Advances in Medical Diagnostics Using LoC and LoPCB Technologies


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Introduction

“The Coronavirus: A Global Pandemic” has become the universal headline. As of mid-March, the World Health Organization characterized the coronavirus as a pandemic, which had already spread to almost 150 countries, areas, and territories, with hundreds of thousands of confirmed cases.

Coronaviruses (CoVs) are a large family of viruses that cause illness ranging from the common cold to more severe diseases such as the Middle East respiratory syndrome (MERS-CoV) and severe acute respiratory syndrome (SARS-CoV). COVID-19 is a new strain that was discovered in 2019 and had not been previously identified in humans.

In an outbreak of a new virus, it is imperative that epidemiologic and clinical investigations are carried out as early as possible, and the recent emergence of COVID-19 precipitated a crucially urgent need to understand transmission patterns, severity, clinical features, and risk factors for infection. Effective testing can both confirm the presence of the disease in an individual and indicate the location, extent, and development of the outbreak.

Several techniques for detection and diagnosis of COVID-19 are currently under development, some of which may detect the novel virus exclusively; others may also detect strains that are genetically similar. A detection kit recently announced uses technology based on a portable lab-on-chip (LoC) platform capable of detecting, identifying, and differentiating MERS-CoV, SARS-CoV, and COVID-2019 in a single test, which integrates two molecular biological applications: polymerase chain reaction (PCR) and DNA microarray screening. Whereas traditional PCR coronavirus detection kits can take a day to produce results, the latest LoC detection kits can produce results in about two hours, and LoC technology may be the key to powerful new diagnostic instruments and point-of-care testing devices.

An LoC is a device that integrates one or several laboratory functions on a single integrated circuit. LoC devices are microelectromechanical systems (MEMS) devices (Figure 1) that function as "micro total analysis systems" (µTAS), generally using microfluidics principles to manipulate minute amounts of fluids. In practical terms, microfluidics is about doing chemistry on a tiny scale and trying to emulate nature. Biomedical microelectromechanical systems (BioMEMS) have emerged as a subset of MEMS devices for applications in biomedical research and medical microdevices, with an emphasis on mechanical parts and microfabrication technologies. Applications include disease detection, chemical monitoring, and drug delivery. There has been rapid market growth for bioMEMS technologies, and many bioMEMS devices are already commercially available; a familiar example is a blood-glucose sensor. There is also great potential for large-scale commercialization of microfluidic-based LoC technologies.

Starkey_Holden_fig1.jpg

Figure 1: (a) MEMS; (b) MEMS integrated into tires for pressure sensing; (c) MEMS used as micromirrors for image projection and communications; (d) integrated MEMS.

LoC is not new. In fact, as long ago as the late 1990s, advances in microfabrication technology had enabled the development of a fully automated LoC, designed to integrate sample preparation, fluid handling, and biochemical analysis. Techniques derived from semiconductor manufacturing enabled the translation of experimental and analytical protocols into chip architectures comprising interconnected fluid reservoirs and pathways (Figure 2). By driving fluids in a controlled manner through selected pathways by electrokinetic or pressure forces, it was possible to create the functional equivalent of valves and pumps capable of performing manipulations, such as dispensing, mixing, incubation, reaction, sample partition, and detection.

The first commercially available LoC product was introduced in 1999 for the analysis of DNA and RNA biomolecules, as well as protein and cell assays, with worldwide sales of more than 7000 instruments. These LoC bioanalyzers could handle nucleic acids, proteins, and cells on the same platform using sample-specific reagents and chips and set an industry-standard for RNA analysis and sequencing. LoC for integrated chemical and biochemical analysis has also grown dramatically in the past decade. Although the primary focus has been on medical uses, the basic technology is applicable to a wide variety of analytical and monitoring functions and fits very logically into the concept of a connected world (Figure 2).

Microfluidic devices can be fabricated with a variety of materials—including glass, rigid polymers, and elastomers—using techniques such as CNC milling, injection molding, and photolithography. The original material was silicon since the fabrication techniques had been derived from semiconductor manufacture, and several alternative processes have been developed because of requirements for specific material properties, as well as lower production costs and faster prototyping. A wide variety of sophisticated chips are increasingly being demonstrated, but it is believed that few of these will be seen on the general market because of the lack of established commercial manufacturing technology. 3D printing has recently emerged as an alternative approach for the fabrication of fluidic devices and may replace soft lithography as a preferred method for rapid prototyping. But existing technologies are not unified, and it remains to be seen which processes and materials will eventually be adopted for high throughput diagnostics.

Starkey_Holden_fig2.jpg

Figure 2: BioMEMS LoC. (Source: HP Laboratories, 1995)

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