Neuman. m.r.""Biomedical Ser The Electrical Engineering Handbook Ed. Richard C. Dorf Boca raton crc Press llc. 2000
Neuman, M.R. “Biomedical Sensors” The Electrical Engineering Handbook Ed. Richard C. Dorf Boca Raton: CRC Press LLC, 2000
114 Biomedical sensors 114.1 Introduction 114.2 Physical Sensors 114.3 Chemical Sensors 114.4 Bioanalytical Sensors Michael R Neuman 114.5 Applicat 114.6 Summary 114.1 Introduction Any instrumentation system can be described as having three fundamental components: a sensor, a signal processor, and a display and/or storage device. Although all these components of the instrumentation system are important, the sensor serves a special function in that it interfaces the instrument with the system being measured In the case of biomedical instrumentation a biomedical sensor(which in some cases may be referred to as a biosensor) is the interface between the electronic instrument and the biologic system. There are some general concerns that are very important for any sensor in an instrumentation system regarding its ability to effectively carry out the interface function. These concerns are especially important for biomedical sensors, since the sensor can affect the system being measured and the system can affect the sensor performance. Sensors must be designed so that they minimize their interaction with the biologic host. It is important that the presen of the sensor does not affect the variable being measured in the vicinity of the sensor as a result of the interaction between the sensor and the biologic system. If the sensor is placed in a living organism, that organism will probably recognize the sensor as a foreign body and react to it. This may in fact change the quantity being sensed in the vicinity of the sensor so that the measurement reflects the foreign body reaction rather than a central characteristic of the host Similarly, the biological system can affect the performance of the sensor. The foreign body reaction might cause the host to attempt to break down the materials of the sensor as a way to remove it. This may, in fact, degrade the sensor package so that the sensor can no longer perform in an adequate manner. Even if the foreign body reaction is not strong enough to affect the measurement, just the fact that the sensor is placed in a warm, aqueous environment may cause water to eventually invade the package and degrade the function of the sensor. Finally, as will be described below, sensors that are implanted in the body are not accessible for calibration Thus, such sensors must be extremely stable so that frequent calibrations are not necessary Biomedical sensors can be classified according to how they are used with respect to the biologic system. Table 114.1 shows that sensors can range from noninvasive to invasive as far as the biologic host is concerned. The most noninvasive of biomedical sensors do not even contact the biological system being measured. Sensors of radiant heat or sound energy coming from an organism are examples of noncontacting sensors. Noninvasive sensors can also be placed on the body surface Skin surface thermometers, biopotential electrodes, and strain gauges placed on the skin are examples of sive sensors. Indwelling sensors are those which can be placed into a natural body cavity that communicates with the outside. These are sometimes referred to as minimally invasive sensors and include such familiar sensors as oral-rectal thermometers, intrauterine pressure transduc- ers,and stomach pH sensors. The most invasive sensors are those that need to be surgically placed and that c 2000 by CRC Press LLC
© 2000 by CRC Press LLC 114 Biomedical Sensors 114.1 Introduction 114.2 Physical Sensors 114.3 Chemical Sensors 114.4 Bioanalytical Sensors 114.5 Applications 114.6 Summary 114.1 Introduction Any instrumentation system can be described as having three fundamental components: a sensor, a signal processor, and a display and/or storage device. Although all these components of the instrumentation system are important, the sensor serves a special function in that it interfaces the instrument with the system being measured. In the case of biomedical instrumentation a biomedical sensor(which in some cases may be referred to as a biosensor) is the interface between the electronic instrument and the biologic system. There are some general concerns that are very important for any sensor in an instrumentation system regarding its ability to effectively carry out the interface function. These concerns are especially important for biomedical sensors, since the sensor can affect the system being measured and the system can affect the sensor performance. Sensors must be designed so that they minimize their interaction with the biologic host. It is important that the presence of the sensor does not affect the variable being measured in the vicinity of the sensor as a result of the interaction between the sensor and the biologic system. If the sensor is placed in a living organism, that organism will probably recognize the sensor as a foreign body and react to it. This may in fact change the quantity being sensed in the vicinity of the sensor so that the measurement reflects the foreign body reaction rather than a central characteristic of the host. Similarly, the biological system can affect the performance of the sensor. The foreign body reaction might cause the host to attempt to break down the materials of the sensor as a way to remove it. This may, in fact, degrade the sensor package so that the sensor can no longer perform in an adequate manner. Even if the foreign body reaction is not strong enough to affect the measurement, just the fact that the sensor is placed in a warm, aqueous environment may cause water to eventually invade the package and degrade the function of the sensor. Finally, as will be described below, sensors that are implanted in the body are not accessible for calibration. Thus, such sensors must be extremely stable so that frequent calibrations are not necessary. Biomedical sensors can be classified according to how they are used with respect to the biologic system. Table 114.1 shows that sensors can range from noninvasive to invasive as far as the biologic host is concerned. The most noninvasive of biomedical sensors do not even contact the biological system being measured. Sensors of radiant heat or sound energy coming from an organism are examples of noncontacting sensors. Noninvasive sensors can also be placed on the body surface. Skin surface thermometers, biopotential electrodes, and strain gauges placed on the skin are examples of noninvasive sensors. Indwelling sensors are those which can be placed into a natural body cavity that communicates with the outside. These are sometimes referred to as minimally invasive sensors and include such familiar sensors as oral-rectal thermometers, intrauterine pressure transducers, and stomach pH sensors. The most invasive sensors are those that need to be surgically placed and that Michael R. Neuman Case Western Reserve University
CARDIAC MONITOR T e basic method of assessing heart function is thermodilution, a procedure that involves insertion f a catheter into the pulmonary artery and is demanding in terms of cost, equipment, and skilled ersonnel time. For monitoring astronauts in flight, NASA needed a system that was non derably less compl n 1965, Johnson Space Center contracted with the University of Minnesota to explore the then-known but little-developed concept of impedance cardiography(ICG)as a means of astronaut monitoring. A five-year program led to the development of the Minnesota Impedance Cardiograph(MIC), an electronic system for measuring impedance changes across the thorax that would be reflective of cardiac function and blood flow from the heart's left ventricle into the aorta ICG clearly had broad potential for hospital applications but further development and refinement was needed. A number of research institutions and medical equipment companies launched development of their own ICGs, using MIC technology as a departure point. Among them were Renaissance Technologies, Inc, Newtown, Pennsylvania, and Drexel University of Philadelphia, who jointly developed the IQ System. The system provides a simple, repeatable non-invasive way of assessing cardiac function at dramatically reduced cost. The IQ System is in wide use in hospital intensive care units, emergency rooms, operating rooms, and laboratories in the U.S. and IQ has two basic elements: the non-invasive, disposable patient interface known as IQ-Connect and the touch screen monitor, which calculates and displays cardiac output values and trends. The hardware design of the original MIC was retained but IQ has advanced automated software that features the signal processing technology known as TFD(Time Frequency Distribution). TFD provides three-dimensional distribution of the hemodynamic signals being measured, enabling visualization of the changes in power, frequency, and time. This clinically proven capability allows IQ to measure all cardiac events without using estimation techniques required in some earlier systems.( Courtesy of National Aeronautics and Space Administration. The IQ-Connect interface electronically measures impedance changes across the thorax to reflect heart function. (Photo courtesy of National Aeronautics and Space Administration. e 2000 by CRC Press LLC
© 2000 by CRC Press LLC CARDIAC MONITOR he basic method of assessing heart function is thermodilution, a procedure that involves insertion of a catheter into the pulmonary artery and is demanding in terms of cost, equipment, and skilled personnel time. For monitoring astronauts in flight, NASA needed a system that was non-invasive and considerably less complex. In 1965, Johnson Space Center contracted with the University of Minnesota to explore the then-known but little-developed concept of impedance cardiography (ICG) as a means of astronaut monitoring. A five-year program led to the development of the Minnesota Impedance Cardiograph (MIC), an electronic system for measuring impedance changes across the thorax that would be reflective of cardiac function and blood flow from the heart’s left ventricle into the aorta. ICG clearly had broad potential for hospital applications but further development and refinement was needed. A number of research institutions and medical equipment companies launched development of their own ICGs, using MIC technology as a departure point. Among them were Renaissance Technologies, Inc., Newtown, Pennsylvania, and Drexel University of Philadelphia, who jointly developed the IQ System. The system provides a simple, repeatable, non-invasive way of assessing cardiac function at dramatically reduced cost. The IQ System is in wide use in hospital intensive care units, emergency rooms, operating rooms, and laboratories in the U.S. and abroad. IQ has two basic elements: the non-invasive, disposable patient interface known as IQ-Connect and the touch screen monitor, which calculates and displays cardiac output values and trends. The hardware design of the original MIC was retained but IQ has advanced automated software that features the signal processing technology known as TFD (Time Frequency Distribution). TFD provides three-dimensional distribution of the hemodynamic signals being measured, enabling visualization of the changes in power, frequency, and time. This clinically proven capability allows IQ to measure all cardiac events without using estimation techniques required in some earlier systems. (Courtesy of National Aeronautics and Space Administration.) The IQ-Connect interface electronically measures impedance changes across the thorax to reflect heart function. (Photo courtesy of National Aeronautics and Space Administration.) T
TABLE 114.1 Classification of TABLE 114.2 Physical Variables Sensed by Biomedical Sensors According Biomedical Sensors to Their Interface with the Host lacement, velocity, acceleration(linear and angular erature Noninvasive Noncontacting (weight and m nvasive Implanted gy(optical) involve some tissue damage associated with their installation. For example, a needle electrode for picking up electromyographic signals directly from muscles; a blood pressure sensor placed in an artery, vein, or the heart itself; or a blood flow transducer positioned on a major artery are all examples of invasive sensors. We can also classify sensors in terms of the quantities that they measure. Physical sensors are used neasuring physical quantities such as displacement, pressure, and flow, while chemical sensors are used to determine the concentration of chemical substances within the host. A subgroup of the chemical sensors that re concerned with sensing the presence and the concentration of biochemical materials in the host are known as bioanalytical sensors, or sometimes they are referred to as biosensors In the following paragraphs we will look at each type of sensor and present so ome of the important issues surrounding these types of sensors. 114.2 Physical Sensors Physical variables associated with biomedical systems are measured by a group of sensors known as physical sensors. A list of typical variables that are frequently measured by these devices is given in Table 114.2. These quantities are similar to physical quantities measured by sensors for nonbiomedical applications, and the devices used for biomedical and nonbiomedical sensing are, therefore, quite similar. There are, however, two principal exceptions: pressure and flow sensors The measurement of blood pressure and blood flow in humans and other animals remains a difficult problem in biomedical sensing. Direct blood pressure measurement refers to evaluation of the blood pressure using a ensor that is in contact with the blood being measured or contacts it through an intermediate fluid such as physiologic saline solution. Direct blood pressure sensors are invasive. Indirect blood pressure measurement involves a sensor that does not actually contact the blood. The most familiar indirect blood pressure measure- ment is the sphygmomanometer cuff that is usually used in most medical examinations. It is a noninvasive instrument. Until recently, the primary sensor used for direct blood pressure measurement was the unbonded strain gauge pressure transducer shown in Fig. 114.1. The basic principle of this device is that a differential pressure seen across a diaphragm will cause that diaphragm to deflect. This deflection is then measured by a displacement transducer In the unbonded strain gauge sensor a closed chamber is covered by a flexible diaphragm. This diaphragm is attached to a structure that has four fine gauge wires drawn between it and the chamber walls. a dome with the appropriate hardware for coupling to a pressure source covers the diaphragm on the side opposite the chamber such that when the pressure in the dome exceeds the pressure in the chamber, the diaphragm is deflected into the chamber. This causes two of the fine wires to stretch by a small amount while the other two wires contract by the same amount. The electrical resistance of the wires that are stretched increases while that of the wires that contract decreases. By connecting these wires, or more correctly these unbonded strain gauges, into a Wheatstone bridge circuit, a voltage proportional to the deflection of the diaphragm can be obtained In recent years semiconductor technology has been applied to the design of pressure transducers. Silicon strain gauges that are much more sensitive than their wire counterparts are formed on a silicon chip, and micromachining technology is used to form this portion of the chip into a diaphragm with the strain gauges integrated into its surface. This structure is then incorporated into a plastic housing and dome assembly. The entire sensor can be fabricated and sold inexpensively so that disposable, single-use devices can be made. These e 2000 by CRC Press LLC
© 2000 by CRC Press LLC involve some tissue damage associated with their installation. For example, a needle electrode for picking up electromyographic signals directly from muscles; a blood pressure sensor placed in an artery, vein, or the heart itself; or a blood flow transducer positioned on a major artery are all examples of invasive sensors. We can also classify sensors in terms of the quantities that they measure. Physical sensors are used in measuring physical quantities such as displacement, pressure, and flow, while chemical sensors are used to determine the concentration of chemical substances within the host. A subgroup of the chemical sensors that are concerned with sensing the presence and the concentration of biochemical materials in the host are known as bioanalytical sensors, or sometimes they are referred to as biosensors. In the following paragraphs we will look at each type of sensor and present some examples as well as describe some of the important issues surrounding these types of sensors. 114.2 Physical Sensors Physical variables associated with biomedical systems are measured by a group of sensors known as physical sensors. A list of typical variables that are frequently measured by these devices is given in Table 114.2. These quantities are similar to physical quantities measured by sensors for nonbiomedical applications, and the devices used for biomedical and nonbiomedical sensing are, therefore, quite similar. There are, however, two principal exceptions: pressure and flow sensors. The measurement of blood pressure and blood flow in humans and other animals remains a difficult problem in biomedical sensing. Direct blood pressure measurement refers to evaluation of the blood pressure using a sensor that is in contact with the blood being measured or contacts it through an intermediate fluid such as a physiologic saline solution. Direct blood pressure sensors are invasive. Indirect blood pressure measurement involves a sensor that does not actually contact the blood. The most familiar indirect blood pressure measurement is the sphygmomanometer cuff that is usually used in most medical examinations. It is a noninvasive instrument. Until recently, the primary sensor used for direct blood pressure measurement was the unbonded strain gauge pressure transducer shown in Fig. 114.1. The basic principle of this device is that a differential pressure seen across a diaphragm will cause that diaphragm to deflect. This deflection is then measured by a displacement transducer. In the unbonded strain gauge sensor a closed chamber is covered by a flexible diaphragm. This diaphragm is attached to a structure that has four fine gauge wires drawn between it and the chamber walls. A dome with the appropriate hardware for coupling to a pressure source covers the diaphragm on the side opposite the chamber such that when the pressure in the dome exceeds the pressure in the chamber, the diaphragm is deflected into the chamber. This causes two of the fine wires to stretch by a small amount while the other two wires contract by the same amount. The electrical resistance of the wires that are stretched increases while that of the wires that contract decreases. By connecting these wires, or more correctly these unbonded strain gauges, into a Wheatstone bridge circuit, a voltage proportional to the deflection of the diaphragm can be obtained. In recent years semiconductor technology has been applied to the design of pressure transducers. Silicon strain gauges that are much more sensitive than their wire counterparts are formed on a silicon chip, and micromachining technology is used to form this portion of the chip into a diaphragm with the strain gauges integrated into its surface. This structure is then incorporated into a plastic housing and dome assembly. The entire sensor can be fabricated and sold inexpensively so that disposable, single-use devices can be made. These TABLE 114.1 Classification of Biomedical Sensors According to Their Interface with the Biologic Host Noninvasive Noncontacting Body surface Invasive Indwelling Implanted TABLE 114.2 Physical Variables Sensed by Biomedical Sensors Displacement, velocity, acceleration (linear and angular) Temperature Force (weight and mass) Pressure Flow Radiant energy (optical)
PreSSUre PORT UNBONDED STRAIN GAUGES FIGURE 114.1 An unbonded strain gauge pressure transducer. have the advantage that they are only used on one patient and they do not have to be cleaned and sterilized etween patients. By using them on only one patient, the risk of transmitting blood-borne infections is eliminated In biomedical applications pressure is generally referenced to atmospheric pressure. Therefore, the pressure in the chamber of the pressure transducer must be maintained at atmospheric pressure. This is done by means of a vent in the chamber wall or a fine bore, flexible capillary tube that couples the chamber to the atmosphere This tube is usually included in the electrical cable connecting the pressure transducer to the external instru mentation such that the tube is open to the atmosphere at the cable connecter In using this sensor to measure blood pressure the dome is coupled to a flexible plastic tube, and the dome and tube are filled with a physiological saline solution. As described by Pascals Law, the pressure in the dome, and hence against the diaphragm, will be the same as that at the tip of the tube provided the tip of the tube at the same horizontal level as the dome. Thus by threading the tube into a blood vessel, an invasive procedure, the blood pressure in that vessel can be transmitted to the dome and hence the diaphragm of the pressure transducer. The pressure transducer will, therefore, sense the pressure in the vessel. This technique is known as external direct blood pressure measurement, and the flexible plastic tube that enters the blood vessel is known catheter. It is important to remember that the horizontal level of the blood pressure transducer dome must be the same as that of the tip of the catheter in the blood vessel to accurately measure the pressure in that vessel without adding an error due to the hydrostatic pressure in the catheter In addition to problems due to hydrostatic pressure differ- DIAPHRAGM ences between the chamber and the dome, catheters introduce pressure errors as a result of the dynamic properties of L (Se EAD WIRES catheter, fluid, dome, and diaphragm. These properties as well bubbles in the catheter, or obstructions due to clotted CATHETER WALL blood or other materials, introduce resonances and damping. These problems can be minimized by utilizing miniature pressure transducers fabricated using microelectronic semi- SEMICONDUCTOR STRAIN GAUGES conductor technology that are located at the tip of a catheter FIGURE 114.2 A catheter tip pressure transducer rather than at the end that is external to the body. A general are integrated into the diaphragm of the transducer such that they detect very small deflections of this arrangement for such a pressure transducer is shown in Fig. 114.2. As with the disposable sensors, strain gaug phragm. Because of the small size, small diaphragm displacement, and lack of a catheter with a fluid column, these sensors have a much broader frequency response, give a clearer signal, and do not have any hydrostatic "It must be pointed out that the use of such a sensor is not limited to blood pressure measurement. The strain gauge pressure sensor can be used to measure the pressure of any fluid to which it is appropriately coupled e 2000 by CRC Press LLC
© 2000 by CRC Press LLC have the advantage that they are only used on one patient and they do not have to be cleaned and sterilized between patients. By using them on only one patient, the risk of transmitting blood-borne infections is eliminated. In biomedical applications pressure is generally referenced to atmospheric pressure. Therefore, the pressure in the chamber of the pressure transducer must be maintained at atmospheric pressure. This is done by means of a vent in the chamber wall or a fine bore, flexible capillary tube that couples the chamber to the atmosphere. This tube is usually included in the electrical cable connecting the pressure transducer to the external instrumentation such that the tube is open to the atmosphere at the cable connecter. In using this sensor to measure blood pressure the dome is coupled to a flexible plastic tube, and the dome and tube are filled with a physiological saline solution.1 As described by Pascal’s Law, the pressure in the dome, and hence against the diaphragm, will be the same as that at the tip of the tube provided the tip of the tube is at the same horizontal level as the dome. Thus by threading the tube into a blood vessel, an invasive procedure, the blood pressure in that vessel can be transmitted to the dome and hence the diaphragm of the pressure transducer. The pressure transducer will, therefore, sense the pressure in the vessel. This technique is known as external direct blood pressure measurement, and the flexible plastic tube that enters the blood vessel is known as a catheter. It is important to remember that the horizontal level of the blood pressure transducer dome must be the same as that of the tip of the catheter in the blood vessel to accurately measure the pressure in that vessel without adding an error due to the hydrostatic pressure in the catheter. In addition to problems due to hydrostatic pressure differences between the chamber and the dome, catheters introduce pressure errors as a result of the dynamic properties of the catheter, fluid, dome, and diaphragm. These properties as well as air bubbles in the catheter, or obstructions due to clotted blood or other materials, introduce resonances and damping. These problems can be minimized by utilizing miniature pressure transducers fabricated using microelectronic semiconductor technology that are located at the tip of a catheter rather than at the end that is external to the body. A general arrangement for such a pressure transducer is shown in Fig. 114.2. As with the disposable sensors, strain gauges are integrated into the diaphragm of the transducer such that they detect very small deflections of this diaphragm. Because of the small size, small diaphragm displacement, and lack of a catheter with a fluid column, these sensors have a much broader frequency response, give a clearer signal, and do not have any hydrostatic pressure error. 1 It must be pointed out that the use of such a sensor is not limited to blood pressure measurement. The strain gauge pressure sensor can be used to measure the pressure of any fluid to which it is appropriately coupled. FIGURE 114.1 An unbonded strain gauge pressure transducer. FIGURE 114.2 A catheter tip pressure transducer
SIL VER ANODE AMMETER PERMEABLE MEMBRANE GOLD CATHODE ELECTROLYTIC SOLUTION FIGURE 114.3 The Clark electrode, an amperometric electrochemical sensor of oxygen. Although the indwelling catheter tip pressure transducer appears to solve many of the problems associated with the external pressure transducer, there are still important problems in pressure transducer design that need to be addressed. Long-term stability of pressure transducers is not very good. This is especially problematic for venous pressure measurements which are carried out at relatively low pressure. Long-term changes in baseline pressure require pressure transducers to be frequently adjusted to be certain of zero pressure. while this can be done relatively easily for external and indwelling pressure transducers, there is no way to carry out this procedure for implanted transducers, since there is not a way to establish zero pressure at the sensor. Thus devices that have very low long-term baseline drift are essential for implantable applications The packaging of the pressure transducer also represents a problem that needs to be addressed. Packaging must both protect the transducer and be biocompatible. It also must allow the appropriate pressure to be transmitted from the biologic fluid to the diaphragm. The amount of packaging material required should be kept at a minimum so as not to substantially increase the size of implantable or indwelling sensors. Furthermore, the material must be mechanically stable so that it does not swell or contract, since this will most likely change he baseline pressure seen by the sensor. These problems need to be overcome before miniature pressure transducers can be used reliably in implantable applications 114.3 Chemical sensors There are many biomedical problems where it is TABLE 114.3 Classifications of Chemical Biomedical Sensors necessary to know the concentration of a particular 1. Electrochemic substance in a biological sample. Chemical sensors a. Amperometric provide the interface between an instrument and b. potentiometric the specimen to allow one to determine this con c. Coulometric centration. These sensors can be used on a biolog 2. Optical a. Colorimetric ical specimen taken from the host and tested in a b. Emission and absorption spectroscopy laboratory, or they can be used for in vivo measure- c.Fluorescence ments either as noninvasive asive sensors, the 3. Thermal methods a. Calorimetry There are many types of chemical sensors used b. thermoconductivity biomedical instrumentation. Table 114.3 lists 4Nuclear magnetic resonance ome general categories of sensors. Electrochemical and optical sensors are most frequently used for biomedical measurements both in vivo and in vitro. An example of an electrochemical sensor is the Clark electrode illustrated in Fig. 114.3. This consists of an electrochemical cell separated from the specimen being measured by an oxygen-permeable membrane. The cell is driven at a fixed potential of 600 mV, and under these conditions the following reaction occurs at the noble metal cathode: O2+4e+H2O→4OH e 2000 by CRC Press LLC
© 2000 by CRC Press LLC Although the indwelling catheter tip pressure transducer appears to solve many of the problems associated with the external pressure transducer, there are still important problems in pressure transducer design that need to be addressed. Long-term stability of pressure transducers is not very good. This is especially problematic for venous pressure measurements which are carried out at relatively low pressure. Long-term changes in baseline pressure require pressure transducers to be frequently adjusted to be certain of zero pressure. While this can be done relatively easily for external and indwelling pressure transducers, there is no way to carry out this procedure for implanted transducers, since there is not a way to establish zero pressure at the sensor. Thus devices that have very low long-term baseline drift are essential for implantable applications. The packaging of the pressure transducer also represents a problem that needs to be addressed. Packaging must both protect the transducer and be biocompatible. It also must allow the appropriate pressure to be transmitted from the biologic fluid to the diaphragm. The amount of packaging material required should be kept at a minimum so as not to substantially increase the size of implantable or indwelling sensors. Furthermore, the material must be mechanically stable so that it does not swell or contract, since this will most likely change the baseline pressure seen by the sensor. These problems need to be overcome before miniature pressure transducers can be used reliably in implantable applications. 114.3 Chemical Sensors There are many biomedical problems where it is necessary to know the concentration of a particular substance in a biological sample. Chemical sensors provide the interface between an instrument and the specimen to allow one to determine this concentration. These sensors can be used on a biological specimen taken from the host and tested in a laboratory, or they can be used for in vivo measurements either as noninvasive or invasive sensors, the latter being the most frequently used. There are many types of chemical sensors used in biomedical instrumentation. Table 114.3 lists some general categories of sensors. Electrochemical and optical sensors are most frequently used for biomedical measurements both in vivo and in vitro. An example of an electrochemical sensor is the Clark electrode illustrated in Fig. 114.3. This consists of an electrochemical cell separated from the specimen being measured by an oxygen-permeable membrane. The cell is driven at a fixed potential of 600 mV, and under these conditions the following reaction occurs at the noble metal cathode: O2 + 4e– + H2O Æ 4OH– FIGURE 114.3 The Clark electrode, an amperometric electrochemical sensor of oxygen. TABLE 114.3 Classifications of Chemical Biomedical Sensors 1. Electrochemical a. Amperometric b. Potentiometric c. Coulometric 2. Optical a. Colorimetric b. Emission and absorption spectroscopy c. Fluorescence d. Chemiluminescence 3. Thermal methods a. Calorimetry b. Thermoconductivity 4. Nuclear magnetic resonance
SENSOR BODY. NNER SOLUTION NNER REFERENCE ELECTRODE EXTERNAL ELECTRODE PH SENSITIVE GLASS FIGURE 114.4 a glass electrode pH sensor This reaction involves the reduction of molecular oxygen that diffuses into the cell through the oxygen permeable membrane. Since the other components of the reaction are in abundance, the rate of the reaction is limited by the amount of oxygen available. Thus, the rate of electrons used at the cathode is directly related to the available oxygen. In other words, the cathode current is proportional to the partial pressure of oxygen in the specimen being measured The electrochemical cell is completed by the silver anode. The reaction at the anode involves forming the low-solubility salt, silver-chloride, from the anode material itself and the chloride ion contained in the electro- lyte. The cell is designed so that these materials are also in abundance so that their concentration does not affect the sensor performance. This type of sensor is an example of an amperometric electrochemical sensor. Another type of electrochemical sensor that is frequently used in biomedical laboratories is the glass electrode illustrated in Fig. 114.4. The acidity or alkalinity of a solution is characterized by its pH. This quantity pH=-logIo [H* where [H+] is the activity of the hydrogen ions in solution, a quantity that is related to the concentration of the hydrogen ions. This sensor only works in an aqueous environment. It consists of an inner chamber containing an electrolytic solution of known pH and an outer solution with an unknown pH that is to be measured. The membrane consists of a specially formulated glass that will in essence allow hydrogen ions to pass in either direction but will not pass other chemical species. If the concentration of hydrogen ions in the external solution is greater than that in the internal solution, there will be a gradient forcing hydrogen ions to diffuse through the membrane into the internal solution. This will cause the internal solution to have a greater positive charge than the external solution so that an electrical potential and, hence, an electric field will exist cross the membrane. This field will counteract the diffusion of hydrogen ions due to the concentration difference and so an equilibrium will be eventually established. The potential across the membrane at this equilibrium condition will be related to the hydrogen ion concentration difference(or more accurately the activity difference) between the inner and outer solutions. This potential is given by the Nernst equatio where E is the potential measured, R is the universal gas constant, T is the absolute temperature, n is the valence of the ion, and a, and a2 are the activities of the ions on each side of the membrane. Thus the potential measured across the glass membrane will be proportional to the pH of the solution being studied. At room temperature e 2000 by CRC Press LLC
© 2000 by CRC Press LLC This reaction involves the reduction of molecular oxygen that diffuses into the cell through the oxygenpermeable membrane. Since the other components of the reaction are in abundance, the rate of the reaction is limited by the amount of oxygen available. Thus, the rate of electrons used at the cathode is directly related to the available oxygen. In other words, the cathode current is proportional to the partial pressure of oxygen in the specimen being measured. The electrochemical cell is completed by the silver anode. The reaction at the anode involves forming the low-solubility salt, silver-chloride, from the anode material itself and the chloride ion contained in the electrolyte. The cell is designed so that these materials are also in abundance so that their concentration does not affect the sensor performance. This type of sensor is an example of an amperometric electrochemical sensor. Another type of electrochemical sensor that is frequently used in biomedical laboratories is the glass pH electrode illustrated in Fig. 114.4. The acidity or alkalinity of a solution is characterized by its pH. This quantity is defined as pH = – log10 [H+] where [H+] is the activity of the hydrogen ions in solution, a quantity that is related to the concentration of the hydrogen ions. This sensor only works in an aqueous environment. It consists of an inner chamber containing an electrolytic solution of known pH and an outer solution with an unknown pH that is to be measured. The membrane consists of a specially formulated glass that will in essence allow hydrogen ions to pass in either direction but will not pass other chemical species. If the concentration of hydrogen ions in the external solution is greater than that in the internal solution, there will be a gradient forcing hydrogen ions to diffuse through the membrane into the internal solution. This will cause the internal solution to have a greater positive charge than the external solution so that an electrical potential and, hence, an electric field will exist across the membrane. This field will counteract the diffusion of hydrogen ions due to the concentration difference and so an equilibrium will be eventually established. The potential across the membrane at this equilibrium condition will be related to the hydrogen ion concentration difference (or more accurately the activity difference) between the inner and outer solutions. This potential is given by the Nernst equation where E is the potential measured, R is the universal gas constant, T is the absolute temperature, n is the valence of the ion, and a1 and a2 are the activities of the ions on each side of the membrane. Thus the potential measured across the glass membrane will be proportional to the pH of the solution being studied. At room temperature FIGURE 114.4 A glass electrode pH sensor. E RT nF a a = - Ê Ë Á ˆ ¯ ˜ ln 1 2
RECOGNITION PROTEINS PhYSICAL TRANSDUCER ELECTRICAL ELECTRODES capacitance THERMAL THERMISTORS MASS SAW DEVICES ELECTRICAL SIGNAL OPTICAL PHOTODETECTORS BIOLOGICAL SENSING REACTION PROTEINS IN SOLUTION FIGURE 114.5 A generalized bioanalytical sensor the theoretical sensitivity of the electrode is approximately 60 mV/pH. It is not practical to measure the potential across the membrane directly and so reference electrodes, sensors that can be used to measure electrical potential of an electrolytic solution, are used to contact the solution on either side of the membrane to measure the potential difference across it. The reference electrodes and the glass membrane are incorporated into the structure shown in Fig. 114.4 known as a glass pH electrode. This is an example of a potentiometric measure- ment made using an ion-selective membrane There are other types of ion-selective membrane potentiometric chemical sensors that are used for biomedical applications. The membranes of these sensors determine the ion being sensed. The membrane can be based upon glass or a polymeric material such as polyvinyl chloride, but the key component is the substance that is added to the membrane that allows it to Important problems in the development of chemical biomedical sensors are similar to those discussed above for the pressure sensor. Issues of long-term stability and packaging are critical to the success of a chemical sensor. The package is even more critical in chemical sensors than it was in pressure sensors in that the package of the sensor that isolation from the solutions being measured while it provides direct contact of the chemically sensitive portions of the sensor to the solution. The maintenance of a window through the package for this contact represents a critical aspect of sensor development. Frequent calibration is lso necessary for chemical sensors. Just about every type of chemical sensor requires some sort of calibration ng a standard solution with known concentration of the analyte being sensed. The best calibration method is a two-point procedure where two standards are used to establish the slope and the intercept of the calibration ine. Some chemical sensors have stable slopes but need to be calibrated in terms of the baseline or intercept. In this case a single-point calibration can be 114.4 Bioanalytical Sensors A special class of sensors of biological molecules has evolved in recent years. These bioanalytical sensors take advantage of one of the following biochemical reactions: (1)enzyme-substrate, (2)antigen-antibody, or(3 ligand-receptor. The advantage of using these reactions in a sensor is that they are highly specific for a particular iological molecule, and sensors with high sensitivity can be developed based upon these reactions. The basic structure of a bioanalytical sensor is shown in Fig. 114.5. There are two principal portions of the sensor. The portion of a bioanalytical sensor is made up of either a physical or chemical sensor that serves as the detector e 2000 by CRC Press LLC
© 2000 by CRC Press LLC the theoretical sensitivity of the electrode is approximately 60 mV/pH.It is not practical to measure the potential across the membrane directly and so reference electrodes, sensors that can be used to measure electrical potential of an electrolytic solution, are used to contact the solution on either side of the membrane to measure the potential difference across it. The reference electrodes and the glass membrane are incorporated into the structure shown in Fig. 114.4 known as a glass pH electrode. This is an example of a potentiometric measurement made using an ion-selective membrane. There are other types of ion-selective membrane potentiometric chemical sensors that are used for biomedical applications. The membranes of these sensors determine the ion being sensed. The membrane can be based upon glass or a polymeric material such as polyvinyl chloride, but the key component is the substance that is added to the membrane that allows it to selectively pass a single ion. Important problems in the development of chemical biomedical sensors are similar to those discussed above for the pressure sensor. Issues of long-term stability and packaging are critical to the success of a chemical sensor. The package is even more critical in chemical sensors than it was in pressure sensors in that the package must protect portions of the sensor that require isolation from the solutions being measured while it provides direct contact of the chemically sensitive portions of the sensor to the solution. The maintenance of a window through the package for this contact represents a critical aspect of sensor development. Frequent calibration is also necessary for chemical sensors. Just about every type of chemical sensor requires some sort of calibration using a standard solution with known concentration of the analyte being sensed. The best calibration method is a two-point procedure where two standards are used to establish the slope and the intercept of the calibration line. Some chemical sensors have stable slopes but need to be calibrated in terms of the baseline or intercept. In this case a single-point calibration can be used. 114.4 Bioanalytical Sensors A special class of sensors of biological molecules has evolved in recent years. These bioanalytical sensors take advantage of one of the following biochemical reactions: (1) enzyme-substrate, (2) antigen-antibody, or (3) ligand-receptor. The advantage of using these reactions in a sensor is that they are highly specific for a particular biological molecule, and sensors with high sensitivity can be developed based upon these reactions. The basic structure of a bioanalytical sensor is shown in Fig. 114.5. There are two principal portions of the sensor. The first contains one component of the biological sensing reaction such as the enzyme or the antibody, and the second component involves a means of detecting whether the biological reaction has taken place. This second portion of a bioanalytical sensor is made up of either a physical or chemical sensor that serves as the detector FIGURE 114.5 A generalized bioanalytical sensor
of the biological reaction. As illustrated in Fig. 114.5, this detector can consist of an electrical sensor such as used in electrochemical sensors, a thermal sensor, a sensor of changes in capacitance, a sensor of changes in mass,or a sensor of optical propertie An example of a bioanalytical sensor is a glucose sensor. The first portion of the sensor contains the enzyme glucose oxidase. This enzyme promotes the oxidation of glucose to glucuronic acid and consumes oxygen in the process. Thus, by placing an oxygen sensor along with the glucose oxidase in the bioanalytical sensor, one can determine the amount of glucose oxidized by measuring the amount of oxygen consumed. An even better approach is to have two identical sensor structures in the same package. The only difference is that only one of the sensors contains the enzyme. When there is no glucose present, both sensors will measure the same oxygen partial pressure. The presence of glucose, however, will cause the sensor with the glucose oxidase to e a reduced partial pressure of oxygen due to the oxygen consumption of the reaction. By making a differential measurement of oxygen partial pressure with both sensors, other factors that can cause an apparent change in oxygen partial pressure such as temperature will have a much lower effect than if a single sensor was used Stability problems are important for bioanalytical sensors, especially those that are used for long-term measurements. Not only are the stability issues the same as for the physical and chemical sensors, but they are also related to preservation of the biological molecules used in the first stage of the sensor. These molecules can often be degraded or destroyed by heat or exposure to light. Even aging can degrade some of these molecules. Thus, an important issue in dealing with bioanalytical sensors is the preservation of the biochemical components of the sensor. Not all biochemical reactions are entirely reversible, and so the bioanalytical sensors based on them will not be reversible as well. This may be acceptable for some applications but not for others and must be taken into consideration in choosing a bioanalytical sensor 114.5 Applications Biomedical sensors and instrumentation are used in biomedical research and patient care applications. In terms of patient care, sensors are used as a part of instruments that carry out patient screening by making measure ments such as blood pressure using automated apparatus. Specimen analysis is another important application of biomedical sensors in patient care. This can include analyses that can be carried out by the patients themselves in their homes such as is done with home blood glucose analyzers. Instrumentation based upon biomedical ensors can be used carrying out some chemical analyses of patient specimens such as urinalysis or elementary blood chemistries such as serum glucose and electrolytes. Sensors also are a part of large multicomponent automatic blood analyzers used in the central clinical laboratory of major medical centers. Another application for biomedical sensors is in patient monitoring. Sensors represent the front end of critical care monitors used in the intensive care unit and in the operating and recovery rooms. Measurements cover a wide range of biomedical variables such as continuous recordings of blood pressure and transcutaneous measurement of the partial pressure of carbon dioxide in the blood. The performance of these instruments is trongly dependent on biomedical sensors. Patient monitoring can also be carried out in the various clinical units of the hospital. Devices such as ambulatory cardiac monitors that allow patients to be observed while they are free to move around if they desire are becoming important in clinical care in"step-down"units for patients who have completed their stay in the intensive care unit. Patient monitoring has even made its way into the home. Home cardiorespiratory monitors are thought to have some potential value in identifying infants at risk of sudden infant death 114.6 Summary Sensors serve an important function in biomedical instrumentation systems in that they provide the interface between the electronic instrument and the biologic system being measured. Very often the quality of the instrument based upon the quality of the sensor at the instrument's front end. Although electronic signal processing has been developed to a high level, the signals are no better than the quality of the sensors that provide them. Although there ave been many advances in biomedical sensor technology, many problems remain. Biomedical sensors will continue to be an import area for research and development in biomedical engineering e 2000 by CRC Press LLC
© 2000 by CRC Press LLC of the biological reaction. As illustrated in Fig. 114.5, this detector can consist of an electrical sensor such as used in electrochemical sensors, a thermal sensor, a sensor of changes in capacitance, a sensor of changes in mass, or a sensor of optical properties. An example of a bioanalytical sensor is a glucose sensor. The first portion of the sensor contains the enzyme glucose oxidase. This enzyme promotes the oxidation of glucose to glucuronic acid and consumes oxygen in the process. Thus, by placing an oxygen sensor along with the glucose oxidase in the bioanalytical sensor, one can determine the amount of glucose oxidized by measuring the amount of oxygen consumed. An even better approach is to have two identical sensor structures in the same package. The only difference is that only one of the sensors contains the enzyme. When there is no glucose present, both sensors will measure the same oxygen partial pressure. The presence of glucose, however, will cause the sensor with the glucose oxidase to have a reduced partial pressure of oxygen due to the oxygen consumption of the reaction. By making a differential measurement of oxygen partial pressure with both sensors, other factors that can cause an apparent change in oxygen partial pressure such as temperature will have a much lower effect than if a single sensor was used. Stability problems are important for bioanalytical sensors, especially those that are used for long-term measurements. Not only are the stability issues the same as for the physical and chemical sensors, but they are also related to preservation of the biological molecules used in the first stage of the sensor. These molecules can often be degraded or destroyed by heat or exposure to light. Even aging can degrade some of these molecules. Thus, an important issue in dealing with bioanalytical sensors is the preservation of the biochemical components of the sensor. Not all biochemical reactions are entirely reversible, and so the bioanalytical sensors based on them will not be reversible as well. This may be acceptable for some applications but not for others and must be taken into consideration in choosing a bioanalytical sensor. 114.5 Applications Biomedical sensors and instrumentation are used in biomedical research and patient care applications. In terms of patient care, sensors are used as a part of instruments that carry out patient screening by making measurements such as blood pressure using automated apparatus. Specimen analysis is another important application of biomedical sensors in patient care. This can include analyses that can be carried out by the patients themselves in their homes such as is done with home blood glucose analyzers. Instrumentation based upon biomedical sensors can be used in the physician’s office for carrying out some chemical analyses of patient specimens such as urinalysis or elementary blood chemistries such as serum glucose and electrolytes. Sensors also are a part of large multicomponent automatic blood analyzers used in the central clinical laboratory of major medical centers. Another application for biomedical sensors is in patient monitoring. Sensors represent the front end of critical care monitors used in the intensive care unit and in the operating and recovery rooms. Measurements cover a wide range of biomedical variables such as continuous recordings of blood pressure and transcutaneous measurement of the partial pressure of carbon dioxide in the blood. The performance of these instruments is strongly dependent on biomedical sensors. Patient monitoring can also be carried out in the various clinical units of the hospital. Devices such as ambulatory cardiac monitors that allow patients to be observed while they are free to move around if they desire are becoming important in clinical care in “step-down” units for patients who have completed their stay in the intensive care unit. Patient monitoring has even made its way into the home. Home cardiorespiratory monitors are thought to have some potential value in identifying infants at risk of sudden infant death. 114.6 Summary Sensors serve an important function in biomedical instrumentation systems in that they provide the interface between the electronic instrument and the biologic system being measured. Very often the quality of the instrument is based upon the quality of the sensor at the instrument’s front end. Although electronic signal processing has been developed to a high level, the signals are no better than the quality of the sensors that provide them. Although there have been many advances in biomedical sensor technology, many problems remain. Biomedical sensors will continue to be an import area for research and development in biomedical engineering
Defining Terms Amperometric sensor: An electrochemical sensor that determines the amount of a substance by means of an oxidation-reduction reaction involving that substance. Electrons are transferred as a part of the reaction,so that the electrical current through the sensor is related to the amount of the substance seen sensor. Analyte: The substance being measured by a chemical or bioanalytical sensor and instrumentation system Bioanalytical sensor: A special case of a chemical sensor for determining the amount of a biochemical abstance. This type of sensor usually makes use of one of the following types of biochemical reactions enzyme-substrate, antigen-antibody, or ligand-receptor Biomedical sensor: A device for interfacing an instrumentation system with a biological system such as a biological specimen or an entire organism. The device serves the function of detecting and measuring in a quantitative fashion a physiological property of the biologic system. Chemical sensor: The interface device for an instrumentation system that determines the concentration of Noninvasive sensor: The interface device of an instrumentation system that measures a physiologic variable from an organism without interrupting the integrity of that organism. This device can be in direct contact with the surface of the organism or it can measure the physiologic quantity while remaining remote from the Physical sensor: An interface device at the input of an instrumentation system that quantitatively measures a physical quantity such as pressure or temperature Potentiometric sensor: A chemical sensor that measures the concentration of a substance by determining the electrical potential between a specially prepared surface and a solution containing the substance being measured Related Topics 56.1 Introduction.56.2 Physical Sensors.56.3 Chemical Sensors.56.4 Biosensors. 56.5 Microsensors References R.S.C. Cobbold, Transducers for Biomedical Measurements: Principles and Applications, New York: John wiley, 1974 BR Biosensors: An Introduction, Chichester; New York: John Wiley, 1996 LAo c.&, W.H. Ko, and M.R. Neuman, Eds, Indwelling and Implantable Pressure Transducers,Cleveland Press, 1977. Geddes, The Direct and Indirect Measurement of Blood Pressure, Chicago: Year Book Medical Publishers, 1970. L.A. Geddes, Electrodes and the Measurement of Bioelectric Events, New York: John Wiley, 1972. w. Gopel, J. Hesse and J N. Zemel, Sensors; A Comprehensive Survey, Weinheim, Germany: VCH Verlagsgesellschaft, 1989 A H. Hall, Biosensors, Englewood Cliffs, N J. Prentice Hall, 1991 J Janata, Principles of Chemical Sensors, New York: Plenum Press, 1989 M.R. Neuman, R.P. Buck, V.V. Cosofret, E. Lindner, and C.C. Liu,Fabricating biomedical sensors with thin film technoogy, IEEE Engineering in Medicine and Biology Magazine, 13, 409-419, 1994 R. Pallas-Areny and J.G. Webster, Sensors and Signal Conditioning, New York: John Wiley, 1991 J.I. Peterson and G.G. Vurek, "Fiber-optic sensors for biomedical applications, Science, vol. 224, PP. 123-127, P. Rolfe, Review of chemical sensors for physiological measurement, J. Biomed. Eng, vol 10, Pp. 138-145, 1988 J.G. Webster, Ed, Encyclopedia of Medical Devices and Instrumentation, New York: John Wiley, 1988 O.S. wolfbeis, Ed, Fiber Optic Chemical Sensors and Biosensors, Boca Raton, Fla: CRC Press, 1991 e 2000 by CRC Press LLC
© 2000 by CRC Press LLC Defining Terms Amperometric sensor: An electrochemical sensor that determines the amount of a substance by means of an oxidation-reduction reaction involving that substance. Electrons are transferred as a part of the reaction, so that the electrical current through the sensor is related to the amount of the substance seen by the sensor. Analyte: The substance being measured by a chemical or bioanalytical sensor and instrumentation system. Bioanalytical sensor: A special case of a chemical sensor for determining the amount of a biochemical substance. This type of sensor usually makes use of one of the following types of biochemical reactions: enzyme-substrate, antigen-antibody, or ligand-receptor. Biomedical sensor: A device for interfacing an instrumentation system with a biological system such as a biological specimen or an entire organism. The device serves the function of detecting and measuring in a quantitative fashion a physiological property of the biologic system. Chemical sensor: The interface device for an instrumentation system that determines the concentration of a chemical substance. Noninvasive sensor: The interface device of an instrumentation system that measures a physiologic variable from an organism without interrupting the integrity of that organism. This device can be in direct contact with the surface of the organism or it can measure the physiologic quantity while remaining remote from the organism. Physical sensor: An interface device at the input of an instrumentation system that quantitatively measures a physical quantity such as pressure or temperature. Potentiometric sensor: A chemical sensor that measures the concentration of a substance by determining the electrical potential between a specially prepared surface and a solution containing the substance being measured. Related Topics 56.1 Introduction • 56.2 Physical Sensors • 56.3 Chemical Sensors • 56.4 Biosensors • 56.5 Microsensors References R.S.C. Cobbold, Transducers for Biomedical Measurements: Principles and Applications, New York: John Wiley, 1974. B.R. Eggins, Biosensors: An Introduction, Chichester; New York: John Wiley, 1996. D.G. Fleming, W.H. Ko, and M.R. Neuman, Eds., Indwelling and Implantable Pressure Transducers, Cleveland: CRC Press, 1977. L.A. Geddes, The Direct and Indirect Measurement of Blood Pressure, Chicago: Year Book Medical Publishers, 1970. L.A. Geddes, Electrodes and the Measurement of Bioelectric Events, New York: John Wiley, 1972. W. Göpel, J. Hesse and J.N. Zemel, Sensors; A Comprehensive Survey, Weinheim, Germany: VCH Verlagsgesellschaft, 1989. A.H. Hall, Biosensors, Englewood Cliffs, N.J.: Prentice Hall, 1991. J. Janata, Principles of Chemical Sensors, New York: Plenum Press, 1989. M.R. Neuman, R.P. Buck, V.V. Cosofret, E. Lindner, and C.C. Liu, “Fabricating biomedical sensors with thin- film technoogy, IEEE Engineering in Medicine and Biology Magazine, 13, 409–419, 1994. R. Pallas-Areny and J.G. Webster, Sensors and Signal Conditioning, New York: John Wiley, 1991. J.I. Peterson and G.G. Vurek, “Fiber-optic sensors for biomedical applications,” Science, vol. 224, pp. 123–127, 1984. P. Rolfe, “Review of chemical sensors for physiological measurement,” J. Biomed. Eng., vol. 10, pp. 138–145, 1988. J.G. Webster, Ed., Encyclopedia of Medical Devices and Instrumentation, New York: John Wiley, 1988. O.S. Wolfbeis, Ed., Fiber Optic Chemical Sensors and Biosensors, Boca Raton, Fla: CRC Press, 1991