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Microchip gets a tip overcome possible interference between QCMs in multiples the channels. They took advantage of the different thicknesses of the etched and Quartz crystal microbalances (QCMs) can nonetched regions. The resonant frequenmonitor slight changes in the amount of cies in those regions differed (10 MHz in material on their surfaces. Most QCMs the wells, and 6 MHz between the wells)) are single-channel devices, which spatially so that the oscillation generated in the average the response. Now, however, etched region could not propagate to the Tetsu Tatsuma, Noboru Oyama, and counetched region. According to Tatsuma, workers at Tokyo University of Agriculno significant interference was observed. ture and Technology and Meidensha "The most important thing is that a mass Corp. (both in Japan) have developed change of a channel does not cause a frethree types of multichannel quartz crystal quency change of the other channels," he microbalances (MQCMs). They describe their work in this issue of Analytical Chem- says. For analyses in electrolyte solutions, the easiest way to avoid interference is istry (p 3632). switching successively from one channel A QCM consists of a quartz disk with to the next electrodes plated on either side. Because the devices are piezoelectric, an oscillating The channel diameter of the current electric field applied across the device indevices is rather large, 8 mm, which limits duces an acoustic wave to propagate the lateral resolution of the device. The through it. The frequency of this acoustic resolution can be improved by making wave depends on the thickness of the deeach channel smaller and thinner. Unforvice and changes with the effective masstunately, a compromise must be struck per-unit area of the device. The mass of a between lateral resolution and frequency thin layer deposited on the crystal can be resolution. "For MQCM with a higher calculated from a measured change in the resonance frequency, the channel can be resonant frequency of the device. made smaller without undue deterioration of the quality factor, although the dynamic The MQCMs operate in a similar fashransre will be limited," says Tatsuma. ion but consist of arrays of resonators fab"Thus, the lateral resolution of MQCM ricated on a single quartz wafer. Each of will be improved in exchange for the S/N the three types has "dents", or wells, with ratio or the dynamic Although it is gold electrodes on the back. The front can have an array of electrodes in wells (the difficult to give the figure for the wells can be the same or various sizes), an lution limit a 150-MHz resonator be array of electrodes in a single large well or 1 5 mm or less We have not vet examined on a flat surface, or a single electrode covthe dependence of the degree of the interering the entire surface. Each of the elecference on the size of the channels and the trodes on the back represents a different distance between them " channel. One channel can be used as a In addition to providing spatial resolureference so that the effects of solution tion, the array can also be used to monitemperature, viscosity, and density can be tor a system using channels with differsubtracted. ent frequencies. A single process can be monitored with both a high-frequency Thus far, Tatsuma and his co-workers channel and a low-frequency channel. have constructed devices with only four The high-frequency channel provides channels. However, he notes, the only sensitivity with a narrow dynamic range, limitation to the number of channels is the whereas the low-frequency channel is size of the plates and channels. less sensitive with a wide dynamic range. Although each of the current devices have four channels, no more than two MQCMs have many potential applicachannels have been monitored simultations. By attaching different receptors to neously. "In the gas phase or nonconducthe individual channels, the array can be tive liquids, in principle, several or more used for multicomponent analysis of mixchannels can be monitored simultaneoustures or as taste or odor sensors using ly," says Tatsuma. "However, in suffipattern recognition techniques. Moreciently conductive liquids, new circuits over, the MQCM with a single electrode should be designed so as to monitor more can perform mass mapping for such apthan two channels simultaneously." plications as corrosion analysis. Tatsuma and his co-workers needed to Celia Henry
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Analytical Chemistry News & Features, September 1, 1999
Electrospray ionization mass spectrometry (ESI-MS) from microchips has been easier said than done. Spraying from the edge of chips decreases, and hydraulic pumping for sample delivery is cumbersome. So Iulia Lazar, Rose Ramsey, and Mike Ramsey at Oak Ridge National Laboratory and Steve Sundberg from Caliper Technologies took another approach. As described in this issue of Analytical Chemistry (p 3627), the researchers attached a nanoelectrospray tip to their microchip and applied a voltage to a fluid reservoir, allowing the sample to go with the flow. 'Typically in nanospray, you don't use any sort of pump or external device to deliver fluid to the tip," says Rose Ramsey. Neither does this group's method, which relies on the tip to draw the fluid through the microchip channel, after a voltage has been applied. The flow rates achieved with this approach (—0.3-0.5 nL s"1) are typical of nanospray, she adds. The stability of the spray is also typical of nanospray with relative standard deviations of —5% for the ion current. In contrast to conventional nanoelectrospray, however, this device has the advantages of microchips. In addition to continuous sample infusion, it can be used for discrete, repetitive analysis of one sample or, with additional sample reservoirs (or other methods of sample accession), for the automated analysis of multiple samples, says Ramsey. In addition, by reserving the main channel for separations and adding an intersecting channel for injections, the researchers already have resolved injected plugs of simple mixtures, such as peptides. Ramsey says this capability has the potential to move LC/MS and CE/MS applications to the microchip domain. The microchip also provides the short analysis times desired for high-throughput applications. The researchers have produced spectra from as little as 340 zmol of a 100-nM solution of gramacidin S in only 10 ms. Such high sensitivity with ESI usually requires much longer integration times, Ramsey notes. "But if you're doing microchip separations, the peak widths are in the millisecond domain, not seconds," she says. "You need to be able to do analyses quickly. And with this hybrid device, we've shown that you can." The sensitivity achieved is due, in part, to the nanospray source and also to the use of a time-of-flight mass spectrometer, which allows signal averaging on short
when it comes to studying the likes of poly- scientists. "Our method is bringing tandem ethylene glycol or polymethylmethacrylate mass spectrometry to polymers," says Derin detail, even the most robust analytical rick. "We obtain detailed structural infortechnique breaks down. On p 3637, Peter J. mation on the sequence of monomers makDerrick and co-workers at the University of ing up a polymer chain as well as salient Warwick (U.K.) discuss a new variation on end-group information." Derrick's use of the MS theme, which will help bring a bet- the word "sequence", which is usually reter understanding of polymers and the poserved for protein chains and DNA strands, lymerization process. Ultimately, with synhints at the new technique's power. Schematic representation of the microchipthetic polymers under the analytical umThe team can obtain this unprecenanoelectrospray tip assembly. brella, creating novel "designer" polymers dented detail from their polymer samples will be possible. using high-energy collisions in the mass spectrometer, which can probe all internal "Polymers are becoming much more time scales to enhance sensitivity. "The bonds without paying any regard to relative sophisticated in terms of molecular design, sensitivity from the nanospray tips is nostrengths. A novel TOF technology, which and the relationships between molecular ticeably better than what we have seen structure and physical properties are becom- is designed to avoid restricting collision from a channel orifice at the edge of a miing clearer," Derrick explained to Analytical energies to low values, then measures the crochip," Ramsey says. "We believe that Chemistry. "The need is to firm up this struc- collision products, so structural informasome type of tip is needed for many highture/property relationship," he added, "then tion can be deduced. sensitivity applications." However, she adds, in areas such as combinatorial library we will be able to design and synthesize the The main area of application includes structures we need for a particular use." Der- designer polymers and synthetic biomicertification, where sample concentrations rick and his team started out developing are high, a channel orifice could provide metic polymers. "We are thinking of conmatrix-assisted laser desorption techniques satisfactory results. trol of chemical composition, topology and that would help them characterize the end tacticity, as well as molecular mass distriOther groups (e.g., those led by Barry groups and structures of various natural butions," explains Derrick. The ease with Karger at Northeastern University and D. compounds. A fortuitous change of tack, which structural information might now be Jed Harrison at the University of Alberta) forced on them by dwindling reagent supobtained will facilitate the task of testing have also shown that there are advantages in attaching capillaries to chips for ESI-MS, plies made them realize that their prototype experimental polymerization schemes and instrument might be better suited for synallow chemists to fine-tune reaction according to Mike Ramsey. "We may not schemes to produce the desired end prodhave yet realized the optimum approach for thetic and biomimetic polymers. uct with less trial and error. including electrospray tips on lab-on-a-chip Gel-permeation chromatography ducks devices," he says, "but it seems clear that the whole "intricate structure" question by Derrick and David Haddleton present chips with tips are better for ESI-MS." providing molecular masses, as long as the preliminary results demonstrating the technique's power at determining the endElizabeth Zubritsky broad structural features of the polymers are known, says Derrick. group functionalities of various strains of polyethylene glycol. "End groups," Derrick By coupling MALDI with high-energy Getting the measure collision-induced points out, "affect durability and degradadissociation, Derrick and tion directly and play an important role in his team have found that they are starting of polymers the final bulk polymer properties." to bring to polymer chemistry a level of For all their complexity, biopolymers are detail that is usually the domain of protein not too difficult to characterize. However, David Bradley NEWS FROM BIOMEMS Elizabeth Zubritsky reports from San Francisco, CA.
Living chips The canary in the coal mine has gone biotech. Colin Brenan, Tanya Kanigan, Karel Domansky, and colleagues in Ian Hunter's and Linda Griffith's groups at the Massachusetts Institute of Technology are developing the modern equivalents of the classic biosensor: cell- and tissue-based sensors on microchips. The focus of the project is to detect biological or chemical warfare agents, but Brenan says the work is branching out
to high-throughput screening, environmental monitoring, and clinical diagnosis. "There are a number of ways to do these sorts of things chemically," Brenan says. "The advantage of a biological sensor ... is that you detect the agent and determine what the effect will be." He adds that this approach may provide better detection limits. Whereas a single virus would go unnoticed in many chemical methods, it may be enough to trigger a cellular response he says. In the typical cell-based device, yeast is cultured in an array of 500- to 2000-umdeep wells (diameter = 200 um) machined
into a silicon or other substrate. To keep the fluids from each well separated on this "living chip", the substrate surface is hydrophobic, and the wells are hydrophilic. However, by varying the surface finish and the substrate, the chips can be tailored for different applications, Brenan adds. Another way to tailor the chips is to genetically engineer the yeast cells. Hunter's group is creating an androgen receptor chip that can detect low levels of steroids, such as estrogen, which correlate with prostate cancer. In theory, different yeast variants could be
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