the generation of helicoidal structures in the myocardium. By combining cyclic stretch and geometric alignment in grooves, an intermediate angle toward favored direction can be achieved experimentally: while cyclic stretch produces a perpendicular orientation, geometric alignment is associated with a parallel one. In our 2D and 3D culture conditions, nonlinear cellular addition of the strains and strain avoidance concept reliably predicted the preferred cellular alignment. The 3D dECM-fibrin model system in this study shows that cyclical stretching supports cell survival and development. Using mechanical stimulation of pre-aligned heart cells, maturation markers are augmented in neonatal cardiomyocytes, while the beating culture period is prolonged, indicating an improved model function. We propose a simplified theoretical model based on numerical simulation and nonlinear strain avoidance by cells to explain oblique alignment angles. Thus, this work lays a possible rational basis for understanding and engineering oblique cellular alignments, such as the helicoidal layout of the heart, using approaches that simultaneously enhance maturation and function.

Cardiomyocyte alignment in myocardium tissue plays a significant role in the physiological, electrical, and mechanical functions of the myocardium. It remains, however, difficult to align cardiac cells in a 3D in vitro heart model. This paper proposes a simple method to align cells using microfabricated Polydimethylsiloxane (PDMS) grooves with large dimensions (of up to 350 µm in width), similar to the dimensions of trabeculae carneae, the smallest functional unit of the myocardium. Two cell groups were used in this work; first, H9c2 cells in combination with Nor10 cells for proof of concept, and second, neonatal cardiac cells to investigate the functionality of the 3D model. This model compared the patterned and nonpatterned 3D constructs, as well as the 2D cell cultures, with and without patterns. In addition to alignment, we assessed the functionality of our proposed 3D model by comparing beating rates between aligned and non-aligned structures. In order to assess the practicality of the model, the 3D aligned structures should be demonstrated to be detachable and alignable. This evaluation is crucial to the use of this 3D functional model in future studies related to drug screening, building blocks for tissue engineering, and as a heart-on-chip by integrating microfluidics.

Recently there has been an explosion of interest in the synthetic community for the addition of radicals into unsaturated organoboron-ate complexes. This review will give a concise outline for radical processes involving boron-ate complexes which trigger a subsequent anionotropic rearrangement.

Common radical fluorination reagents, such as Selectofluor®, are penalized by the need for metal catalysts and possible oxidation side reactions. Here, the authors reported the synthesis and application of N-fluoro-N-arylsulfonamides (NFASs) as third generation of radical fluorinating reagents to overcome those limitations.

Current approaches studying the collection of extracellular fluid to monitor neurological disorders have temporal resolution limitations. Here the authors show functional in vivo validation of a droplet collection system included at the tip of a neural probe.

Droplet microfluidics are characterized by the generation and manipulation of discrete volumes of solutions, generated with the use of immiscible phases. Those droplets can then be controlled, transported, analyzed or their content modified. In this wide droplet microfluidic toolbox, no means are available to generate, in a controlled manner, droplets co-encapsulating to aqueous phases. Indeed, current methods rely on random co-encapsulation of two aqueous phases during droplet generation or the merging of two random droplets containing different aqueous phases. In this study, we present a novel droplet microfluidic device to reliably and efficiently co-encapsulate two different aqueous phases in micro-droplets. In order to achieve this, we combined existing droplet microfluidic modules in a novel way. The different aqueous phases are individually encapsulated in droplets of different sizes. Those droplet populations are then filtered in order to position each droplet type towards its adequate trapping compartment in traps of a floating trap array. Single droplets, each containing a different aqueous phase, are thus paired and then merged. This pairing at high efficiency is achieved thanks to a unique combination of floating trap arrays, a droplet railing system and a droplet size-based filtering mechanism. The microfluidic chip design presented here provides a filtering threshold with droplets larger than 35 μm (big droplets) being deviated to the lower rail while droplets smaller than 20 μm (small droplets) remain on the upper rail. The effects of the rail height and the distance between the two (upper and lower) rails were investigated. The optimal trap dimensions provide a trapping efficiency of 100% for small and big droplets with a limited double trapping (both compartments of the traps filled with the same droplet type) of 5%. The use of electrocoalescence enables the generation of a droplet while co-encapsulating two aqueous phases. Using the presented microfluidic device libraries of 300 droplets, dual aqueous content can be generated in less than 30 min.

A convenient strategy for molecular editing of available ent-kauranic natural scaffolds has been developed based on radical mediated C–C bond formation. Iodine atom transfer radical addition (ATRA) followed by rapid ionic elimination and radical azidoalkylation were investigated. Both reactions involve radical addition to the exo-methylenic double bond of the parent substrate. Easy transformations of the obtained adducts lead to extended diterpenes of broad structural diversity and artificial diterpene-alkaloid hybrids possessing lactam and pyrrolidine pharmacophores. The cytotoxicity of selected diterpenic derivatives was examined by in vitro testing on several tumor cell lines. The terpene-alkaloid hybrids containing N-heterocycles with unprecedented spiro-junction have shown relevant cytotoxicity and promising selectivity indexes. These results represent a solid basis for following research on the synthesis of such derivatives based on available natural product templates.

While gustatory systems have been extensively studied in adult Drosophila, not much is known about taste coding at the larval stage. Here, the authors investigate gustatory receptor neurons in larvae and find single neurons are capable of responding to more than one taste modality.

Polydimethylsiloxane (PDMS) and SU-8 are currently two very commonly used polymeric materials in the microfluidics field for biological applications. However; there is a pressing need to find a simple, reliable, irreversible bonding method between these two materials for their combined use in innovative integrated microsystems. In this paper, we attempt to investigate the aminosilane-mediated irreversible bonding method for PDMS and SU-8 with X-Ray Photoelectron Spectroscopy (XPS) surface analysis and bonding strength tests. Additionally, the selected bonding method was applied in fabricating a microelectrode array (MEA) device, including microfluidic features, which allows electrophysiological observations on compartmentalized neuronal cultures. As there is a growing trend towards microfluidic devices for neuroscience research, this type of integrated microdevice, which can observe functional alterations on compartmentalized neuronal culture, can potentially be used for neurodegenerative disease research and pharmaceutical development.

Several recent detector technologies developed for particle physics applications are based on microfabricated structures. Detectors built with this approach generally exhibit the overall best performance in terms of spatial and time resolution. Many properties of the SU-8 photoepoxy make it suitable for the manufacturing of microstructured particle detectors. This article aims to review some emerging detector technologies making use of SU-8 microstructuring, namely micropattern gaseous detectors and microfluidic scintillation detectors. The general working principle and main process steps for the fabrication of each device are reported, with a focus on the advantages brought to the device functionality by the use of SU-8. A novel process based on multiple bonding steps for the fabrication of thin multilayer microfluidic scintillation detectors developed by the authors is presented. Finally, a brief overview of the applications for the discussed devices is given.

Total knee arthroplasty is a widely performed surgical technique. Soft tissue force balancing during the operation relies strongly on the experience of the surgeon in equilibrating tension in the collateral ligaments. Little information on the forces in the implanted prosthesis is available during surgery and post-operative treatment. This paper presents the design, fabrication and testing of an instrumented insert performing force measurements in a knee prosthesis. The insert contains a closed structure composed of printed circuit boards and incorporates a microfabricated polyimide thin-film piezoresistive strain sensor for each condylar compartment. The sensor is tested in a mechanical knee simulator that mimics in-vivo conditions. For characterization purposes, static and dynamic load patterns are applied to the instrumented insert. Results show that the sensors are able to measure forces up to 1.5 times body weight with a sensitivity fitting the requirements for the proposed use. Dynamic testing of the insert shows a good tracking of slow and fast changing forces in the knee prosthesis by the sensors.

Biomimetics often provides efficient ways to create a product incorporating novel properties. Here we present the replication of the Pieris rapae butterfly optical structure. This butterfly has white wings with black spots. The white coloration is produced by light scattering on pterin beads ranging from 100 to 500 nm whereas black spots correspond to areas without pterin beads, thus revealing a highly pigmented layer underneath. In order to mimic the butterfly wing structure, we deposited SU-8 beads produced by electrospraying on a black absorbing layer made of black SU-8. We thereby replicated the optical effect observed on Pieris rapae. Additional experiments showed that the white coloration replication is a structural color. Finally, we further demonstrate that these optical engineered surfaces can be used for sucrose sensing in the range of 1 g/L to 250 g/L.

The radical azidoalkylation of alkenes that was initially developed with α-iodoesters and α-iodoketones was extended to other activated iodomethyl derivatives. By using iodomethyl aryl sulfones, the preparation of γ-azidosulfones was easily achieved. Facile conversion of these azidosulfones to homoallylic azides using a Julia−Kocienski olefination reaction is reported, making the whole process equivalent to the azidoalkenylation of terminal alkenes.

In 1997, the first paper using SU-8 as a material for microfabrication was published [1], demonstrating the interest of this negative photoresist for the near-UV structuration of thick layers and the manufacturing of high aspect-ratio components.[...]

Here we present an electrical lysis throughput of 600 microliters per minute at high cell density (108 yeast cells per ml) with 90% efficiency, thus improving the current common throughput of one microliter per minute. We also demonstrate the extraction of intracellular luciferase from mammalian cells with efficiency comparable to off-chip bulk chemical lysis. The goal of this work is to develop a sample preparation module that can act as a stand-alone device or be integrated to other functions already demonstrated in miniaturized devices, including sorting and analysis, towards a true lab-on-a-chip.

We present the fabrication and evaluation of microdebubblers that are able to remove large bubbles while keeping a very low dead volume. The devices use a polytetrafluoroethylene membrane that is permeable to air in order to filter air bubbles out of an aqueous sample. The dead volume of the devices is less than one microliter, but bubbles as large as 60 microliters can be removed. This simple solution can be very useful for microfluidic devices for chemical or biological analysis that suffer from channel clogging due to the presence of bubbles in their sample. One embodiment is particularly suited for buffer solutions with living cells.

Advances in 3D printing have enabled the use of this technology in a growing number of fields, and have started to spark the interest of biologists. Having the particularity of being cell friendly and allowing multimaterial deposition, extrusion-based 3D printing has been shown to be the method of choice for bioprinting. However as biologically relevant constructs often need to be of high resolution and high complexity, new methods are needed, to provide an improved level of control on the deposited biomaterials. In this paper, we demonstrate how microfluidics can be used to add functions to extrusion 3D printers, which widens their field of application. Micromixers can be added to print heads to perform the last-second mixing of multiple components just before resin dispensing, which can be used for the deposition of new polymeric or composite materials, as well as for bioprinting new materials with tailored properties. The integration of micro-concentrators in the print heads allows a significant increase in cell concentration in bioprinting. The addition of rapid microfluidic switching as well as resolution increase through flow focusing are also demonstrated. Those elementary implementations of microfluidic functions for 3D printing pave the way for more complex applications enabling new prospects in 3D printing.

Water or low molecular weight alcohols are, due to their availability, low price and low toxicity ideal reagents for organic synthesis. Recently, it was reported that, despite the very strong BDE of the O–H bond, they can be used as hydrogen atom donors in place of expensive and/or toxic group 14 metal hydrides when boron and titanium(III) Lewis acids are present. This finding represents a considerable innovation and uncovers a new perspective on the paradigm of hydrogen atom transfers to radicals. We discuss here the influence of complex formation and other association processes on the efficacy of the hydrogen transfer step. A delicate balance between activation by complex formation and deactivation by further hydrogen bonding is operative.

We present a novel study on label-free recognition and distinction of drug resistant breast cancer cells (MCF-7 DOX) from their parental cells (MCF-7 WT) via impedimetric measurements. Drug resistant cells exhibited significant differences in their dielectric properties compared to wild-type cells, exerting much higher extracellular resistance (Rextra ). Immunostaining revealed that MCF-7 DOX cells gained a much denser F-actin network upon acquiring drug resistance indicating that remodeling of actin cytoskeleton is probably the reason behind higher Rextra , providing stronger cell architecture. Moreover, having exposed both cell types to doxorubicin, we were able to distinguish these two phenotypes based on their substantially different drug response. Interestingly, impedimetric measurements identified a concentration-dependent and reversible increase in cell stiffness in the presence of low non-lethal drug doses. Combined with a profound frequency analysis, these findings enabled distinguishing distinct cellular responses during drug exposure within four concentration ranges without using any labeling. Overall, this study highlights the possibility to differentiate drug resistant phenotypes from their parental cells and to assess their drug response by using microelectrodes, offering direct, real-time and noninvasive measurements of cell dependent parameters under drug exposure, hence providing a promising step for personalized medicine applications such as evaluation of the disease progress and optimization of the drug treatment of a patient during chemotherapy.

Native functional brain circuits show different numbers of synapses (synaptic densities) in the cerebral cortex. Until now, different synaptic densities could not be studied in vitro using current cell culture methods for primary neurons. Herein, we present a novel microfluidic based cell culture method that combines 3D micropatterning of hydrogel layers with linear chemical gradient formation. Micropatterned hydrogels were used to encapsulate dissociated cortical neurons in laminar cell layers and neurotrophic factors NGF and B27 were added to influence the formation of synapses. Neurotrophic gradients allowed for the positioning of distinguishable synaptic densities throughout a 3D micropatterned neural culture. NGF and B27 gradients were maintained in the microfluidic device for over two weeks without perfusion pumps by utilizing a refilling procedure. Spatial distribution of synapses was examined with a pre-synaptic marker to determine synaptic densities. From our experiments, we observed that (1) cortical neurons responded only to synergistic NGF/B27 gradients, (2) synaptic density increased proportionally to synergistic NGF/B27 gradients; (3) homogeneous distribution of B27 disturbed cortical neurons in sensing NGF gradients and (4) the cell layer position significantly impacted spatial distribution of synapses.

Radical reactions offer many advantages over conventional chemical reactions, lending themselves to numerous bond forming processes and rearrangements that are, clean, rapid, and tolerant of a wide range of functional groups. This review provides a brief overview of the design concepts behind new reactions illustrating, in particular, their relevance for the efficient synthesis of biomolecules. Two general reactions are highlighted: single electron transfer (SET) using SmI2 and hydrogen transfer using reagents such as those based on tin, thiols and phosphorous reagents. Intermolecular influences that may direct radical reactions, such as partial protonation and radical complexation, are also discussed.

The stereochemical outcome of intramolecular radical mediated hydrogen transfer (= radical translocation) is discussed. Low to excellent levels of stereocontrol are observed making such processes attractive for applications in target-oriented synthesis.

Nature Communications 7: Article number: 10687 (2016); Published: 11 February 2016; Updated: 14 March 2016. The affiliation details for Martino Colombo, Rémy Bruggmann and Richard Benton are incorrect in this article. The correct affiliations for these authors are listed below. Martino Colombo, RémyBruggmann Interfaculty Bioinformatics Unit and Swiss Institute of Bioinformatics, University of Berne, Berne 3012, Switzerland.

The radical reduction of B-alkylcatecholboranes into alkanes using alcohols and water as hydrogen atom source is described. This process involves a completely unexpected mechanism: the alcohol (or water) complexed to a borate derivative acts as a reducing agent. The complexation activates the alcohol resulting in a decrease of the O–H bond dissociation energy. This approach offers promising opportunities for the development of tin-free radical reducing agent. Closely related reports from the recent literature involving boron and titanium derivatives are also presented.

The intramolecular Schmidt reaction was first described at the beginning of the 1990s and rapidly proved to be a powerful tool for the fast assembly of complex nitrogen-containing heterocycles. This review focuses on the application of this reaction in the synthesis of natural products and other biologically relevant compounds.

Cylindricines, lepadiformine, and fasicularin are marine alkaloids with a common novel pyrrolo- and pyrido[1,2-j]quinoline skeleton. They have recently been isolated from various tunicates and have shown interesting cytotoxic effects which could be attributed to covalent interactions with DNA, as well as cardiovascular effects. The promising biological activities together with the unique structural features make these alkaloids interesting targets for natural product synthesis. This review focuses on the different approaches developed for their synthesis with a particular emphasis on the key step where the quaternary amino substituted carbon center is created.

Radical coupling of B-alkylcatecholboranes, in situ generated from the corresponding alkenes, with ethyl 2-(benzenesulfonylamino)acrylate is reported. This reaction represents an extension of the radical allylation of Balkylcatecholboranes by allylsulfones. This unique process allows the preparation of various ?-ketoesters (alkylated pyruvates) in a straightforward manner. It also demonstrates the generality of the radical mediated C–C bond formation starting from organoboranes and allylic benzenesulfonyl derivatives.

The radical carboazidation of alkenes could be achieved in water using triethylborane as initiator. This efficient process is complete in one hour at room temperature in an open system. These new tin-free azidation and carboazidation conditions are environmentally friendly and enable reactions to be run with an excess of either the alkene or the radical precursor. Furthermore, 3-pyridinesulfonyl azide could be used in order to avoid tedious purifications, especially when the reaction product has a similar chromatographic behavior to benzenesulfonyl azide, our original azidation reagent.