Molecular Diagnostic Lab-on-Chip for the Detection of Drug-Resistance Tuberculosis

Dr. Rosemary Tan, CEO of Veredus Laboratories Pte Ltd talks to AZoSensors about Sensor Technology for the Detection of Drug-Resistance Tuberculosis.

Can you provide me with an introduction to Veredus Laboratories and your inspiration behind the development of the VereMTB diagnostic chip?

Veredus Laboratories Pte Ltd was founded in 2003 and launched its first products in 2005. Veredus is a Singapore-based majority-owned subsidiary of STMicroelectronics (NYSE: STM). Veredus specializes in the development, manufacture, and marketing of innovative multiplexed molecular solutions in the clinical, specialty and custom testing markets based on STMicroelectronics’ proprietary Lab-on-Chip platform. The Lab-on-Chip platform, marketed as the VereIDTM biosystem, combines Micro-Electro-Mechanical-Systems (MEMS) with micro-fluidics to integrate multiplexed DNA amplification with microarray detection for rapid, cost-effective, and accurate analysis of biological materials. The technology enables multiple diseases to be detected in a single test.

TB occurs in every part of the world. In 2011, the largest number of new TB cases occurred in Asia, accounting for 60% of new cases globally. However, Sub-Saharan Africa carried the greatest proportion of new cases per population with over 260 cases per 100,000 population in 2011. In 2011, about 80% of reported TB cases occurred in 22 countries. Standard anti-TB drugs have been used for decades, and resistance to the medicines is growing. Disease strains that are resistant to a single anti-TB drug have been documented in every country surveyed. Multidrug-resistant tuberculosis (MDR-TB) is a form of TB caused by bacteria that do not respond to, at least, isoniazid and rifampicin, the two most powerful, first-line (or standard) anti-TB drugs.

The primary cause of MDR-TB is inappropriate treatment. Inappropriate or incorrect use of anti-TB drugs, or use of poor quality medicines, can all cause drug resistance. MDR-TB is treatable and curable by using second-line drugs. However, second-line treatment options are limited and recommended medicines are not always available. The extensive chemotherapy required (up to two years of treatment) is more costly and can produce severe adverse drug reactions in patients. There were about 310,000 cases of MDR-TB among notified TB patients with pulmonary TB in the world in 2011.

VereIDTM biosystem is able to detect multiple gene targets in a single sample and hence is an ideal platform to detect Mycobacterium Tuberculosis Complex (TB) and its drug-resistant mutant variants, as well as 9 other non-TB mycobacterium infections.

Veredus Laboratories have launched a multiplexed molecular diagnostic chip for the detection of Mycobacterium Tuberculosis Complex (MTBC). Can you describe this chip and how it works?

VereMTBTM is a multiplexed molecular diagnostic Laboratory-on-Chip enables quick diagnosis of Mycobacterium Tuberculosis Complex (TB) and its drug-resistant mutant variants, as well as 9 other non-TB mycobacterium infections that are often misdiagnosed as TB due to similar symptoms. All these strains and mutations can be identified with a single test from direct sputum or cultured samples in less than 3 hours. Traditional methods of diagnosis can take up to 8 weeks and provide a less comprehensive list of identified strains.

What structural and functional principles to this chip allow for fast and accurate detection of MTBC and its mutations?

VereMTB is a disposable cartridge that serves as an on-chip DNA lab. It combines Micro-Electro Mechanical Systems (MEMS) with microfluidics to create a bank of micro-reactor chambers in silicon. To carry out a diagnosis, its channels are filled with sample DNA taken from the sputum of a suspected TB patient, which is then amplified into a usable quantity through a process called Polymerase Chain Reaction (PCR). The amplified DNA sample then passes into the microchip’s microarray-based detection area where its DNA is matched against the DNA of TB, its mutations and non-TB cousins.

How does the application of this chip for the detection of MTBC compare to traditional methods for the detection of Mycobacterium Tuberculosis?

For general detection, microscopy is the historical diagnostic method but is crude, requires highly trained personnel, has a very low sensitivity, and cannot detect drug resistance. For detection of drug resistance, typically real-time PCR is used, The “gold standard” is Drug Susceptibility Testing (DST), but it takes up to 8 weeks to get results and is expensive. Another alternative is Line Prob Assays which take about a day to get results, but are more complex to use than VereMTB.

When considering the global healthcare burden, the rise of multi-drug resistant Tuberculosis is a big challenge. How will application of the VereMTB multiplexed molecular diagnostic Lab-on-Chip technology - a fast and accurate diagnostic chip – prevent multi-drug resistant TB strains from reinvigorating the global spread of Tuberculosis (TB)?

The rise of multi-drug-resistant Tuberculosis (TB) is a global healthcare challenge. Effective treatment of TB involves accurate and fast diagnosis followed by a strict regimen of the right drugs. Shortcomings in this treatment can cause the TB infection to mutate into drug-resistant strains that can become increasingly difficult and expensive to treat. Conventional methods of accurately identifying TB infections can take up to 8 weeks. In contrast, VereMTB can complete the diagnosis and identify the specific mycobacterium causing the infection and drug resistance in less than 3 hours from natural samples*, avoiding the need for culturing, the most time-consuming part of the traditional method.

In 2011, 8.7 million people were diagnosed with TB and 1.4 million people died from the disease. With its ranking by the World Health Organization as the second greatest killer from a single infectious agent worldwide1, faster diagnosis and appropriate treatment of this highly infectious disease is critical.

*Natural samples refer to direct sputum coughed out by TB patients.

How will this chip be deployed in a wider range of settings on a global scale?

Due to its compact size, the system can be deployed in a wide range of settings at point-of-need.

According to statistics by the World Health Organisation 2012, 40% of the world’s TB cases are in India and China. With this in mind, how will application of this diagnostic sensor chip see a change in these statistics across both nations and globally?

The 40% referred to represents literally millions of cases. We cannot at this early point extrapolate the adoption of VereMTB to a purely speculative level of being able to calculate its projected effect on such a large base - which is further influenced by other factors such as government policy, local funding, adoption and availability. Furthermore, VereMTB is a diagnostic tool which is only part of the picture. The rest depends on the treatment process and patient management – which are again influenced by a host of other factors.

How will the detection capability of this chip perform when exposed to newly emerging drug-resistant strains of TB?

VereMTB works on the principle of capturing DNA sequences – if a new drug-resistant strain emerges, we can quickly create the probes for the sequences of the new strain and put it into the VereMTB chip so that it can also test for the new strain.

Bio-chips for the diagnostic of diseases are now commonly applied in the healthcare industry. How do you see this technology shaping the healthcare industry and how is this likely to have an impact on the patients and healthcare professionals managing TB?

Lab-on-chip has simplified molecular biology testing, making it more accessible, portable and hence translating conventional molecular tests into something which healthcare professional can now adopt in decentralized settings.

What are the future challenges ahead for diagnostic tools in the healthcare industry and how will the healthcare industry and manufacturers such as Veredus Laboratories work together to help meet these challenges?

The biggest challenges are quick sample to answer and simplifying workflow. By working together with the healthcare industry and other manufacturers, we can identify critical unmet needs and provide solutions to meet these challenges.

Reference

World Health Organisation - Global Tuberculosis Report 2012