RE: MICROELECTRONIC PILLS
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The invention of the transistor enabled the first radio telemetry capsules, which utilized simple circuits for in vivo telemetric studies of the gastro-intestinal tract. These units could only transmit from a single sensor channel, and were difficult to assemble due to the use of discrete components. The measurement parameters consisted of temperature, pH or pressure, and the first attempts of conducting real-time noninvasive physiological measurements suffered from poor reliability, low sensitivity, and short lifetimes of the devices. The first successful pH gut profiles were achieved in 1972, with subsequent improvements in sensitivity and lifetime. Single-channel radio telemetry capsules have since been applied for the detection of disease and abnormalities in the GI tract where restricted access prevents the use of traditional endoscopy.
Most radio telemetry capsules utilize laboratory type sensors such as glass pH electrodes, resistance thermometers, or moving inductive coils as pressure transducers. The relatively large size of these sensors limits the functional complexity of the pill for a given size of capsule. Adapting existing semiconductor fabrication technologies to sensor development has enabled the production of highly functional units for data collection, while the exploitation of integrated circuitry for sensor control, signal conditioning, and wireless transmission, and has extended the concept of single-channel radio telemetry to remote distributed sensing from microelectronic pills.
Our current research on sensor integration and onboard data processing has, therefore, focused on the development of Microsystems capable of performing simultaneous multiparameter physiological analysis. The technology has a range of applications in the detection of disease and abnormalities in medical research. The overall aim has been to deliver enhanced functionality, reduced size and power consumption, through system-level integration on a common integrated circuit platform comprising sensors, analog and digital signal processing, and signal transmission.
In this report, we present a novel analytical micro system which incorporates a four-channel micro sensor array for real-time determination of temperature, pH, conductivity and oxygen. The sensors were fabricated using electron beam and photolithographic pattern integration, and were controlled by an application specific integrated circuit (ASIC), which sampled 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. Real-time wireless data transmission is presented from a model in vitro experimental setup, for the first time.
Details of the sensors are provided in more detail later, but included: a silicon diode to measure the body core temperature, while 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.
For example, temperature sensors will not only be used to mea-sure changes in the body core temperature, but may also identify local changes associated with tissue inflammation and ulcers. Likewise, the pH sensor may be used for the determination of the presence of pathological conditions associated with abnormal pH levels, particularly those associated with pancreatic disease and hypertension, inflammatory bowel disease, the activity of fermenting bacteria, the level of acid excretion, re-flux to the oesophagus, and the effect of GI specific drugs on target organs. The conductivity sensor will be used to monitor the contents of the GI tract by measuring water and salt absorption, bile secretion and the breakdown of organic components into charged colloids. Finally, the oxygen sensor will measure the oxygen gradient from the proximal to the distal GI tract. This will, in future enable a variety of syndromes to be investigated including the growth of aerobic bacteria or bacterial infection concomitant with low oxygen tension, as well as the role of oxygen in the formation of radicals causing cellular injury and path physiological conditions (inflammation and gastric ulceration). The implementation of a generic oxygen sensor will also enable the development of first generation enzyme linked amperometric biosensors, thus greatly extending the range of future applications to include, e.g., glucose and lactate sensing, as well as immune sensing protocols.
MICROELECTRONIC PILL DESIGN AND FABRICATION
This new line of pH meters and probes, based on ISFET (Ion Sensitive Field Effect Transistor) sensor technology, includes four pH meters and 10 pH probes. The pH meters are designed for ease-of-use and feature an interactive graphics LCD display with on-board Help and Auto-Read functions. All meters constantly monitor and display probe status and an estimation of its remaining life. The advanced meters have real-time clocks for time/date stamping, calibration alerts and high/low pH alarms. Titan Bench top pH meters operate on AC or battery power and offer a host of sophisticated features, including programmable user alarms and data logging. Argus Portable meters are rugged, waterproof and operate on a long-life rechargeable battery. Each meter is available in simple or advanced versions and is supported by a variety of probes covering almost every application. The portable Argus uses an inductive (contact-less) battery charging system and IR data transfer eliminating the need for battery replacement or open contact points. This design ensures a completely watertight (IP67) rating.
Three new series of ISFET probes include the Red-Line general purpose series for routine applications, the Hot-Line series for testing to 105°C and in aggressive samples, and the Stream-Line series that are temperature and chemically resistant, and employ a flow-type reference junction to maximize performance in difficult samples.
2.2. pH value
pH is a measure of the acidity or basicity of an aqueous solution. Pure water is said to be neutral, with a pH close to 7.0 at 25 °C (77 °F). Solutions with a pH less than 7 are said to be acidic and solutions with a pH greater than 7 are basic or alkaline. pH measurements are in important in medicine, biology, chemistry, food science, environmental science, oceanography, civil engineering and many other applications.
In a solution pH approximates but is not equal to p[H], the negative logarithm (base 10) of the molar concentration of dissolved hydronium ions (H3O+); a low pH indicates a high concentration of hydronium ions, while a high pH indicates a low concentration. Crudely, this negative of the logarithm matches the number of places behind the decimal point, so for example 0.1 molar hydrochloric acid should be near pH 1 and 0.0001 molar HCl should be near pH 4 (the base 10 logarithms of 0.1 and 0.0001 being −1, and −4, respectively). Pure (de-ionized) water is neutral, and can be considered either a very weak acid or a very weak base (center of the 0 to 14 pH scale), giving it a pH of 7 (at 25 °C (77 °F)), or 0.0000001 M H+. For an aqueous solution to have a higher pH, a base must be dissolved in it, which binds away many of these rare hydrogen ions. Hydrogen ions in water can be written simply as H+ or as hydronium (H3O+) or higher species (e.g. H9O4+) to account for solvation, but all describe the same entity. Most of the Earth's freshwater surface bodies are slightly acidic due to the abundance and absorption of carbon dioxide; in fact, for millennia in the past most fresh water bodies have long existed at a slightly acidic pH level.
The sensors were fabricated on two silicon chips located at the front end of the capsule. Chip 1 comprises the silicon diode temperature sensor, the pH ISFET sensor and a two electrode conductivity sensor. Chip 2 comprises the oxygen sensor and an optional nickel-chromium (NiCr) resistance thermometer. The silicon platform of Chip 1 was based on a research product from Ecole Superieure D’In-genieurs en Electro technique et Electronique with predefined n-channels in the p-type bulk silicon forming the basis for the diode and the ISFET. A total of 542 of such de-vices were batch fabricated onto a single 4-in wafer. In contrast, Chip 2was batch fabricated as a 9X9 array on a 380-m-thick single crystalline 3n Silicon wafer with <100>lattice orientation, precoated with 300 nm Si3N4, silicon nitride. One wafer yielded 80,5X5 mm2 sensors (the center of the wafer was used for alignment markers)
2.3.1. Sensor Chip 1
An array of 4X2 combined temperature and pH sensor platforms were cut from the wafer and attached on to a 100-m-thick glass cover slip using S1818 photo resist cured on a hotplate. The cover slip acted as temporary carrier to assist handling of the device during the first level of lithography (Level 1) when the electric connection tracks, the electrodes and the bonding pads were defined. The pattern was defined in S1818 resist by photolithography prior to thermal evaporation of 200 nm gold (including an adhesion layer of 15 nm titanium and 15 nm palladium). An additional layer of gold (40 nm) was sputtered to improve the adhesion of the electroplated silver used in the reference electrode. Liftoff in acetone detached the chip array from the cover slip. Individual sensors were then diced prior to their re-attachment in pairs on a 100-m-thick cover slip by epoxy resin. The left-hand-side (LHS) unit comprised the diode, while the right-hand-side (RHS) unit comprised the ISFET. The 15X600 m (LXW) floating gate of the ISFET was precovered with a 50-nm-thick proton sensitive layer of Si3N4 for pH detection. Photo curable polyimide de-fined the 10-nL electrolyte chamber for the pH sensor (above the gate) and the open reservoir above the conductivity sensor (Level 2).
Photolithography (or "optical lithography") is a process used in microfabrication to selectively remove parts of a thin film or the bulk of a substrate. It uses light to transfer a geometric pattern from a photo mask to a light-sensitive chemical "photoresist", or simply "resist," on the substrate. A series of chemical treatments then either engraves the exposure pattern into, or enables deposition of a new material in the desired pattern upon, the material underneath the photo resist. In complex integrated circuits, for example a modern CMOS, a wafer will go through the photolithographic cycle up to 50 times.
Photolithography shares some fundamental principles with photography in that the pattern in the etching resist is created by exposing it to light, either directly (without using a mask) or with a projected image using an optical mask. This procedure is comparable to a high precision version of the method used to make printed circuit boards. Subsequent stages in the process have more in common with etching than to lithographic printing. It is used because it can create extremely small patterns (down to a few tens of nanometers in size), it affords exact control over the shape and size of the objects it creates, and because it can create patterns over an entire surface cost-effectively. Its main disadvantages are that it requires a flat substrate to start with, it is not very effective at creating shapes that are not flat, and it can require extremely clean operating conditions.