EUREKA MAY 2003 COVER FEATURE STORY

Chip devices give boost to medicine

Tom Shelley reports on some latest developments in chip based biosensing and analysis

Laboratories on a chip, predicted in Eureka's September 1996 cover story are now a reality and set to become the basis of a multi billion dollar industry.

New configuration devices use optical readout of fluorescence effects, with electrically read devices for future hand held systems following hard on their heels. Long predicted sensing devices using immobilised cells are under development.

Primary intended uses are for DNA testing and drug development although chemical and biological analyses are obvious further applications. The makers, however, consider their devices unsuitable for military and security applications and make it very clear that they have no wish to become involved in such markets.

The labs on a chip are the brainchild of Infineon Technologies in Munich, www.infineon.com the world's sixth largest semiconductor manufacturer by sales, second in the world in automotive and third in DRAM products. The breakthrough made by Infineon is to etch their 'Flow-Thru' silicon chips into an array of vertical flow through passages as opposed to horizontal passages on top surfaces.



According to Austrian born Infineon researcher, Dr Michaela Fritz, the chips are 500 microns thick, and patterned into an array of 10 micron holes, each a tenth of the diameter of a human hair. There are a million of these per square centimetre, so the chips are mostly holes in a honeycomb arrangement. Infineon has teamed up with Gettysburg USA based MetriGenix to seed the arrays with up to 400 samples of DNA strands. The DNA strands (nucleotides) attach themselves to the walls of the channels. Each gene sample is distributed across around 100 holes. Three reagents are then pumped through in sequence. The first is a blocker, the second the tissue or blood sample under test and the third, a fluorescing reagent dye. Some of the genes in the fluid under study bind to some of the immobilised genes. The others are washed off. The bindings are detected by means of a marker, such as a luminescent dye that is split up by an added enzyme, which causes it to release light, detected by a CCD camera. If the pattern of light regions matches that of healthy tissue, medical treatment is judged to be effective. Unhealthy patterns can be matched against patterns arising from known diseases or known organisms.

Because molecules are repeatedly pumped through the chips as opposed to relying on diffusion, and because the channel structure allows more molecules to react with each other, total test time is about two hours, as opposed to 16 to 24 hours with conventional equipment. Seeded chips cost euros 200 to 250 each and total system cost is euros 60,000. Standard products available at the present time include arrays for the identification of breast cancer, tissue proliferation and inflammation, and for the detection of neural changes that are the causes of diseases such as Alzheimers, Parkinson's or Multiple Sclerosis. Thirty systems have been sold so far.

Dr Thomas Klaue, Infineon's Vice President for Business Development described how the technology involved working with 5nanolitre quantities, a thousandth of the volume of the average mosquito bite. The company refers to its development as 4D, because the chip is three dimensional and additionally aims to compress timescales for the development of new drugs by one to two years, not to mention faster DNA analysis. It is expected to be possible to establish which patients have genetic propensities for certain diseases, and has already been shown able to detect DNA from cancerous tissue and identify which type of cancer it is. Making an early and correct diagnosis can be of immense benefit in initiating the most suitable treatment. Wrong treatments can in many cases make patients worse.

Dr Klaue also claimed that by using a slightly different process, it should be possible to use the chip to detect antibiotic resistant germs, and quickly establish which antibiotics from a range of possibles will kill them. According to research by Heinrich Heine University in Dusseldorf, about 10,000 patients die each year in Germany alone from multi antibiotic resistant germs picked up in hospitals. "A rather quick test will also show if food has been genetically modified" he added. In the longer term, based on blood samples, it is hoped that it will be possible to identify exactly what an individual patient is suffering from, pre-test medications, and devise an optimum treatment optimised for their particular needs.

Dr Klaue then went on to reveal fully electronic Biochips which are expected to be ready for launch in two to three years. Initial devices have a 16 x 8 array of sensors areas in a device die 4.5mm x 6.4mm. Each sensor consists of a series of parallel gold finger electrodes on a passivated CMOS surface. For DNA assessment, the nucleotides are attached to the gold electrodes. Binding causes an electrochemical redox reaction. The electric currents produced are in the picoamp to nanoamp range, so signal processing has to be undertaken on chip.

The main intended field of application is in doctor's office or hospital bedside assessment of what patients might be suffering from and the rapid development of suitable treatments.

The stage beyond that is the devlopment of the Neuro-Chip, in which nerve cells are grown on a biocompatible surface on a chip, and interrogated electrically. Working with the Max-Plank Institute for Biochemistry in Martinsried, Munich, a device has been developed with 128 x 128 sensors in a one millimetre square area. Each sensor collects are least 2,000 electrical signals per second from the nerve cells, amplifies and forwards them to the monitoring computer system.

Intended applications are the non invasive long term study of networks of nerve cells and the development of new drugs.

Eureka asked what turned out to have been an anticipated question as to whether any of the devices could form the basis of better sensors for the detection of chemical or biological warfare agents. Dr Klaue, supported by researchers present at the briefing, insisted that the only applications of the devices were medical. The optically and electronic read chips were regarded as much too slow to be useful in a military or security application. The Neuro-Chip is fast enough but it was pointed out that it requires care in keeping the immobilised cells alive, even though some US firms are claiming that such devices will be suitable for detecting chemical and biological agents. Cells can be kept alive for several weeks apparently, but no longer. It would seem that in this sphere, little improvement has so far been made over keeping a canary in a cage. The world wide medical market for biochips, associated equipment and related services for the medical market on the other hand is predicted to reach $4 billion by 2009.

Pointers

* Optically read new silicon biochips bring about a dramatic acceleration in DNA testing and other biological and medical analysis tasks

* Electronically read versions now in preparation will bring about an equally dramatic reduction in cost and system size, reducing table top systems to hand held size

* Long predicted immobilised cell biosensors show signs of coming to market within the next very few years

For more technical developments see www.eurekamagazine.co.uk

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