Sci-Fi or the future of near-patient testing?

Wireless handheld diagnostic devices, utilising biosensors for the detection of diseases, sounds like something straight out of Star Trek, but serious research and development by major players is showing that such technologies may hold the key to the future of medical diagnostics

In today’s fast-paced world, diagnostic tests are a vital part of the healthcare system, playing important roles in disease diagnosis, monitoring and the timely administration of appropriate therapies. As diagnostic technologies have improved, the much-heralded move towards near-patient testing is quickly becoming a reality.

Even so, many traditional diagnostic methods remain time-consuming and labour intensive. In an ideal world, diagnostic technologies would deliver rapid detection and identification – and yet be simple, low cost and robust. Similarly, given the need for rapid response, clinical information processing and remote or rural testing, the best products would also need to offer wireless connectivity.

The development of wireless electronic handheld devices, capable of detecting infections and diseases, could revolutionise patient testing, allowing for rapid sensitive detection at the point of care, where there is no need for complicated equipment and wireless transmission can send results instantly to a network.

Example uses could be a doctor testing a person for a virus in the African wilderness, sending results back to a hospital in a main city, or a farmer testing for Foot & Mouth disease in a field in the British countryside with results being sent straight back to DEFRA for co-ordinated result control.

But how close to reality is this idea, and what technology is behind it? Biosensor diagnostics is the answer. The technology consists of two main components: a recognition element that provides specificity and selectivity and a physical transducer that translates the reaction event into an electronic signal. Such technology is already widely used in the medical industry, in example glucose monitoring in diabetes patients, however in order for it to complete the outlined task, it requires serious advances in two areas – nanobiotechnology and microelectronics – and then the successful convergence and integration of these two fields.  

Happily, breakthroughs leading to a new generation of highly ordered antibody surfaces, combined with techniques such as surface plasmon resonance (SPR) and surface acoustic wave (SAW) technology have the prospect of meeting these needs. They are already being applied to the diagnosis of many important human ailments such as tuberculosis, flu and sexually-transmitted diseases.

Antibodies are often used as the recognition element of diagnostic tests – but do not always meet the level of excellence that we require. Sometimes this is due to lack of specificity, but often it’s just down to the way we use them. Many current rapid diagnostic tests including the likes of home pregnancy testing kits, are based on lateral flow technology. Whilst effective for some applications, there are some limitations – they often lack sensitivity, or are only semi-quantitative or based upon a visual reading.

However, new biotechnologies are appearing that have radically simplified the production of immobilised, highly ordered protein surfaces – and that’s not all. At the same time, these breakthroughs have improved the functionality and utility of the diagnostic devices resulting and dramatically improved their suitability for large-scale manufacture.

One such technology is provided by UK nanobiotechnology company Orla Protein Technologies. The company has produced a self-assembling protein scaffold. When proteins such as antibodies are incorporated into it, they are automatically presented in the right spatial orientation for interaction with analytes. Moreover, the protein scaffold assembles in such as way that it “hides” everything else, except the antibody recognition element, which is presented outwards and upwards into the test space.

Orla has spent years studying and modifying bacterial membrane proteins to create a range of workhorse scaffold units that auto-adhere to metal, glass or other surfaces in precisely known spatial orientations and dimensions. It works particularly well on smooth surfaces such as gold, where it creates perfect mono-layer “membranes” of almost crystalline protein density. Recognition antibodies are selectively incorporated into it then the resulting product is applied to the sensor surface in aqueous solution, where the scaffold auto-adheres in the correct orientation. A simple wash step removes excess protein, leaving behind a precisely oriented monolayer.

Spaces between the recognition proteins are then covered by a ‘filler’ molecule that also auto-orients on the surface and plays two roles – stabilising the scaffold protein and masking it, so that only the recognition protein is exposed at the surface. The system is inexpensive and robust – and its ability to incorporate a wide range of antibodies means that it can be applied to an almost endless range of applications.

The theory may sound complex, but the reality is not. Sensors manufactured in this way are robust; stable; give a high signal to noise ratio; high sensitivity; rapid reaction times and good dynamic range.

For mobile diagnostics, the new antibody surfaces are being combined with shear-horizontal surface acoustic wave (SH-SAW) devices that act as physical transducers. The resulting combination is already demonstrating huge promise.  

SAW filters have long been used in wireless communication radios, such as mobile phones. Now, though recognising the potential that they have in combination with biodiagnostics, Japanese electronics company Japan Radio has formed OJ-Bio, a joint-venture with Orla, and developed innovative SAW devices with air-cavities above the transducer chip with an epoxy wall and glass “lid” covers.  

These devices can be directly dipped into liquids as a single-user sensor device – the measurement module’s electrical circuits act as the signal generator and processer, with the resulting signal being similar to transmitting-receiving wireless technology for radio transceivers. Cleverly, an electronic mixing function has been incorporated to improve reaction kinetics and enhance sensitivity – and the surface acoustic wave itself can be used to move samples around the sensor surface, negating the need for complex micro-fluidics or pumps. Essentially, the result is a small, hand-held measurement module that costs about the same as a mobile phone.

Managing director of OJ-BIO, Dale Athey believes the benefits of such an invention will be huge for health services around the globe and will dramatically change the way potentially fatal conditions are diagnosed and treated.

He said: “There is a clear need for improved methods for easy, rapid, cost effective detection and identification of infectious diseases. OJ-Bio is developing a range of wireless rapid wireless diagnostic biosensor products to meet this need.

“The market for rapid detection of infectious agents is dominated by lateral flow assays, and assays based upon nucleic acid detection (primarily PCR). These are limited in their sensitivity, speed, robustness, availability in convenient format, and ability to connect to wireless networks.  

“Our devices seek to overcome these shortcomings, offering faster decision making, faster intervention, and reduction in spread of infection.”  

OJ-Bio secured funding from the UK Technology Strategy Board (TSB) and is now applying the technology, together with the Health Protection Agency in North East England, to develop rapid diagnostics for large-scale human infectious diseases such as flu and sexually-transmitted diseases (STDs) like Chlamydia. The reasons for this are clear. As well as the misery of catching the ailment in question, there is a huge economic cost of preparing to combat flu pandemics, amply demonstrated in recent years with over £1 billion spent by the UK in the last year or two alone. Similarly, STDs are on the increase, with Chlamydia becoming a growing problem in the UK and other locations around the world.

There are plenty of other diseases to target, too. In another move that could see significant advances in the detection and eradication of tuberculosis (TB), one of the UK's leading science and research facilities, the National Physical Laboratory (NPL) has also entered the fray. It has also secured TSB funding and will use it to combine NPL’s advanced measurement technology with Orla’s protein scaffolds to develop a radically improved method of TB detection.

Mycobacterium tuberculosis (MTB) is the pathogenic bacterium which causes almost all cases of TB – and more than five thousand people die from the ailment every day, largely in the developing world, where TB is also one of the major lethal factors among AIDS patients. Current methods of TB detection suffer from the needs for large sample volumes and long preparation times, plus the fact that variable results are obtained from different patient groups. This has led to a demand for more sensitive and rapid approaches and the NPL consortium aims to meet this challenge by producing systems which dramatically advance current capability; with improved sensitivity, specificity, cost and speed of results.

As Max Ryadnov, the project leader at NPL says: "The main objective is to demonstrate the possibility of detecting MTB quickly and cost effectively in both clinical and near-patient settings. To do this, we need protein-patterned surfaces responsive to MTB biomarkers, making the manufacture and use of TB biomarker detection dramatically simpler – this is a Holy Grail of modern diagnostics of TB and success would significantly impact the UK and global healthcare markets."

The technology also has the potential to offer rapid test results for viruses and bacteria, for example bacterial infections such as ‘super-bug’ MRSA and protein markers of conditions such as heart attacks.

Where does this leave us? New generations of biosensors will have to offer several major benefits over current diagnostic methods. They must be:
•    Easy to use: simple instruments that can be operated easily using minimal reagents – and they must work even when applied to detecting analytes in complex fluids such as saliva, serum, whole blood or urine.  
•    Fast: the sensor must respond immediately to analytes binding to the surface, with most assays needing to be complete in less than five minutes.
•    Cost-effective: both the device and any necessary sensor chips must be amenable to mass production/low-cost manufacturing techniques such as those commonly used in today’s electronics industry.
•    Connectivity: the devices must be small, portable and ideally offer wireless connectivity. 
•    Platform Flexibility: In a perfect world, the technology would be readily adaptable to current lateral flow devices and lab instrumentation, offering enhanced functionality for existing product ranges and enabling providers to enter new markets with minimum development time.  

Whilst much remains to be done, it is clear that integrating the new generation of antibody-based surface scaffolds with SAW and other electronic technology is making major inroads into making these ideals a reality.