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School of Biomedical Engineering, Science and Health Systems

V 1.0 [MS010517]


Biosensors

Initiative Collage

Drexel University

Philadelphia, PA

www.biomed.drexel.edu

Ryszard Lec

Professor of Biomedical
& Electrical Engineering

School of Biomedical Engineering, Science and Health Systems

V 1.0 [MS010517]


Nano
-
Biosensor Science, Engineering
and Technology
: The Challenges


Attain a fundamental understanding of nanoscale
biosensing phenomena.


Design and fabricate biologically active sensing
interfaces:
DNA, proteins, cells, tissues, other.


Design and fabricate solid
-
state based transducer
structures capable of simultaneous detection of multiple
biological substances and processes:
biosensor chips,
biosensor arrays, other.


Novel theoretical and experimental tools for a rapid
development of the Nano
-
Biosensor technology.


Integration of biological, physical (mechanical, optical,
acoustic) and electronic components into
multifunctional biosensor systems:
novel immobilization
techniques; solid
-
state transducer nano/microfabrication
technologies; microfluidic systems; IC circuits for signal
conditioning and processing; smart biosensors and
biosensor systems.

0
5
10
15
20
25
30
0
50
100
150
200
250
300
Time in Minutes
Amplitude in dB
Endothelial Cell Proliferation

Sedimentation, adhesion, and proliferation
of Endothelial Cell Proliferation

Deposition of super collagen on the gold
surface in 0.1 mol of HCl solution

Sedimentation

Adhesion

Proliferation

School of Biomedical Engineering, Science and Health Systems

V 1.0 [MS010517]


Nano
-
Biosensor Science, Engineering and Technology

Objective: Development of Piezoelectric Nano
-
Biosensor
Technology Platform

Important Features:


Multidomain Piezoelectric Sensing Mechanisms:

mass,

viscosity, elasticity, electric conductivity, and dielectric

constants.



Real
-
time Piezoelectric Monitoring of Interfacial

Biological Phenomena:

the depth of monitoring ranges

from a single to hundreds nanometers with the time resolution

of milliseconds.



Piezoelectric Biotransducer Technology:

IC compatible,

MEMS/NEMS; sensing and actuating; multiple
-
sensing
-


wave transducers, piezo
-
bio
-
chips and arrays, other.



Bio
-
Piezo
-
Interfaces:

design and synthesis of surfaces at the

atomic level to produce sensing interfaces with desired

properties and functions.



Integrated Electronic Signal Processing and Display

Technologies:
fast, miniature, inexpensive, reliable.



Smart Biosensors:
self
-
calibration, self
-
diagnostic,

self
-
repair, other.

Electrode
Piezoelectric Quartz
x
y
ASW
Frequency
10 kHz
1 MHz
100 MHz
Penetration
Depth
δ
~
10
μ
m
~
1
μ
m
~
0.1
μ
m
Electrode
Excitation
Voltage
)]
(
exp([
)
exp(
y
V
t
i
y
u
x
u
x
o
















2
,
2
1



x
V
Liquid
(H
2
O)
ASW
Frequency
5 MHz
Penetration
Depth
δ
0.5
μ
m
Decay of Acoustic
Shear Wave
(Envelope)
Displacement
Solid/Liquid Interface
(Boundary Conditions)
Air
Electrode
Piezoelectric Quartz
x
y
ASW
Frequency
10 kHz
1 MHz
100 MHz
Penetration
Depth
δ
~
10
μ
m
~
1
μ
m
~
0.1
μ
m
Electrode
Excitation
Voltage
)]
(
exp([
)
exp(
y
V
t
i
y
u
x
u
x
o
















2
,
2
1



x
V
Liquid
(H
2
O)
ASW
Frequency
5 MHz
Penetration
Depth
δ
0.5
μ
m
Decay of Acoustic
Shear Wave
(Envelope)
Displacement
Solid/Liquid Interface
(Boundary Conditions)
Air
Piezoelectric Quartz
Excitation
Voltage
First
(Fundamental)
Third
Fifth
Seventh
.
.
Decay of Acoustic
Shear Wave
(Envelope)
Air
Harmonic Frequency
Liquid
(H
2
O)
Piezoelectric Quartz
Excitation
Voltage
First
(Fundamental)
Third
Fifth
Seventh
.
.
Decay of Acoustic
Shear Wave
(Envelope)
Air
Harmonic Frequency
Liquid
(H
2
O)
Top View
Electrode
Cross Section
Array Transducer Design
Piezoelectric Crystal
Top View
Electrode
Cross Section
Array Transducer Design
Piezoelectric Crystal
PNBS

Frequency

1 MHz

100 MHz

1 GHz

PNBS

Frequency

500 MHz

980 nm

98 nm

28 nm

Penetration
Depth

37 nm

10 MHz

100 MHz

1 GHz

Shear
-
Mode Piezo
-
Biosensor (Fundamental)

Shear
-
Mode Piezo
-
Biosensor (Harmonics)

Piezo
-
Bio
-
Array

School of Biomedical Engineering, Science and Health Systems

V 1.0 [MS010517]


Nano
-
Biosensor Science, Engineering and Technology

Objective: Novel Applications of Piezoelectric Nano
-
Biosensor Technology

Vector

Voltmeter

System

Impedance

Meter

Time

Domain

Analyzer

Control

Signal

Processing

Data Acquisition

and Control

Computer

Magnitude Display

Phase Display

Signal

Receiver

-
1.20E+02

-
1.00E+02

-
8.00E+01

-
6.00E+01

-
4.00E+01

-
2.00E+01

0.00E+00

2.00E+01

4.00E+01

6.00E+01

8.00E+01

1.00E+02

4.97E+06

4.98E+06

4.99E+06

5.00E+06

5.01E+06

5.02E+06

5.03E+06

5.04E+06

-
8.00E+01

-
7.00E+01

-
6.00E+01

-
5.00E+01

-
4.00E+01

-
3.00E+01

-
2.00E+01

-
1.00E+01

0.00E+00

4.97E+06

4.98E+06

4.99E+06

5.00E+06

5.01E+06

5.02E+06

5.03E+06

5.04E+06

Portable Measurement System

Oscillator, Phase Lock Loop System

(T, RH,C0

2

, pH, etc.)

Measurement

Signal Out

Liquid Chamber

Piezoelectric Crystal

Electronic

Compartment

Liquid

Flow

System

Signal

Generator

Network Analyzer

-
1.20E+02

-
1.00E+02

-
8.00E+01

-
6.00E+01

-
4.00E+01

-
2.00E+01

0.00E+00

2.00E+01

4.00E+01

6.00E+01

8.00E+01

1.00E+02

4.97E+06

4.98E+06

4.99E+06

5.00E+06

5.01E+06

5.02E+06

5.03E+06

5.04E+06

-
8.00E+01

-
7.00E+01

-
6.00E+01

-
5.00E+01

-
4.00E+01

-
3.00E+01

-
2.00E+01

-
1.00E+01

0.00E+00

4.97E+06

4.98E+06

4.99E+06

5.00E+06

5.01E+06

5.02E+06

5.03E+06

5.04E+06

Measurement Cell

2

Temperature

Signal In

Signal Out

Liquid Chamber

Piezoelectric Crystal

Electronic

Compartment

-

antigen

-

antibody


DNA sensors/chips:

genetic screening and diseases, drug testing,
environmental monitoring, biowarfare, bioterrorism, other.



Immunosensors:

HIV, hepatitis, other viral diseases, drug
testing, environmental monitoring, biowarfare, bioterrorism, other.




Cell
-
based sensors:

functional sensors, drug testing,
environmental monitoring, biowarfare, bioterrorism, other.



Point
-
of
-
care sensors:

blood, urine, electrolytes, gases, steroids,
drugs, hormones, proteins, other.



Bacteria sensors
(E
-
coli, streptococcus, other): food industry,
medicine, environmental, other.



Enzyme sensors:

diabetics, drug testing, other.



Market:
clinical diagnostic, environmental monitoring,
biotechnology, pharmaceutical industry, food analysis, cosmetic
industry, other.




* Immunosensors: about 1 billion annually



* DNA probes: about 1.5 billion annually

Integrated Laboratory System for Testing
and Calibration of Piezoelectric Biosensors

School of Biomedical Engineering, Science and Health Systems

V 1.0 [MS010517]


Top View
Electrode
Cross Section
Array Transducer Design
Piezoelectric Crystal
Top View
Electrode
Cross Section
Array Transducer Design
Piezoelectric Crystal
Nano
-
Biosensor Research Laboratory

Project Title: Sensing Principles of Piezoelectric Nano
-
Biochemical Sensors (PNBS)

Michael Francois (Ph.D), Sun Jong Kwoun (MS Student)

Advisors: Dr. Ryszard M. Lec, Dr.
Kambiz Pourrezaei

Electrode
Piezoelectric Quartz
x
y
ASW
Frequency
10 kHz
1 MHz
100 MHz
Penetration
Depth
δ
~
10
μ
m
~
1
μ
m
~
0.1
μ
m
Electrode
Excitation
Voltage
)]
(
exp([
)
exp(
y
V
t
i
y
u
x
u
x
o
















2
,
2
1



x
V
Liquid
(H
2
O)
ASW
Frequency
5 MHz
Penetration
Depth
δ
0.5
μ
m
Decay of Acoustic
Shear Wave
(Envelope)
Displacement
Solid/Liquid Interface
(Boundary Conditions)
Air
Electrode
Piezoelectric Quartz
x
y
ASW
Frequency
10 kHz
1 MHz
100 MHz
Penetration
Depth
δ
~
10
μ
m
~
1
μ
m
~
0.1
μ
m
Electrode
Excitation
Voltage
)]
(
exp([
)
exp(
y
V
t
i
y
u
x
u
x
o
















2
,
2
1



x
V
Liquid
(H
2
O)
ASW
Frequency
5 MHz
Penetration
Depth
δ
0.5
μ
m
Decay of Acoustic
Shear Wave
(Envelope)
Displacement
Solid/Liquid Interface
(Boundary Conditions)
Air
PNBS

Frequency

1 MHz

100 MHz

1 GHz

980 nm

98 nm

28 nm

PNBS

Frequency

500 MHz

37 nm

Piezoelectric Quartz
Excitation
Voltage
First
(Fundamental)
Third
Fifth
Seventh
.
.
Decay of Acoustic
Shear Wave
(Envelope)
Air
Harmonic Frequency
Liquid
(H
2
O)
Piezoelectric Quartz
Excitation
Voltage
First
(Fundamental)
Third
Fifth
Seventh
.
.
Decay of Acoustic
Shear Wave
(Envelope)
Air
Harmonic Frequency
Liquid
(H
2
O)
10 MHz

100 MHz

1 GHz

1
10
100
1000
1
10
100
1,000
10,000
Freq. (MHz)
Fig. 1. PNBS operating at the fundamental frequency

Fig. 2. PNBS operating at the harmonic frequencies

Fig. 3. Probing depth of the PNBS as a function of frequency

Fig. 4. A PNBS Biochip

Penetration

Depth

[nanometers]

School of Biomedical Engineering, Science and Health Systems

V 1.0 [MS010517]


Nano
-
Biosensor Research Laboratory

Project Title: A Novel Polymer Nanofiber Interface


for Biochemical Sensor Applications

Sun Jong Kwoun (MS Student)

Advisors: Dr. Ryszard M. Lec (Biomed.), Dr.
Frank K. Ko (Material Eng. Dept.)

NF Sensor

Air

Fig. 1. Photograph of the TSM sensor
with deposited nanofiber film.

Fig. 2. SEM picture of the nanofiber

film at 6000X magnifications.

Fig. 3. Cell growth on nano fibrous matrix (after 1 day).

Fig. 4. The S
21

amplitude of the nanofiber deposited sensors
in air as a function of frequency for five different deposition
time (corresponding to different NF film thickness).

Fig. 3. Endothelial cell attached
to the nanofiber matrix.

School of Biomedical Engineering, Science and Health Systems

V 1.0 [MS010517]


Nano
-
Biosensor Research Laboratory

Project Title: Piezoelectric Biosensor for Monitoring the Interaction of



a single cell with solid surfaces: Endothelial Cell on Gold Surface

Qiliang Zhang (Ph.D student)

Advisors: Dr. Ryszard M. Lec (Biomed), Dr.
Kambiz Pourrezaei (ECE)

k

r

R

Equivalent Electromechanical Circuit

Nano
-
Microparticle
-
Cell

m



mass

k



effective elasticity
representing interfacial
bonding energy

r



dissipative losses

Piezoelectric Sensor:

M



mass

k



elasticity

r



dissipative losses

Frequency (MHz)

Reference Sensor Response

Sensor Response with a
Nanoparticle


f

10.00000

10.10000

Amplitude


Piezoelectric Sensor

Nano
-
Microparticle
-
Cell on
the surface of the sensor

Piezoelectric Sensor

Piezoelectric Sensor

Piezoelectric Sensor

High

Frequency
Excitation

Nano
-
Microparticle
-
Cell
on the surface of the sensor

School of Biomedical Engineering, Science and Health Systems

V 1.0 [MS010517]


Nano
-
Biosensor Research Laboratory


Project Title:

Piezoelectric Nano
-
Biosensor for Monitoring Interfacial Cell Processes:


Endothelial Cell Properties such as sedimentation, adhesion, proliferation and fixation



Students:
Vadivel Devaraju, (PhD) and Joe Sorial, (MS)

Faculty:

Dr. Ryszard M. Lec and Dr. Kenneth Barbee

Solution
Electrode
Brass housing
Piezoelectric
Plate
O
-
ring
Solution
Electrode
Brass housing
Piezoelectric
Plate
O
-
ring
Electrode
Brass housing
Piezoelectric
Plate
O
-
ring
Figure 1
. (a) Sedimentation, adhesion and proliferation profile of endothelial cells as a function of time measured



using 25 MHz piezoelectric resonant sensor + the caption for the second picture

Sedimentation

Attachment

Proliferation

5MHz

15MHz

Fixation

Fixation


School of Biomedical Engineering, Science and Health Systems

V 1.0 [MS010517]


Nano
-
Biosensor Research Laboratory


Project Title:

Piezoelectric Nano
-
Biosensor for Monitoring Interfacial Protein Processes



Student:
Vadivel Devaraju, (PhD)


Faculty:

Dr. Ryszard M. Lec and Dr. Andrew Fertala

Deposition of Collagen on the gold surface
(50ul of Collagen in 0.1mol of Hcl)
Frequency Response at Fundamental Frequency
9.97
9.975
9.98
9.985
9.99
9.995
10
10.005
10.01
10.015
0
50
100
150
200
250
300
Time in Minutes
Frequency in MHz
Deposition of Collagen on the gold surface
(50ul of Collagen in 0.1mol of Hcl)

Amplitude Changes at Fundamental Frequency
0
10
20
30
0
50
100
150
200
250
300
Time in Minutes
Amplitude in
dB
Deposition of Collagen on the gold surface
(50ul of Collagen in 0.1mol of Hcl)
Phase Variation at Fundamental Frequency
0
20
40
60
80
100
0
50
100
150
200
250
300
Time in Minutes
Phase in Degree
Electrode

Piezoelectric Quartz

x

y

Electrode

Excitation

Voltage

PNBS

Frequency

10 MHz


Probing

Depth

178 nm



Decay of Acoustic

Shear Wave

(Envelope)

Displacement

Solid/Liquid Interface

(Boundary Conditions)

School of Biomedical Engineering, Science and Health Systems

V 1.0 [MS010517]


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School of Biomedical Engineering,

Science & Health Systems