Examples of existing and emerging wearable sensors for chemical and biological threat agents are reviewed and essential enabling developments identified. Wearables are described as inward looking sensors (self-monitoring) and outward looking sensors (environmental sensors). The future potential for wearable sensors, expected capabilities, and key challenges are summarized.
The global wearables market was valued at USD $22 billion in 2016 and is expected to reach almost USD $100 billion by 2023 , which includes smart watches, head-mounted displays, wearable cameras, Bluetooth headsets, wristbands, smart clothing, chest straps, sports watches, and others. The global healthcare wearables market was valued at USD $13 billion in 2016. These wearables offer improved monitoring of at-risk patients with inherent overall medical cost savings and are rapidly growing in capability and utility, but they are generally very bulky. Wearables are also used to monitor farm animals, high-value animals (e.g. zoo animals, racehorses), and pets, though their capabilities are limited to physiological and biomechanical measurements.
While most consumer products measure only a subset of the following parameters, more specialized wearables, including those used in health care, may include:
Skin temperature (core body temperature is still under development)
UV light exposure
Blood pressure (systolic and diastolic)
Acoustic measurements (coughing, wheezing, heart sounds)
Biomechanical measurements (e.g. via 3-axis accelerometers)
Additionally, using advanced algorithms, “composite” sensor measurements can provide estimates of activity/mobility/falls (using 3-axis accelerometers), distance traveled, calories burned, sleep quality, stress/exertion/fatigue, among many others. Research demonstrating wearables for more advanced measurements is ongoing, but there is currently little market pull for biothreat related capabilities and few examples of wearables for biodetection.
The wearables discussed above are mostly “inward looking” sensors (i.e. self-monitoring). While not traditionally considered a “wearable,” dosimeters or belt-worn devices (“outward looking” or environmental sensors) can offer valuable information for improved safety and health, particularly for emergency responders or inspectors. For example, individuals with asthma or other respiratory ailments can currently wear small, real-time respirable particulate monitors. Miniaturized analytical instruments and dosimeters are also available for measuring various chemical species.
Because they are easier to measure using relatively simple sensors, electrolytes, metabolites, small molecules, proteins, metals, and gases have been shown to be measurable in sweat, tears, saliva, blood, and breath. Additionally, there are some reports of detection of biomarkers in a form-factor adaptable to wearables. It should be emphasized that all of these approaches are at the research stage and need significant engineering to improve robustness, as well as improvements to detection approaches to enable them to be used for more than a few days.
Examples of existing outward looking sensors (e.g. belt-worn environmental monitoring) include personal particulate monitors and miniaturized analytical instruments (e.g. Raman). While microfluidics in a wearable format has also been developed, these approaches are still based on traditional reagents and have the same performance limitations as their laboratory counterparts (hours to result, use of traditional reagents), so significant development is needed in multiple areas before a wearable polymerase chain reaction (PCR) platform can ever be realized.
Continued developments are still needed in several areas to enable a biothreat detection or exposure indicator wearable including:
Miniaturization to achieve desirable form-factors
Improved sensors utilizing stable/reversible chem/bio affinity ligands to minimize/eliminate reagents
Nanomaterials to enable faster, more sensitive detection
Robust/flexible electrical systems, which have been demonstrated and continue to be improved
Transdermal biological fluid extraction to enable detection of biomarkers or indicators of chem/bio exposure, which have been demonstrated
Biomarkers of disease or chem/bio exposure that can be readily measured over longer time periods
Microscale power/storage for longer term use
Communications to enable efficient data transmission, storage, management, analytics in a secure manner (e.g. using the cloud)
Examples of self-monitoring (inward looking) wearables are given below. Some systems are fully automated from sample-to-answer, while others require some steps to be performed manually (e.g. sample introduction). While some of these examples are not fully integrated systems, they demonstrate the detection capabilities and form-factors possible that could enable future wearables for chem/bio exposure monitoring.
A highly integrated wearable system including a heater, temperature, humidity, glucose, and pH sensors was demonstrated on diabetic mice. The electrochemical device used a thermally activated polymeric microneedle array for sampling interstitial fluid and administering drugs .
Cai et al. developed an Integrated microfluidic device for pathogen identification in blood. Four channels process independent samples and identify up to 20 different pathogens. Pathogens are first extracted from blood by dielectrophoresis before multiplex PCR in nanoliter volumes with end-point fluorescence detection within 3 h . Another example of microfluidic PCR that is approaching a form factor that could be adapted to a wearable device was demonstrated by Diakite et al. . The 1.5 h assay utilizes a cartridge for mRNA extraction from a drop of blood, followed by tens of parallel RT-qPCR reactions.
These approaches demonstrate multiplexed pathogen detection in a very small form-factor that could theoretically be adapted and combined with transdermal biological fluid extraction microneedle arrays to achieve an integrated system. PCR assays typically require 30–60 min with another 1–2 h required for sample preparation, which does not meet the needs of detect-to-warn applications, but could be useful in detect-to-treat applications. While PCR requires primer/probe reagents, several commercial field PCR systems offer lyophilized reagents for numerous biothreat agents in cartridges or tubes that are stable for up to 1 year without refrigeration, so it is reasonable to assume that similar reagent packs could be developed for wearable formats for chem/bio exposure detection.
Another less invasive bodily fluid that can be monitored for various biomarkers is sweat. Sweat is convenient to utilize as a sample and contains a wide variety of physiological status indicators, as well as a wealth of biomarkers related to disease, chem/bio exposure, etc. These biomarkers enter sweat from cells that form the walls of sweat ducts inside the skin . Several approaches exist for inducing the extremely small volumes of sweat needed for analysis.
Gao demonstrated an unprecedented degree of integration of a multiplexed in situ sweat sensor that incorporates complex signal conditioning on a flexible printed circuit board combined with a skin-interfaced flexible sensor array for monitoring hydration status in real-time . The sensors measure metabolites (glucose and lactate) and electrolytes (sodium and potassium ions) and use a skin temperature sensor to improve accuracy. Results are wirelessly transmitted to a smartphone. The wrist-worn system was demonstrated by monitoring real-time hydration status of humans engaged in prolonged indoor and outdoor physical activities. This work bridges the technological gap between signal transduction, conditioning (amplification and filtering), processing and wireless transmission in wearable biosensors by merging plastic-based sensors that interface with the skin with silicon integrated circuits consolidated on a flexible circuit board for complex signal processing. This application could not have been realized using either of these technologies alone owing to their respective inherent limitations.
These examples demonstrate the ability to multiplex for biothreat pathogen detection with sensitivity comparable to laboratory PCR. The extension to monitoring other biomolecules indicative of exposure to chemical or biological agents would be relatively straightforward. However, most of these examples are in the early research stage, with significant further development and integration with other components needed to achieve a practical system. While physiological parameters in sweat can be measured rapidly and are closer to practical deployment, direct measurement of pathogens or biomarkers of chem/bio exposure, with necessary sample preparation, takes hours.
Tattoo sensors have been developed for measuring a variety of parameters in bodily fluids and parameters that may be useful for composite assays (i.e. combining measurements of multiple parameters to predict chem/bio exposure or health status). Below is an example of a stretchable tattoo sensor (the “Biostamp”), which presents a platform that could be used to support a variety of other sensors (Fig. 1). The Biostamp includes arrays of transistors, diodes, capacitors, inductors, LC oscillators, temperature sensors, strain gauges, an LED, inductive coil and antenna. This work was led by John Rogers at the University of Illinois, Urbana-Champaign.
Roger’s group has also developed a battery-free tattoo blood oximetry device that receives power wirelessly (Fig. 2). While this was designed for pulse oximetry, it could possibly be adapted for a future wearable optoelectronic particle counter or light source for conducting colorimetric/fluorimetric chemical or biological assays if other necessary components and functions are integrated into a system. Another example of a self-monitoring sensor is an implantable glucose sensor that is commercially available in Europe and is made by Abbott (Fig. 3).
Detection of a fluorescent biological particle indicates a possible biothreat agent (e.g. aerosolized Bacillus anthracis) or it could be a benign particle such as pollen or diesel soot, so fluorescent particle detectors are simply triggers that indicate the possible presence of a biological agent.
Research Technology International’s MicroPEM can measure particulates, but does not include fluorescence detection, which is needed to discriminate biological/organic particulates from other particulates like dust (Fig. 4). The device is small and offers a platform that could be further developed to provide rapid biothreat agent screening. Specifications include:
48–176 h battery life
PM2.5 or PM10 particulate ranges
1 s readout
Includes filter for additional optional analysis
Networking of multiple devices possible
Wireless data transfer
Basic OEM particle filters can be mass produced at low-cost. These base units require additional supporting electronics, control, display, alarms, etc., but have the advantage of low cost (Fig. 5). These illustrate that the potential for large numbers of distributed fixed, mobile or wearable sensors are within the realm of possibility from a cost perspective. Rather than measuring chemical or biological components in the air, these devices would enable collection on a filter, with subsequent processing of the filter using microfluidics/reagents or direct interrogation of the filter (e.g. using Raman spectroscopy for detection of chemicals).
Particulate monitors are small and offer a potential trigger/alert for near real-time monitoring of aerosolized biothreat agents. Various particulate monitors are commercially available, but the only products designed for biothreat agent monitoring are transportable devices that weigh 10 pounds or more .
While there are no significant technological barriers to making small bioaerosol detectors based on laser-induced fluorescence (LIF), there is no civilian market driver for any company to develop such a product. In addition, the various features needed to improve performance of a LIF system necessarily lead to a significant increase in size (high flow rate pumps, programming and communication options, lower cost components that are not miniaturized). To reduce false positives due to environmental background such as pollen, larger and more expensive LIF particle detectors include measurement of multiple emission wavelengths, particle size/shape measurement, and may include fluorescence lifetime measurements.
Analytical instruments continue to be reduced in size including mass spectrometers, infrared spectrometers, and Raman spectrometers, with the latter recently achieving an impressive form-factor while retaining high performance (Fig. 6). Specifications for this system are listed below:
Raman spectral range: 400–2300 cm−1
Laser output power: 70 mW at sample, adjustable
Display: 2.8″ OLED resistive touch screen
Size: (H×W×D) 3.6″×2.80″×1.5″
System weight: 11.75 oz.
Power: 2 AA batteries
Raman has been shown to be able to detect signatures of biothreat agents  as well as a variety of chemicals, so it is possible this type of product could be integrated with a sample collection device (e.g. the MicroPEM, which includes a particulate collection filter that could be interrogated periodically by Raman). A significant limitation of this particular palm-sized Raman (and other more expensive Raman systems) is the cost (~$20,000 US).
Wang’s research group have developed several wearable chemical sensors, with the most recent version being a ring-based sensor for measuring explosives and nerve agent simulants . The ring-based device uses screen-printed electrochemical sensors and miniaturized electronics for detection of threat agents. Methyl paraoxon is used as an organophosphate nerve agent simulant and is detected via oganophosphorous hydrolase, peroxide is detected via carbon/Prussian blue, and square-wave voltammetry is used for stepwise reduction/detection of dinitrotoluene. A semi-solid conductive agarose hydrogel covers sensor surface to promote analyte diffusion to the electrodes. This represents a significant reduction in form-factor by using a stamp-size wireless potentiostat. It is applicable to vapors, aerosols and liquids and expandable to other chemical threat agents.
Capacitive micro-machined ultrasonic transducers (CMUT) offer potential for future wearables chemical sensor development owing to their small size, ease of fabrication of large arrays of sensors, ease of integration with other electronics, and extraordinarily low power requirements (sub-milliwatt) . Low parts-per billion levels of dimethyl methylphosphonate (DMMP), a common simulant for sarin gas, have been detected in <10 s . For arrays, each sensor in the array is coated with a different semi-selective polymer that preferentially absorbs certain chemical classes and causes a measurable shift in resonant frequency proportional to concentration. A response pattern generated by the sensor arrays produces different patterns for different chemical vapors [18, 19]. However, complex mixtures can be challenging to deconvolute.
Wearable devices show great promise for enabling the detection of chemical and biological agents, as well as exposure in individuals. These sensors also have the potential to be a low enough cost that they could be widely distributed in fixed, mobile and/or wearable formats. However, the use of wearables for chem/bio detection requires development in numerous areas. Key enabling technology development areas for the application of wearables for chem/bio detection include: (1) identification of biomarker panels of chem/bio exposure, (2) stable/reversible chem/bio affinity reagents, (3) nanomaterials to enable faster, smaller, and more sensitive detection, and (4) continued advances in microfluidics and microfabrication. As with the evolution of cell phones, wearables are expected to improve in capability, usability, and affordability as enabling technology allows higher degrees of integration into ever smaller form-factors. However, while miniaturization is a critical part of the future of wearables, very little current wearables development efforts are focused on chem/bio detection. Therefore, focused investment is needed to drive the development of wearables for chem/bio detection.
One area where research is needed is to understand early chem/bio exposure indicators from aggregated physiological, biomechanical, biochemical/biomarkers. While one or two parameters may not be able to accurately detect exposure, a suite of wearable sensor data (both self-monitoring of sweat/blood parameters and environmental monitoring of indicators of threat presence) may be able to indicate early exposure to chem/bio agents with greatly improved accuracy.
Biothreat detection and identification must be simple and, ideally, reagentless for wearable devices. Promising research in this area has demonstrated stable and reversible affinity ligands, but applications for chem/bio exposure detection are lacking. Synthetic bioaffinity ligands like aptamers or proteins need to be more stable and have the ability to be regenerated for long-term use in biological exposure monitoring.
Nanomaterials is another rapidly evolving area that enables faster, more sensitive assays (up to 1000-fold faster), as well as reducing the volume of sample needed to miniscule amounts. Continued advancements are needed in this area to realize small wearable devices that can detect chem/bio agents or biomarkers of exposure.
Minimally invasive and small-format transdermal biological fluid extraction approaches allow biomarkers to be readily accessed in blood or sweat and, with appropriate biomarker availability in the particular bodily fluid, represent a logical path forward to the development of wearable chem/bio exposure monitoring devices.
A fundamental need to enable early detection of chem/bio exposure is to better understand which biomarkers in sweat and blood are indicative of different types of exposure, identify suitable biomarkers that can be detected with appropriate reversible affinity reagents at required sensitivities, and understand baseline and exposure event concentration fluctuations.
The potential for implantable sensors is exemplified by commercially available glucose sensors which can last 14 days if self-implanted (see Fig. 6), or, if implanted in a doctor’s office, they can last up to 6 months. DARPA recently awarded $7.5M to Profusa to develop an implantable sensor to measure oxygen, glucose, lactate, urea, and ions. However, given the challenges of measuring more complex biomarker molecules indicative of exposure, implantables for chem/bio exposure monitoring are not likely possible in the near future.
Environmental monitoring wearables for detection of chemical and biological agents are closer to becoming a reality as demonstrated by the small size and cost of existing particulate monitors. However, these systems have not been developed for biothreat agent detection (as triggers/alerts) or chemical detectors and would need to be tailored with necessary functionality (e.g. fluorescence detection, Raman interrogation of a continuous miniature air sampling filter, etc.). Significant challenges remain for LIF bioaerosol detection to reduce false positives, so research to improve confidence is needed and could include the cost/benefit of using detection of multiple emission wavelengths, particle sizing/morphology, time resolution, polarization, microscopic imaging, ultrasonic particulate concentrators, etc.
The limit of detection for particle detectors is 100–1000 s of particles per liter above background particulate levels. However, because these background particulate levels can fluctuate rapidly an order of magnitude in short time periods, understanding particulate level concentration fluctuation and composition is a necessary research effort needed to not only guide design of low false-positive biological triggers, but also to validate their performance. In addition, approaches that can distinguish bioparticles of interest from the background particles are needed to improve sensitivity and lower false alarms. For the broad application of environmental monitoring wearables, field trials will be needed in real-world scenarios and multiple/diverse geographic locations and environmental conditions to validate performance.
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