Integrated measurement of the mass and surface charge of discrete microparticles using a suspended microchannel resonator

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 Biotechnologie

Suspended microchannel resonators for biomolecular detection

Thesis (Ph. D.)--Massachusetts Institute of Technology, Dept. of Electrical Engineering and Computer Science, 2005.Includes bibliographical references (leaves 115-124).Microfabricated transducers enable the label-free detection of biological molecules in nanoliter sized samples. Integrating microfluidic detection and sample-preparation can greatly leverage experimental efforts in systems biology and pharmaceutical research by increasing analysis throughput while dramatically reducing reagent cost. Microfabricated resonant mass sensors are among the most sensitive devices for chemical detection, but degradation of the sensitivity in liquid has so far hindered their successful application in biology. This thesis introduces a type of resonant transducer that overcomes this limitation by a new device design: Adsorption of molecules to the inside walls of a suspended microfluidic channel is detected by measuring the change in mechanical resonance frequency of the channel. In contrast to resonant mass sensors submersed in water, the sensitivity and frequency resolution of the suspended microchannel resonator is not degraded by the presence of the fluid. Our device differs from a vibrating tube densitometer in that the channel is very thin, and only molecules that bind to the walls can build up enough mass to be detected; this provides a path to specificity via molecular recognition by immobilized receptors.(cont.) Suspended silicon nitride channels have been fabricated through a sacrificial polysilicon process and bulk micromachining, and the packaging and microfluidic interfacing of the resonant sensors has been addressed. Device characterization at 30 mTorr ambient pressure reveals a quality factor of more than 10,000 for water filled resonators; this is two orders of magnitude higher than previously demonstrated Q-values of resonant mass sensors for biological measurements. Calculation of the noise and the sensitivity of suspended microchannel resonators indicate a physical limit for mass resolution of approximately 0.01 ng/cm2 (1 Hz bandwidth). A resolution of -0.1 ng/cm2 has been experimentally demonstrated in this work. This resolution constitutes a tenfold improvement over commercial quartz crystal microbalance based instruments. The ability to detect adsorbing biomolecules by resonance frequency has been validated through binding experiments with avidin and various biotinylated proteins.by Thomas P. Burg.Ph.D

Toward Attogram Mass Measurements in Solution with Suspended Nanochannel Resonators

Using suspended nanochannel resonators (SNRs) we demonstrate measurements of mass in solution with a resolution of 27 ag in a 1 kHz bandwidth, which represents a 100-fold improvement over existing suspended microchannel resonators and, to our knowledge, is the most precise mass measurement in liquid today. The SNR consists of a cantilever that is 50 μm long, 10 μm wide, and 1.3 μm thick, with an embedded nanochannel that is 2 μm wide and 700 nm tall. The SNR has a resonance frequency near 630 kHz and exhibits a quality factor of approximately 8,000 when dry and when filled with water. In addition, we introduce a new method that uses centrifugal force caused by vibration of the cantilever to trap particles at the free end. This approach eliminates the intrinsic position dependent error of the SNR and also improves the mass resolution by increasing the averaging time for each particle.Center for Integration of Medicine and Innovative Technology (CIMIT Contract 09-440)United States. Army Research Office (Institute for Collaborative Biotechnologies Grant (DAAD1903D0004))Max Planck Institute for Biophysical Chemistr

Constraining q_0 with Cluster Gas Mass Fractions: A Feasibility Study

As the largest gravitationally bound objects in the universe, clusters of galaxies may contain a fair sample of the baryonic mass fraction of the universe. Since the gas mass fraction from the hot ICM is believed to be constant in time, the value of the cosmological deceleration parameter $q_0$ can be determined by comparing the calculated gas mass fraction in nearby and distant clusters (Pen 1997). To test the potential of this method, we compare the gas fractions derived for a sample of luminous ($L_X > 10^{45}$erg s$^{-1}$), nearby clusters with those calculated for eight luminous, distant ($0.3 < z < 0.6$) clusters using ASCA and ROSAT observations. For consistency, we evaluate the gas mass fraction at a fixed physical radius of 1 $h_{50}^{-1}$ Mpc (assuming $q_0=0.0$). We find a best fit value of $q_0 = 0.07$ with -0.47 < q_0 < 0.67 at 95% confidence. We also determine the gas fraction using the method of Evrard, Metzler, & Navarro (1997) to find the total mass within $r_{500}$, the radius where the mean overdensity of matter is 500 times the critical density. In simulations, this method reduces the scatter in the determination of gravitational mass without biasing the mean. We find that it also reduces the scatter in actual observations for nearby clusters, but not as much as simulations suggest. Using this method, the best fit value is $q_0 = 0.04$ with -0.50 < q_0 < 0.64. The excellent agreement between these two methods suggests that this may be a useful technique for determining $q_0$. The constraints on $q_0$ should improve as more distant clusters are studied and precise temperature profiles are measured to large radii.Comment: 8 pages, 4 figures, uses emulateapj.sty, onecolfloat.st

Protective Filtration for Microfluidic Nanoparticle Precipitation for Pharmaceutical Applications

Microfluidic processes are of great interest for the production of nanoparticles with reproducible properties. However, in real systems, it is difficult to completely exclude incidental production of larger particles, which can contaminate the product or clog downstream process modules. A class of microfluidic filters was devised for eliminating particulate contamination in multistage continuous‐flow processes. To achieve high throughput and filtration efficiency, a high‐surface‐area filter with an application‐adapted bonding method was developed. As a model application, the filtration efficiency was analyzed for lipid nanoparticles made by microfluidic antisolvent precipitation and the results were compared with requirements of the European and US guidelines

Clinic Blood Pressure Underestimates Ambulatory Blood Pressure in an Untreated Employer-Based US Population: Results From the Masked Hypertension Study

Background: Ambulatory blood pressure (ABP) is consistently superior to clinic blood pressure (CBP) as a predictor of cardiovascular morbidity and mortality risk. A common perception is that ABP is usually lower than CBP. The relationship of the CBP minus ABP difference to age has not been examined in the United States. Methods: Between 2005 and 2012, 888 healthy, employed, middle-aged (mean±SD age, 45±10.4 years) individuals (59% female, 7.4% black, 12% Hispanic) with screening BP <160/105 mm Hg and not taking antihypertensive medication completed 3 separate clinic BP assessments and a 24-hour ABP recording for the Masked Hypertension Study. The distributions of CBP, mean awake ABP (aABP), and the CBP−aABP difference in the full sample and by demographic characteristics were compared. Locally weighted scatterplot smoothing was used to model the relationship of the BP measures to age and body mass index. The prevalence of discrepancies in ABP- versus CBP-defined hypertension status—white-coat hypertension and masked hypertension—were also examined. Results: Average systolic/diastolic aABP (123.0/77.4±10.3/7.4 mm Hg) was significantly higher than the average of 9 CBP readings over 3 visits (116.0/75.4±11.6/7.7 mm Hg). aABP exceeded CBP by >10 mm Hg much more frequently than CBP exceeded aABP. The difference (aABP>CBP) was most pronounced in young adults and those with normal body mass index. The systolic difference progressively diminished, but did not disappear, at older ages and higher body mass indexes. The diastolic difference vanished around age 65 and reversed (CBP>aABP) for body mass index >32.5 kg/m2. Whereas 5.3% of participants were hypertensive by CBP, 19.2% were hypertensive by aABP; 15.7% of those with nonelevated CBP had masked hypertension. Conclusions: Contrary to a widely held belief, based primarily on cohort studies of patients with elevated CBP, ABP is not usually lower than CBP, at least not among healthy, employed individuals. Furthermore, a substantial proportion of otherwise healthy individuals with nonelevated CBP have masked hypertension. Demonstrated CBP−aABP gradients, if confirmed in representative samples (eg, NHANES [National Health and Nutrition Examination Survey]), could provide guidance for primary care physicians as to when, for a given CBP, 24-hour ABP would be useful to identify or rule out masked hypertension

Safeguarding children in dentistry: 1. Child protection training, experience and practice of dental professionals with an interest in paediatric dentistry

* Few dental professionals with child protection training have experience of making referrals. * There is a wide gap in practice between recognising signs of child abuse and neglect and responding effectively. * This may indicate missed opportunities to save children from continuing abuse. * There is a need for improved child protection information, support and training for dental professionals. Abstract Following several highly publicised inquiries into the deaths of children from abuse and neglect, there has been much recent interest in the role and responsibility of all health professionals to protect children at risk of maltreatment. The findings of a postal questionnaire, sent in March 2005 to 789 dentists and dental care professionals with an interest in paediatric dentistry working in varied settings in the UK, are presented in a two-part report and discussed in the context of current multi-agency good practice in safeguarding and promoting the welfare of children. This first part explores reported child protection training, experience and practice. There was a significant gap between recognising signs of abuse and responding effectively: 67% of respondents had suspected abuse or neglect of a child patient at some time in their career but only 29% had ever made a child protection referral. The dental profession is alerted to the need to ensure necessary appropriate action to safeguard children is always taken when child abuse or neglect are suspected

Robust Smartphone Assisted Biosensing Based on Asymmetric Nanofluidic Grating Interferometry.

Point-of-care systems enable fast therapy decisions on site without the need of any healthcare infrastructure. In addition to the sensitive detection, stable measurement by inexperienced persons outside of laboratory facilities is indispensable. A particular challenge in field applications is to reduce interference from environmental factors, such as temperature, to acceptable levels without sacrificing simplicity. Here, we present a smartphone-based point-of-care sensor. The method uses an optofluidic grating composed of alternating detection and reference channels arranged as a reflective phase grating. Biomolecules adsorbing to the detection channel alter the optical path length, while the parallel reference channels enable a direct common mode rejection within a single measurement. The optical setup is integrated in a compact design of a mobile readout device and the usability is ensured by a smartphone application. Our results show that different ambient temperatures do not have any influence on the signal. In a proof-of concept experiment we measured the accumulation of specific molecules in functionalized detection channels in real-time and without the need of any labeling. Therefore, the channel walls have been modified with biotin as capture molecules and the specific binding of streptavidin was detected. A mobile, reliable and robust point-of-care device has been realized by combining an inherently differential measurement concept with a smartphone-based, mobile readout device

Nanofluidic Immobilization and Growth Detection of Escherichia coli in a Chip for Antibiotic Susceptibility Testing

Infections with antimicrobial resistant bacteria are a rising threat for global healthcare as more and more antibiotics lose their effectiveness against bacterial pathogens. To guarantee the long-term effectiveness of broad-spectrum antibiotics, they may only be prescribed when inevitably required. In order to make a reliable assessment of which antibiotics are effective, rapid point-of-care tests are needed. This can be achieved with fast phenotypic microfluidic tests, which can cope with low bacterial concentrations and work label-free. Here, we present a novel optofluidic chip with a cross-flow immobilization principle using a regular array of nanogaps to concentrate bacteria and detect their growth label-free under the influence of antibiotics. The interferometric measuring principle enabled the detection of the growth of Escherichia coli in under 4 h with a sample volume of 187.2 µL and a doubling time of 79 min. In proof-of-concept experiments, we could show that the method can distinguish between bacterial growth and its inhibition by antibiotics. The results indicate that the nanofluidic chip approach provides a very promising concept for future rapid and label-free antimicrobial susceptibility tests

Evidence and Ideology in Macroeconomics: The Case of Investment Cycles

The paper reports the principal findings of a long term research project on the description and explanation of business cycles. The research strongly confirmed the older view that business cycles have large systematic components that take the form of investment cycles. These quasi-periodic movements can be represented as low order, stochastic, dynamic processes with complex eigenvalues. Specifically, there is a fixed investment cycle of about 8 years and an inventory cycle of about 4 years. Maximum entropy spectral analysis was employed for the description of the cycles and continuous time econometrics for the explanatory models. The central explanatory mechanism is the second order accelerator, which incorporates adjustment costs both in relation to the capital stock and the rate of investment. By means of parametric resonance it was possible to show, both theoretically and empirically how cycles aggregate from the micro to the macro level. The same mathematical tool was also used to explain the international convergence of cycles. I argue that the theory of investment cycles was abandoned for ideological, not for evidential reasons. Methodological issues are also discussed