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Neurons in the central nervous system (CNS) fail to regenerate axons after injuries due to the diminished intrinsic axon growth capacity of mature neurons and the hostile extrinsic environment composed of a milieu of inhibitory factors. Recent studies revealed that targeting a particular group of extracellular inhibitory factors is insufficient to trigger long-distance axon regeneration. Instead of antagonizing the growing list of impediments, tackling a common target that mediates axon growth inhibition offers an alternative strategy to promote axon regeneration. Neuronal growth cone, the machinery that derives axon extension, is the final converging target of most, if not all, growth impediments in the CNS. In this study, we aim to promote axon growth by directly targeting the growth cone. Here we report that pharmacological inhibition or genetic silencing of nonmuscle myosin II (NMII) markedly accelerates axon growth over permissive and nonpermissive substrates, including major CNS inhibitors such as chondroitin sulfate proteoglycans and myelin-associated inhibitors. We find that NMII inhibition leads to the reorganization of both actin and microtubules (MTs) in the growth cone, resulting in MT reorganization that allows rapid axon extension over inhibitory substrates. In addition to enhancing axon extension, we show that local blockade of NMII activity in axons is sufficient to trigger axons to grow across the permissive-inhibitory border. Together, our study proposes NMII and growth cone cytoskeletal components as effective targets for promoting axon regeneration. [ABSTRACT FROM AUTHOR]

The advent of stem cell based therapies has brought regenerative medicine into an increased focus as a part of the modern medicine practice, with a potential to treat a myriad of intractable diseases in the future. Stem cells reside in a complex microenvironment presenting them with a multitude of potential cues that are chemical, physical, and mechanical in nature. Conventional techniques used for experiments involving stem cells can only poorly mimic the physiological context, and suffer from imprecise spatial and temporal control, low throughput, lack of scalability and reproducibility, and poor representation of the mechanical and physical cell microenvironment. Novel lab-on-a-chip platforms, on the other hand, can much better mimic the complexity of in vivotissue milieu and provide a greater control of the parameter variation in a high throughput and scalable manner. This capability may be especially important for understanding the biology and cementing the clinical potential of stem cell based therapies. Here we review microfabrication- and microfluidics-based approaches to investigating the complex biology of stem cell responses to changes in the local microenvironment. In particular, we categorize each method based on the types of controlled inputs it can have on stem cells, including soluble biochemical factors, extracellular matrix interactions, homotypic and heterotypic cell-cell signaling, physical cues (e.g.oxygen tension, pH, temperature), and mechanical forces (e.g.shear, topography, rigidity). Finally, we outline the methods to perform large scale observations of stem cell phenotypes and high-throughput screening of cellular responses to a combination of stimuli, and many new emerging technologies that are becoming available specifically for stem cell applications. [ABSTRACT FROM AUTHOR]

Most microfluidic devices developed to date for the analysis of live cells incorporate channels with relatively simple constant rectangular or semi-circular cross-sections, relying on complex channel network geometries rather than alteration of the shapes of the channels themselves for development of diverse functional fluidic controls, e.g., spatial gradients of bioactive ligands. In this study we describe a simple alternative method to create highly defined and predictable gradients of surface bound molecules. This method relies on the generation of a considerable variation in the spatial distribution of flow velocities within a channel with a triangular cross-section. The triangular shape can be easily implemented by using bulk wet etching and polydimethylsiloxane (PDMS) replica molding techniques. By analytical modeling and simulation, we predict that the deposition of the solute onto a channel boundary depends on the local flow rate values, yielding gradient spanning the whole width of the channel. This prediction was validated by direct visualization of the flow rate and fibronectin–rhodamine deposition in a fabricated microchannel. Using this experimental platform, we assessed cell migration in response to a fibronectin gradient deposited in the microchannels. We find that this gradient could induce robust haptotaxis of Chinese Hamster Ovary (CHO) cells towards the areas of higher fibronectin surface density. We propose that the described simple gradient generation method can help to avoid complexity present in many current device designs, allowing to introduce more easily other potentially useful design features. [ABSTRACT FROM AUTHOR]

As everybody knows, Coca-Cola is a symbol for the American consumer culture, at the same time, it is a top global brand-value drink. However, at its early stage, Coca-Cola was advertised and sold as a patent medicine for headaches, gastroenteritis, or tonic. If then, why has its usage been switched from patent medicine to soft drink despite its ingredients has been little changed more than 120 years? This article tries to answer to this question by way of analyzing the advertisements of Coca-Cola. Unlike the existing interpretation, Joseph Pemberton, the inventor of Coca-Cola, sold it as a soda beverage. As its sale was very bad, however, he switched its selling target into a patent medicine for the white-collar. Due to Pemberton's untimely death, Asa Candler undertook Pemberton's business. He also posited its goal as a patent medicine. Once its purchasers had been diverse, about after 1890s he also advertised it as a soft drink for the mass consumers. At that time, in particular, Frank Robinson being responsible for its advertisement keenly recognized the advent of mass consumer society in America. Even though this kind of Candler's dual strategy seems to be ambiguous whether it was patent medicine or soft drink, in fact, he seemed to strive for two purposes at the same time. During the Spanish-American War of 1898, when the federal government imposed taxes to the medicinal goods the Coca-Cola Company stood at the crossroad. Furthermore, when the federal government basing on the Pure Food and Drug Act of 1906 raised a lawsuit against the Coca-Cola Company, its advertising strategy had been changed. As a result, at its ad copies words such as 'relieve fatigue,' 'tonic,' 'nerve' had disappeared, instead, words such as 'fun,' 'pleasure,' 'satisfying,' 'thirst' had shown up. [ABSTRACT FROM AUTHOR]

During early development, the chorion envelope of the zebrafish embryo undergoes a thinning process called "chorion softening," which has so far only been characterized chemically. In this study, a micromechanical force sensing system was used to characterize and quantitate mechanical modifications of the zebrafish embryo chorion during early development. Quantitative relationships between applied forces and chorion structural deformations were established at various embryonic stages. The measured penetration force into the chorion at the blastula stage was 1.3-fold greater than those at the prehatching stage. Furthermore, chorion elastic modulus values were determined by using a biomembrane elastic model. The elastic modulus of the chorion at the blastula stage was 1.66-fold greater than that at the prehatching stage, thus indicating that the chorion envelope become mechanically "softened" at the prehatching stage. The experimental results quantitatively describe "chorion softening," which is most likely due to proteolytic activities at the prehatching stage. Gradual chorion softening during embryonic development was also artificially achieved by treating blastula chorion with pronase, a proteolytic enzyme. The forces required to penetrate the pronase-treated chorion were similar to those at the prehatching stage. This similarity suggests that "chorion softening" may be induced by the release of protease from the embryos, and the chemical nature of the process involves proteolytic fragmentation of the ZP2 protein. [ABSTRACT FROM PUBLISHER]

In this paper, a flexible microassembly system based on hybrid manipulation scheme is proposed to apply to the assembly of photonics components such as lensed optical fiber ferrules and laser diode (LD) pumps. In order to achieve both high precision and dexterity in microassembly, we propose a hybrid microassembly system with sensory feedbacks of vision and force. This system consists of the distributed six degrees of freedom (DOF) micromanipulation units, the stereomicroscope, and haptic interface for the force feedback-based microassembly. A hybrid assembly method, which combines the vision-based microassembly and the scaled teleoperated microassembly with force feedback, is proposed. The feasibility of the proposed method is investigated via experimental studies for assembling micro-optoelectrical components. Experimental results show that the hybrid microassembly system is feasible for applications to the assembly of photonic components in the commercial market with better flexibility and efficiency. [ABSTRACT FROM AUTHOR]

This paper presents the design and control of a sensorized microgripper using a voice coil motor and a flexure mechanism. To increase the gripping sensitivity, shape design and determination of sensor attachment position are performed using finite element analysis. Empirical models of the microgripper are acquired for the design of position control and gripping force control. By using the identified models, both the perfect tracking controller for position control and the adaptive zero-phase error tracking controller for force control are implemented. The effectiveness of the proposed model-based control methods is verified by experimental studies. [ABSTRACT FROM PUBLISHER]

A simple kinetic model is presented to describe the capillary rise of a thin polymer film into a less permeable polyurethane acrylate mold. In this model, capillarity is explained by the competition between capillary and hydrodynamic forces in the course of pattern formation. For a less permeable mold, it was found that the capillary rise increases linearly with time. In addition, the contribution of viscosity and film thickness disappears such that the kinetics is solely governed by the permeation kinetics and capillary force. The present model would be useful to describe the evolution of molded nanostructures when a less permeable mold material other than polydimethylsiloxane is used for the patterning. Moreover, nanostructures with different tip shapes (rounded or dimpled) were observed depending on the fabrication temperature. The structures were tested for potential nanotribological applications such as reduction in adhesive and friction forces. [ABSTRACT FROM AUTHOR]

We report a simple and versatile method for in vitro fabrication of scaffold-free tissue-engineered constructs with predetermined cellular alignment, by combining magnetic cell levitation with thermoresponsive nanofabricated substratum (TNFS) based cell sheet engineering technique. The TNFS based nanotopography provides contact guidance cues for regulation of cellular alignment and enables cell sheet transfer, while magnetic nanoparticles facilitate the magnetic levitation of the cell sheet. The temperature-mediated change in surface wettability of the thermoresponsive poly(N-isopropylacrylamide), substratum enables the spontaneous detachment of cell monolayers, which can then be easily manipulated through use of a ring or disk shaped magnet. Our developed platform could be readily applicable to production of tissue-engineered constructs containing complex physiological structures for the study of tissue structure–function relationships, drug screening, and regenerative medicine. [ABSTRACT FROM AUTHOR]

Human organ-on-a-chip models are powerful tools for preclinical research that can be used to study the mechanisms of disease and evaluate new targets for therapeutic intervention. Lung-on-a-chip models have been one of the most well-characterized designs in this field and can be altered to evaluate various types of respiratory disease and to assess treatment candidates prior to clinical testing. These systems are capable of overcoming the flaws of conventional two-dimensional (2-D) cell culture and in vivo animal testing due to their ability to accurately recapitulate the in vivo microenvironment of human tissue with tunable material properties, microfluidic integration, delivery of precise mechanical and biochemical cues, and designs with organ-specific architecture. In this review, we first describe an overview of currently available lung-on-a-chip designs. We then present how recent innovations in human stem cell biology, tissue engineering, and microfabrication can be used to create more predictive human lung-on-a-chip models for studying respiratory disease. Finally, we discuss the current challenges and future directions of lung-on-a-chip designs for in vitro disease modeling with a particular focus on immune and multiorgan interactions. [ABSTRACT FROM AUTHOR]

Mutations in A-type nuclear lamins cause dilated cardiomyopathy, which is postulated to result from dysregulated gene expression due to changes in chromatin organization into active and inactive compartments. To test this, we performed genome-wide chromosome conformation analyses in human induced pluripotent stem cell–derived cardiomyocytes (hiPSCCMs) with a haploinsufficient mutation for lamin A/C. Compared with gene-corrected cells, mutant hiPSC-CMs have marked electrophysiological and contractile alterations, with modest gene expression changes. While large-scale changes in chromosomal topology are evident, differences in chromatin compartmentalization are limited to a few hotspots that escape segregation to the nuclear lamina and inactivation during cardiogenesis. These regions exhibit up-regulation of multiple noncardiac genes including CACNA1A, encoding for neuronal P/Q-type calcium channels. Pharmacological inhibition of the resulting current partially mitigates the electrical alterations. However, chromatin compartment changes do not explain most gene expression alterations in mutant hiPSC-CMs. Thus, global errors in chromosomal compartmentation are not the primary pathogenic mechanism in heart failure due to lamin A/C haploinsufficiency. [ABSTRACT FROM AUTHOR]