Lecture 9 Biomedical Microtechnology and Nanotechnology Microfabrication and Nanofabrication applied to Biomedical Instrumentation
Why Micro/Nano? SCALING OF PARAMETERS The values of various parameters depends on the dimensions of the system and this proves to be helpful in a number of cases. Example : Cantilever bending (Mechanical Parameters) Density of Material = 3.5 x 10 3 kg/m 3 Force F Young s Modulus = 10 12 N/m 2 Deflection d Material properties such as Young s modulus remain approximately the same in the micro and macro versions. However, they are relatively more different in case of nano dimensions because nano dimensions come closer to molecular level.
Why Micro/Nano? SCALING OF PARAMETERS Consider that the dimensions of the cantilever are reduced 10000 times, i.e the length, breadth and thickness change from 100 cm, 10cm and 1cm to 100microns, 10 microns and 1 micron respectively. If S represents any dimension in general then, Mass Mass = Density x Volume = Constant x S 3 Therefore mass goes down (10 4 ) 3 or is reduced 10 12 times as the original beam Strength to Mass Ratio Total strength scales with its cross-sectional area. Hence, total strength scales as S 2. Hence, total strength to mass ratio scales as S -1. As a result, the micro cantilever is 10 4 times stronger than the macro model.
Why Micro/Nano? SCALING OF PARAMETERS Deflection Force Young s Modulus 3 Fl 4Fl d = = 3EI Ebt 3 3 breadth Moment of Inertia length thickness Force will vary with cross-sectional area if the stress is to be kept constant Therefore, deflection is proportional to S 1. Therefore, the same stress is generated in the two models if the deflection in the microcantilever is 10-4 times the deflection in the macro model, thus maintaining the bending shape. A much smaller force can be sensed (10-8 times) with the micro cantilever.
Why Micro/Nano? SCALING OF PARAMETERS Frequency Frequency scales as the square root of the ratio of the stiffness and mass. Thus, frequency scales as S -1. Hence, micro and nano applications can be high frequency applications. Huang et al have achieved a nanomechanical silicon carbide resonator for ultra high frequency applications. Resonant frequencies have been as high as 632 MHz. Reference : http://www.bu.edu/nems/sic%20high%20frequency%20henry.pdf
Why Micro/Nano? SCALING OF PARAMETERS Example : Capacitor (Electrical Parameters) If the same electric field E = 10 8 V/m needs to be mainitained between the plates of a micro sized capacitor and a macro sized capacitor, then Voltage Voltage = E x gap Thus, voltage will scale as the gap between the plates. Therefore a much smaller voltage will be required in the micro case to produce the same effect. + V gap gnd
Why Micro/Nano? SCALING OF PARAMETERS Electrostatic Force Electrostatic force = Area x (electrostatic field) 2 Thus, electrostatic force scales as S 2 if electrostatic field is maintained same. However, if voltage is to be maintained same, electrostatic force would be independent of scaling. However, its effect in the micro case would be more pronounced because relatively, inertial forces are very low. Electromagnetic force scales as S 4 if magnetic field is to be constant and thus, the world of mems relies on electrostatic motors as opposed to electromagnetic motors. Capacitance Capacitance scales as S 1.
Why Micro/Nano? SCALING OF PARAMETERS An electrostatic micromotor An electrostatic comb drive actuator
Advantages of Micro/Nano Fluidics for Biomedical Applications Device size for hand-held instrumentation and point-of-care testing is minimal. Provides for efficient use of expensive chemical reagents and low production costs per device allowing disposable microfluidic systems. Precise volumetric control of samples and reagents is possible, which leads to higher sensitivities. High-throughput biological screening is made possible by faster sampling times through parallel processing of samples. In-situ production of unstable compounds for biological assays is also possible. Ratio of surface area to volume is high and thus, the sensing is more effective in case of electrochemical sensors etc.
Disadvantages of Micro/Nano Fluidics for Biomedical Applications Bubbles block exits. This could be controlled by either priming at high pressures or by using different priming agents such as ethanol or carbon dioxide. Unwanted particles Fine filtering of solutions becomes important. Surface tension plays funny. Microscale modeling needs to be done and mechanics is not particularly intuitive. However, surface tension forces could be exploited as well! Interfacing with the macroscale equipment is not easy.
Micro/Nano applied to BME Taken from : http://mems.colorado.edu/c1.res.ppt/ppt/g.tutorial/ppt.htm
Micro/Nano applied to BME Taken from : www.heartcenteronline.com
Micro/Nano applied to BME Balloon Angioplasty and Stent Procedure http://www.med.umich.edu/1libr/aha/aha_dil ation_art.htm Stent Procedure Balloon Angioplasty http://www.mdmercy.com/vascular/discoveri es/balloon_stent_gif_big.html
Micro/Nano applied to BME Micromachined silicon neural probe arrays Michigan Probe Taken from http://www.ee.ucla.edu/~jjudy/publications/conference/msc_2000_judy.pdf
Micro/Nano applied to BME Drug Delivery Probes
Micro/Nano applied to BME
Micro/Nano applied to BME An implantable blood pressure sensor developed by CardioMEMS Surgical microgripper actuated by SMA Taken from http://www.ee.ucla.edu/~jjudy/publications/conference/msc_2000_judy.pdf
Micro/Nano Fabrication Techniques
Generalized Microfabrication Taken from : http://mems.colorado.edu/c1.res.ppt/ppt/g.tutorial/ppt.htm
Photolithography Clean wafer : to remove particles on the surface as well as any traces of organic, ionic, and metallic impurities Dehydration bake: to drive off the absorbed water on the surface to promote the adhesion of PR Coating : a) Coat wafer with adhesion promoting film (e.g., HMDS) (optional) b) Coat with photoresist Soft bake : to drive off excess solvent and to promote adhesion Exposure Post exposure bake (optional): to suppress standing wave-effect Develop Clean, Dry Hard bake: to harden the PR and improve adhesion to the substrate
Photolithography Taken from : http://www2.ece.jhu.edu/faculty/andreou/495/2003/lecturenotes/handout3a_photolithographyi.pdf
Additive Processes Oxidation Thermal Oxidation of Silicon is done in a furnace in wet or dry conditions
Additive Processes Doping Purpose of Doping in MEMS - Make P++ etch stop - Change restivity of the film (e.g. make piezoresistor,connecting wire) Dopants : N type (Phosphorous, Arsenic), P type (Boron) Doping Methods 1. Diffusion Dopants are diffused thermally into the substrate in furnace at 950 1280 0 C. It is governed by Fick s Laws of Diffusion. 2. Ion Implantation Dopant ions bombarded into targeting substrate by high energy. Ion implantation are able to place any ion at any depth in sample.
Additive Processes Physical Vapor Deposition (PVD) 1. Evaporation Deposition is achieved by evaporation or sublimation of heated metal onto substrate. This can be done either by resistance heating or by e-beam bombardment. Thermal Evaporator
Additive Processes Physical Vapor Deposition (PVD) 2. Sputtering Sputtering is achieved by accelerated inert ion (Ar+) by DC or RF drive in plasma through potential gradient to bombard metallic target. Then the targeting material is sputtered away and deposited onto substrate placed on anode.
Additive Processes Physical Vapor Deposition (PVD)
Additive Processes Chemical Vapor Deposition (CVD) Materials deposited Polysilicon, silicon nitride (Si3N4), silicon oxide (SiOx), silicon carbide (SiC) etc. How does CVD Work? Gaseous reactants are introduced into chamber at elevated temperatures. Reactant reacts and deposits onto substrate Types of CVD LPCVD (Low Pressure CVD), PECVD (Plasma Enhanced CVD) Salient Features CVD results depend on pressure, gas, and temperature Can be diffusion or reaction limited Varies from film composition, crystallization, deposition rate and electrical and mechanical properties
Subtractive Processes Dry Etching 1. Dry Chemical Etching HF Etching HF is a powerful etchant and hence, highly dangerous. XeF 2 Etching 2XeF2+Si 2Xe+SiF4 Isotropic etching (typically 1-3µm/min) Does not attack aluminum, silicon dioxide, and silicon nitride
Subtractive Processes Dry Etching Plasma Etching Reaction Mechanism Produce reactive species in gas-phase Reactive species diffuse to the solid Adsorption, and diffuse over the surface Reaction Desorption Diffusion
Subtractive Processes Dry Etching 3. Deep Reactive Ion Etching (DRIE) A very high-aspect-ratio silicon etch method (usually > 30:1) BOSCH Process Etch rate is 1.5 4 µm/min SF6 to etch silicon Approx. 10nm flourcarbon polymer (similar is plasma deposited using C 4 H 8 Energetic ions (SF + 6 ) remove protective polymer at the bottom trench
Subtractive Processes DRIE Etched Pillars
Subtractive Processes Wet Etching Isotropic Wet Etching Isotropic etchants etch in all directions at nearly the same rate. Commonly use chemical for Silicon is HNA (HF/HNO 3 /Acetic Acid) This results in a finite amount of undercutting
Subtractive Processes Wet Etching Anisotropic Wet Etching Anisotropic etchants etch much faster in one direction than in another. Etchants are generally Alkali Hydroxides (KOH, NaOH, CeOH,..) KOH on silicon Slower etch rate on (111) planes Higher etch rate on (100) and (110) planes (400 times more faster than the (111) plane) Typical concentration of KOH is around 40 wt% Reaction : Silicon (s) + Water + Hydroxide Ions Silicates + Hydrogen
Metal Patterning
Surface Micromachining
Example 1. Pumping membrane 2. Pumping chamber 3. Inlet 4. Outlet 5. Large mesa 6. Upper glass plate 7. Bottom glass plate 8. patterned thin layer (for improved fluidics) An insulin pump fabricated by classic MEMS technology (Surface Micromachining)
MEMS Packaging
Fabrication of Microfluidic Channels
Materials Silicon / Si compounds - Classical MEMS approach - Etching involved Polymers / Plastics - Newer methods - primary die yet needed - easy fabrication of subsequent components
Etching Methods Step 1 : Etching of Si - Isotropic / Anisotropic - HNA for isotropic - KOH/EDP/TMAH for anisotropic - RIE can also be used for high aspect ratios
Etching Methods Step 2 : Closure of channel a) Bonding another substrate b) LPCVD coating c) Ground Plate Supported Insulating Channels
Etching Methods Step 2 : Closure d) Closing Holes in the mask material - channel is defined by a sequence of holes. - channel formed by underetching
Etching Methods Step 2 : Closure e) Burying channels beneath surface - Trench made using RIE. - KOH etching to form microchannels - Oxide fills trench
Surface Micromachining
A Comparative study
Using Polymers/Plastics Imprinting and Hot Embossing Injection Molding Laser Photoablation Soft Lithography X ray Lithography (LIGA)
Imprinting/Embossing Stamp made in Si or metal Stamp pressed on Plastic to form microfluidic channels Many common plastics successfully imprinted
Elastomeric polymer cast in a Si stamp and cured Polymer is peeled off Channel architecture thus transferred to the polymer PDMS technology is becoming popular Soft Lithography
Laser Photoablation High aspect ratio channels achievable Laser pulses in the UV region used Sealing by thermal lamination with a PET/PE film at 125 0 C Depth controllable
References http://www.kuos.org/archives/mems%20short%20course.pdf http://mems.colorado.edu/c1.res.ppt/ppt/g.tutorial/ppt.htm http://mems.cwru.edu/shortcourse/ http://www2.ece.jhu.edu/faculty/andreou/495/2003/lecturenotes/handout3a_ph otolithographyi.pdf http://www.memsnet.org
Lecture 9 Biomedical Microtechnology and Nanotechnology Microfabrication and Nanofabrication applied to Biomedical Instrumentation
Why Micro/Nano? SCALING OF PARAMETERS The values of various parameters depends on the dimensions of the system and this proves to be helpful in a number of cases. Example : Cantilever bending (Mechanical Parameters) Density of Material = 3.5 x 10 3 kg/m 3 Force F Young s Modulus = 10 12 N/m 2 Deflection d Material properties such as Young s modulus remain approximately the same in the micro and macro versions. However, they are relatively more different in case of nano dimensions because nano dimensions come closer to molecular level.
Why Micro/Nano? SCALING OF PARAMETERS Consider that the dimensions of the cantilever are reduced 10000 times, i.e the length, breadth and thickness change from 100 cm, 10cm and 1cm to 100microns, 10 microns and 1 micron respectively. If S represents any dimension in general then, Mass Mass = Density x Volume = Constant x S 3 Therefore mass goes down (10 4 ) 3 or is reduced 10 12 times as the original beam Strength to Mass Ratio Total strength scales with its cross-sectional area. Hence, total strength scales as S 2. Hence, total strength to mass ratio scales as S -1. As a result, the micro cantilever is 10 4 times stronger than the macro model.
Why Micro/Nano? SCALING OF PARAMETERS Deflection Force Young s Modulus 3 Fl 4Fl d = = 3EI Ebt 3 3 breadth Moment of Inertia length thickness Force will vary with cross-sectional area if the stress is to be kept constant Therefore, deflection is proportional to S 1. Therefore, the same stress is generated in the two models if the deflection in the microcantilever is 10-4 times the deflection in the macro model, thus maintaining the bending shape. A much smaller force can be sensed (10-8 times) with the micro cantilever.
Why Micro/Nano? SCALING OF PARAMETERS Frequency Frequency scales as the square root of the ratio of the stiffness and mass. Thus, frequency scales as S -1. Hence, micro and nano applications can be high frequency applications. Huang et al have achieved a nanomechanical silicon carbide resonator for ultra high frequency applications. Resonant frequencies have been as high as 632 MHz. Reference : http://www.bu.edu/nems/sic%20high%20frequency%20henry.pdf
Why Micro/Nano? SCALING OF PARAMETERS Example : Capacitor (Electrical Parameters) If the same electric field E = 10 8 V/m needs to be mainitained between the plates of a micro sized capacitor and a macro sized capacitor, then Voltage Voltage = E x gap Thus, voltage will scale as the gap between the plates. Therefore a much smaller voltage will be required in the micro case to produce the same effect. + V gap gnd
Why Micro/Nano? SCALING OF PARAMETERS Electrostatic Force Electrostatic force = Area x (electrostatic field) 2 Thus, electrostatic force scales as S 2 if electrostatic field is maintained same. However, if voltage is to be maintained same, electrostatic force would be independent of scaling. However, its effect in the micro case would be more pronounced because relatively, inertial forces are very low. Electromagnetic force scales as S 4 if magnetic field is to be constant and thus, the world of mems relies on electrostatic motors as opposed to electromagnetic motors. Capacitance Capacitance scales as S 1.
Why Micro/Nano? SCALING OF PARAMETERS An electrostatic micromotor An electrostatic comb drive actuator
Advantages of Micro/Nano Fluidics for Biomedical Applications Device size for hand-held instrumentation and point-of-care testing is minimal. Provides for efficient use of expensive chemical reagents and low production costs per device allowing disposable microfluidic systems. Precise volumetric control of samples and reagents is possible, which leads to higher sensitivities. High-throughput biological screening is made possible by faster sampling times through parallel processing of samples. In-situ production of unstable compounds for biological assays is also possible. Ratio of surface area to volume is high and thus, the sensing is more effective in case of electrochemical sensors etc.
Disadvantages of Micro/Nano Fluidics for Biomedical Applications Bubbles block exits. This could be controlled by either priming at high pressures or by using different priming agents such as ethanol or carbon dioxide. Unwanted particles Fine filtering of solutions becomes important. Surface tension plays funny. Microscale modeling needs to be done and mechanics is not particularly intuitive. However, surface tension forces could be exploited as well! Interfacing with the macroscale equipment is not easy.
Micro/Nano applied to BME Taken from : http://mems.colorado.edu/c1.res.ppt/ppt/g.tutorial/ppt.htm
Micro/Nano applied to BME Taken from : www.heartcenteronline.com
Micro/Nano applied to BME Balloon Angioplasty and Stent Procedure http://www.med.umich.edu/1libr/aha/aha_dil ation_art.htm Stent Procedure Balloon Angioplasty http://www.mdmercy.com/vascular/discoveri es/balloon_stent_gif_big.html
Micro/Nano applied to BME Micromachined silicon neural probe arrays Michigan Probe Taken from http://www.ee.ucla.edu/~jjudy/publications/conference/msc_2000_judy.pdf
Micro/Nano applied to BME Drug Delivery Probes
Micro/Nano applied to BME
Micro/Nano applied to BME An implantable blood pressure sensor developed by CardioMEMS Surgical microgripper actuated by SMA Taken from http://www.ee.ucla.edu/~jjudy/publications/conference/msc_2000_judy.pdf
Micro/Nano Fabrication Techniques
Generalized Microfabrication Taken from : http://mems.colorado.edu/c1.res.ppt/ppt/g.tutorial/ppt.htm
Photolithography Clean wafer : to remove particles on the surface as well as any traces of organic, ionic, and metallic impurities Dehydration bake: to drive off the absorbed water on the surface to promote the adhesion of PR Coating : a) Coat wafer with adhesion promoting film (e.g., HMDS) (optional) b) Coat with photoresist Soft bake : to drive off excess solvent and to promote adhesion Exposure Post exposure bake (optional): to suppress standing wave-effect Develop Clean, Dry Hard bake: to harden the PR and improve adhesion to the substrate
Photolithography Taken from : http://www2.ece.jhu.edu/faculty/andreou/495/2003/lecturenotes/handout3a_photolithographyi.pdf
Additive Processes Oxidation Thermal Oxidation of Silicon is done in a furnace in wet or dry conditions
Additive Processes Doping Purpose of Doping in MEMS - Make P++ etch stop - Change restivity of the film (e.g. make piezoresistor,connecting wire) Dopants : N type (Phosphorous, Arsenic), P type (Boron) Doping Methods 1. Diffusion Dopants are diffused thermally into the substrate in furnace at 950 1280 0 C. It is governed by Fick s Laws of Diffusion. 2. Ion Implantation Dopant ions bombarded into targeting substrate by high energy. Ion implantation are able to place any ion at any depth in sample.
Additive Processes Physical Vapor Deposition (PVD) 1. Evaporation Deposition is achieved by evaporation or sublimation of heated metal onto substrate. This can be done either by resistance heating or by e-beam bombardment. Thermal Evaporator
Additive Processes Physical Vapor Deposition (PVD) 2. Sputtering Sputtering is achieved by accelerated inert ion (Ar+) by DC or RF drive in plasma through potential gradient to bombard metallic target. Then the targeting material is sputtered away and deposited onto substrate placed on anode.
Additive Processes Physical Vapor Deposition (PVD)
Additive Processes Chemical Vapor Deposition (CVD) Materials deposited Polysilicon, silicon nitride (Si3N4), silicon oxide (SiOx), silicon carbide (SiC) etc. How does CVD Work? Gaseous reactants are introduced into chamber at elevated temperatures. Reactant reacts and deposits onto substrate Types of CVD LPCVD (Low Pressure CVD), PECVD (Plasma Enhanced CVD) Salient Features CVD results depend on pressure, gas, and temperature Can be diffusion or reaction limited Varies from film composition, crystallization, deposition rate and electrical and mechanical properties
Subtractive Processes Dry Etching 1. Dry Chemical Etching HF Etching HF is a powerful etchant and hence, highly dangerous. XeF 2 Etching 2XeF2+Si 2Xe+SiF4 Isotropic etching (typically 1-3µm/min) Does not attack aluminum, silicon dioxide, and silicon nitride
Subtractive Processes Dry Etching Plasma Etching Reaction Mechanism Produce reactive species in gas-phase Reactive species diffuse to the solid Adsorption, and diffuse over the surface Reaction Desorption Diffusion
Subtractive Processes Dry Etching 3. Deep Reactive Ion Etching (DRIE) A very high-aspect-ratio silicon etch method (usually > 30:1) BOSCH Process Etch rate is 1.5 4 µm/min SF6 to etch silicon Approx. 10nm flourcarbon polymer (similar is plasma deposited using C 4 H 8 Energetic ions (SF + 6 ) remove protective polymer at the bottom trench
Subtractive Processes DRIE Etched Pillars
Subtractive Processes Wet Etching Isotropic Wet Etching Isotropic etchants etch in all directions at nearly the same rate. Commonly use chemical for Silicon is HNA (HF/HNO 3 /Acetic Acid) This results in a finite amount of undercutting
Subtractive Processes Wet Etching Anisotropic Wet Etching Anisotropic etchants etch much faster in one direction than in another. Etchants are generally Alkali Hydroxides (KOH, NaOH, CeOH,..) KOH on silicon Slower etch rate on (111) planes Higher etch rate on (100) and (110) planes (400 times more faster than the (111) plane) Typical concentration of KOH is around 40 wt% Reaction : Silicon (s) + Water + Hydroxide Ions Silicates + Hydrogen
Metal Patterning
Surface Micromachining
Example 1. Pumping membrane 2. Pumping chamber 3. Inlet 4. Outlet 5. Large mesa 6. Upper glass plate 7. Bottom glass plate 8. patterned thin layer (for improved fluidics) An insulin pump fabricated by classic MEMS technology (Surface Micromachining)
MEMS Packaging
Fabrication of Microfluidic Channels
Materials Silicon / Si compounds - Classical MEMS approach - Etching involved Polymers / Plastics - Newer methods - primary die yet needed - easy fabrication of subsequent components
Etching Methods Step 1 : Etching of Si - Isotropic / Anisotropic - HNA for isotropic - KOH/EDP/TMAH for anisotropic - RIE can also be used for high aspect ratios
Etching Methods Step 2 : Closure of channel a) Bonding another substrate b) LPCVD coating c) Ground Plate Supported Insulating Channels
Etching Methods Step 2 : Closure d) Closing Holes in the mask material - channel is defined by a sequence of holes. - channel formed by underetching
Etching Methods Step 2 : Closure e) Burying channels beneath surface - Trench made using RIE. - KOH etching to form microchannels - Oxide fills trench
Surface Micromachining
A Comparative study
Using Polymers/Plastics Imprinting and Hot Embossing Injection Molding Laser Photoablation Soft Lithography X ray Lithography (LIGA)
Imprinting/Embossing Stamp made in Si or metal Stamp pressed on Plastic to form microfluidic channels Many common plastics successfully imprinted
Elastomeric polymer cast in a Si stamp and cured Polymer is peeled off Channel architecture thus transferred to the polymer PDMS technology is becoming popular Soft Lithography
Laser Photoablation High aspect ratio channels achievable Laser pulses in the UV region used Sealing by thermal lamination with a PET/PE film at 125 0 C Depth controllable
References http://www.kuos.org/archives/mems%20short%20course.pdf http://mems.colorado.edu/c1.res.ppt/ppt/g.tutorial/ppt.htm http://mems.cwru.edu/shortcourse/ http://www2.ece.jhu.edu/faculty/andreou/495/2003/lecturenotes/handout3a_ph otolithographyi.pdf http://www.memsnet.org
Applications
WPI s Nitric Oxide Nanosensor
Nitric Oxide Sensor Developed at Dr.Thakor s Lab, BME, JHU Electrochemical detection of NO Left: Schematic of the 16-electrode sensor array. Right: Close-up of a single site. The underlying metal is Au and appears reddish under the photoresist. The dark layer is C (300µm-x-300µm)
A E B F C G D H Cartoon of the fabrication sequence for the NO sensor array A) Bare 4 Si wafer B) 5µm of photoresist was spin-coated on to the surface, followed by a pre-bake for 1min at 90 C. C) The samples were then exposed through a mask for 16s using UV light at 365nm and an intensity of 15mW/cm 2. D) Patterned photoresist after development. E) 20nm of Ti, 150nm of Au and 50nm of C were evaporated on. F) The metal on the unexposed areas was removed by incubation in an acetone bath. G)A 2nd layer of photoresist, which serves as the insulation layer, was spun on and patterned. H) The windows in the second layer also defined the microelectrode sites.
NO Sensor Calibration
NO Sensor Calibration
Multichannel NO Recordings
Michigan Probes for Neural Recordings
Neural Recording Microelectrodes Reference : http://www.acreo.se/acreo-rd/images/publications/proceedings/abstract- KINDLUNDH.PDF
Multi-electrode Neural Recording Reference : http://www.cyberkineticsinc.com/technology.htm Reference : http://www.nottingham.ac.uk/neuronal-networks/mmep.htm
Intraocular Stimulation Electrodes Reference : Lutz Hesse, Thomas Schanze, Marcus Wilms and Marcus Eger, Implantation of retina stimulation electrodes and recording of electrical stimulation responses in the visual cortex of the cat, Graefe s Arch Clin Exp Ophthalmol (2000) 238:840 845