Biomedical microsensors : Course outline

Transcription

1 10 & 20 October 2014 Biomedical microsensors : Course outline Microsensors - Overview - Definitions Microsensors types: - Strain - Displacement - Pressure - Temperature - Gas (Electrode-based) - Chemical sensors (ISFET, CHEMFET) Biosensors Lab-on-chip technology GBM8320 Dispositifs médicaux intelligents 2 1

2 Microsensors? Microsensors are small devices that convert physical or chemical signals to electrical signals. They enable objects to interface to the real world; Implantable microsensors enables monitoring biological parameters. They could allow real-time measurement of temperature, pressure, ph, oxygen and nitric oxide concentrations in vivo; Biosensors allow to help the medical research community in learning about the progression of diseases and assess degree of response to treatment; More & better access to measurement sites - Do not perturb the system under test - Accurate measurements and less invasive - Less psychological trauma & feedback More functionality, better portability, and lower cost. Pressure sensor Gas sensor GBM8320 Dispositifs médicaux intelligents 3 Sensors / microsensors: Definitions Microsensor A microdevice that transforms a signal in measured/analyte format in an electrical signal. Direct sensor Signal to be measured is directly transformed to electrical signal. - Example: photo-conductor converts light to change of resistance. Indirect sensor Signal to be measured is first converted to some other variable that is then converted to an electrical signal - Example: acceleration sensor converts acceleration to strain which is then sensed. Biosensor A microsensor dedicated for medical implantable and cellular devices. GBM8320 Dispositifs médicaux intelligents 4 2

3 Sensor Performance Characteristics Transfer Function: The functional relationship between physical input signal and electrical output signal. Sensitivity: The sensitivity is the ratio between a small change in electrical signal resulting from a small change in the physical signal to be measured. Dynamic Range: The range of input physical signals which may be converted to electrical signals by the sensor. Signals outside of this range are expected to cause unacceptably large inaccuracy. Non-Linearity: The maximum deviation from a linear transfer function over the specified dynamic range. Accuracy: Generally defined as the largest expected error between actual and ideal output signals. Resolution: The minimum detectable signal fluctuation. GBM8320 Dispositifs médicaux intelligents 5 Sensor Performance Characteristics Hysteresis: Some sensors do not return to the same output value when the input stimulus is cycled up or down. The width of the expected error in terms of the measured quantity is defined as the hysteresis. Noise: All sensors produce some output noise in addition to the output signal. The noise of the sensor limits the performance of the system based on the sensor. Noise is generally distributed across the frequency spectrum. Bandwidth: All sensors have finite response times to an instantaneous change in physical signal. In addition, many sensors have decay times, which would represent the time after a step change in physical signal for the sensor output to decay to its original value. The reciprocal of these times correspond to the upper and lower cutoff frequencies, respectively. The bandwidth of a sensor is the frequency range between these two frequencies. GBM8320 Dispositifs médicaux intelligents 6 3

4 Microsensors: General architecture A generalized architecture of a microsensor system: Inputs Sensor/Actuator Array Signal Conditioners ( Digital (Analog + Drivers Embedded Controller (Calibrate-measure, process & compress, store & forward) Comm. Interface GBM8320 Dispositifs médicaux intelligents 7 Microsensors Example: Complete device Microsensors are often complete microsystems that include microelectronic circuits for A/D and D/A conversion, storage, communciation, etc. Hierlemann et al., Microfabrication techniques for.., Proc. of the IEEE, V 91, GBM8320 Dispositifs médicaux intelligents 8 4

5 Biomedical microsensors : Course outline Microsensors - Overview - Definitions Microsensors types: - Strain - Piezoelectric - Displacement (LVDT) - Acceleration (capacitive) - Pressure - Temperature - Gas (ph, O2, CO2, etc..) - Chemical sensors (ISFET, CHEMFET) Biosensors Lab-on-chip technology GBM8320 Dispositifs médicaux intelligents 9 Physical Variables and Sensors Physical Quantity Sensor Variable Fluidic Force Torque Geometric Kinematic Thermal Pressure Transducer Flow meter Load cell Strain Gauge L. Var. Diff. Transf. (LVDT) Ultrasonic transit time Velocimeter Accelerometer Thermometer Thermal flux sensor Pressure Flow Applied force Applied torque Strain Displacement Displacement Velocity Acceleration Temperature Heat flux Blood flow/ pressure Impact, acceleration Surgical forceps to measure force applied Airbag Body temperature GBM8320 Dispositifs médicaux intelligents 10 5

6 Sensor Application Signal Range Liquid metal strain Gage Breathing movement mm Magnetic displacement sensor Breathing movement 0-10 mm Linear Var. Diff. Transf. (LVDT) Muscle contraction Uterine contraction sensor 0-20 mm 0-5 mm Load cell Electronic scale kg Accelerometer Subject activity 0-20 m/s2 Miniature silicon pressure sensor Electromagnetic flow sensor Intra-arterial blood pressure Urinary bladder pressure Intrauterine pressure Cardiac o/p (with integrator) Organ blood flow mm Hg 0-70 mm Hg mm Hg ml/min ml/min GBM8320 Dispositifs médicaux intelligents 11 Strain sensors - Resistive Resistance is related to length and area of cross-section of the resistor and resistivity of the material as By differentiating both sides, the equation becomes Piezoresistance Dimensional Strain gage component can be related by Poisson s ratio (v) as Length Transfer Function : Input is strain, output is dr. Webster, Medical Instrumentation GBM8320 Dispositifs médicaux intelligents 12 6

7 Strain sensors - Resistive Gage Factor of a strain gage G is a measure of sensitivity ε = dl/l Put mercury strain gage around an arm or chest to measure force of muscle contraction or respiration, respectively Used in prosthesis or neonatal apnea detection, respectively. Webster, Medical Instrumentation GBM8320 Dispositifs médicaux intelligents 13 Strain sensors - Resistive Strain gages are generally mounted on cantilevers and diaphragms and measure the deflection of these. More than one strain gage is generally used and the readout generally employs a bridge circuit. GBM8320 Dispositifs médicaux intelligents 14 7

8 Piezoelectric Sensors What is piezoelectricity? Strain causes a redistribution of charges and results in a net electric dipole q = k f & V = q / C where q = charge, f = force k = 2.3 pc/n for quartz = 140 pc/n for Barium Different transducer applications: - Accelerometer, - Microphone. group27imaging.com/respiratorysensor.aspx GBM8320 Dispositifs médicaux intelligents 15 Piezoelectric Sensors : principle and circuits When force is applied in the L,W or t directions respectively, output voltages are given by these equations. 31 & 33 denote the crystal axis. Charge generator q = Kx Charge generator is = Kdx/dt Webster, Medical Instrumentation GBM8320 Dispositifs médicaux intelligents 16 8

9 Displacement Sensor - LVDT An LVDT (Linear Variable Differential Transformer) is used as a sensitive displacement sensor: for example, in a cardiac assist device or a basic research project to study displacement produced by a contracting muscle. Inductive displacement sensors: - Self inductance; - Mutual inductance; - Differential transformer. Signal Conditioning Electronics Muscle LVDT GBM8320 Dispositifs médicaux intelligents 17 Capacitance-based Sensors Variable Area Mode Variable Dielectric Mode Differential Mode GBM8320 Dispositifs médicaux intelligents 18 9

10 Acceleration sensor Accelerometer for displacement monitoring - Surface micromachined, capacitive sensor - Sensor + Electronics on same substrate= smart g Analog Devices ADXL-50 C1 C2 GBM8320 Dispositifs médicaux intelligents 19 Pressure sensors Miniature Passive Pressure Transensor for Implanting in the Eye Measurement of intraocular and other physiological pressures. Displacement transducer contained in a small distensible pillbox. This passive resonant transensor absorbs energy from an oscillating detector coil outside of the animal at a frequency dependent upon the pressure in the eye. Collins Miniature Passive Pressure Transensor for Implanting, GBM8320 Dispositifs médicaux intelligents 20 10

11 Pressure sensors 21 Wireless micromachined ceramic pressure sensors. High temperature self packaged wireless ceramic pressure sensor. Allen, GA Tech, GBM8320 Dispositifs médicaux intelligents 21 Pressure sensors 22 Flexible Wireless Passive Pressure Sensors for Biomedical Applications. The sensor consists of a cavity, bounded on 2 sides by capacitor plates interconnected with inductance. The value of capacitor change with pressure due to the deflectable diaphragm. This variation change the resonant frequency of the LC circuit and is measured wirelessly. Allen, GA Tech, PTFE = Polytetrafluoroethylene FEP = Fluorinated Ethylene Propylene Ceramic chamber GBM8320 Dispositifs médicaux intelligents 22 11

12 Pressure sensors Completely encapsulated Intraocular Pressure (IOP) sensor equipped with telemetric signal and energy transfer integrated into a silicone disc for implantation into the eye. Biocompatible encapsulation in polydimethylsiloxane. Management and other basic research for mechanisms of glaucoma. This sensor is used for Abdominal Aorta Aneurysm (AAA): Permanently implanted, RF transmission, RF powered, Size of a paper clip, Biocompatible. Rosengren, GBM8320 Dispositifs médicaux intelligents 23 Micromachined pressure sensors Pressure Sensor - Resistive / capacitive based measurements - Thin Silicon Membrane deforms with pressure - Piezoresistors change with strain induced by bending membrane - Packaging requires sealing to maintain pressure differential. High sensitivity capacitive strain sensor. GBM8320 Dispositifs médicaux intelligents 24 12

13 Temperature sensors Temperature sensors have become common elements in wide range of modern integrated circuits The main parameters of temperature sensors are: temperature range, sensitivity, output range, linearity, and accuracy. Types of integrated temperature sensors: - Resistance based : Thermistors, RTDs - Thermocouples & CMOS PTAT references. GBM8320 Dispositifs médicaux intelligents 25 Thermistors Thermistors are made from semiconductor material Generally, they have a negative temperature coefficient (NTC), that is NTC thermistors are most commonly used Ro is the resistance at a reference point (in the limit, absolute 0), B is material constant, and T and T0 are absolute and reference temperatures. Absolute 0 = 0 K = -273 C Webster, Medical instrumentation GBM8320 Dispositifs médicaux intelligents 26 13

14 Thermocouples A conductor generates a voltage when subjected to a temperature gradient. To measure this voltage, one must use a second conductor material which generates a different voltage under the same temperature gradient. So, Thermocouples measure temperature differences and need a known reference temperature to yield the absolute readings. When a pair of dissimilar metals are joined at one end, and there is a temperature difference between the joined ends and the open ends, thermal electromotive force (emf) is generated, which can be measured in the open ends. There are three major effects involved : the Seebeck, Peltier, and Thomson. Webster, Medical Instrumentation GBM8320 Dispositifs médicaux intelligents 27 Thermocouples The Seebeck, Peltier, and Thomson effects : Seebeck effect describes the voltage induced by the temperature gradient along the wire. The change in material EMF with temperature is called the Seebeck coefficient or thermoelectric sensitivity. This coefficient is usually a nonlinear function of temperature. Peltier effect describes the temperature difference generated by EMF and is the reverse of Seebeck effect. Thomson effect relates the reversible thermal gradient and EMF in a homogeneous conductor. Peletier emf Homogeneous Intermediate metal Intermediate temperatures Webster, Medical Instrumentation GBM8320 Dispositifs médicaux intelligents 28 14

15 CMOS temperature sensor A bipolar transistor can be used as a temperature sensor by using its baseemitter voltage as a measure of temperature. V BE is CTAT (Complementary To Absolute Temperature) at roughly -2.2 mv/ C at room temperature. V EB1 (T) = kt q ln I E I S V EB 2 (T) = kt q ln pi E I S Pertijs et al, Precision Temperature Measurement using, IEEE Sensors, v4, GBM8320 Dispositifs médicaux intelligents 29 CMOS temperature sensor The voltage difference between the two diodes, operated at a different current density, is used to generate a Proportional To Absolute Temperature (PTAT) current. This voltage difference is PTAT with a temperature coefficient of mv/ C at room temperature. V BE 2 V BE1 = ΔV BE (T) = kt q ln pi E kt I S2 q ln I E = kt Ir S1 I /r q ln p r s2 [ ] Pertijs et al, Precision Temperature Measurement using, IEEE Sensors, v4, GBM8320 Dispositifs médicaux intelligents 30 15

16 CMOS temperature sensor : Complete PTAT circuit V X V Y V R1 = V Y V Z V X V Z V R1 = V EB1 V EB 2 = kt q ln A 1 A 2 I R1 = I 2 = V R 1 = 1 kt R 1 R 1 q ln A 1 A 2 The current mirrored at the output is PTAT: I PTAT = I 5 =W 5 /W 4 *I 2 GBM8320 Dispositifs médicaux intelligents 31 CMOS temperature sensor : Complete PTAT circuit GBM8320 Dispositifs médicaux intelligents 32 16

17 CMOS temperature sensor : Complete PTAT circuit GBM8320 Dispositifs médicaux intelligents 33 CMOS temperature sensor : Complete PTAT circuit GBM8320 Dispositifs médicaux intelligents 34 17

18 ph Electrodes Glass electrodes develop a gel layer with mobile hydrogen ions when dipped into an aqueous solution; ph changes cause ion diffusion processes generating an electrode potential. Lithium-rich glasses are well suited for this purpose; The potential is measured in comparison to a reference electrode which is usually an Ag/AgCl system; The electric circuit is closed via a diaphragm separating the reference electrolyte from the solution. Sonnleitner, Bioanalysis and Biosensors for Bioprocess Monitoring, Springer, GBM8320 Dispositifs médicaux intelligents 35 Oxygen Partial Pressure (po 2 ) Electrode A membrane through which oxygen must diffuse separates the measuring solution from the electrolyte Oxygen is reduced by electrons coming from the central platinum cathode which is surrounded by a glass insulator. This design, a so-called polaro-graphic electrode, needs an external power supply. For oxygen, the polarization voltage is in the order of 700 mv and the typical current for atmospheric po 2 is in the order of 10 7 A. Sonnleitner, Bioanalysis and Biosensors for Bioprocess Monitoring, Springer, GBM8320 Dispositifs médicaux intelligents 36 18

19 Carbon Dioxide Partial Pressure (pco 2 ) Electrode CO 2 diffuses through the membrane into or out of the electrolyte where it equilibrates with HCO 3 thus generating or consuming protons. The respective ph change of the electrolyte is sensed with a ph electrode and is logarithmically proportional to the pco 2 in the measuring solution. Sonnleitner, Bioanalysis and Biosensors for Bioprocess Monitoring, Springer, GBM8320 Dispositifs médicaux intelligents 37 ISFET/CHEMFET sensors Ion-Sensitive Field Effect Transistors (ISFETS and CHEMFETs) are basically metal oxide semiconductor field-effect devices. The construction of an ISFET differs from the conventional MOSFET devices, in that the gate metal is omitted and replaced by a membrane sensitive to the ions of interest. Shepherd, Weak Inversion ISFETs Sensing, S&A B, v107, GBM8320 Dispositifs médicaux intelligents 38 19

20 ph ISFET The ISFET is based on a MOSFET with a remote gate (reference electrode, G) exposing a chemically-sensitive insulator (G ) to an electrolyte. Voltage applied to the reference electrode is capacitively-coupled via the electrolyte to the insulator surface, where a ph dependent charge from ions on this interface modulates the channel current, causing shifts in the ISFET I D -V GS characteristic. unit.aist.go.jp/.../sfd-project-isfet.htm GBM8320 Dispositifs médicaux intelligents 39 ph ISFET equivalent model Macromodel ph-isfet The drain current for the weak inversion ISFET in saturation is given by: Shepherd & Toumazou, Weak Inversion ISFETs for Ultra-Low Power Biochemical Sensing, Sensors and Actuators B (Chemical), v107, GBM8320 Dispositifs médicaux intelligents 40 20

21 Biomedical microsensors : Course outline Microsensors - Overview - Definitions Microsensors types: - Strain - Pressure - Displacement - Temperature - Gas (Electrode-based) - Chemical sensors (ISFET, CHEMFET) Biosensors Lab-on-chip technology GBM8320 Dispositifs médicaux intelligents 41 Biosensing: Conceptual principle A biosensor can be defined as a device that consists of a biological recognition system, often called a bioreceptor, and a transducer A biochip consists of an array of individual biosensors that can be individually monitored and generally are used for the analysis of multiple analytes The interaction of the analyte with the bioreceptor is designed to produce an effect measured by the transducer, which converts the information into a measurable effect, such as an electrical signal. Ferrari et al, BioMEMS and Biomedical Nanotechnology: Vol IV: Biomolecular Sensing, Processing and Analysis, Springer, GBM8320 Dispositifs médicaux intelligents 42 21

22 Classification of biosensors Ferrari et al, BioMEMS and Biomedical Nanotechnology: Vol IV: Biomolecular Sensing, Processing and Analysis, Springer, GBM8320 Dispositifs médicaux intelligents 43 Biosensors A bioreceptor is a biological molecular species (e.g., an antibody, an enzyme, a protein, or a nucleic acid) or a living biological system (e.g., cells, tissue, or whole organisms) that utilizes a biochemical mechanism for recognition. The sampling component of a biosensor contains a bio-sensitive layer. The layer can either contain bioreceptors or be made of bioreceptors covalently attached to the transducer. The most common forms of bioreceptors for biosensing are based on: - Antibody / Antigen interactions - Nucleic acid interactions (biological molecules) - Enzymatic interactions - Cellular interactions (i.e. microorganisms, proteins) - Interactions using biomimetic materials (i.e., synthetic bioreceptors). GBM8320 Dispositifs médicaux intelligents 44 22

23 Example : Glucose Sensors Enzymatic Approach O2 Glucose H2O2 Gluconic acid Makes use of catalytic (enzymatic) oxidation of glucose O2 O2 The setup contains an enzyme electrode and an oxygen electrode and the difference in the readings indicates the glucose level. Plastic membrane The enzyme electrode has glucose oxidase immobilized on a membrane or a gel matrix*. Platinum electrode Glu coseoxidase Glu cose + O GluconicAcid + H O Silver anode *In the enzyme electrode, when glucose is present it combines with O2, so less O2 arrives to the cathode. Webster, Medical Instrumentation GBM8320 Dispositifs médicaux intelligents 45 Example : Glucose Sensors Affinity Approach (Optical) This approach is based on the immobilized competitive binding of a particular metabolite (glucose) and its associated fluorescent label with receptor sites specific to the metabolite and the labeled ligand. This change in light intensity is then picked up. Hollow dialysis fiber Excitation Emission Optical Fiber Glucose 3 mm Measure of glucose concentration by detecting changes in fluorescent light intensity caused by competitive binding of a fluorescein-labeled indicator. 0.3 mm Schultz et al, Affinity sensor : A new technique, Diabetes Care, GBM8320 Dispositifs médicaux intelligents 46 23

24 Current limitations of biosensors Several other techniques and technologies are undertaken these days Electronic Noses Lab-on-chip based sensing devices.. - Optical (CMOS based imaging) - Charge-Based Capactive Measurement (CBCM) Miniaturized biosensors have yet to achieve their full potential. They must accomodate: High noise levels in chemical composition of the field environment. Highly variable environmental conditions (temperature, humidity). GBM8320 Dispositifs médicaux intelligents 47 Lab-on-chip biosensors? A multidisciplinary approach to miniaturize biological assays or procedures in analytical chemistry. To embed the required equipments for performing the biological assays in a single chip for single purpose. GBM8320 Dispositifs médicaux intelligents 48 24