40 Years of ISFET Technology: from Neuronal Sensing to DNA Sequencing
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An interview with the ISFET inventor Professor Piet Bergveld, by Chris Toumazou and Piet Bergveld Pantelis Georgiou 40 years of ISFET technology: From neuronal sensing to DNA sequencing apparatus as part of my collection of classic we followed were still concerning tubes!). I medical equipment at the University [of Twente]. remember that at a certain moment I thought After World War Two the physicians there to myself: Well, then you can also make a pill, also started operations to take away part of or a with an oscillator and a sensor that changes complete lung, and I remember my father an FM signal with pH and pressure for talking about a patient that had died instance, which can then be remotely received unexpectedly after an operation. In fact nobody using an FM receiver. So, in 1963 I developed knew beforehand who could withstand such an a telemetric lab-in-a-pill, based on a operation and who could not. And I remember transistorised Hartley oscillator in the group that they therefore decided to build next to the of Measurement Technology, to measure existing mechanical and electrical workshops, pressure and temperature in the intestines where I spent much of my free time, of patients. The ultimate goal was to also a new workshop for making biomedical measure pH, but on studying pH glass measurement instruments. These instruments electrodes I discovered that they were not yet were made to measure, in the laboratory, patient small enough to be incorporated into my pill. blood parameters such as CO2, oxygen and pH. Nevertheless, this was my fi rst acquaintance With these they could then decide whether a with pH electrodes. certain patient could be operated on or not. I think that that experience, at the age of about The invention of the ISFET after 10–12 years, inspired me and made me decide the creation of the MOSFET that developing new measurement equipment for medical applications would be my profession in Q: What was the fi rst idea concerning the the future. ISFET? A: From 1964-65, I did my Master’s degree at An early vision: invention of Philips in Eindhoven at the Natlab in the group a lab-in-a-pill of the late Dr. Klein, who became Professor later on at the Technical University of Delft. Q: Did you study biomedical engineering at a At that time they were developing ECG, This article presents a personal account of the ABOVE: Professor Piet Bergveld university? EMG and EEG amplifi ers, still based on life and scientifi c journey of Professor Piet holding one of the very fi rst A: When the time came to go to university in the application of vacuum tubes, and they had Bergveld, the inventor and founding father of the ISFET wafers 1960, I decided I was keener on electrical started to look at using transistors, with BOTTOM RIGHT: One of the Ion-Sensitive Field Effect Transistor (ISFET). fi rst 1 inch wafers as produced engineering than medicine. I felt I had enough junction fi eld effect transistors in the fi rst stage, The interview gives a unique overview of how by the technician Arie Kooi, experience from the mechanical, electrical and because of their high input impedance. It ISFET technology has evolved over the years, containing 6 ISFETs. The source instrumental workshops from the sanatorium, was my task to develop a differential amplifi er and drain connections are at and the challenges faced during the development the side of one single ISFET, to and that it would be better for the patient that I that made use of the high impedance transistors from its initial use in neuronal sensing to the be able to mount them on the be an engineer rather than a medic. That was for differential measurements, but solving in technology we see today, which has huge small end of a Perspex holder, the reason why I studied electrical engineering the meantime the problem of their bad with connections at the side. potential in the current era of genetic at the University of Eindhoven. This output resistance. I did this by technology. university was founded two years applying cascades of JFETs and before I enrolled as a new bipolar transistors and reached Introduction to the biomedical fi eld technical university in the in this way rejection ratios Netherlands, although there of the order of 10,000 for Q: How did you get into the biomedical fi eld? was no biomedical a differential amplifi er. This A: I was already involved in this area because as engineering, which I preferred. was the subject of my Master’s a child I lived from 1948–1960 with my family at But I got a good education with thesis. the TBC health-resort Sanatorium Beatrixoord, a fair engineering approach and I It was also the time that in the southern part of the province Friesland. My always did my practical work on a Philips had developed their father was the economic director, so we lived in medical subject which I thought out very fi rst MOSFETs, which I heard the campus of the hospital which was in the forest myself, and I looked for a group which was about because I worked in the Natlab. But as the TB patients were, before World War Two, willing to accept this for the credit points. in those early days you could hardly fi nd two treated only with clean air. At that time the only This was at the time that AM radio was MOSFETs with the same set of properties, thing that they could measure was taking Röntgen replaced by FM and transistors also came into so it was not yet useful for the new images of the lungs. I still have the old Röntgen existence (although the courses in electronics differential amplifi ers. ❯❯ doi: 10.1049/el.2011.3231 Electronics Letters Dec. 2011 – Special Supplement: Semiconductors in Personalised Medicine S7 But then, having had experience with reactions on glass for sensing pH from my lab-in-a-pill work at the university, I proposed to Dr Klein that we could potentially use the silicon oxide of these MOSFETs directly as a glass membrane, similar to the pH probe. This was when I came up with the idea for creating an ISFET. Dr Klein’s response was: “We at Philips do our utmost to encapsulate chips as well as possible against moisture and you want to put it directly in contact with the liquid? Forget about it.’’ To which I replied “Well, you should never say something like that to somebody from Friesland, because then you are sure that he will do it anyway.” [laughs] It is clear that at that time this initial idea for using the silicon oxide layer of a MOSFET as a sensing layer was not well received, and was not pursued by Philips. Many years later I discovered that somebody from Philips Natlab had written a small piece on my idea in an obscure German journal called Neues aus der Technik; done to prevent someone, including myself, from patenting it. Waiting for a fi eld to emerge; ABOVE: A photo of an Initially I created the amplifi ers and the fi rst extended gate FET experimental set-up with an colleagues created the signal processing Parkinson’s disease, but also necessary for ISFET placed on the fl exor tibialis of a locusta instrumentation, in addition to my fi rst physical executing my ISFET plans. Q: How did you proceed? ABOVE RIGHT: Cover of sensor, which was a tremor sensor, fi rst based on A: I then moved to work at the University Bergveld’s doctorate thesis a microphone and later on so-called pixie Creation of the fi rst ISFET which shows how axons and of Twente, in Enschede. This third technical microelectronics may meet beams. for neuronal sensing university of the Netherlands was founded in each other in the future For the measurement of the electrical 1961, and started lecturing in 1963, so I was one BELOW: One of the ISFETs brain activity we used very long glass Q: How did you develop the fi rst ISFETs? mounted on a Perspex holder, of its fi rst academics. to be able to place it on a nerve needles with a 50 micron-thick platinum wire A: Some years later, in 1967, the late Prof. O.W. I was still highly interested in biomedical or muscle passing through the tip, which I then had to make Memelink from Philips was appointed at our engineering but, of course, it did not yet exist in into a shielded cable to connect to the amplifi er. department to start a chair on Solid State those days. My fi rst boss, Prof. Ir. M.P. The problem was, however, you could not Electronics. He decided to found a clean room Breedveld, however, was interested in starting it measure fairly steep action potentials due to the facility focused on the fabrication of MOSFETs. up in the future, and this was why I chose capacitance of the line. With my knowledge from I was his fi rst client; I said: “I can use your Twente. Nevertheless, in the fi rst years the my Master’s degree at Philips, I realised you MOSFETs. Bring them here, but don’t bring the courses that I had to give were pure electrical, could fi x this problem using a fi eld effect gate metal,” as I wanted to try out sensing ions mechanical and chemical engineering. But in the transistor, built in the tip of the electrode as a remotely in the brain based on my original evenings I studied physiology, biology and single chip, with the 50 micron wire directly ISFET concept.