Infectious diseases afflict millions of people every year. These hard-hitting viruses can rapidly sweep through populations and, in some cases, whole continents in a matter of weeks.
Identifying and treating these diseases has considerable cost implications for health protection services, and places a further strain on already overburdened healthcare systems, delaying treatment and endangering human lives.
Speed is of the essence for the successful treatment of many infectious diseases. Antiviral drugs are at their most effective within the first three days of onset of symptoms, so the value to medical staff of having access to easy-to-use, quick and reliable ways to test patients, whether they are in a local clinic or a remote village hundreds of miles from the nearest healthcare facility, cannot be overstated. As a result, there is a strong international trend to move the testing and monitoring of infectious diseases outside the confines of specialist hospitals by using point-of-care (POC) diagnostics.
A new generation of advanced POC testing and detection technologies leverage biosensors and smartphones and have the potential to transform the way flu and other infectious diseases are diagnosed.
Advanced POC diagnostics combines specialist biosensor materials and electronics in a handheld device for the accurate detection of illnesses from patient supplied samples. One example is a mobile phone–enabled biosensor from medical device and diagnostic specialist OJ-Bio, a joint venture between UK-based biotechnology company Orla Protein Technologies Ltd. and the Japan Radio Co. (JRC).
In this collaboration, Orla provides the specialist biosensor materials that are combined with JRC’s advanced electronics capability to create a specialist biochip technology platform.
Shear horizontal surface acoustic wave (SAW) chips are coated with protein-based capture reagents to create a device that gives highly specific responses when coming into contact with samples containing markers of the disease concerned. The reaction that takes place is turned into an electronic signal, which can be captured by a small reader that receives and transmits data in real time.
SAW chips have been commercially available for more than 40 years; they are widely used in the telecommunications industry and base stations where they act as band-pass filters. The combination of novel antibodies, nanoparticles and multiplexing methods enables SAW technology to be used effectively with biological samples for the first time. The resulting devices already can detect antigens in samples from serum, urine, or saliva.
The chips are designed and manufactured to operate in liquids with high sensitivity and to perform as an immunoassay device that detects mass and viscosity changes caused by binding of the target analyte to the surface of the SAW sensor device.
The chips are fabricated using a delay line on quartz substrates that comprise transmitting and receiving interdigital transducers and a biochemical reaction area. The transducers are protected from liquids by a glass lid, epoxy walls and a membrane constructed using a photolithograpy technique. This architecture allows liquid samples to be applied directly onto the chip.
The sensor area is modified with capture antibodies that are specific to each target marker and are held in the correct orientation to react with disease antigens. When the target marker in solution binds to the immobilised capture antibody, the added mass of the binding causes a shift in the phase angle of the SAW as it passes across the chip surface and is translated into an electronic signal.
Different capture coatings can be tested immediately on a working prototype measurement unit for the development of robust assays. The data are transferred to a simple handheld device, such as a mobile phone, where the results are displayed. In this way, disposable SAW sensors can be inserted into an electric reader to detect multiple antigen-antibody reactions via changes in the phase/amplitude of the input/output signals. This will allow medical staff to perform rapid near-patient testing without the need for complex or cumbersome equipment.
The technology is ideal for remote disease monitoring, and has many applications in rural settings or situations where clinical readings are needed without patient transfer. It is equally well-suited for use in walk-in clinics and for consumer diagnostics applications.
POC Diagnosis of Respiratory Viruses
As part of the initial research into the development of accurate, rapid and low-cost POC testing for respiratory viruses, OJ Bio recently led a project in which a new SAW biosensor was developed and tested in collaboration with the Health Protection Agency (HPA) in Newcastle, UK.
The VIRASENS project, funded by the UK Technology Strategy Board, was undertaken to pioneer the combination of electronics and biotechnology as part of the development of a prototype POC diagnostic biosensor device for respiratory virus detection.
Work was channeled into the detection of three respiratory viruses—respiratory syncytial virus (RSV), influenza A, and influenza B—in clinical samples collected by the HPA laboratory in Newcastle-upon-Tyne.
During the initial stages of product research and development, the HPA collected nasal secretions, nose/throat swabs, and nasal aspirates from patients. These samples were used to test the capability of the OJ-Bio biosensor against the current benchmark polymerase chain reaction (PCR) method as well as another commercial POC test.
Assays were performed by mounting SAW chips into specially designed fixtures connected to a control box. Clinical samples and controls were added to the chip surface followed by virus-specific gold-conjugated secondary antibody for five minutes. The amount of virus binding to the chip surface was recorded in degrees of phase shift, with a reduction in the phase angle (i.e., a negative phase shift) indicating the presence of the influenza virus.
Data showed that the SAW biosensor technology can provide accurate results within minutes, has good levels of diagnostic sensitivity for the three test viruses (totalling 93% when compared with the HPA lab-based PCR method, which is considered the gold standard for respiratory testing), and does not produce any false positives, showing 100% specificity even when other viral analytes were present.
These results compare favourably with currently available rapid tests for flu and RSV diagnosis, which have demonstrated sensitivity between 4.4 and 70% and specificity between 50.5 and 100%. They demonstrate that SAW technology can provide a sensitive POC test for influenza and RSV diagnosis.
Importantly, along with the POC potential, results from the SAW biosensor device can be displayed on a complementary (app-enabled) handheld reading device such as a mobile phone and can be wirelessly transmitted to a central resource.
Government funding for further development work has been secured from the UK Technology Strategy Board’s Biomedical Catalyst programme. The funding will enable the company to continue its work by developing the lab-based prototypes described above into a fully functional pilot device capable of carrying out large-scale clinical trials.
The next stage of manufacture will involve considerable innovation in design and production of the SAW biochip, including the design and first testing of a new multiparameter chip, and the reader, where functions will be placed within a wireless-enabled handheld device.
In addition, software designed for the PC interface on the current prototype will be developed for the handheld device. The optimised assays that have been developed for flu types A and B and RSV on the existing prototypes will be optimised on the current platform for transfer to the new devices and biochips.
As a final stage, more extensive trials will be performed on the device, which will be close to the final product format.
SAW biosensor technology has effectively demonstrated its potential as a low-cost tester that has the potential to revolutionize the speed of diagnosis and treatment, hitting the flu virus hard at its source and inhibiting its ability to spread.
However, the potential applications of this concept are far broader. At its core lies a versatile biochip platform technology for rapid wireless immunodiagnostic testing that could be adapted for other POC applications such as HIV and periodontal gum disease, which also affect millions of people and cost billions of dollars in treatment programs.
In a separate project, OJ Bio is working with researchers from University College London (UCL) on the development of a POC device capable of detecting HIV marker proteins in human blood quickly and effectively.
So far the technology has been proven to work using model HIV samples, and new funding from the National Institute for Health Research (NIHR) Invention for Innovation (i4i) program will enable early-stage clinical work to be undertaken on the technology’s ability to detect HIV marker proteins in human blood quickly and effectively.
The beauty of this technology in this application is its inherent sensitivity to low levels of multiple markers, with the potential for much earlier diagnosis of HIV. This will empower patients to gain earlier access to antiretroviral treatment and achieve better health outcomes.