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Summary
There is a rapidly growing need for reliable sensor-based measurement technology which can quickly provide actionable outputs for on-site and local chemical/biochemical analyses. Samples can be presented in the gas-phase or solution-phase, for wide-ranging, application-specific tasks from environmental monitoring and manufacturing process control, to pathogen and disease state detection. The impact of sensor-based measurements resides in providing user-friendly, specific and direct monitoring, with little or no sample preparation, at costs and settings untenable for operator-based analytical instruments. To realize these attributes scientific studies endeavor to enable high performance microsensors which can detect and quantify chemicals and biomolecular species at appropriate concentrations in practical backgrounds. The research efforts are very multidisciplinary. Transduction principles often evolve from physics and chemistry, but other areas like biology, nanotechnology, surface science, electrical engineering, and advanced signal processing can be critical to realizing concepts that offer sensor-based analyses which are fast, sensitive, selective and reliable.
Description
Dogs and insects have incredibly sensitive chemical sensing capabilities which are difficult to emulate in manufactured sensor devices.
The objective of our program is the development of advanced sensing concepts and components aimed at overcoming performance shortfalls in existing technology. Sensing observed in nature and biological systems serves as a difficult-to-emulate inspiration to our studies. Research efforts have involved wafer-based and micromachined platform fabrication, nanostructured materials and interfaces, biomolecular receptors, thermal programming, and machine learning. These approaches have been used synergistically to enhance the capabilities of tiny devices that measure effects from chemical interactions which induce electrical, optical, or electrochemical property changes in well-designed sensing materials incorporated onto the microdevices. Data analysis methods can be extremely important for extracting valuable insights from acquired signals. The work illustrated by the following examples demonstrates, in particular, the importance of both high-surface area nanoscale materials/interfaces and temperature variation for enhancing sensing capabilities.
Major Accomplishments
Microhotplate Gas Sensor Arrays with Rapid Temperature Programming
To realize enhanced analytical capabilities for gas sensing with inexpensive electronic sensors, we employed Si wafer processing technology and micromachining to produce array-configured microdevices. The microhotplate sensor platforms we designed include electrodes for measurement of electronic transport variation in deposited sensing materials exposed to gaseous environments, as well as an embedded polysilicon resistive heater for temperature measurement and control between 20 °C and 500 °C. For gaining large amounts of analytical information the microhotplates are configured in multielement arrays consisting of four to thirty-six elements, each element being individually addressable to acquire electrical signals and also allow thermal control so that interfacial chemical interactions can be purposefully altered as a function of time.
Films of varied materials (including nanostructured oxides, polymers and catalytic additives), which respond differently to sample gases, can be incorporated onto each tiny (100 µm x 100 µm) suspended element by drop-casting/drying, inkjet printing/drying, self-lithographic chemical vapor deposition, or electrochemical processing. The signal streams for gas-phase analyses of target species in mixtures are further enriched by running rapid thermal programs (millisecond-range time constant) on the individual microhotplate elements which have a (pre-sensing film) mass of only ~ 250 ng. Large sets of time-varying chemiresistive data are collected from the multiple elements within the arrays and analyzed using dimensionality reduction and machine learning methods. The chemiresistive sensor arrays have been applied to characterize simulated planetary environments (for NASA), detect toxic industrial chemicals in mixed backgrounds (for DHS), and ultra-low concentration chemical warfare agents (for DOD). The technology has also been explored as a means of noninvasive analysis of disease biomarkers in simulated breath.
Electrochemical Microsensors for Biomolecular Analyses
For biochemical analyses in solution-phase samples, electrochemical sensing offers a sensitive and cost-effective option for detecting biochemical targets and monitoring biochemical processes. Such sensing capabilities can play a key role in areas such as biomedical diagnostics, biomanufacturing and biochemical science. Using facilities available at the NIST NanoFab we have fabricated planar 3-electrode electrochemical microdevices.
Besides including small planar versions of the traditional working-electrode, counter-electrode and reference-electrode, our electrochemical platforms also include an embedded microheater, allowing one to study temperature-dependent biochemical phenomena. Temperature ramping allows melting curves to be obtained from a variety of solution-phase samples, and such measurements have been utilized to characterize single nucleotide polymorphisms (SNPs), and the ways in which small molecules may interact with (duplex) DNA to alter its melting behavior. The electrochemical sensors have also been applied to studies of conformational changes in oligonucleotides, for 10mers to 50mers strands, caused by physical and chemical stressing.
Nanoengineered Optical Sensors
Our efforts to develop chemiresistive arrays and planar electrochemical technology targeted enabling analysis of gas-phase and solution-phase samples, respectively. However, optical sensing platforms have been developed with versatility for measurements on both gas-phase and solution-phase samples. Specifically, we have demonstrated how localized surface plasmon resonance (LSPR) sensing technology, supported by nanoengineered structures, can quantify disease biomarkers in simulated breath, monitor the binding properties of DNA strands in buffers, and detect the capture of protein targets by surface-immobilized aptamers.
The ability of LSPR platforms to show chemically-induced spectral shifts for sensing is entirely dependent on the nanoengineering of interface nm-scale structures that produce a high near-surface electromagnetic enhancement. These “hot spot” containing interfaces are realized using equipment at the NIST NanoFab, such as electron beam lithography, to produce regions of precise, repeatable nanohole, nanodome, and nanopillar features. The platforms are assembled with very thin metal films (Ag, Au) deposited over the patterned insulator structures. When target molecules bind to appropriately-selected probe/receptors immobilized on the metal coatings in the areas near the hot spots, localized changes in the index of refraction result in spectral shifts of the optical resonance that is characteristic of the given nanostructured platform. Spectral analyses, performed either through imaging or mathematical evaluation of the spectral features, have been successfully used to study gas-phase disease markers in simulated breath (for diabetes and cystic fibrosis). LSPR spectral changes are also being used to optimize spatial features and receptor densities in solution-phase samples for DNA hybridization analysis and the sensing of antibody proteins.
Testing Technologies for Use in Chemical Analyses During Biomanufacturing Processes
Certain quantities such as temperature, pH and dissolved oxygen are rather routinely measured on-line with existing technologies in cell cultures employed for manufacturing biotherapeutics. However there is an increasing demand for process analytical technology (PAT) capable of tracking other process variables relating to cell culture chemical components including metabolites, protein products and varied types of contaminants. Efforts at NIST and through collaborations seek to provide in-line and at-line sensor-based biochemical measurement technology that can inform process control to produce better products, such as therapeutic antibodies. Scientific studies aim to enable fast and continuous sensor measurements employing techniques such as optical resonators and high-resolution surface enhanced Raman spectroscopy (SERS) to tackle these challenging analytical problems. These emerging sensor technologies hold the promise of allowing more rapid process adjustments at greatly reduced cost when compared to diagnostics now performed by drawing off and preparing samples for instrumental analysis.