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In what is an annual prespring rite, instrumentation gurus and science experts flocked to the Pittsburgh Conference on Analytical Chemistry & Applied Spectroscopy earlier this month to survey the latest measurement tools and techniques.
Sensors Monitor Wound Healing
Biomarkers such as nitric oxide and pH provide clues to whether a wound is healing.
Better Electrodes For Neurochemistry
New materials overcome shortcomings of conventional carbon microfibers.
Those who made the trek to New Orleans for Pittcon’s symposia, workshops, and poster sessions also got up close and personal with the latest analytical instruments. More than 900 exhibitors showcased offerings. They ranged from the largest of high-performance consoles fortified with automation features and software to the tiniest of semiconductors for pocket-sized measurement devices.
Unlike last year, when frigid weather and canceled flights prevented many from attending the meeting in Chicago, most travelers made it to this year’s gathering without a hitch. About 14,270 exhibitors and conferees descended on the Big Easy. Chicago, a more centrally located city, drew 16,200 attendees.
Although attendance was cool compared with Chicago, instrumentation executives anticipated a warm reception to their product offerings this year. At the same time, U.S.-based companies were bracing for the impact the strong dollar will have on their bottom lines.
“Business improved overall in 2014,” said Arthur Caputo, executive vice president of chromatography at Waters Corp. The U.S. and Europe are chugging along nicely, he said. After elections, India is back on track with a pro-development government in place. Caputo also has seen a recent uptick in business from China, which underperformed most of last year.
But the strong U.S. dollar, which has appreciated 30% against the euro over the past year, is taking a bite out of profits. In a call with investors to discuss 2014 results, Waters Chief Executive Officer Douglas Berthiaume said foreign currency headwinds reduced the year’s earnings per share by 4%.
“We can’t do a whole lot about the currency situation,” Caputo told C&EN. A large part of Waters’s manufacturing operations are in the U.S., so the continued strong dollar will likely have an impact on 2015 earnings as well, he cautioned.
“We are all dealing with currency exchange issues,” noted Dan Shine, president of Thermo Fisher Scientific’s chromatography and mass spectrometry business. To cope, Thermo Fisher, one of the world’s largest instrument makers, will try to supply European customers from manufacturing plants in Asia instead of facilities in the U.S.
The strong U.S. dollar is also taking a toll at nuclear magnetic resonance specialist Bruker Corp. Although the firm has a significant manufacturing footprint in Europe, it reports results in U.S. dollars. Bruker’s fourth-quarter revenues were 6% lower than they would have been without the stronger dollar. Currency translation took a 1% bite out of revenues for the full year.
Bruker President Frank Laukien said currency exchange relief may be on the horizon. He expects the strong dollar to persist through the first half of 2015 and then subside. However, he pointed to other headwinds, calling sales in Europe anemic and noting a drop in sales to Russia in part because of a depreciated currency and trade sanctions linked to the conflict over Ukraine.
Jon DiVincenzo, senior vice president of PerkinElmer, agreed that currency issues will pose a challenge. On the positive side, he anticipates that sales in China could increase at a faster pace than last year because a business slowdown stemming from government actions to eliminate corruption appears to be over. PerkinElmer CEO Robert Friel said he feels good about North American instrument demand, adding that customers continue to invest in environmental analysis and human health diagnostic tools.
PerkinElmer, back at Pittcon after a four-year absence, used the scene to showcase a number of tools, including an advanced liquid chromatography system, the Altus UPLC, for environmental and industrial analysis. It’s controlled with Empower 3 software from competitor Waters.
Other firms also emphasized software to handle the ever-increasing volume of data pouring out of analytical instruments. Waters, for instance, showed customers its NuGenesis laboratory information management system, which it claimed is less cumbersome than competing systems.
Thermo Fisher unveiled its AppsLab online database, which chromatography Vice President Jakob Gudbrand called an “iTunes-like library for chromatography methods with a checklist for reagents to do the tests.”
Thermo Fisher also touted a collaboration to link its SampleManager lab information management system with Capgemini’s enterprise resource management software. The effort with Capgemini, an information technology and consulting firm, will help customers manage data, improve forecasting, and take quality assurance steps, the partners say.
Aside from software initiatives, instrument makers expanded into new areas of business. Shimadzu, best known for its liquid chromatography/mass spectrometry tools, entered the market for supercritical fluid chromatography (SFC) with its Nexera Unified Chromatography system.
The new entry allows Shimadzu to compete with major SFC providers such as Jasco Analytical Instruments and Waters, which bought SFC toolmaker Thar Instruments in 2009. According to Shimadzu, its instrument can process samples and produce results within five minutes of pushing a button. The firm developed the Nexera UC with help from Japan’s Osaka University, Kobe University, and Miyazaki Agricultural Research Institute.
Making a move into instrument miniaturization was Jupiter, Fla.-based BioTools, which debuted a family of portable Raman microscopes. The firm is best known as a provider of benchtop instruments to characterize the structure of chiral drugs and protein-based biopharmaceuticals.
Rina Dukor, BioTools’s president, predicted that the portable tools would do some of the grunt work in characterizing forensic, food, and archaeology field samples. “Doctors’ offices and clinics will eventually be a target for us too,” she said.
Other toolmakers are working to shrink discrete instrument components. Among them is Si-Ware Systems, an Egyptian semiconductor maker, which brought out a complete module containing its microelectromechanical systems (MEMS) chip for Fourier transform infrared spectrometers. The chip digitizes the analog functions of a traditional spectrometer.
Diaa Khalil, chief technical officer of Si-Ware and an engineering professor at Cairo’s Ain Shams University, said one of his students designed the module’s MEMS chip, which was further perfected by Si-Ware engineers. “We own the recipe for the chip but subcontract the fabrication to a foundry in France,” he explained.
One customer, Netherlands-based research firm Dutch Sprouts, is adopting the module to create a portable farm soil tester, Khalil said. Instrument makers might also adopt it for portable biofuels testers, solvent analyzers, and counterfeit drug detectors.
Texas Instruments offered spectroscopy module makers a light-handling MEMS chip. It’s half the size of one introduced last year and uses 50% less power, said Mike Walker, business development manager.
Whereas last year’s chip was targeted at benchtop analyzers, the new chip is optimized for pocket-sized devices. Walker envisions a generation of wireless-enabled tools based on the Texas Instruments chip that everyday consumers could use to monitor the quality of foods, beverages, and their overall health.
Such miniaturization efforts were just some of many initiatives showcased at Pittcon and intended to expand the use of advanced scientific instruments that today are mostly available to trained specialists. This year the industry will also have to manage currency fluctuations if it is to make good on promises of better software to handle big data and more accurate tools that are easier to use.
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For most people, cuts and scrapes are nothing to worry about. They usually heal quickly with minimal scarring. But some wounds, such as diabetic foot ulcers, venous leg ulcers, and pressure ulcers, don’t heal normally. By the time doctors realize a wound isn’t healing, they’ve wasted time and money. The chances that a wound will heal get worse the longer it takes a doctor to notice something is wrong.
Chronic wounds result from a breakdown in the normal healing process. Wound healing proceeds through four stages, and the healing of chronic wounds stalls at the second stage, inflammation, before healthy tissue can redevelop.
Clinicians assess wound healing through visual inspection and lab tests. But distinguishing a wound that’s healing from one that’s not is difficult to do early enough to make a difference.
Researchers hope to change that. They are finding biomarkers in the fluid exuded from a wound that can flag whether it’s healing properly. In a symposium at Pittcon organized by Mark H. Schoenfisch, a chemistry professor at the University of North Carolina, Chapel Hill, analytical chemists described tools they’re developing to measure some of those biomarkers.
One such biomarker is nitric oxide. NO plays a role in many physiological processes, some of which promote wound healing and some of which hinder it. For example, NO is involved in cell migration and the formation of new tissue and blood vessels, but it is also a sign of an overactive immune response.
As a result, too little or too much NO can derail the healing process. Stéphanie Bernatchez, a scientist at 3M Health Care, said that if the combined nitrite and nitrate levels in a wound are between 10 and 60 μM, the wound is likely to heal properly. Because NO oxidizes to nitrite and nitrate, researchers use concentrations of the two as a proxy for NO levels.
To measure NO directly, Schoenfisch and coworkers have developed a microfluidic sensor that detects NO electrochemically. Schoenfisch is also a founder of Clinical Sensors, a start-up company in Research Triangle Park, N.C., that hopes to commercialize the sensors.
To make the device, the researchers coat micropatterned electrodes with a fluorinated silane xerogel that forms a gas-permeable membrane, imparting selectivity for NO over other molecules. Recently, they switched their working electrode material from platinum to gold to lower costs. The group also reported the use of thiol-based trimethoxysilanes to modify the gold surface and enhance xerogel membrane adherence and durability. Increasing the thickness of the xerogel coating and the curing time between coats altered both the sensitivity and selectivity of their sensor.
Using the device, they measured NO in simulated wound fluid made with varying percentages of fetal bovine serum. The sensitivity, detection limit, and dynamic range were not dramatically altered by the large amounts of protein in the simulated wound fluid. The detection limits were in the nanomolar range.
Schoenfisch and coworkers are working to simultaneously measure NO and S-nitrosothiols, which are biological carriers of NO in blood (Anal. Chem. 2015, DOI: 10.1021/ac503220z). Natural NO transporters are likely involved in immune processes related to wound healing.
NO isn’t the only potential wound-healing biomarker that analytical chemists are targeting. Frank V. Bright, a chemistry professor at the University at Buffalo, SUNY, is developing xerogel-based optical sensors for protein biomarkers of wound healing. The plan is to incorporate the sensors into a biodegradable “smart bandage” that can monitor and accelerate wound healing.
Bright’s sensors consist of protein-imprinted xerogels with integrated emission sites, or PIXIES. PIXIES contain many different types of binding groups and an organic luminescent molecule in a xerogel matrix. The structure polymerizes around a target protein, which is then removed, leaving an imprint site that can recognize the protein later. The researchers tweak the xerogel composition to find the one that works best for each protein. Binding of a target protein leads to changes in luminescence.
In the symposium, Bright described a sensor for a protein involved in wound healing: keratinocyte growth factor (KGF). His collaborators want to measure the distribution of the protein as a function of time during wound healing. In a tissue culture of wounded respiratory epithelial tissue, they found that the amount of KGF present decreases with time.
They still face challenges moving forward. The xerogel sensor film is not homogeneous, which means that the whole film must be calibrated, not just isolated spots. When they make the sensors, they observe phase separation that depends on the chemistry of the specific xerogel precursors. In some cases, they have to abandon that formulation. Also, the current PIXIES are planar, but animals and humans are not. The researchers need to figure out ways to make the sensors conformable to a wound site. This problem is particularly relevant for their ultimate target, the trachea.
Anna McLister, a student of James Davis’s at the University of Ulster, in Northern Ireland, focused on pH as yet another biomarker of wound healing. During healing, wound pH jumps from less than pH 6 to more than pH 7. In normal wound healing, the pH drops again, but in chronic wounds it hovers above pH 7. If the pH remains high, the wound probably isn’t healing.
The conventional potentiometric method for measuring pH directly is incompatible with a wound system. Instead, McLister measures pH voltammetrically via the oxidation of urate, which is found in all biological fluids. The electrical potential at which urate oxidizes depends on pH, and the concentration of urate is an indicator of wound severity. In another sensing strategy, McLister and her colleagues use a polypeptide of tryptophan to measure pH. They incorporate the peptide in a thin film on top of an electrode. It is electrochemically converted to a redox system. As with urate, the oxidation peak position is an indirect measure of wound pH.
They make both kinds of sensors with carbon mesh that can be incorporated between the layers of existing wound dressing materials to form a smart bandage. They are preparing to take the smart bandages into clinical trials for diabetic foot ulcers.
Most of the sensors that they described are still in the early phases of development. But a colorimetric nitrite/nitrate sensor developed by 3M’s Bernatchez and Joseph V. Boykin, a physician with HCA Virginia Health System, has been tested in patients. The sensor can detect concentrations as low as 5 μM in samples as small as 10 μL.
But before they could make the sensor, they needed to find a nitrate-free material for sample collection to reduce background signal. The researchers found that many supposedly nitrate-free materials contained concentrations of nitrate above the detection limit of the assay. After testing many materials, they finally found one that’s used in wound dressings.
To detect the nitrite/nitrate, they react it with VCl3 to form nitrite. A red line is visible in the presence of nitrite. The assay can be read visually or with a spectrophotometer.
They measured the nitrite/nitrate levels of wound fluids from 50 patients at various stages of healing using a lab-based version of the assay. More work is needed to develop a point-of-care version. For business reasons, 3M decided not to move forward with either version of the assay. The patented technology is available for licensing.
Nevertheless, the hope remains that it and other sensors described at Pittcon will one day find their way into the clinic.
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For decades, neurochemists have used carbon fiber microelectrodes to measure electrical activity or detect neurotransmitters and other chemicals among nerve cells. The electrodes have worked well, but they have their drawbacks. They typically achieve spatial resolution of only tens of micrometers. They get fouled easily. They come in limited shapes and sizes. And researchers make the electrodes individually, so no two are identical.
But in recent years, researchers have come up with new electrodes that address some of the shortcomings of carbon fibers. In a symposium at Pittcon, cosponsored by the Society for Electroanalytical Chemistry and organized by B. Jill Venton, a chemistry professor at the University of Virginia, electrochemists described a variety of electrodes that could supplant carbon fiber microelectrodes for neurochemical applications.
All the electrodes described in the symposium are carbon based. But they incorporate different forms of carbon than the carbon fiber used in conventional electrodes. Some of them are based on carbon nanomaterials. Others are made of microfabricated pyrolyzed carbon. And still others are made of boron-doped diamond.
“New materials can expand the experiments you can do,” said Michael L. Heien, one of the presenters and a bioanalytical chemist at the University of Arizona.
For example, Venton’s group uses nanomaterials because they lead to sensitive and fast electrodes that resist fouling so they work longer than carbon fiber microelectrodes. In the symposium, Cheng Yang, one of Venton’s graduate students, described four kinds of electrodes made of carbon nanomaterials that improve spatial and temporal resolution compared with microelectrodes.
Venton’s group made some electrodes by depositing carbon nanotubes as a coating on metal. For others, they spun the nanotubes into yarn. The yarn electrodes can handle faster voltage changes than conventional microelectrodes, allowing the nanotube electrodes to achieve higher temporal resolution. The electrodes are also sensitive, detecting as little as 5-nM dopamine (Anal. Chem. 2014, DOI: 10.1021/ac5003273).
Carbon “nanospike” electrodes are another type Yang worked with. They consist of nanostructured thin films completely covered with 50-nm-long spikes grown using plasma-enhanced chemical vapor deposition. Similar electrodes were originally developed by Adam J. Rondinone and coworkers at Oak Ridge National Laboratory (J. Electrochem. Soc. 2014, DOI: 10.1149/2.0891409jes). The most sensitive nanospike electrodes for neurochemical applications are made by a 7.5-minute deposition on tantalum wires, Yang said.
The Venton group also used carbon nanopipette electrodes developed by Haim H. Bau of the University of Pennsylvania (Anal. Chem. 2015, DOI: 10.1021/ac504596y). These electrodes have tips that are about 250 nm wide, an order of magnitude smaller than conventional microelectrodes.
Of these types of electrodes, the nanospikes are the easiest to fabricate, but the nanopipette is the best choice for in vivo measurements, Yang said.
Sabine Szunerits, a professor in the Institute of Electronics, Microelectronics & Nanotechnology at Lille 1 University of Science & Technology, in Villeneuve d’Ascq, France, and her colleagues also use nanomaterials to make electrodes. They deposit reduced graphene oxide films on conductive surfaces, typically glassy carbon electrodes.
Szunerits and her colleagues modify the reduced graphene oxide with electrocatalysts to make chemical sensors. The reduced graphene oxide holds the catalyst in place and makes the resulting sensor more stable. For example, they have used reduced graphene oxide modified with cobalt phthalocyanine tetracarboxylic acid as a chemical sensor for peroxynitrite and other reactive oxygen and nitrogen species (RSC Adv. 2015, DOI: 10.1039/c4ra09781e).
Instead of nanomaterials, Arizona’s Heien is testing conducting polymers as possible electrode materials. They could be used as the electrode material itself, or they could improve the selectivity and biocompatibility of other materials for detecting neurotransmitters such as dopamine. To block interference from other molecules in experiments, his group coats carbon fiber electrodes with a polymer film made of Nafion and poly(3,4-ethylenedioxythiophene) (PEDOT) (Anal. Chem. 2015, DOI: 10.1021/ac502165f). Nafion is an ionic polymer based on sulfonated tetrafluoroethylene. The coated electrodes discriminated between dopamine, ascorbic acid, and a dopamine metabolite called 3,4-dihydroxyphenylacetic acid.
Unlike the coated electrodes Yang described, the conducting polymers are not the electroactive material on Heien’s electrodes. Instead, Heien said, the PEDOT probably anchors the Nafion to the electrode. The combined coating protects the underlying electrode from fouling.
In addition, the coating allows researchers to tune the electrode’s properties by changing the PEDOT concentration, Heien said. In measurements of dopamine release in the rat brain, electrodes with more PEDOT responded to dopamine more slowly but more sensitively than electrodes with less PEDOT.
Gregory S. McCarty, a biomedical engineer at North Carolina State University and Pine Research Instrumentation, is collaborating with chemistry professor R. Mark Wightman of the University of North Carolina, Chapel Hill, to develop arrays of microelectrodes made of pyrolyzed carbon on a silicon substrate. They can manipulate the silica through microfabrication methods used in the semiconductor industry. This enables straightforward batch fabrication and improved spatial control of the sensors’ dimensions.
Recently, McCarty has used the microfabrication approach to make a three-electrode system for sensing background and slowly changing levels of neurotransmitters. Fast-scan cyclic voltammetry is usually employed to detect fast-changing levels of these chemicals.
In this device, McCarty measures species at a central collector electrode and manipulates the local electrochemical environment with generator electrodes that flank it. In the case of sensing dopamine, this allows researchers to block interfering signals from ascorbic acid.
The distinctive behavior of ascorbic acid and dopamine can be used to discriminate between them, McCarty said. Ascorbic acid gets consumed at the generator electrodes, so the concentration decreases at the collector electrode.
In contrast, dopamine undergoes a reversible reaction in which it adsorbs on and then desorbs from the generator electrodes. The result is a type of stripping voltammetry that is seen as an initial decrease followed by a large increase in concentration.
“It’s easy to use temporal changes in the signal to increase the selectivity of the sensor,” McCarty said. If desired, the central electrode can be used by itself for conventional fast-scan cyclic voltammetry measurements.
Of all the forms of carbon, diamond seems like the least obvious choice for electrodes. “Diamond by itself with no impurities is one of Mother Nature’s best electrical insulators. It would be a horrible electrode,” Greg M. Swain, a chemistry professor at Michigan State University, told C&EN. “We dope it with boron to impart electrical conductivity.”
The resulting electrodes are more stable than carbon fiber ones, Swain said, and they also resist fouling.
Swain uses the boron-doped diamond electrodes to make measurements in the peripheral nervous system rather than the brain. For example, his group measures norepinephrine release from sympathetic nerves that stimulate arteries and veins. A goal of the work is to understand how sympathetic nerves communicate with smooth muscle cells to regulate vascular tone and how the signaling mechanisms are dysregulated in obesity-linked hypertension.
Despite the success of these new electrode materials, carbon fiber microelectrodes aren’t going away anytime soon. Instead, scientists now have more and better options.
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Sensors Monitor Wound Healing
Biomarkers such as nitric oxide and pH provide clues to whether a wound is healing.
Better Electrodes For Neurochemistry
New materials overcome shortcomings of conventional carbon microfibers.
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