Microfluidics in the “Open Space” for Performing Localized Chemistry on Biological Interfaces

Local interactions between (bio)chemicals and biological interfaces play an important role in fields ranging from surface patterning to cell toxicology. These interactions can be studied using microfluidic systems that operate in the “open space”, that is, without the need for the sealed channels and chambers commonly used in microfluidics. This emerging class of techniques localizes chemical reactions on biological interfaces or specimens without imposing significant “constraints” on samples, such as encapsulation, pre‐processing steps, or the need for scaffolds. They therefore provide new opportunities for handling, analyzing, and interacting with biological samples. The motivation for performing localized chemistry is discussed, as are the requirements imposed on localization techniques. Three classes of microfluidic systems operating in the open space, based on microelectrochemistry, multiphase transport, and hydrodynamic flow confinement of liquids are presented.     

“intelligent” polymers in medicine and biotechnology

One can define “intelligent” polymers as those polymers which respond with large property changes to small physical or chemical stimuli. These polymers may be in various forms, such as in solution, on surfaces, or as solids. One may also combine “intelligent” aqueous polymer systems with biomolecules, to yield a large family of polymers which respond “intelligently” to physical, chemical or biological stimuli. This article overviews such interesting and versatile polymer systems.     

Competitive reactivities of vinylthiyl radicals thermally generated from haloethylenes and hydrogen sulfide

Acetylene and its derivatives have been used for the first time as “traps” for vinylthiyl radicals generatedin situ from hydrogen sulfide and haloethylenes in gas-phase processes. The competitive reactivity of the vinylthiyl radicals has been studied at 500–570 °C in the presence of two chemical “traps.” The efficiency of chemical “traps” for the vinylthiyl radicals decreases in the following sequence: HC≡CPh > HC≡CH > MeC≡CH > CH₂=CHCl. Acetylene is a more efficient “trap” for the vinylthiyl radicals than 1,2-dichloroethylene, from which they have been generated. The β-phenylvinylthiyl radicals generated during cothermolysis of halostyrene-hydrogen sulfide-acetylene component ternary systems undergo first of all intramolecular ring closure to give benzothiophene, which is a thermodynamically favorable system; the reaction of these radicals with acetylene and its derivatives occurs much more slowly than heterocyclization. Phenylacetylene is a more efficient “trap” than acetylene. α-Phenylvinylthiyl radicals mostly react with acetylene to yield 2-phenylthiophene.     

Groups of Organic Molecules That Operate Collectively

A “chemical system” is defined as an assemblage of molecules that collectively does something interesting or useful. The key word here is “collectively”, a word that implies an interdependency and a group behavior that can be quite different from that of individual molecules. Batteries, computer chips, concrete, mayonnaise, shampoo, paint, liquid crystal displays, composites, and viruses are all examples of commonly encountered systems. A host–guest or “supramolecular” complex, on the other hand, would not be considered a system (as defined here), because only two species are involved. A chemical system is multimolecular, a collection of molecules interlocked in a tangle of dependencies. The review delves into a variety of chemical systems investigated by the author, including micelles, water pools, films, vesicles, and polymers. All of them can be categorized as “self-assembling” or “self-organizing” in the sense that defined structures arise spontaneously owing to noncovalent forces among the component molecules. Such chemical systems are useful for many purposes, including decontamination of environmentally dangerous substances, drug delivery, and separation of organic compounds.     

Self-Assembly in Natural and Unnatural Systems

Although there are no fundamental factors hindering the development of nanoscale structures, there is a growing realization that “engineering down” approaches, in other words a reduction in the size of structures generated by lithographic techniques below the present lower limit of roughly 1 μm, may become impractical. It has, therefore, become increasingly clear that only by the development of a fundamental understanding of the self-assembly of large-scale biological structures, which exist and function at and beyond the nanoscale, downwards, and the extension of our knowledge regarding the chemical syntheses of small-scale structures upwards, can the gap between the promise and the reality of nanosystems be closed. This kind of construction of nanoscale structures and nanosystems represents the so-called “bottom up” or “engineering up” approach to device fabrication. Significant progress can be made in the development of nanoscience by transferring concepts found in the biological world into the chemical arena. Central to this mission is the development of simple chemical systems capable of instructing their own organization into large aggregates of molecules through their mutual recognition properties. The precise programming of these recognition events, and hence the correct assembly of the growing superstructure, relies on a fundamental understanding and the practical exploitation of non-covalent bonding interactions between and within molecules. The science of supramolecular chemistry—chemistry beyond the molecule in its very broadest sense—has started to bridge the yawning gap between molecular and macro-molecular structures. By utilizing inter-actions as diverse as aromatic π–π stacking and metal–ligand coordination for the information source for assembly processes, chemists have, in the last decade, begun to use biological concepts such as self-assembly to construct nanoscale structures and superstructures with a variety of forms and functions. Here, we provide a flavor of how self-assembly operates in natural systems and can be harnessed in unnatural ones.     

Chemical Syntheses and Chemical Biology of Carboxyl Polyether Ionophores: Recent Highlights

A central goal of chemical biology is to develop molecular probes that enable fundamental studies of cellular systems. In the hierarchy of bioactive molecules, the so‐called ionophore class occupies an unflattering position in the lower branches, with typical labels being “non‐specific” and “toxic”. In fact, the mere possibility that a candidate molecule possesses “ionophore activity” typically prompts its removal from further studies; ionophores—from a chemical genetics perspective—are molecular outlaws. In stark contrast to this overall poor reputation of ionophores, synthetic chemistry owes some of its most amazing achievements to studies of ionophore natural products, in particular the carboxyl polyethers renowned for their intricate molecular structures. These compounds have for decades been academic battlegrounds where new synthetic methodology is tested and retrosynthetic tactics perfected. Herein, we review the most exciting recent advances in carboxyl polyether ionophore (CPI) synthesis and in addition discuss the burgeoning field of CPI chemical biology.     

Der globale Kohlenstoffkreislauf im Anthropozän. Betrachtung aus meereschemischer Perspektive

By burning of fossil fuels humankind emits more than 8 billion tons of carbon (Gt C) in the form of CO₂ to the atmosphere. Since the onset of the industrial revolution the cumulative emissions have led to an increase of the atmospheric CO₂ concentration which corresponds to an additional radiative forcing in the atmosphere. Of the three reservoirs which exchange carbon on the time scale of centuries – atmosphere, terrestrial biosphere, and ocean – the ocean is by far the largest. The marine CO₂ system comprises the chemical species HCO₃^–, CO₃^2–, and CO₂(aq). This gives rise to the pH‐buffering nature of seawater as well as its high uptake capacity for anthropogenic CO₂. Four measurement parameters of the marine CO₂ system are available for an accurate analytical characterization. These parameters also provide a means of sensing the role of physical, chemical, and biological drivers for the marine carbon cycle. The marine carbon cycle features major natural processes that exchange carbon with the atmosphere and re‐distribute it throughout the ocean. These are known as “pumps” and driven by physical and biological factors. While the “physical pump” is inevitably enhanced by the oceanic uptake of anthropogenic CO₂, even the sign of the response is currently not clear for the “biological pumps”. A host of potential consequences of global change (temperature rise, ocean carbonation, ocean acidification) have been identified. These are currently studied intensively with respect to their climate sensitivity as well as the climate feedback potential.     

Bioinspired Chemical Communication between Synthetic Nanomotors

While chemical communication plays a key role in diverse natural processes, the intelligent chemical communication between synthetic nanomotors remains unexplored. The design and operation of bioinspired synthetic nanomotors is presented. Chemical communication between nanomotors is possible and has an influence on propulsion behavior. A chemical “message” is sent from a moving activator motor to a nearby activated (receiver) motor by release of Ag⁺ ions from a Janus polystyrene/Ni/Au/Ag activator motor to the activated Janus SiO₂/Pt nanomotor. The transmitted silver signal is translated rapidly into a dramatic speed change associated with the enhanced catalytic activity of activated motors. Selective and successive activation of multiple nanomotors is achieved by sequential localized chemical communications. The concept of establishing chemical communication between different synthetic nanomotors paves the way to intelligent nanoscale robotic systems that are capable of cooperating with each other.     

Light-Induced Dimerization Approaches to Control Cellular Processes

Light-inducible approaches provide a means to control biological systems with spatial and temporal resolution that is unmatched by traditional genetic perturbations. Recent developments of optogenetic and chemo-optogenetic systems for induced proximity in cells facilitate rapid and reversible manipulation of highly dynamic cellular processes and have become valuable tools in diverse biological applications. New expansions of the toolbox facilitate control of signal transduction, genome editing, “painting” patterns of active molecules onto cellular membranes, and light-induced cell cycle control. A combination of light- and chemically induced dimerization approaches have also seen interesting progress. Herein, an overview of optogenetic systems and emerging chemo-optogenetic systems is provided, and recent applications in tackling complex biological problems are discussed.     

From One‐Photon to Two‐Photon Probes: “Caged” Compounds,Actuators, and Photoswitches

Molecular systems that can be remotely controlled by light are gaining increasing importance in cell biology, physiology, and neurosciences because of the spatial and temporal precision that is achievable with laser microscopy. Two‐photon excitation has significant advantages deep in biological tissues, but raises problems in the design of “smart” probes compatible with cell physiology. This Review discusses the chemical challenges in generating suitable two‐photon probes.     

On de-smearing of heat-flow curves in calorimetry

The calorimetrically measured heat-flow curves of physical, chemical or biological processes are recorded with an intrinsic error, due to the slow heat conduction phenomenon. Mathematical calculations have shown that the size and type of “smearing” is a function of the size, geometry and heat the conductivity of the sample. Under certain conditions, it is possible to mathematically eliminate the “smearing” by employing the Convolution-Integral equation. It is necessary, that one is familiar with the apparatus function. It is demonstrated how one can obtain the apparatus function and steps required for the calculation of “de-smearing”     

Supramolecular Inorganic Chemistry: Small Guests in Small and Large Hosts

A key reaction in the biological and material world is the controlled linking of simple (molecular) building blocks, a reaction with which one can create mesoscopic structures, which, for example, contain cavities and display specifically desired properties, but also compounds that exhibit typical solid-state structures. The best example in this context is the chemistry of host–guest interactions, which spans the entire range from three- and two-dimensional to one- and “zero-dimensional”, discrete host structures. Members of the class of multidimensional compounds have been classified as such for a long time, for example, clathrates and intercalation compounds. Thus far, however, there are no classifications for discrete inorganic host–guest compounds. The first systematic approach can be applied to novel polyoxometalates, a class of compounds which has only recently become known. Molecular recognition; tailor-made, molecular engineering; control of fragment linkage of spin organization and crystallization; cryptands and coronands as “cages” for cations, anions or anion–cation aggregates as sections of ionic lattices; anions within anions, receptors; host–guest interactions; complementarity, as well as the dialectic terms reduction and emergence are important terms and concepts of supramolecular inorganic chemistry. Of particular importance for future research is the comprehension of the mesoscopic area (molècular assemblies)—that between individual molecules and solids (“substances”)—which acts in the biological world as carrier of function and information and for which interesting material properties are expected. This area is accessible through certain variations of “controlled” self-organization processes, which can be demonstrated by using examples from the chemistry of polyoxometalates. The comprehension of the laws that rule the linking of simple polyhedra to give complex systems enables one to deal with numerous interdisciplinary areas of research: crystal physics and chemistry, heterogeneous catalysis, bioinorganic chemistry (biomineralization), and materials science. In addition, conservative self-organization processes, for example template-directed syntheses, are of importance for natural philosophy in the context of the question about the inherent properties of material systems.     

Entropic concepts in electronic structure theory

It is argued that some elusive “entropic” characteristics of chemical bonds, e.g., bond multiplicities (orders), which connect the bonded atoms in molecules, can be probed using quantities and techniques of Information Theory (IT). This complementary perspective increases our insight and understanding of the molecular electronic structure. The specific IT tools for detecting effects of chemical bonds and predicting their entropic multiplicities in molecules are summarized. Alternative information densities, including measures of the local entropy deficiency or its displacement relative to the system atomic promolecule, and the nonadditive Fisher information in the atomic orbital resolution(called contragradience) are used to diagnose the bonding patterns in illustrative diatomic and polyatomic molecules. The elements of the orbital communication theory of the chemical bond are briefly summarized and illustrated for the simplest case of the two-orbital model. The information-cascade perspective also suggests a novel, indirect mechanism of the orbital interactions in molecular systems, through “bridges” (orbital intermediates), in addition to the familiar direct chemical bonds realized through “space”, as a result of the orbital constructive interference in the subspace of the occupied molecular orbitals. Some implications of these two sources of chemical bonds in propellanes, π-electron systems and polymers are examined. The current–density concept associated with the wave-function phase is introduced and the relevant phase-continuity equation is discussed. For the first time, the quantum generalizations of the classical measures of the information content, functionals of the probability distribution alone, are introduced to distinguish systems with the same electron density, but differing in their current(phase) composition. The corresponding information/entropy sources are identified in the associated continuity equations.     

Mechanisms of Autocatalysis

Self‐replication is a fundamental concept. The idea of an entity that can repeatedly create more of itself has captured the imagination of many thinkers from von Neumann to Vonnegut. Beyond the sciences and science fiction, autocatalysis has found currency in economics and language theory, and has raised ethical fears memorably summed up by the “gray goo” trope. Autocatalysis is central to the propagation of life and intrinsic to many other biological processes. This includes the modern conception of evolution, which has radically altered humanity’s image of itself. Organisms can be thought of as imperfect self‐replicators which produce closely‐related species, allowing for selection and evolution. Hence, any consideration of self‐replication raises one of the most profound questions of all: what is life? Minimal self‐replicating systems have been studied with the aim of understanding the principles underlying living systems, allowing us to refine our concepts of biological fitness and chemical stability, self‐organization and emergence, and ultimately to discover how chemistry may become biology.     

Strategies for development of optogenetic systems and their applications

It has become clear that biological processes are highly dynamic and heterogeneous within and among cells. Conventional analytical tools and chemical or genetic manipulations are unsuitable for dissecting the role of their spatiotemporally dynamic nature. Recently, optical control of biomolecular signaling, a technology called “optogenetics,” has gained much attention. The technique has enabled spatial and temporal regulation of specific signaling pathways both in vitro and in vivo. This review presents strategies for optogenetic systems development and application for biological research. Combinations with other technologies and future perspectives are also discussed herein. Although many optogenetic approaches are designed to modulate ion channel conductivity, we mainly examine systems that target other biomolecular reactions such as gene expression, protein translocations, and kinase or receptor signaling pathways.     

Analytical Methods for Characterizing the Nanoparticle–Protein Corona

When nanoparticles (NPs) enter a biological environment, medium components, especially proteins, compete for binding to the NP’s surface, leading to development of a new interface, commonly referred to as the “protein corona.” This rich protein shell gives the NPs a biological identity that can be very different from their synthetic one, in terms of their chemical–physical properties. Understanding NP–protein interaction is crucial for both the bioapplications and safety of nanomaterials. The protein corona provides the primary contact to the cells and their receptors. It defines in vivo fate of the delivery systems, governing the stability, immunogenicity, circulation, clearance rates and organ biodistribution of the NPs. Given its importance, the application and the development of analytical methods to investigate the protein corona are crucial. This review gives an overview of chromatographic, electrophoretic, mass spectrometric and proteomic methods because these techniques have the advantage to be able to identify and quantify individual proteins adsorbed onto the corona. This capability opens up the possibility to exploit the protein corona for specific cell targeting.     

Casting New Physicochemical Light on the Fundamental Biological Processes in Single Living Cells by Using Raman Microspectroscopy

This Personal Account highlights the capabilities of spontaneous Raman microspectroscopy for studying fundamental biological processes in a single living cell. Raman microspectroscopy provides time‐ and space‐resolved vibrational Raman spectra that contain detailed information on the structure and dynamics of biomolecules in a cell. By using yeast as a model system, we have made great progress in the development of this methodology. The results that we have obtained so far are described herein with an emphasis placed on how three cellular processes, that is, cell‐division, respiration, and cell‐death, are traced and elucidated with the use of time‐ and space‐resolved structural information that is extracted from the Raman spectra. For cell‐division, compositional‐ and structural changes of various biomolecules are observed during the course of the whole cell cycle. For respiration, the redox state of mitochondrial cytochromes, which is inferred from the resonance Raman bands of cytochromes, is used to evaluate the respiration activity of a single cell, as well as that of isolated mitochondrial particles. Special reference is made to the “Raman spectroscopic signature of life”, which is a characteristic Raman band at 1602 cm^?1 that is found in yeast cells. This signature reflects the cellular metabolic activity and may serve as a measure of mitochondrial dysfunction. For cell‐death, “cross‐talk” between the mitochondria and the vacuole in a dying cell is suggested. DOI 10.1002/tcr.201200008     

Monitoring chemical impacts on cell cultures by means of image analyses

Many chemical processes are involved in the interactions of living cells with their environment; however, monitoring such processes often requires sophisticated analyzers. In this study, a sensing strategy based on imaging techniques has been developed to (i) enable cell discrimination based on their physical appearance such as size and shape and (ii) to build predictive models that relate the measured cell appearance to chemical parameters in their environment. Both goals aim at innovative and straightforward sensing strategies for analyzing cell–environment interactions. Image analyses offer several advantages such as the use of simpler, more robust sensors and the omission of extensive sample/sensor preparations. Imaging can analyze numerous cells and thus gains a culture representative insight rather than a potentially nonrepresentative single‐cell response. As a proof‐of‐principle application, different species of microalgae cells have been exposed to various nutrient conditions. Microalgae are known to sensitively adapt to changing nutrient conditions and could potentially become biological “probes” for chemical shifts in ecosystems. Because of considerable spreads of cell size and shapes within one class, size and shape distributions have been derived from visible images of cell cultures. It is shown that the novel image analyses are capable of discriminating different cell species based on their cell shapes and sizes. It is also demonstrated that in conjunction with the recently introduced, nonlinear multivariate “predictor surfaces”, the nutrient availability has a quantifiable impact on the cell size distributions. In this application, predictor surfaces are somewhat more precise than partial least squares. Copyright © 2012 John Wiley & Sons, Ltd.     

Analytical Methods for Characterizing the Nanoparticle–Protein Corona

When nanoparticles (NPs) enter a biological environment, medium components, especially proteins, compete for binding to the NP’s surface, leading to development of a new interface, commonly referred to as the “protein corona.” This rich protein shell gives the NPs a biological identity that can be very different from their synthetic one, in terms of their chemical–physical properties. Understanding NP–protein interaction is crucial for both the bioapplications and safety of nanomaterials. The protein corona provides the primary contact to the cells and their receptors. It defines in vivo fate of the delivery systems, governing the stability, immunogenicity, circulation, clearance rates and organ biodistribution of the NPs. Given its importance, the application and the development of analytical methods to investigate the protein corona are crucial. This review gives an overview of chromatographic, electrophoretic, mass spectrometric and proteomic methods because these techniques have the advantage to be able to identify and quantify individual proteins adsorbed onto the corona. This capability opens up the possibility to exploit the protein corona for specific cell targeting.