'Lab-on-a-chip' (LOC) technology is a rapidly growing research topic within the Instrumentation and Healthcare industries. The principle is to produce an automated, microscale (or nano-scale) laboratory to enable sample preparation, fluid handling, analysis and detection steps to be carried out within the confines of a single microchip. Here Thomson Derwent's Kim Rabbitts takes a brief look at commercialisation of this technology, and at the rise of patenting activities within this field. Links to sources of further information are also included.
The drive for miniaturisation
Commercial developments
Microarrays
Polymer Microchips
Investment and market growth
Patenting activities
Government initiatives
Nanotechnology publications
Further Reading
The drive for miniaturisation
LOC technology exploits the microfabrication and electronic techniques used in semiconductor and sensor devices, to develop new techniques for the manipulation and characterisation of both chemicals and biochemical material. Experimental and analytical protocols, developed in software, are translated into chip architectures consisting of interconnected fluid reservoirs and pathways. This enables total automation and integration of materials handling: eliminating the need for human intervention and drastically reducing sample size requirements. In addition, many chemical processes such as chromatography and mixing are limited by diffusion, so significantly reducing the dimensions of the diffusion on a chip can speed the chemical process and improve its efficiency.
This 'miniaturisation' is driven by the increasing need for laboratories to be able to cope with higher sample throughputs, and by stringent environmental regulations that force reduction of the use of harmful and damaging materials. Laboratories are recognising that if they are to remain competitive, there is a need for their science to be smaller, cleaner, cheaper and faster. The portability of the resulting technology is also advantageous for remote testing of samples, such as toxicity testing of seawater, or clinical diagnosis tests in doctor's surgeries.
LOC technology is one of the fastest growing areas of nanotechnology development, combining and miniaturising many technologies to develop applications in a wide range of disciplines including genetic analysis, drug development and materials chemistry.
Commercial developments
The first example of an analytical device on a chip was reported in the 1970s by researchers at Stanford University, USA1. The 'Stanford GC' was a complete working gas chromatograph on a silicon wafer, including column, injector and detector. Attempts were made to commercialise the design, but it was ahead of its time and it is only relatively recently that microengineered components have begun to appear in modern gas chromatographs.
Microarrays
The commercialisation of miniaturised analysis devices is most advanced in the DNA analysis sector. DNA chips (also called DNA microarrays) are generated by high-speed robotics, and consist of an orderly arrangement of nucleic acid probes or oligonucelotides, on glass or nylon substrates. Complementary binding (hybridisation) to these probes is then used to detect the identity or abundance of the DNA or RNA samples being tested. This technology has applications in nucleic acid sequence identification, for example in the human genome project, and in measuring the expression levels of particular genes, for example in human and livestock disease testing. Single DNA chips can contain thousands of samples, enabling researchers to obtain information on many genes in a single assay.
Mass production of these chips is the key to driving down both manufacturing and testing costs, and one company focusing on this area is STMicroelectronics, who recently announced a prototype silicon chip for DNA analysis that integrates both DNA amplification and detection on the same chip2. The microfluidic technology used in this device builds on the company's experience in the manufacture of inkjet printer chips combining electronic and fluidic elements. The DNA device is based on Micro-Electro-Mechanical-System (MEMS) technology, combining mechanical, electrical, fluidic and optical elements. Its power and portabillity should find many applications in the biomedical field.
Protein (or proteome) chips - microarrays containing spots of proteins - are also in development, to enable rapid screening of thousands of small-molecule drug candidates to determine their potential to affect specific proteins. The technique may ultimately enable scientists to create protein 'snapshots' of cells - profiling the massive number of enzymes and other proteins, and distinguishing normal from diseased states. For example, screening may distinguish the protein profiles of normal cells, early-stage cancer cells, and malignant cancer cells.
Polymer Microchips
For some applications the silicon-based fabrication technologies for LOC are being replaced with manufacturing technologies based in plastics and moulding. Plastic-based chips with integrated circuits are less expensive than their silicon counterparts, and are easier to manufacture and handle, enabling the development of lower cost, more rugged and flexible electronic devices.
Polymer-based chips can be patterned using techniques such as hot embossing, injection moulding, and laser ablation. Plastic Logic, based in Cambridge, UK, is one company targeting this area by printing polymer circuitry onto flexible substrates3. In the USA, Lucent Technologies are focusing on an alternative technique of printing semiconductors onto plastic chips with stamps.
Although not yet powerful enough to run a PC, these polymer microchips hold the promise of adding processing power to devices where cost is currently prohibitive, such as smart electronic tags for merchandise. There is also the opportunity to develop miniaturised components - such as chromatography and electrophoresis separation columns, polymerase chain reaction vessels, pumps, and valves - for use on centimeter-sized microchips with a plethora of applications in medical and environmental testing.
Investment and market growth
Some major companies - including Hitachi, IBM and Texas Instruments - have started to invest in DNA and protein chip technology. Analyst predictions for market growth include market value of $2.6 billion by 2004 (Frost and Sullivan) and $950 million by 2005 (BioInsights). The favourite entry strategy of the high-tech majors has been to tie up with smaller biotech companies, for example Motorola has associated itself with over half-a-dozen companies, and has taken over California-based Clinical Micro Sensors to acquire its biochip technology.
Most of these companies are breaking new ground by combining their intellectual property and industrial expertise to make their own chips. Nanogen, a company specialising in the integration of microelectronics and molecular biology, is working on a DNA array that allows researchers to focus at the levels of electrons, for better flexibility, speed, and accuracy. Orchid BioComputer Inc. is applying semiconductor technology to provide high-throughput drug discovery and diagnostic tests for the emerging field of pharmacogenomics.
The first commercial product incorporating lab-on-a-chip technology was launched in 2001 - Agilent's 2100 Bioanalyzer. This integrates sample handling, separation, detection and data analysis onto one platform, and is designed to streamline processes including RNA isolation, gene expression analysis, protein expression and protein purification.
Patenting activities
Looking at the distribution of lab-on-a-chip patent applications across the world during 2001, the USA took the lead with 926. The closest competition came from Japan, with just over a quarter of this amount (Table 1).
Research by Thomson Derwent has shown recent acceleration in both the patenting activities and the number of patentees in this field. Incyte Genomics Inc, University of California and Matsushita Denki Sangyo KK are currently the three most active organisations researching and developing lab on a chip technology (Table 2). Approximately 365 patents are currently being filed every month in this technology area, compared to approximately 300 patents for same period in 2001. This represents an increase of 20% and the trend is set to continue (see Graph 1).
Government initiatives
Governments are also taking an active interest in lab on a chip technology. The US has a National Nanotechnology Initiative that brings together a number of government departments and independent agencies. The Initiative has submitted a budget request of over $710 million, for 2003, to fund long-term, fundamental research and educational activities on advances in nanoscience and nanotechnology. Also in the US, the National Institute of Standards and Technology's (NIST) Advanced Technology Program has awarded Motorola, CFDRC and Arizona State University $4.4 million for a 3-year project to develop a biochip-based device.
Although European investment is more modest, the trend is definitely the same - upward. The UK government is backing the Lab on a Chip Consortium, a large, multidisciplinary collaboration working on microchip-based chemical analysis and synthesis. Seven universities and twelve companies are participating in this project, carrying out pre-competitive research leading to full commercial exploitation.
Nanotechnology publications
LOC is a multidisciplinary technology, and it can be difficult for researchers to understand advances outside their own technical discipline. Thomson Derwent has launched a trio of Profiles that report global patented advances in miniaturised technologies, and one of these focuses specifically on LOC technology. These Profiles clearly explain and illustrate each new invention, so non-specialists can easily understand applications of the new technology. In addition to acting as a current awareness source, the Profiles also highlight major commercial players and key inventors in this fast moving technology area. You can read more about this Profile at www.derwent.com/sp/labchip-itp/
