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Common techniques used to synchronize eukaryotic cells in the cell cycle often impose metabolic stress on the cells or physically select for size rather than age. To address these deficiencies, a minimally perturbing method known as the “baby machine” was developed previously. In the technique, suspension cells are attached to a membrane, and as the cells divide, the newborn cells are eluted to produce a synchronous population of cells in the G1 phase of the cell cycle. However, the existing “baby machine” is only suitable for cells which can be chemically attached to a surface. Here, we present a microfluidic “baby machine” in which cells are held onto a surface by pressure differences rather than chemical attachment. As a result, our method can in principle be used to synchronize a variety of cell types, including cells which may have weak or unknown surface attachment chemistries. We validate our microfluidic “baby machine” by using it to produce a synchronous population of newborn L1210 mouse lymphocytic leukemia cells in G1 phase., National Cancer Institute (U.S.). Physical Sciences-Oncology Center (U54CA143874), National Institute of General Medical Sciences (U.S.) (EUREKA R01GM085457)

Precise characterization of biological materials ranging from single cells (~1-20 microns) to extracellular vesicles (20-200 nm) is of fundamental interest because of their biological and translational value. Here we discuss the value of precision mass measurements in solution for informing various physical and biological parameters, such as mass accumulation rate, longitudinal cell growth or cell density. We introduce how the limits of the single-particle mass measurements can be pushed down to nano-scale dimensions enabling the resolution of extracellular vesicles and viruses in solution. We believe with future advancements on the precision and throughput of this approach, the capability of analyzing biologically relevant particles in solution will have broad biological and translational impact.

Microbes are an essential component of marine food webs and biogeochemical cycles, and therefore precise estimates of their biomass are of significant value. Here, we measured single-cell biomass distributions of isolates from several numerically abundant marine bacterial groups, including Pelagibacter (SAR11), Prochlorococcus and Vibrio using a microfluidic mass sensor known as a suspended microchannel resonator (SMR). We show that the SMR can provide biomass (dry mass) measurements for cells spanning more than two orders of magnitude and that these estimates are consistent with other independent measures. We find that Pelagibacterales strain HTCC1062 has a median biomass of 11.9±0.7 fg per cell, which is five- to twelve-fold smaller than the median Prochlorococcus cell’s biomass (depending upon strain) and nearly 100-fold lower than that of rapidly growing V. splendidus strain 13B01. Knowing the biomass contributions from various taxonomic groups will provide more precise estimates of total marine biomass, aiding models of nutrient flux in the ocean., National Science Foundation (U.S.) (OCE-1129359), Simons Foundation (337262), United States. Army Research Office (W911NF-09-D-0001)

Cellular physical properties are important indicators of specific cell states. Although changes in individual biophysical parameters, such as cell size, density, and deformability, during cellular processes have been investigated in great detail, relatively little is known about how they are related. Here, we use a suspended microchannel resonator (SMR) to measure single-cell density, volume, and passage time through a narrow constriction of populations of cells subjected to a variety of environmental stresses. Osmotic stress significantly affects density and volume, as previously shown. In contrast to density and volume, the effect of an osmotic challenge on passage time is relatively small. Deformability, as determined by comparing passage times for cells with similar volume, exhibits a strong dependence on osmolarity, indicating that passage time alone does not always provide a meaningful proxy for deformability. Finally, we find that protein synthesis inhibition, cell-cycle arrest, protein kinase inhibition, and cytoskeletal disruption result in unexpected relationships among deformability, density, and volume. Taken together, our results suggest that by measuring multiple biophysical parameters, one can detect unique characteristics that more specifically reflect cellular behaviors., National Cancer Institute (U.S.) (Physical Sciences Oncology Center grant U54CA143874 and CCNE-T grant 26697290-47281-A)

We use a suspended microchannel resonator to characterize the water and small-molecule permeability of Bacillus subtilis spores based on spores' buoyant mass in different solutions. Consistent with previous results, we found that the spore coat is not a significant barrier to small molecules, and the extent to which small molecules may enter the spore is size dependent. We have developed a method to directly observe the exchange kinetics of intraspore water with deuterium oxide, and we applied this method to wild-type spores and a panel of congenic mutants with deficiencies in the assembly or structure of the coat. Compared to wild-type spores, which exchange in approximately 1 s, several coat mutant spores were found to have relatively high water permeability with exchange times below the ∼200-ms temporal resolution of our assay. In addition, we found that the water permeability of the spore correlates with the ability of spores to germinate with dodecylamine and with the ability of TbCl₃ to inhibit germination with l-valine. These results suggest that the structure of the coat may be necessary for maintaining low water permeability., United States. Army Research Office (W911F-09-1-0286), United States. Army Research Office (W911NF-09-0001)

Multiple myeloma (MM) has benefited from significant advancements in treatment that have improved outcomes and reduced morbidity. However, the disease remains incurable and is characterized by high rates of drug resistance and relapse. Consequently, methods to select the most efficacious therapy are of great interest. Here we utilize a functional assay to assess the ex vivo drug sensitivity of single multiple myeloma cells based on measuring their mass accumulation rate (MAR). We show that MAR accurately and rapidly defines therapeutic susceptibility across human multiple myeloma cell lines to a gamut of standard-of-care therapies. Finally, we demonstrate that our MAR assay, without the need for extended culture ex vivo, correctly defines the response of nine patients to standard-of-care drugs according to their clinical diagnoses. This data highlights the MAR assay in both research and clinical applications as a promising tool for predicting therapeutic response using clinical samples.

We present a method for direct non-optical quantification of dry mass, dry density and water mass of single living cells in suspension. Dry mass and dry density are obtained simultaneously by measuring a cell’s buoyant mass sequentially in an H[subscript 2]O-based fluid and a D[subscript 2]O-based fluid. Rapid exchange of intracellular H[subscript 2]O for D[subscript 2]O renders the cell’s water content neutrally buoyant in both measurements, and thus the paired measurements yield the mass and density of the cell’s dry material alone. Utilizing this same property of rapid water exchange, we also demonstrate the quantification of intracellular water mass. In a population of E. coli, we paired these measurements to estimate the percent dry weight by mass and volume. We then focused on cellular dry density – the average density of all cellular biomolecules, weighted by their relative abundances. Given that densities vary across biomolecule types (RNA, DNA, protein), we investigated whether we could detect changes in biomolecular composition in bacteria, fungi, and mammalian cells. In E. coli, and S. cerevisiae, dry density increases from stationary to exponential phase, consistent with previously known increases in the RNA/protein ratio from up-regulated ribosome production. For mammalian cells, changes in growth conditions cause substantial shifts in dry density, suggesting concurrent changes in the protein, nucleic acid and lipid content of the cell., National Cancer Institute (U.S.). Physical Sciences-Oncology Center (U54CA143874), National Institutes of Health (U.S.) (Center for Cell Division Process Grant P50GM6876), National Institutes of Health (U.S.) (Contract R01CA170592), United States. Army Research Office (Institute for Collaborate Biotechnologies Contract W911NF-09-D-0001)

We demonstrate a method to enhance the time resolution of a commercial Coulter counter and enable continuous and long-term cell size measurements for growth rate analyses essential to understanding basic cellular processes, such as cell size regulation and cell cycle progression. Our simple modifications to a commercial Coulter counter create controllable cell culture conditions within the sample compartment and combine temperature control with necessary adaptations to achieve measurement stability over several hours. We also wrote custom software, detailed here, to analyze instrument data files collected by either this continuous method or standard, periodic sampling. We use the continuous method to measure the growth rate of yeast in G1 during a prolonged arrest and, in different samples, the dependency of growth rate on cell size and cell cycle position in arrested and proliferating cells. We also quantify with high time resolution the response of mouse lymphoblast cell culture to drug treatment. This method provides a technique for continuous measurement of cell size that is applicable to a large variety of cell types and greatly expands the set of analysis tools available for the Coulter counter., National Institutes of Health (U.S.) (EUREKA Exceptional, Unconventional Research Enabling Knowledge Acceleration (R01GM085457)), National Institutes of Health (U.S.) (contract R21CA137695), National Cancer Institute (U.S.). Physical Sciences-Oncology Center (U54CA143874)

Cell growth comprises changes in both mass and volume—two processes that are distinct, yet coordinated through the cell cycle. Understanding this relationship requires a means for measuring each of the cell’s three basic physical parameters: mass, volume, and the ratio of the two, density. The suspended microchannel resonator weighs single cells with a precision in mass of 0.1% for yeast. Here we use the suspended microchannel resonator with a Coulter counter to measure the mass, volume, and density of budding yeast cells through the cell cycle. We observe that cell density increases prior to bud formation at the G1/S transition, which is consistent with previous measurements using density gradient centrifugation. To investigate the origin of this density increase, we monitor relative density changes of growing yeast cells. We find that the density increase requires energy, function of the protein synthesis regulator target of rapamycin, passage through START (commitment to cell division), and an intact actin cytoskeleton. Although we focus on basic cell cycle questions in yeast, our techniques are suitable for most nonadherent cells and subcellular particles to characterize cell growth in a variety of applications., National Institutes of Health (U.S.) EUREKA (R01GM085457), Center for Cell Decision Process (grant P50GM68762), National Institutes of Health (U.S.) (Grant GM056800)

Cytokine regulation of lymphocyte growth and proliferation is essential for matching nutrient consumption with cell state. Here, we examine how cellular biophysical changes that occur immediately after growth factor depletion promote adaptation to reduced nutrient uptake. After growth factor withdrawal, nutrient uptake decreases, leading to apoptosis. Bcl-xL expression prevents cell death, with autophagy facilitating long-term cell survival. However, autophagy induction is slow relative to the reduction of nutrient uptake, suggesting that cells must engage additional adaptive mechanisms to respond initially to growth factor depletion. We describe an acute biophysical response to growth factor withdrawal, characterized by a simultaneous decrease in cell volume and increase in cell density, which occurs before autophagy initiation and is observed in both FL5.12 Bcl-xL cells depleted of IL-3 and primary CD8+ T cells depleted of IL-2 that are differentiating toward memory cells. The response reduces cell surface area to minimize energy expenditure while conserving biomass, suggesting that the biophysical properties of cells can be regulated to promote survival under conditions of nutrient stress.

We used a suspended microchannel resonator (SMR) combined with picoliter-scale microfluidic control to measure buoyant mass and determine the 'instantaneous' growth rates of individual cells. The SMR measures mass with femtogram precision, allowing rapid determination of the growth rate in a fraction of a complete cell cycle. We found that for individual cells of Bacillus subtilis, Escherichia coli, Saccharomyces cerevisiae and mouse lymphoblasts, heavier cells grew faster than lighter cells., National Institutes of Health (U.S.) (MIT Center for Cell Decision Processes Grant P50GM68762), United States. Army Research Office (Institute for Collaborative Biotechnologies Grant DAAD1903D0004)

Physical characterization of nanoparticles is required for a wide range of applications. Nanomechanical resonators can quantify the mass of individual particles with detection limits down to a single atom in vacuum. However, applications are limited because performance is severely degraded in solution. Suspended micro- and nanochannel resonators have opened up the possibility of achieving vacuum-level precision for samples in the aqueous environment and a noise equivalent mass resolution of 27 attograms in 1-kHz bandwidth was previously achieved by Lee et al. [(2010) Nano Lett 10(7):2537–2542]. Here, we report on a series of advancements that have improved the resolution by more than 30-fold, to 0.85 attograms in the same bandwidth, approaching the thermomechanical noise limit and enabling precise quantification of particles down to 10 nm with a throughput of more than 18,000 particles per hour. We demonstrate the potential of this capability by comparing the mass distributions of exosomes produced by different cell types and by characterizing the yield of self-assembled DNA nanoparticle structures., Institute for Collaborative Biotechnologies (Contract W911NF-09-D-0001), United States. Army Research Office (Center for Integration of Medicine and Innovative Technology Contract 09-440), National Science Foundation (U.S.) (Grant 1129359), National Cancer Institute (U.S.) (Grant P30-CA14051)

We have used a microfluidic mass sensor to measure the density of single living cells. By weighing each cell in two fluids of different densities, our technique measures the single-cell mass, volume, and density of approximately 500 cells per hour with a density precision of 0.001 g mL-1. We observe that the intrinsic cell-to-cell variation in density is nearly 100-fold smaller than the mass or volume variation. As a result, we can measure changes in cell density indicative of cellular processes that would be otherwise undetectable by mass or volume measurements. Here, we demonstrate this with four examples: identifying Plasmodium falciparum malaria-infected erythrocytes in a culture, distinguishing transfused blood cells from a patient’s own blood, identifying irreversibly sickled cells in a sickle cell patient, and identifying leukemia cells in the early stages of responding to a drug treatment. These demonstrations suggest that the ability to measure single-cell density will provide valuable insights into cell state for a wide range of biological processes., EUREKA (Exceptional, Unconventional Research Enabling Knowledge Acceleration (R01GM085457)), National Institutes of Health (U.S.) (NIH Cell Decision Process Center Grant (P50GM68762)), United States. Army Research Office (Institute for Collaborative Biotechnologies Grant (W911NF-09-D-0001)), Massachusetts Institute of Technology (Whitaker Health Sciences Graduate Fellowship), National Institutes of Health (U.S.) (Grant R01HL094270), National Institute of Diabetes and Digestive and Kidney Diseases (U.S.) (Grant DK083242)

We report on a fabrication and packaging process for a microsystem consisting of a mass-based protein detector and a fully integrated preconcentrator. Preconcentration of protein is achieved by means of a nanofluidic concentrator (NC), which takes advantage of fast nonlinear electroosmotic flow near a nanochannel-microchannel junction to concentrate charged molecules inside a volume of fluid on the order of 1 pL. Detection of preconcentrated protein samples is accomplished by passing them through a suspended microchannel resonator (SMR), which is a hollow resonant cantilever serially connected to the NC on the same device. The transit of a preconcentrated sample produces a transient shift in the cantilever's resonance frequency that is proportional to the density of the sample and, hence, the concentration of protein contained in it. A device containing both NC and SMR structures was produced using a novel fabrication process which simultaneously satisfies the separate packaging requirements of the two structures. The initial testing of this prototype device has demonstrated that the integrated SMR can accurately measure the concentration of a bovine serum albumin solution, that was preconcentrated using the integrated NC. Future improvements in the fabrication process will allow site-specific surface modification of the device and compatibility with separation methods, which will create opportunities for its application to immunoassays and universal detection., National Cancer Institute (U.S.) (Contract R01CA119402), National Institutes of Health (U.S.) (NIH Cell Decision Process Center P50-GM68762)

Energy dissipation experienced by vibrating microcantilever beams immersed in fluid is strongly dependent on the mode of vibration, with quality factors typically increasing with mode number. Recently, we examined energy dissipation in a new class of cantilever device that embeds a microfluidic channel in its interior—the fundamental mode of vibration only was considered. Due to its importance in practice, we examine the effect of mode number on energy dissipation in these microfluidic beam resonators. Interestingly, and in contrast to other cantilever devices, we find that the quality factor typically decreases with increasing mode number. We explore the underlying physical mechanisms leading to this counterintuitive behavior, and provide a detailed comparison to experimental measurements for which good agreement is found., United States. Army Research Office (Institute for Collaborative Biotechnologies Contract No. W911NF-09-D-0001), National Institutes of Health (U.S.) (NIH Cell Decision Process Center P50-GM68762), Australian Research Council (Grants Scheme)

We have used a microfluidic mass sensor to measure the density of single living cells. By weighing each cell in two fluids of different densities, our technique measures the single-cell mass, volume, and density of approximately 500 cells per hour with a density precision of 0.001 g mL-1. We observe that the intrinsic cell-to-cell variation in density is nearly 100-fold smaller than the mass or volume variation. As a result, we can measure changes in cell density indicative of cellular processes that would be otherwise undetectable by mass or volume measurements. Here, we demonstrate this with four examples: identifying Plasmodium falciparum malaria-infected erythrocytes in a culture, distinguishing transfused blood cells from a patient’s own blood, identifying irreversibly sickled cells in a sickle cell patient, and identifying leukemia cells in the early stages of responding to a drug treatment. These demonstrations suggest that the ability to measure single-cell density will provide valuable insights into cell state for a wide range of biological processes., EUREKA (Exceptional, Unconventional Research Enabling Knowledge Acceleration (R01GM085457)), National Institutes of Health (U.S.) (NIH Cell Decision Process Center Grant (P50GM68762)), United States. Army Research Office (Institute for Collaborative Biotechnologies Grant (W911NF-09-D-0001)), Massachusetts Institute of Technology (Whitaker Health Sciences Graduate Fellowship), National Institutes of Health (U.S.) (Grant R01HL094270), National Institute of Diabetes and Digestive and Kidney Diseases (U.S.) (Grant DK083242)

Improved methods are needed for routine, inexpensive monitoring of biomarkers that could facilitate earlier detection and characterization of cancer. Suspended microchannel resonators (SMRs) are highly sensitive, batch-fabricated microcantilevers with embedded microchannels that can directly quantify adsorbed mass via changes in resonant frequency. As in other label-free detection methods, biomolecular measurements in complex media such as serum are challenging due to high background signals from nonspecific binding. In this report, we demonstrate that carboxybetaine-derived polymers developed to adsorb directly onto SMR SiO[subscript 2] surfaces act as ultralow fouling and functionalizable surface coatings. Coupled with a reference microcantilever, this approach enables detection of activated leukocyte cell adhesion molecule (ALCAM), a model cancer biomarker, in undiluted serum with a limit of detection of 10 ng/mL., National Cancer Institute (U.S.) (contract R01CA119402), SAIC-Frederick (contract 28XS119), National Institutes of Health (U.S.). Biotechnology Training Fellowship

Supporting Information Available: Detailed examinations of the algorithms that have been described in the manuscript for use in signal processing. (PDF) This information is available free of charge via the Internet at http://pubs.acs.org., Measurements of the mass and surface charge of microparticles are employed in the characterization of many types of colloidal dispersions. The suspended microchannel resonator (SMR) is capable of measuring individual particle masses with femtogram resolution. Here, we employ the high sensitivity of the SMR resonance frequency to changes in particle position, relative to the cantilever tip, to determine the electrophoretic mobility of discrete particles in an applied electric field. When a sinusoidal electric field is applied to the suspended microchannel, the transient resonance frequency shift corresponding to a particle transit can be analyzed by digital signal processing to extract both the buoyant mass and electrophoretic mobility of each particle. These parameters, together with the mean particle density, can be used to compute the size, absolute mass, and surface charge of discrete microspheres, leading to a true representation of the mean and polydispersity of these quantities for a population. We have applied this technique to an aqueous suspension of two types of polystyrene microspheres, to differentiate them based on their absolute mass and their surface charge. The integrated measurement of electrophoretic mobility using the SMR is determined to be quantitative, based on comparison with commercial instruments, and exhibits favorable scaling properties that will ultimately enable measurements from mammalian cells., National Cancer Institute (U.S.) (Platform Partnership Grant R01-CA119402), Institute for Collaborative Biotechnologies

Cell growth comprises changes in both mass and volume—two processes that are distinct, yet coordinated through the cell cycle. Understanding this relationship requires a means for measuring each of the cell’s three basic physical parameters: mass, volume, and the ratio of the two, density. The suspended microchannel resonator weighs single cells with a precision in mass of 0.1% for yeast. Here we use the suspended microchannel resonator with a Coulter counter to measure the mass, volume, and density of budding yeast cells through the cell cycle. We observe that cell density increases prior to bud formation at the G1/S transition, which is consistent with previous measurements using density gradient centrifugation. To investigate the origin of this density increase, we monitor relative density changes of growing yeast cells. We find that the density increase requires energy, function of the protein synthesis regulator target of rapamycin, passage through START (commitment to cell division), and an intact actin cytoskeleton. Although we focus on basic cell cycle questions in yeast, our techniques are suitable for most nonadherent cells and subcellular particles to characterize cell growth in a variety of applications., National Institutes of Health (U.S.) EUREKA (R01GM085457), Center for Cell Decision Process (grant P50GM68762), National Institutes of Health (U.S.) (Grant GM056800)

The fluid–structure interaction of resonating microcantilevers immersed in fluid has been widely studied and is a cornerstone in nanomechanical sensor development. In many applications, fluid damping imposes severe limitations by strongly degrading the signal-to-noise ratio of measurements. Recently, Burg et al. (Nature, vol. 446, 2007, pp. 1066–1069) proposed an alternative type of microcantilever device whereby a microfluidic channel was embedded inside the cantilever with vacuum outside. Remarkably, it was observed that energy dissipation in these systems was almost identical when air or liquid was passed through the channel and was 4 orders of magnitude lower than that in conventional microcantilever systems. Here, we study the fluid dynamics of these devices and present a rigorous theoretical model corroborated by experimental measurements to explain these observations. In so doing, we elucidate the dominant physical mechanisms giving rise to the unique features of these devices. Significantly, it is found that energy dissipation is not a monotonic function of fluid viscosity, but exhibits oscillatory behaviour, as fluid viscosity is increased/decreased. In the regime of low viscosity, inertia dominates the fluid motion inside the cantilever, resulting in thin viscous boundary layers – this leads to an increase in energy dissipation with increasing viscosity. In the high-viscosity regime, the boundary layers on all surfaces merge, leading to a decrease in dissipation with increasing viscosity. Effects of fluid compressibility also become significant in this latter regime and lead to rich flow behaviour. A direct consequence of these findings is that miniaturization does not necessarily result in degradation in the quality factor, which may indeed be enhanced. This highly desirable feature is unprecedented in current nanomechanical devices and permits direct miniaturization to enhance sensitivity to environmental changes, such as mass variations, in liquid.

Dissipation of mechanical energy underlies the sensitivity of many nanomechanical devices, with environmental effects often having a significant effect. One case of practical relevance is the interaction of elastic beam resonators with fluid, which is known to dramatically increase energy dissipation. Recently, we investigated energy dissipation in a different class of elastic beam resonator that embeds a microfluidic channel in its interior. In this paper, we examine the effect of the beam material Poisson ratio on these devices and discover that it can strongly affect energy dissipation—this is in direct contrast to conventional cantilever beams immersed in fluid. Increasing the Poisson ratio in these microfluidic devices is found to decrease energy dissipation, with the incompressible material limit providing minimum energy dissipation. Our paper establishes that, in this limit, placement of the fluid channel away from the beam neutral axis has negligible effect on energy dissipation in many cases of practical interest. The physical implications of these findings are discussed, and a detailed comparison with available experimental results is provided., Institute of Collaborative Biotechnologies (Contract No. W911NF-09-D-0001), National Institutes of Health (U.S.). Cell Decision Process Center (Grant No. P50-GM68762)

Cantilever sensors have attracted considerable attention over the last decade because of their potential as a highly sensitive sensor platform for high throughput and multiplexed detection of proteins and nucleic acids. A micromachined cantilever platform integrates nanoscale science and microfabrication technology for the label-free detection of biological molecules, allowing miniaturization. Molecular adsorption, when restricted to a single side of a deformable cantilever beam, results in measurable bending of the cantilever. This nanoscale deflection is caused by a variation in the cantilever surface stress due to biomolecular interactions and can be measured by optical or electrical means, thereby reporting on the presence of biomolecules. Biological specificity in detection is typically achieved by immobilizing selective receptors or probe molecules on one side of the cantilever using surface functionalization processes. When target molecules are injected into the fluid bathing the cantilever, the cantilever bends as a function of the number of molecules bound to the probe molecules on its surface. Mass-produced, miniature silicon and silicon nitride microcantilever arrays offer a clear path to the development of miniature sensors with unprecedented sensitivity for biodetection applications, such as toxin detection, DNA hybridization, and selective detection of pathogens through immunological techniques. This article discusses applications of cantilever sensors in cancer diagnosis., United States. Dept. of Energy

We used a suspended microchannel resonator (SMR) combined with picoliter-scale microfluidic control to measure buoyant mass and determine the 'instantaneous' growth rates of individual cells. The SMR measures mass with femtogram precision, allowing rapid determination of the growth rate in a fraction of a complete cell cycle. We found that for individual cells of Bacillus subtilis, Escherichia coli, Saccharomyces cerevisiae and mouse lymphoblasts, heavier cells grew faster than lighter cells.

Nanomechanical resonators enable a range of precision measurements in air or vacuum, but strong viscous damping makes applications in liquid challenging. Recent experiments have shown that fluid damping is greatly reduced in fluidic embedded-channel microcantilevers. Here we report the discovery of nonmonotonic energy dissipation due to the fluid in such devices, which leads to the intriguing prospect of enhancing the quality factor upon miniaturization. These observations elucidate the physical mechanisms of energy dissipation in embedded-channel resonators and thus provide the basis for numerous applications in nanoscience and biology., NIH Cell Decision Process Center, Australian Research Council Grants Scheme, Institute for Collaborative Biotechnologies

Biosensors suitable for providing informed rapid treatment analysis for soldiers and real-time environmental monitoring of toxic agents were developed. In particular, glass encapsulated field-effect sensors that are chemically robust and batch-fabricated by a conventional 6" wafer process were developed and demonstrated for the following applications: (i) Polymerase Chain Reaction (PCR) product quantification, (ii) Integrated microelectronic device for label-free nucleic acid amplification and detection, and (iii) Monitoring of heparin and its low molecular weight analogs., The original document contains color images.

Research highlights describing this include: (1) Improving the resolution of scanning probe microscopy in order to enhance the imaging quality of nanostructure materials. In particular, disturbance suppression schemes were implemented with the scanning tunneling microscope (Section I) and with conventional tapping mode (Section II). (2) Development of an ultrasensitive mass sensor known as the suspended microchannel resonator. As described in Section III, the quality factor (and hence mass resolution) was improved by nearly ten-fold with a wafer-scale vacuum packaging technique that was developed at MIT's Microsystems Technology Laboratory., The original document contains color images.