Biomedical

Microelectromechanical !
Systems!
(BioMEMS)"

INME 5015/6065
Dr. Pedro J. Resto
Saliterman S. (2005) Fundamentals of BioMEMS and Medical Microdevices
Washington US, SPIE
Outline"

1.  Introduction to what BioMEMS are and what advantages they bring
versus current methods. "
2.  Fabrication techniques, including silicon and "soft" techniques. The course
will also discuss some of the most popular polymer materials used. "
3.  Microfluidic principles to be considered in the design of BioMEMS"
4.  Applications as microsensors and microactuators"
5.  Clinical laboratory use of BioMEMS"
6.  Lab-on-a-chip devices"
7.  Detection"
8.  Genomics"
9.  Proteomics"
10.  FDA and ISO regulations"
11.  Emerging technologies and the future of BioMEMS"
"
Introduction to BioMEMS "

•  Biomedical Microelectromechanical Systems (BioMEMS) "

o  Area of science and engineering that develops miniaturized
devices to study the living world at the micro-scale. "
o  They have applications in diagnostics, drug delivery and
discovery, biomedical research, tissue engineering,
genomics and in medicine. "
o  The field uses knowledge from polymer science,
microfluidic physics, surface chemistry, microfabrication
techniques, biology and mechanical, chemical and electrical
engineering. "
"
Introduction to BioMEMS "

"
•  Fabrication"
o  BioMEMS are descendents of integrated circuit manufacturing
technologies."
"
•  Size"
o  Typically have at least one feature between ~100 nm to ~200um. "
"
•  Can be used in vivo and in vitro"
o  In vivo - experiment using whole living organism (e.g implant)"
o  In vitro - experimentation in Petri dish or test tube (e.g cells in
dish)"
Advantages over current methods"

•  Advantages:"
o  Lower manufacturing costs"
o  Reproducibility"
o  Small sample size"
o  Small reagent use"
"
•  Challenges:"
o  Reliability"
o  Biocompatibility"
"
Biomedical Systems"

•  Diagnostics"
•  Medical R&D"
•  Research on improving current systems and therapies"
•  Personalized medicine"
•  Drug delivery"
•  Minimally invasive procedures"
Microfab"  "
MEMS materials"

} Same materials used for microelectronics"

} Silicon wafers - substrate"
} Polysilicon - resistive elements"
} Aluminum, Copper, Gold - conductors"
} Silicon oxide - insulation and as sacrificial layer"
} Silicon nitride, titanium nitride - electrical insulation"
Silicon microfabrication"

•  Lithography"
•  Etching"
•  Thin-film Deposition"
•  Ion Implantation"
•  Isotropic and Anisotropic
etching"
•  Deep reactive ion etching
(DRIE)"
•  Electroplating"
•  Bonding"
"

Image reference: An Introduction to MEMs Engineering - Nadim Maluf and Kirt Williams
 Lithography"

•  Spin photoresist and soft bake"

o  Soft baking - heating substrate
with deposited photoresist before
exposure"
•  Expose photoresist through
lithographic mask"
•  Develop photoresist and hard bake"
o  develop - place exposed substrate
in developing solution to dissolve
unexposed photoresist"
o  hard bake - heat substrate with
exposed photoresist"

Image reference: www.memsnet.org

Etching"

•  Dry etching"
§  bombarding substrate
surface with ions to
erode surface"
o  Plasma"
o  Reactive ion"
o  Physical sputtering"
o  Ion beam milling"
"
•  Wet etching"
§  chemical bath to
controllably etch
substrate surface"
Thin-film Deposition"

•  Physical vapor deposition "

§  Making a vapor by physical means and subsequent
deposition of vapor on susbtrate"
o  Evaporation"
o  Sputtering"
"
•  Chemical vapor deposition"
o  Deposition of solid on heated substrate from a chemical reaction
in the vapor phase."
"
•  Ion implantation (Doping)"
Isotropic and Anisotropic etching"

•  Isotropic etching"
o  Orientation independent"
"
•  Anisotropic etching"
o  Orientation dependent"
o  Anisotropic etching
follows Miller indices"

Image reference: An Introduction to MEMs Engineering - Nadim Maluf and Kirt Williams
Anisotropic etching"

Image reference: http://www.mems-exchange.org/

Deep reactive ion etching (DRIE)"

•  Dry etching technique where plasma is used to build high aspect-

ratio microstructures"

Image reference: An Introduction to MEMs Engineering - Nadim Maluf and Kirt Williams
Electroplating"

}  Similar
to thin film
deposition but with thicker
coatings"

o Cathode: Substrate to be
coated"

o Anode:Desired metal to
be deposited "

o Applied current deposits

ions on substrate surface"

Image ref: Soft lithography: www.wikipedia.org"

Bonding"

}  Silicon to Silicon - Silicon direct bonding"

} Clean surfaces"
} Chemically treat them to make hydrophilic"
} Place tightly together"
} Anneal at high temperature"
Bonding"

} Silicon to glass – anodic bonding"

} Make
sure glass used and silicon have same thermal
expansion coefficients"
} Compress"

} Heat at high temperature, 300C – 400C"

} Apply high DC voltage – 1000V – with glass as cathode and
silicon as anode"
Bonding"

} Adhesive layers and glue"

} Lasers"

} Laser welding"
} Avoids
adhesive residues, low bonding strength of some
polymers, heating and distortion of entire part"
Microfabrication: "soft" techniques"

} Biomaterials"

} Soft lithography"
} Micromolding"

} 3D photopolymerization"
} Hydrogels"

} Nanoimprints and SAM's"

Biomaterials"

}  Natural or synthetic materials that will be in contact with human "

} Blood, urine, cerebral spinal fluid, organs, skin, muscle"
} Products"

} Corneal transplants"
} Hip replacements"
} Skin grafts"
} Heart valve replacements"
}  Nucleic
acids and peptide chains used to modify surface of
biomaterials for enhanced biocompatibility"
Soft lithography"

}  Making a mold"
} Deposit photoresist on substrate"
} Make
mold by selectively polymerizing
photoresist using mask"
} Pouring molding material into mold
(PDMS)"
} Peel PDMS device"

Image ref: Soft lithography: www.wikipedia.org"

Soft lithography: Microcontact printing"

} Microcontact printing "
} Use PDMS device as stamp"
} Pour
desired patterning material
(“ink”)"
} Allow ink to evaporate, leaving thin
film"
} Use mold as stamp"

Image ref: Soft lithography: www.wikipedia.org"

Soft lithography: Microtransfer molding
The image cannot be displayed. Your computer may not have enough memory to open the image, or the image may have been corrupted. Restart
your computer, and then open the file again. If the red x still appears, you may have to delete the image and then insert it again.

• Fill mold with polymer

• Stamp filled mold on substrate
• Remove mold

Image ref: Soft lithography: G.M. Whitesides, Angewandte Chemie 37, 550-575 (1998)
Micromolding: Hot embossing"

} Applying heat and pressure to mold thermoplastic material"

Image reference: www.memsnet.org

Micromolding: Injection molding"

} Thermoplastic
pellets poured in hopper, melted, transported by a
screw mechanism and injected into mold"

Image reference: Rock Star of the ninetenth century, University of Alberta Industrial Design via www.wikipedia.org
3D photopolymerization"

}  Stereolithography"
"
} Computer driven laser
scans photocurable resin
layer by layer creating a
3D structure from the
ground up"
Hydrogels"

}  Smart
polymer that changes in characteristic with
environmental stimuli"
} pH"

} Solvent"

} Temperature "
} Magnetic field"
} Electrical potential, voltage"
} UV light"
Self assembled monolayers (SAM's)"

}  Spontaneousorganization of
molecules on substrate via non-
covalent weak bonds into well
defined hierarchical structure"
} Hydrogen bonds"
} Ionic bonds"
} Van der Waal’s bonds"
Microfluidics"
 "
Microfluidics"

•  Microfluidic devices"
•  Fabrication"
•  Laminar flow"
•  Diffusion"
•  Electrokinetics"
•  Microvalves"
•  Micropumps"
Microfluidic devices"

}  Microfluidic
is the study of
transport phenomena in
microchannels"
} Most
miniaturized systems
have a microfluidic component"
} Microfluidics
is the backbone
of Lab on a Chip (LoC) and
uTAS (micro Total Analysis
Systems) devices"

Image reference: G.M. Whitesides, The origins and the future of microfluidics, Nature 442, 368-373(27 July 2006) ;
Balagaddé, F. K., You, L., Hansen, C. L., Arnold, F. H. & Quake, S. R. Long-term monitoring of bacteria undergoing programmed
population control in a microchemostat. Science 309, 137–140 (2005)
Dominant forces"

}  Dominant forces at micro-scale"

}  Surface tension, van der Waals forces, electrostatic force,
capillary action, viscosity, laminar flow, diffusion, fluidic
resistance and surface area to volume ratios "
}  Dominant forces at macro-scale. "
}  Momentum, turbulence and gravity "
Fabrication"
"
 Make use of “hard” and “soft” manufacturing methods
} 
previously described."
}  Microfluidic devices of higher complexity use a mix of
methods"
Must take into account the properties of fluids and
} 
materials at the micro- and nano-scale."
}  Electrokinetic effects"
}  Chemical reactions"
Laminar flow"
"
•  Flow can be laminar, transitional or turbulent"

ρVD
Re =
" µ
¨  ρ is fluid density"
¨  V is average fluid velocity"

¨  D is pipe diameter"

¨  μ is fluid viscosity"

}  Circular tube" •  Rectangular tube"

}  Laminar flow" • Laminar flow"
}  Re ≤ 2100" • Re ≤ 200"
}  Transitional flow" • Transitional flow"
}  2100 < Re ≤ 4000" • 200 < Re ≤ 700"
}  Turbulent flow" • Turbulent flow"
}  Re > 4000" • Re > 700"
Flow, velocity and area"
}  Flow rate related to pressure drop through channel and
fluidic resistance, Rw

( Δp )
Circular tube
Q= Vmax = 2V
Rw
Rectangular channel

V=
Q
A
( )
Vmax = 3 2 V
Poiseuille flow"
V is average velocity in channel
Q
V= Q is flow rate
A is cross-sectional area
A Vmax is the maximum (center) velocity
du
Shear = −µ
dr
Circular tube
4 µQ
Vmax = 2V Shear =
πr 3

Rectangular channel

Vmax ( )
= 32 V Shear =
6µQ
wh 2
Fluid Resistances for various shapes"
Poiseuille flow in circular channel"

Q=
( Δp ) 8η L
Rw = 4
Rw πr

Δpπ r 4
Q=
8η L

• Q: volume flow rate through pipe

• R is the radius of tube
• VC: centerline or maximum velocity
Poiseuille flow in circular channel"

Δpπ r 4 Q
Q= V=
8η L A
Δpπ r 4 Δpr 2 ΔpD 2
V= = =
8η Lπ r 2
8η L 32η L

• Q: volume flow rate through pipe

• R is the radius of tube
• VC: centerline or maximum velocity
Poiseuille flow in circular channel"

1 ⎛ dp ⎞ 2 ⎛ ΔpD ⎞ ⎡
2
⎛ 2r ⎞ ⎤
2

vr = ⎜⎝ ⎟⎠ r − R
4 µ dz
2
( ) =⎜ ⎟ ⎢1 − ⎜⎝ ⎟⎠ ⎥
⎝ 16 µ L ⎠ ⎣ D ⎦
•  Vr is the velocity as a function of radial
position in channel.
•  dp/dz is the pressure gradient along length of
channel from inlet to outlet. Assuming flow occurs
in the z-direction
•  r is distance to center of tube
•  R is tube radius
Poiseuille flow in circular channel"

⎡ ⎛ 2r ⎞ ⎤ 2

ur = VC ⎢1 − ⎜ ⎟ ⎥
⎣ ⎝ D ⎠ ⎦

• VC is the centerline or maximum

velocity
•  r is the distance from the center of
tube
•  D is the diameter of tube
•  Average velocity, V = Q/A
•  VC = 2V
Poiseuille flow in rectangular channel"

Q=
( Δp )
Rw =
12η L 1
* 3
Rw ⎛ h⎞ h w
1 − 0.63 ⎜ ⎟
⎝ w⎠

Δph w ⎛
3
⎛ h ⎞⎞ Q
Q= * ⎜ 1 − 0.63 ⎜ ⎟ ⎟ ;h < w V=
12η L ⎝ ⎝ w⎠⎠ A
Poiseuille flow in other shaped channel"
Diffusion"
•   Two laminar streams flowing next to each other only mix by diffusion"
"
Limited planar source " " Constant planar source "
" " ""

⎛ −x 2 ⎞
"
n0 ⎜ ⎟
⎝ 4 Dt i ⎠
⎛ x ⎞
c(x,t) = e c(x,t) = n 0 * erf ⎜⎜ ⎟⎟
πDt i ⎝ 4Dt i ⎠
Electrokinetics"
•   Study of electrical effects on particles in flow"
•   Important for LoC and μTAS"
•  Electro-osmosis"
•  Fluid moves relative to stationary charged surface by applying an
electric field. "
•  Electrophoresis"
•  Motion of electrostatically charged particle (particle with surface
charge) in bulk liquid by applying an electric field. Mainly used for
separation."
•  Dielectrophoresis"
•  Force exerted on dielectric particle (insulator that can be polarized) by
applying non-uniform electric field."
Microvalves"
Passive valve using hydrogel " Passive valve using hydrophobicity"

"

"
Image ref: Beebe et al., PNAS, (2000) vol 97, no 25, p13488 and Feng et al. Sensors and Actuators A: Physical (2003) vol 108, iss1-3, pp. 138-143
Microvalves"
"
•  Active microvalves"
•  Pneumatic"
•  Piezoelectric"
•  Electrostatic"
•  Electromagnetic"
•  Electrocapillary force valves"
Pneumatic microvalves"

Unger et al., Science 288, 113 (2000)

Pneumatic microvalves"

Following “soft” manufacturing

processes previously discussed

Unger et al., Science 288, 113 (2000)

Piezoelectric microvalves"

Park et al., J. Micromech. Microeng. 18 (2008) 015023 (10pp)

Piezoelectric microvalves"

Following “hard” manufacturing

processes previously discussed

Park et al., J. Micromech. Microeng. 18 (2008) 015023 (10pp)

Micropumps"
• Electrokinetic pumps
 "
• Capillary force drive pump
• Surface tension pump
• Gravity
• Mechanical pump
• Syringe pump
• Peristaltic
• Rotary
• Centrifugal
• Ultrasonic
Micropumps"
• Electrokinetic pumps
 "

Wheeler Microfluidic lab @ University of Toronto, http://microfluidics.utoronto.ca/

Micropumps"
• Capillary force drive pump (SlipChip)
 "
Micropumps"
• Surface tension driven pump
 "

Dr. David Beebe, Microtechnology Medicine Lab @ UW-Madison, http://mmb.bme.wisc.edu/?id=home

Micropumps"
• Mechanical pump
 "
• Syringe pump

Cole-Palmer & Kat’s Scientific

Micropumps"
• Mechanical pump
 "
• Peristaltic
Microsensors"
 "
Microsensors"

A sensor converts one form of energy to another, i.e. converts a

measureand into a signal that carries information"
Ø  Thermal sensors"
Ø  Mechanical sensors"
Ø  Flow sensors"
Ø  Piezoelectricity"
Ø  Electrochemical detection"
Ø  Applications in medicine"
Thermal sensors"

 Measure heat flow, temperature and thermal conductivity"

•  Thermocouple"
ΔV is electrical voltage
" ΔV = α sΔT αs is Seebeck coef. in [volts/K]
ΔT is temperature difference
•  Thermodiode"
kb is Boltzman constant
kB T ⎛ I ⎞ T is temperature
V= ln⎜ + 1⎟ q is charge on an electron
q ⎝ Is ⎠ I is operating current
Is is saturation current
Mechanical sensors"
Measurand Device Type
Displacement Capacitor
Velocity, flow Thermal microbridge
Acceleration Microresonator
Force, torque Microcantilever
Stress, pressure Silicon diaphragm
Strain Piezoresistor
Stiffness, compliance Microstructure
Mass, density Piezoelectric crystal
Shape, roughness STM (Scanning Tunneling Microscopy)
Viscosity Microbridge
Acoustic, ultrasound Microphone

Gardner et al. (2001), John Wiley & Sons Ltd.

Flow sensors"
•  Positive displacement flow meter"

•  Measuring weight of liquid using scale"

"

•  Pressure differential, Venturi meter"

" Q = v1 A1 = v 2 A2
ρ 2
( )
"
p1 − p2 = v 2 − v1
2

 "
2
•  Thermal flow sensor"
"
Ph Qm is mass flow rate
Qm = (T2 − T1 ) Ph is heat transfer per time
cm cm is specific heat capacity of fluid
Piezoelectricity"

Piezoelectric materials convert mechanical energy to electrical energy

and vice-versa"
Ø  Quartz"
Ø  Tourmaline"
Ø  Rochelle salt"
"
Linear effect where deformation is proportional to electric field:"

S is the mechanical strain

S = dE d is the piezoelectric coefficient
E is the electric field
Electrochemical detection"

Analysis of chemical solutions by measuring voltage, current and

charge in order to understand the composition of the solution
and the reaction kinetics of its components"

Ø  Potentiometry – no current flow, voltage measured relative to

reference electrode"
Ø  Voltammetry – using 3 electrode arrangement to measure
current flow as a function of electrode potential"
Ø  Conductometry – measure of electrical conductance of
electrolyte solution"
"
Applications in medicine"

} Thermometers for measuring temperature"

} Blood pressure monitors"
} Intraocular pressure monitoring for Glaucoma screening"
} Oximetry for measuring oxigen levels in blood"
} Spirometry for measuring pulmonary indices such as ling volume and
flow"
} Intravenous line for hospital patient drug and nutrient application"
} Cardiac pacemakers"
Microactuators"
 "
Microactuators"

Actuators are used in BioMEMS for microfluidic valve control,

pumping, positioning, alignment and medication dispensing"
"
} Electrical activation"
} Electromagnetic activation"
} Mechanical activation"
} Microactivators for microfluidics"
Electrical activation"

Electrical actuation depends on electrical properties of materials

to induce displacement or exert force"
"
" F is the Electrostatic force between two
2
" V eA oppositely charged plates
" Fx = 2 V is applied voltage
" 2d d is distance between plates
" e is the permittivity of air [F/m]
" A is the surface area of capacitor plates
Piezoelectric activation"
S is the mechanical strain
S = dE d is the piezoelectric coefficient
E is the electric field
Magnetic activation!
"
 " Lorentz forces

F = q[E + (v × B)]
F is the force on a point charge due to electromagnetic field [Newtons]
E is the electric field [volts/m]
B is the magnetic field [teslas]
q is the electric charge of the particle [coulombs]
v is the instantaneous velocity of the particle [m/s]
× is the vector cross product
Mechanical activation!
"
 "
Actuating forces Actuating mechanisms
Ø Displacement Ø Gears
Ø Velocity Ø Links
Ø Acceleration Ø Joint
Ø Rotational motion
Microactuators for microfluidics"
Ø Used for microvalve and micropump applications
 "
Ø Actuator performance a function of energy density
F * Δx E’ is energy density
E'= F is actuator force
V Δx is displacement
V is actuator volume
Thermomechanical
1 E is Young’s Modulus
E tm '= E(γΔT) 2
γ is thermal expansion coef
2 ΔT is temp difference

Piezoelectric
E is Young’s Modulus
1 E el Eel is Electric field strength
E pz '=
2 (d33 E) 2 d33 is piezoelectric coef
Microactuators for microfluidics"

 " Electrostatic
Eel is Electric field strength
1 ε is dielectric constant of medium between
E es '= εE el
2
ε = εr × ε0 the two electrodes
2 εr is relative dielectric constant
ε0 is permittivity of vacuum
Electromagnetic
2 B is magnetic flux density
E pz '=
1B µ = µr × µ0 µ is permeability of medium
2 µ µr is relative permeability of material
µ0 is permeability of vacuum
Drug delivery"
 "
Drug delivery"

} Current approaches"
} Microneedles"

} Micropumps"

} Microreservoirs"

} Biodegradable polymers"
Current approaches"

 " Ø Topically"
Ø Orally"
Ø Nasally"
Ø Subcutaneously"
Ø Intramuscularly"
Ø Intravenously"
Ø Via catheters"
"
Factors to take into account:"
Ø Dose, frequency, duration, toxicity "
Microneedles!
"
 "

Image ref: www.rsc.org

Micropumps!
"
 "

Cao et al. Sensors and Actuators A 94 (2001) 117-126

Microreservoirs!
"
 "

Santini et al, Nature 397, 335-338

Biodegradable polymers"

 "

Richards Grayson AC et al. J Biomed Mater Res A. 2004 Jun 1;69(3):502-12

Clinical laboratory use of
BioMEMS"
 "
Clinical laboratory use of BioMEMS"

} Chemistry"

} Hematology"

} Immunology"

} Microbiology"
Chemistry!
" ELISA
Used to detect presence of antibody in sample. Uses antigen-
antibody interaction that releases light upon binding.
(1) 
 " Capture antibody placed in
well
(2)  Sample is added, antigen
binds to capture antibody
(3)  Detection antibody added,
binds to antigen
(4)  Enzyme-linked secondary
antibody is added, binds to
detecting antibody
(5)  Substrate specific to
enzyme added, emitting
color
Chemistry!
"
Chemiluminescence
 "
Release of visible, ultraviolet or infrared light from released
energy of chemical reaction.

Image ref: www.howstuffworks.com

Hematology!
"Automated blood cell counter"
Performs automated blood cell counts."
Based on DC impedance spectroscopy."
(1)  Cells are suspended in electrolytic solution and drawn through small aperture"
(2)  As cells pass through aperture, they are detected as a change in conductivity
between electrodes"
(3)  Can be used to count cells, detect cell size and volume, determine size
distributions within cell populations"
Hematology!
"
FACS
Fluorescence Activated
Cell Sorting

Image ref: www.igem.org

Immunology!
" Based in antibody interactions
Antinuclear Antibody"
} Used
for detecting auto-antibodies directed against antigens in body, i.e. autoimmune
disorders. Uses fluorescent labeles antibodies for detection. "
"
Direct Antiglobulin tests"
} Used
for detecting the presence of immunoglobulin on red blood cells. Decreased levels of
immonuglobulin can signify an immunodeficiency disorder."

Indirect Antiglobulin tests"

} Used to detect antibodies to red blood cells in donor plasma."

Immunoelectrophoresis"
} Used
to identify a specific immunoglobulin in serum, urine or cerebro-spinal fluid by
using electrophoretic separation of proteins"

Immunofluorescence"
} Fluorescent labeled antibody to find specific antigen in specimens"
Microbiology"

Gram Stain"
} Infectious
agent placed on glass slide and stained followed by
morphological identification of stain, i.e. clusters, rods and color"

Bacterial culture"
} Biological
sample placed in Petri dish and incubated for further
species identification "
Detection"
 "
Detection"
Detection schemes"
} Colourimetric"
} Electrochemical"
} Nano-Particle based"
} Chemi- and Bio-Luminescence"
} Electrochemiluminescence"
} Fluorescence"

Detection systems"
} Confocal laser microscopy"
} Interferometry"
} SPR spectroscopy"
} TEM and SEM"
} AFM"
Detection Schemes"

 "
Electrochemical!
"
Measuring"
} Potential"

} Current"

} Charge"

To learn about composition

and reaction kinetics of
solution"

Bodner research group, Purdue University, IN

Electrochemical!
"

Current transients measured by

introduction of liquid into
microfluidic channel

Chen et al. Anal Chem. 2009 December 15; 81(24): 9955–9960I

Chemi- and Bio-Luminescence!
" Release of light from chemical reaction. No excitation source needed.
 "

Bacterial
Bioluminescence

Bioluminescence as function of
toxin concentrations

Makemson, Bacterial Bioluminescence lab, FIU

Glover lab, University of Aberdeen
Fluorescence"
Release of light due to excitation source. Dependent on excitation
 " wavelength.

Cellular fluorescence
after fluorescent
labeling.
Fluorescence"

 "

Cellular staining of adhered cells presenting adhesion peptide of interest

Koepsel et al Langmuir. 2009 November 3; 25(21): 12825–12834

Detection Systems"
 "
Confocal laser microscopy!
"
 "

Technique for obtaining high-

resolution optical images with
depth selectivity

Nikon Instrument A1 confocal laser scanning microscope

Interferometry!
" Uses interference patterns from the superposition of two or more
 "
electromagnetic waves to create image

Kurganskaya et al. http://cnx.org/content/m22326/1.4/

Waters at al APPLIED AND ENVIRONMENTAL MICROBIOLOGY, Mar. 2009, p. 1445–1449
SPR ( Surface Plasmon Resonance) spectroscopy!
"Techniques where surface electromagnetic waves (surface plasmons)
propagate through the contact plane of the metal-environment
interface. Used in BioMEMS to study ultra thin films and characterize
immobilized molecules in a BioMEMS device. "

Richens et al Respiratory Research 2009, 10:29

SEM (Scanning electron microscopy)!
"
Creates images by scanning a sample with a
 "
high-energy beam of electrons.

Images courtesy of www.wikipedia.org and Analytical Answers Inc.

TEM (Transmission electron microscopy)!
" Image is formed when a beam of electrodes goes through
and interacts with a thin specimen."

Department of Physics, UCF

Center for Biologic Counterterrorism and Emerging Diseases
AFM"
Instrument that creates an image of a surface as a laser detects small
 "
movements in an AFM cantilever tip as it interacts with the Van de
Waals forces of surface atoms.

Uppsala Universitet, Faculty of Pharmacy

Genomics"
 "
Genomics"

Part of genetics that is involved with the genomes of organisms. "

"
} Genome - hereditary information contained in the DNA. "

} DNA -
nucleic acid that contains the genetic instructions of an
organism. "
} Genomicsis involved in the understanding of DNA replication,
protein synthesis, gene expression, recombination of genetic material
and deals with advanced techniques as PCR and DNA sequencing."
} PCR"

} Gene expression profiling"

} DNA Microarrays"
PCR"

PCR - In vitro replication of

DNA sequences "
}  Millions of copies over a
short period."

Image ref: http://www.fei-online.com/

PCR"
}  Used for genetic analysis of any
organism that contains DNA "
}  To determine which genes are present
in a sample DNA"

Comparison of genes in sample 1, 2 and 3 (control)

Gene expression profiling"
Gene expression
profiling is used
to measure the
expression
(activity) of genes
present in
organism."
"
Heat maps show
gene expression
as a function of
experimental
conditions."
DNA Microarrays"

Allow for a high-throughput method of understanding gene existence and

expressions, mutations and bacterial and viral identification.

http://www.affymetrix.com/
Proteomics"
 "
Proteomics"

 Study of proteins including the stud of their abundance, distribution,

functions and interactions."
"
Proteins mediate gene regulation, enzymatic catalysis, cellular metabolism,
DNA replication and cell division."
"
Proteomics experiments consist of:"
1)  Protein preparation and analysis"
2)  Mass spectrometry"
3)  Bioinformatics"

Mass spectrometry - technique to measure the mass of particles, determine the

composition of a sample and the chemical structures of molecules."
"
"
Protein microarrays"

}  Used for high

throughput
study of protein
abundance and
function"

(a) Chips used for monitoring protein expression level, protein profiling and
clinical diagnostics. (b) used to analyse protein activities, binding properties and
post-translational modifications
Phizicky et al. Nature 422, 208-215(13 March 2003)
FDA and ISO"
 "
FDA and ISO"
}  FDA has “Good Guidance Practices” guidance reports for the
processing, content and evaluation of regulatory submission and the
design, production, manufacturing and testing of regulated products
and the inspection and enforcement of procedures. "
}  The guidance report refers to ISO 10993 for the biological evaluation
of medical devices. Medical devices are categorized by the nature of
contact with the body and include surface contact devices (skin,
mucosal membrane, breached or compromised surface), external
communicating devices (blood path, tissue, bone, dentin, circulating
blood) and implanted devices (tissue, bone and blood)."
}  This excludes Lab on a Chip and micro Total Analysis Systems used
in lab instrumentation, point-of-care systems or handheld devices
that DO NOT contact or penetrate skin and medical imaging devices."
FDA and ISO"
}  Biological evaluation tests of materials inside and outside of
device, including materials encountered during
manufacturing. These include manufacturing materials,
additives, contaminants, leachable substances and
degradation products:"
}  Cytotoxicity"
}  Sensitization"
}  Irritation/intracutaneous reactivity"
}  Acute system toxicity"
}  Genotoxicity"
}  Implantation"
}  Hemocompatibility"
}  Chronic toxicity"
}  Carcinogenecity"
}  Reproduction/development"
}  Biodegradation"
Emerging technologies"
 "
Minimally invasive surgery"

 Goal is to perform surgery with minimized intrusion, harm and risk to

patient. Results offer less pain, shorter hospital stays, faster recovery
and less scarring."
"
} Improve current surgical tools"
} New types of implants"
} Use electrical signaling to enhance sensation or movement"
} Stents"
} Operations through small holes rather than large incisions"
"
Point-of-care diagnostics"

 Development of biochips for clinical diagnostics at site of patient care,

rather than at an external laboratory. This streamlines results from
medical tests. May be used for at home testing."

} Miniaturization results in cheaper, smaller, faster tests"

} Fast result turnaround helps doctors make faster decisions"
} Faster reaction time to emergency condition"
"
"
"
"
Cardiovascular"

To maintain vigilance on patient health and to perform in-vitro research

and development of cutting edge cardiovascular therapies. "

} Miniaturized blood pressure monitors"

} Miniaturized blood flow monitors"
} In-vitro study of cardiac muscle function"
} Implantable, real-time monitoring of cardiac rhythm"
Diabetes"

Better point-of-care and in-home monitoring of patient health."

 "
} Continuous glucose monitoring"
} In-vitro analysis of glucose in blood microdrops"
} Future:
development of automated feed-back system for real-time
glucose monitoring and automated insulin injection "
Neuroscience"

To understand how brain works and controls body. Technology can

help patient care, diagnosis and rehabilitation."
"
} In vivo devices help measure intracranial pressure."
} In vivo probes help monitor neural activity."
} In
vitro microfluidic devices help understand neuronal control and
nerve regeneration."
} Prosthetics."

} Brain-computer interfaces – controlling your external environment

with thought."
Oncology"

To develop better and faster ways to detect and treat cancer. In vivo
systems allow for cancer screening. In vitro systems allow for
development of cancer treatments."
"
} High throughput cancer screening."

} High throughput and high sensitivity early detection methods."

} In
vitro systems for studying cancer, developing screening and
treatment technologies."
Ophthalmology"

To prevent sight loss in patients with ophthalmic diseases."

 "
} Ophthalmic implants for continuous intraocular pressure in glaucoma
patients"
} Stimulation of retinal nerve cells in patients with retinitis pigmentosa"
} Future:Retinal prosthetics where a man-made optical system delivers
electrical signals to retinal nerve to be converted into images by brain. "
"
"
"
Tissue Engineering"

}  Microfluidic
devices help in advancing tissue engineering by
providing the physical systems, such as scaffolds and nutrient delivery,
necessary to grow cells and study physiological responses to stimuli."
} Skin,
bone, cartilage, bladder, blood vessel and muscle tissue have
been engineered and grown in microfluidic devices."
Biosensors"
 Sensing environment using electrochemical, electrical or other
approaches. Used for detecting, identifying and sorting of organisms or
particles in bulk samples."

} Electrophoresis for separating particle/organism of interest from bulk

sample."
} Dielectrophoresis
for selectively sorting and trapping particle/
organism of interest from bulk sample."
} Ramanspectroscopy for high-throughput detection of explosive
residues in air or water."
} Microfluidic devices for detecting bacteria in sample."
} Piezoelectric sensors for chemical and biological detection."
Lab-on-a-Chip (LoC) and
micro-Total-Analysis
(uTAS) systems"
Lab-on-a-chip devices"

!Miniaturization at the micro- and nano-scale of

systems that deal with the sciences, physics, medicine,

engineering and materials science!

Lab on a Chip http://pubs.rsc.org"
Lab on a Chip http://pubs.rsc.org"
Lab on a Chip http://pubs.rsc.org"
Lab on a Chip http://pubs.rsc.org"
Lab on a Chip http://pubs.rsc.org"
Lab on a Chip http://pubs.rsc.org"
Lab on a Chip http://pubs.rsc.org"
Lab on a Chip http://pubs.rsc.org"
Lab on a Chip http://pubs.rsc.org"
Lab on a Chip http://pubs.rsc.org"
Lab on a Chip http://pubs.rsc.org"
Lab on a Chip http://pubs.rsc.org"
Lab on a Chip http://pubs.rsc.org"
Lab on a Chip http://pubs.rsc.org"
Lab on a Chip http://pubs.rsc.org"
Lab on a Chip http://pubs.rsc.org"
Lab on a Chip http://pubs.rsc.org"
Lab on a Chip http://pubs.rsc.org"
Lab on a Chip http://pubs.rsc.org"
Lab on a Chip http://pubs.rsc.org"
Lab on a Chip http://pubs.rsc.org"
Lab on a Chip http://pubs.rsc.org"
Book Reference"
Steven S. Saliterman (2006). Fundamentals of
BioMEMS and Medical Microdevices. Bellingham,
Washington: SPIE Press"