Application of programmable bio-nano-chip system for the quantitative detection of drugs of abuse in oral fluids☆
Graphical abstract
Introduction
Driving under the influence of drugs is a problem of growing concern in many countries, including the United States (US) and the United Kingdom (UK). In spite of the most stringent drug policies and punitive laws, in 2008 the US had the highest levels of lifetime illegal cocaine and marijuana use, with these and other drugs and their metabolites being increasingly detected in impaired and injured automobile drivers (http://oas.samhsa.gov/nsduh.htm). Drug use is a contributory factor to a significant percentage of fatal road traffic collisions. In the UK, in 2010/2011, an estimated 19% of adult drivers who had taken illegal drugs reported driving at least once or twice within the last 12 months while they were affected by or under the influence of illegal drugs (http://assets.dft.gov.uk/statistics/releases/road-accidents-and-safety-annual-report-2011/rrcgb2011-05.pdf).
Despite these dire facts, neither the US nor UK, nor any other country for that matter, has access to a reliable method analogous to the alcohol breath-alyzer to detect drugged-drivers. Likewise, practical limitations associated with the current sampling approaches to collect forensic specimens, as well as lack of suitable technologies that could efficiently, accurately and sensitively determine drug concentrations outside of the laboratory setting have hindered progress in this area.
Current approaches involve blood sampling, which is invasive, and requires specialized sample collection and preparatory work prior to sample analysis. This process is time-consuming and, in most cases, confined to a laboratory setting. In some situations urine sampling is a better alternative, but associated with privacy issues, concerns with chain of custody and vulnerability to adulteration. Hence, there is a pressing need for alternative diagnostic fluids/matrices, such as hair, sweat and oral fluids for drug testing.
Indeed, in recent reviews saliva is presented as a clinically informative biological fluid that is increasingly shown to be useful for prognosis, laboratory or clinical diagnosis, and monitoring and management of patients with both oral and systemic diseases (Malamud and Rodriguez-Chavez, 2011, Lee et al., 2009, Wong, 2008, Parisi et al., 2009, White et al., 2009).
Oral fluid-based immunochromatographic strip (ICS) tests have been developed with capabilities in various drug testing/screening settings outside the laboratory (Crouch et al., 2008, Vanstechelman et al., 2012). However, these tests are not quantitative, thereby limiting access to potential impairment status, as well as they exhibit only restricted multiplexed capabilities, making them less practical for point-of-need settings (Bosker and Huestis, 2009).
The marriage of noninvasive sampling with portable detection capabilities afforded with lab-on-a-chip systems provides an ideal opportunity to address unmet needs for the drug testing and monitoring areas. Over the past two decades much progress has been made in the direction of development of new chip-based systems. Indeed, pioneering work by Whitesides in the basic sciences defined the ideal coatings, materials and designs for the development of microfluidic channels and manipulations of biological fluids (Whitesides, 2006), while Quake's group advanced the ‘large-scale integration’ of microfluidics, analogous to the electronics field (Thorsen et al., 2002). Other groups, such as those of Mirkin, Wang and Heath, measured diverse sample types and created a variety of assembly types by using precious metal nanoparticles, nanowires, and magnetic techniques, respectively (Goluch et al., 2006, Osterfield et al., 2008, Qin et al., 2009). Advancements by Sia via micro-electromechanical systems and Singh using chip-based separation and quantitation benefited integration of such systems (Srivastava et al., 2009, Chin et al., 2007). Both Singh and Ligler have extended their integrated approaches into the rapid, multiplexed detection of analytes, such as toxins and other bio-threats (Kim et al., 2009), while Walt's work with electronic noses used arrays of optical fibers as the underlying infrastructure for biological sensing systems (Walt, 2005). Finally, researchers in the Toner group have explored a number of novel methods for the isolation and enumeration of lymphocytes, erythrocytes and circulating tumor cells (Cheng et al., 2009, Maheswaran et al., 2008). While such chip-based detection modalities have strong potential for use in clinical and sensor applications, the development of fully integrated and clinically validated structures remains a significant barrier for these structures, including for those intended for drug testing point-of-need applications (Bell and Hanes, 2007, Bruls et al., 2009, Qiang et al., 2009, Zhou et al., 2012). In the area of oral fluid testing, additional challenges are presented with respect to the management and processing of oral fluid samples due to the high viscosity and complex nature of such specimens.
The purpose of this article is to describe recent work that is leading to the development of new oral fluid detection capabilities, whereby multiple drug and metabolites can be detected and quantitated using Programmable bio-nano-chips (p-BNCs; Christodoulides et al., 2002, Christodoulides et al., 2012, Floriano et al., 2009, Goodey et al., 2001, Raamanathan et al., 2012, Rodriguez et al., 2005). These efforts place into the pipeline new options for drug testing that have significant potential to influence measurement of drug samples for a wide variety of settings.
Section snippets
Patient recruitment
This study was approved by the Rice University, Baylor College of Medicine (BCM) and Michael De Bakey Veterans Affairs Medical Complex (MEDVAMC) Institutional Review Boards (IRBs). Recruitment of study participants and saliva donors for p-BNC forensic challenge and elucidation of time-course of select drugs experiments was coordinated and carried out at the MEDVAMC, Houston, Texas. All study participants (n = 78) were at least 18 years old and provided informed consent after complete description
Results
The bead-based p-BNC drug tests reported here function with non-invasive oral fluid sampling, that involves use of an oral swab to brush the entire upper and lower gum line (Fig. 1A), and then insertion of the swab into a specimen collection tube to extract the sample into the assay fluid that includes the tracer antibody used in bead/chip-based competitive immunoassay (Fig. 1B). The ‘macro’ laboratory-based iteration of the p-BNC reveals if there are specific drugs (i.e., drug
Discussion
Currently, police officers stop suspect motorists at the roadside and impairment tests are then conducted, followed by an alcohol breath test. If there is evidence, after clinical evaluation, that the driver is impaired, the individual is taken to the police station to be examined by a forensic practitioner who rules whether the suspect has a condition due to drugs. In both the UK and US, if the forensic practitioner decides there is basis for suspicion for drug use, a blood sample is taken for
Role of funding source
Funding support for this work was provided by the United Kingdom (UK) Home Office Center of Applied Science and Technology (CAST) (PO7165721). This sponsor was involved in the design of the study and contributed suggestions on the interpretation of data and definition of the next steps. Support for the p-BNC core instrumentation work was provided also by the (NIH) through the National Institute of Dental and Craniofacial Research (award number 5U01 DE017793).
Part of this work is the result of
Contributions
Dr. J. T. McDevitt served as overall Principal Investigator (PI) of this study. As such, he was involved in this study by providing oversight for the p-BNC group at Rice University. Dr. R. De La Garza served as the lead clinical PI from Baylor College of Medicine, the recruitment site at which this addiction portion of the study was conducted. Dr. N. Christodoulides has served as the director of assay development for the p-BNC drug tests. Dr. P. Floriano served as the director of data and image
Conflict of interest
Principal Investigator, John T. McDevitt, has an equity interest in SensoDX, LLC. Inc, and also serves on Scientific Advisory Board. The terms of this arrangement have been reviewed by Rice University and he is currently under a management plan in accordance with its conflict of interest policies.
Acknowledgements
Acknowledged here is the funding support and guidance provided for this work by the United Kingdom (UK) Home Office Centre of Applied Science and Technology (CAST). Also acknowledged is the support for the p-BNC core instrumentation work as provided by the National Institutes of Health (NIH) through the National Institute of Dental and Craniofacial Research (award number 5U01 DE017793). Part of this work is the result of work facilitated with resources and the use of the infrastructure at the
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Supplementary material can be found by accessing the online version of this paper. See Appendix A for more details.