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Lab-on-a-Chip Technology, as a Remote Distributed Format for Disease Analysis:
Professor Jon Cooper, University of Glasgow

Previously, Lab-on-a-Chip technologies have exploited many aspects of microsystems technology, including sensor miniaturisation and microfluidics, in order to deliver a variety of applications, particularly those associated with DNA analysis, proteomics and diagnostics. Despite the numerous analytical advantages that are delivered as a consequence of device miniaturisation, the vast majority of all devices that have been proposed either as commercial instruments or as research projects, have required to be based on a laboratory bench. In contrast, Lab-on-a-Pill technology now has the proven ability to deliver both remote and-or distributed analysis, resulting in a wide range of potential applications, including those associated with biomedical analysis in the gastro-intestinal tract, process control in industry and the functional foods industry.


Lab-on-a-Pill: The International Context of the Work:

The invention of the transistor enabled the implementation of the first radiotelemetry ingestible capsules, which utilised simple circuits for in vivo telemetric studies of the gastro-intestinal (GI) tract [1]. These units could only transmit from a single sensor channel, and were difficult to assemble due to the use of discrete components [2]. The measurement parameters consisted of either temperature, pH or pressure. These first attempts of conducting real time non-invasive physiological measurements (understandably, given the extent of technology in 1957) suffered from poor reliability, low sensitivity and short lifetimes of the devices. Despite this, the first successful pH gut profiles were achieved in 1972 [3], with subsequent
improvements in sensitivity and lifetime [4, 5]. Single channel radiotelemetry capsules have since found limited applications for the detection of disease and abnormalities in the GI tract [6-8] where restricted access prevents the use of traditional endoscopy [9]. Most radiotelemetry capsules utilise laboratory type sensors such as glass pH electrodes, resistance thermometers [10] or moving inductive coils as pressure transducers [11]. However, the relatively large size of these sensors
limits the functional complexity of the pill for a given size of capsule.

The concept of remote and distributed miniaturised sensing has been most dramatically exemplified by the camera-on-a-pill technology, associated with video endoscopy within the gastro-instestinal tract [9]. The important contrast between this seminal work in video imaging (e.g. that produced by IMC, Korea and Given Imaging), and of our own work is that whilst the camera-on-a-pill seeks to create a visual image of the remote area being sensed, we wish to develop a remote chemical image
of that site.

Name of Manufacturer - Technology:

= Mackay/Jacobson, Nature, 179, 1239-40 (1957) - Endoradiosonde, Single transistor (9x28 mm)
= HC Noiler, Telefunken, Germany (1965) - Heidelberg pH capsule (8x20 mm)
= M2A, Given Imaging, Israel (2001) - Video Capsule (11x26 mm)
= Norika 3, RF System Lab, Japan (2002) - Video Capsule (9x23 mm)
= IMP, IMC, KIST Korea (1999-2009) - Endoscopic Microcapsule (10x30 mm)
= IDEAS, Glasgow Uni. UK (2001-2004) - Microelectronic pill Chemical imaging (16 x 55 mm)


Current Activity at the University of Glasgow: Our current research on sensor integration and onboard data processing has focused on the development of microsystems capable of performing simultaneous multiparameter physiological analysis both in vivo and in vitro. The technology has a range of applications in the detection of disease and abnormalities in medical research. Our overall aim has been to deliver enhanced sensor functionality, reduced size and low power consumption,
through system level integration on a common integrated circuit platform comprising sensors, analogue and digital signal processing, and signal transmission. We have therefore created a platform which comprises a novel analytical microsystem incorporating a four channel microsensor array for real time determination of temperature, pH, conductivity and oxygen (work pioneered by Professor Jon Cooper and Dr Erik Johanessen). The sensors have been fabricated using standard
photolithographic pattern integration, and are controlled using a custom made application specific integrated circuit (ASIC), designed in Glasgow (by Dr Dave Cumming and Dr Wang Li) and fabricated by Europractice. The ASIC samples the data with 10 bit resolution prior to communication off chip as a single interleaved data stream. An integrated radio transmitter sends the signal to a local receiver (base station), prior to data acquisition on a computer. A receiver allows remote control of the Lab-on-a-Pill’s function, switching sensors and-or power on and off, on demand.






The sensors comprise a silicon diode to measure the body core temperature, whilst also compensating for temperature induced signal changes in the other sensors; an ion selective field effect transistor, ISFET to measure pH; a pair of direct contact gold electrodes to measure conductivity; and a three-electrode electrochemical cell, to detect the level of dissolved oxygen in solution. All of these measurements will, in the future, be used to perform in vivo physiological analysis of the GI-tract. These four sensors (pH, s, T, pO2) not only provide useful information for applications in industry and biomedicine per se, but also are a platform that will enable greater sensor functionality to be created (e.g. the electrochemical oxygen sensor could be readily modified in order to develop a sensor interface for the implementation of immunoassay technology).
We have now presented real time wireless data transmission from a model in vitro experimental setup, for the first time, and are currently working with the Veterinary School at the University of Glasgow on performing multi-channel in vivo experiments. Extensive literature searching has revealed that we are the only group world-wide working at this state of the art in multi-channel remote wireless sensing (e.g. there is already a class of oesophageal pH sensors that are available in
clinical practice). There has also recently been serious interest from two multinational electronics companies in obtaining IP generated through this work.

References:
1. S. Mackay and B. Jacobson, "Endoradiosonde," Nature, vol. 179, pp. 1239-1240, 1957.
2. H. S. Wolff, "The radio pill," New Scientist, vol 12, pp. 419-421, 1961.
3. S. J. Meldrum, B. W. Watson, H. C. Riddle, R. L. Bown and G.E. Sladen, "pH Profile of gut as measured by radiotelemetry capsule," Brit. Med. Journal, vol 2, pp. 104-106, 1972.
4. D. F. Evans, G. Pye, R. Bramley, A. G. Clark, T. J. Dyson and J. D. Hardcastle, "Measurement of gastrointestinal pH profiles in normal ambulant human subjects," Gut, vol. 29, no. 8, pp. 1035-1041, Aug. 1988.
5. R. H. Colson, B. W. Watson, P. D. Fairlclough, J. A. Walker-Smith, C. A. Campell, D. Bellamy and S. M. Hinsull, "An accurate, long-term, pH sensitive radio pill for ingestion and implantation," Biotelem. Pat. Mon., vol. 8, no. 4, pp. 213-227, 1981.
6. S. S. Kadirkamanathan, E. Yazaki, D. F. Evans, C. C. Hepworth, F. Gong and C. P. Swain, "An ambulant porcine model of acid reflux used to evaluate endoscopic gastroplasty," Gut, vol. 44, no. 6, pp. 782-788, June 1999.
7. A. G. Press, I. A. Hauptmann, L. Hauptmann, B. Fuchs, K. Ewe and G. Ramadori,"Gastrointestinal pH profiles in patients with inflammatory bowel disease," Aliment Pharm.Therap., vol. 12, no. 7, pp. 673-678, Jul. 1998.
8. G. Pye, D. F. Evans, S. Ledingham and J. D. Hardcastle, "Gastrointestinal intraluminal pH in normal subjects and those with colorectal adenoma or carcinoma," Gut, vol. 31, no. 12, pp.1355-1357, Dec. 1990.
9. G. Iddan, G. Meron, A. Glukhovsky and P. Swain, "Wireless capsule endoscopy," Nature, vol. 405, no. 6785, pp. 417, May 2000.
10. G. X. Zhou, "Swallowable or implantable body temperature telemeter - Body temperature radio pill," in Proc. IEEE Fifteenth Ann. Northeast Bioeng. Conference, Boston, MA, 1989, pp. 165-166.
11. S. Mackay, "Radio telemetering from within the body," Science, vol. 134, pp. 1196-1202, 1961.