Saliterman, Fundamentals of BioMEMS and Medical Microdevices, Ch.

INTRODUCTION TO
BIOMEMS
Erik Johannessen, PhD
MN-BIO4600 Lecture 1
ErikJohannessen
RoomG221
eaj@hbv.no
31009385
 BioMEMS
Biomedical Micro Electro-Mechanical Systems
Special class of MEMS interacting with biological matter
measured
manipulated
integrated
as part of a transducer mechanism of a physical device under
any class of scientific study.

Interdisciplinary subject
biology
chemistry
physics
mechanical
electrical & electronic engineering
 Learning Objectives

Relate to the different scientific disciplines that encompass the

BioMEMS field.
Identify tools required to fabricate BioMEMS devices using both
traditional silicon microfabrication methodologies as well as the
use of soft lithographic processes.
Name key biochemical processes and structures in the cell and
describe how biological detection mechanisms may be used in the
field of BioMEMS.
Recognize the differences between biocompatibility and
biofouling, how these effects are triggered and how it may affect
device performance.
Describe the analytical advantages of BioMEMS, and their key
application areas within screening, diagnostics, monitoring, and
therapy.
1) MN-BIO4600 Introduction to BioMEMS
2) B31QC Micro & Nano Biological Systems

10 credit course running in the spring semester:

Lectures (20 x 2 hours + 4 x 2 hours optional tuition/problem solving)
Laboratories (4 x 3 hours) + Home (project) assignment
Written exam (5 hours)

Curriculum:
Introduction to BioMEMS
Principles of Biochemistry
Silicon and Soft Fabrication Techniques
Microfluidic Principles
Sensor Principles and Microsensors
Microactuators and Drug Delivery
Micro-Total-Analysis Systems
Genomics and DNA Microarrays
Proteomics and Protein Microarrays
Emerging BioMEMS technologies
Packaging, Power, Data, and RF Safety
ISBN: 9780819459770
Biocompatibility, FDA and ISO 10993
 Reading List

Author Title Publisher Year ISBN no Curriculum

Steven S. Fundamentals of SPIE Press 2006 978- Ch. 1-15

Saliterman BioMEMS and Medical 0819459770 (610 pages)
Microdevices
Mathews, Van Biochemistry, 3rd ed. Addison Wesley 2000 978- Ch. 1 (p. 2-20)
Holde and 0805330663 Ch. 4 (p.84-91)
Ahern Ch. 5 (126-147)
Ch. 9 (278-279)
Ch.10 (315-326)

Johannessen Home assignment 2015 TBA

Johannessen Laboratory exercises 2015 TBA

 Assessment
Laboratories: Group (peer-controlled) work (2-4 students).
Deliverable: Individual report (2-4 pages) containing the sections:
(i) introduction, (ii) material &methods, (iii) results, (iv) discussion
and (v) conclusion. A template available at the course website.
Assessed upon delivery as pass or fail. These would need to
be approved with a pass in order to sit the exam

Home assignment: Group (peer-controlled) work (2-4 students).

Deliverable: CAD design + 1 page description of the device (.GDS
and names of the group participants (file name + design)). The
design will be incorporated on a glass mask produced externally
and used for the subsequent laboratory in microfabrication.
Assessed upon delivery as pass or fail. Would need to be
approved with a pass in order to sit the exam
 Assessment

Exam: Written examination, spring, 5 hours, 100%.

The exam will reflect the course content (curriculum and lecture
slides) as well as the work related to the laboratories and home
assessment (see reading list).
 Lectures
Time/Day Monday Tuesday Wednesday Thursday Friday Saturday Sunday
0800 08151145
MNBIO4600
0900 D3107
B144
1000 D272
C396
1100
Lunch
1200
1300

1400 12151355
MNBIO4600
1500 B144

1600
1700
 Course Plan Spring 2017
Week Date Topic Misc.
1 2-6. Jan Enrolment / start of semester

2 9-13. Jan Introduction to BioMEMS

Microfluidic Principles, Part I
3 16-20. Jan Microfluidic Principles, Part I/II

4 23-27. Jan Microfluidic Principles, Part II Home Assignment

(Microfluidic system)

5 30. Jan -3. Feb Principles of Biochemistry

6 6-10. Feb Silicon and Soft Fabrication Deadline, Home

Techniques assignment
7 13-17. Feb Polymer Materials

9 27. Feb -3. March Sensor Principles and Microsensors

10 6 10.March Microactuators and Drug Delivery Laboratory 2
(Microfabrication)
11 13-17. March Clinical Laboratory Medicine

12 20-24. March Micro-Total-Analysis Systems

13 27- 31. March Detection and Measurement Methods Laboratory 3

(Replica moulding)
14 3 7. April Genomics and DNA Microarrays

15

16 18-21. April Proteomics and Protein Microarrays Laboratory 4

(Microfluidic titration)
17 24-28. April Emerging BioMEMS technologies

18 2-6. May Biocompatibility, FDA & ISO 10993

19 8.-12. May Reserve

20

21 xx. May BIO4600/B31QC Examination Day

B31QC, Laboratory Group Members

Group 4 Group 6
Adakhamjonov Ikboljon Ahmed Jamal
Damys Nuk Latas Jaime
Parajuli Madan Potekhina Alissa
Astarlioglu Taner Aziz

Group 5 Group 7
Ahmed Doha Al - Sakkaf Ahmed Gaafar
Haque Md Ehtashamul Marques Abelardo Caraveo Daniel
Pejovic Vladimir Solis Villegas Erick Osvaldo
Andreas Emil Niemi
 Home Assignment
Design of a microfluidic system

Fig. 1: Illustration of a
photolithography
Requires the maskuse of L-Edit
Lecture Halls
D2-72 D3-107
Thursday, 16th Feb Thursday, 12th Jan

X X

C3-96
Thursday, 27th April

X
B1-44
Mondays
Thursday 19th Jan 9th Feb
Laboratory, D2-43

X
Laboratory, G2-33

X
BioMEMS
 BackgroundBackground

Biology Engineering

Nano Macro
Analytical Techniques
(sensing, measurement, manipulation)
Metres

10-9 10-8 10-7 10-6 10-5 10-4 10-3 10-2 10-1 1

DNA Proteins Cells Organs

RNA Organelles Whole body

Genomics Proteomics Screening Effect

Opportunities:

Drug Discovery
Diagnostics
Better treatment

All part of the information age

 Revolution

Microelectronics
industry

Discrete components Integrated Circuits

Analytical
chemistry

Biochemical laboratory Lab-on-a-Chip

 Why make it small?

x2 cube (x) volume time (t)

t
2D 1 mm 1 L 500 s

100 m 1 nL 5s

10 m 1 pL 50 ms

x D = 10 -5 cm -2 s -1

Smaller,reducedcost,power&reagentconsumption
Increasedsurface:volumeratio
Controlofheatflux(rapidheating&cooling PCR)
Miniaturisesensortosystemunderinvestigation
 Microfabrication
Based on precision lithography and mask
production from MEMS.

Micromachining
Additive processes (deposition)
Evaporation (physical/chemical)
Sputtering
Electroplating
Oxidation
Subtractive processes (etching)
Chemical dry etch (gas)
Chemical wet etch (liquid)

Substrate bonding

Dicing and packaging

Emphasis on:
Silicon
Glass Surface science
Polymers & microfluidics
Ceramics

Fig 1: Cleanroom (UC Berkeley)

 Nanofabrication
Merger of two approaches:
Top-down manufacture
Isometric scaling:
Change in size does not change
proportions
Allometric scaling:
Scaling that deviates from isometry

Bottom-up manufacture
Nanochemistry
The construction of nanodevices
Biomimetric approach
Self assembly
Massive parallel direct assembly
Molecular mechanisms

Fig 2: Isometric scaling with top-down manufacture. Direct assembly of

atoms/ molecules in bottom-up manufacture.
Components&
FocusPoints
 Biosensors

Fig 7: Elements and selected components of a typical biosensor (Grieshaber, Sensors 2008, 8, 1400).
 MicroelectronicsArchitecture
1 mm

Integratedcircuits
Applicationspecificintegrated
circuit(ASIC)
Ultralowpower~2W
Chipsize~1x1mm2
Gatetechnology<90nm
Weakinversion
Operatingvoltage~1volts
Inductivepowerand
communicationslink
Analoguefrontend(sensors),
voltagereference,ADC,buffer,
rectifiers,shifterandoffset/noise
cancelling.
Digitalbackend(datastorageand
Fig. 10: System architecture, ASIC. transmission)
 Microfluidics

Science of fluid behavior in

microchannels
Sample preparation and
analysis on chip
Microreservoirs
Microchannels
Microfilters
Microvalves
Micropump
Microneedles
Microreaction chambers

Fig 11: Chip with integrated microfluidics

 Packaging
Micro-Total-Analysis-Systems (TAS)

Full integrated autonomous unit.

Increased efficiency through smaller scales.
One or several sensor functions.
Microactuator controlled sampling/liquid handling.
ASIC/Microprocessor controlled operation.
Optional microfluidic network.
Network oriented and small.

Fig 15: Implantable TAS glucose monitor

 Biocompatibility

Biocompatibility testing
answers two
fundamental questions:

1) Is the material safe

2) and does it have the

physical and mechanical
properties for its
proposed function?

Fig 17: Complement activation of selected biomaterial candidates as measured

by enzyme-linked immunosorbentassays (ELISA)
Applications
Research

10 mm
 Lab on a Chip

Technical Data:
Autozero
Vn = 8.5 nV Hz-0.5
from dc - 1 kHz
Battery powered
Integrated incub.
Microscope stage

Fig 32: Nanocalorimeter for cell based primary screening of drugs

 Cell based screening

Employ living cells as part of

sensory action

Cell sized transducers

Identifies drugs as function

of changes in the metabolic
rate

Metabolic rate mirrors the

activity of the nanomachines

Fig 25: Metabolic response from cell based primary screen assay for novel drug discovery.
 Lab in a Pill

10 mm

Fig 33: Electronic pill for gastro intestinal analysis.

 Lab in a Pill

iPill(Philips)
Controlledreleaseof
medication.
Microprocessor
controlled
Wirelessradio
Pump
Drugreservoir

Fig 34: Electronic pill for gastro intestinal drug delivery.

 Lab in a Pill
A) Microprocessor
(location based on
temp and pH)
B) pH Sensor
C) Temperature
sensor
D) Fluid pump (motor
& screw rod driven
piston)
E) Wireless
transceiver
F) Battery (silver
oxide, 48 h)

Fig 35: Components of the iPill.

 Commercial Product:
Video Pill
Injection moulded
polymer capsule

Gastro/Endoscopy

Cost: $ 200-250

Size: 11x21 mm
21 mm Embedded CCD

Rate: 2 frames/s

Lifetime: 8 hours

Wireless transmission

Disposable

Excreted naturally
after use

11 mm
Fig. 36, Given Imaging, Israel, PillCamTM
Implantable sensors: Glucose

Fig 44: GLUCOSENS - Subcutaneous implantable

continuous osmotic glucose sensor
 Glucose Fuel Cell

Fig 5: CLUCOCELL Harvesting

power from the catalysis of glucose.
 High throughput screening (HTS)
Starting point for drug design
or to understand a particular
biochemical process
Rapid parallel identification of
bioactive components:
Genes
Proteins
Antibodies
Primary screen:
Unspecific biomolecular
pathway
Secondary screen
Specific biomolecular pathway
96 3456 well plates
Fig 18: Standard 96 well microtitre plate.
 Microfluidic systems

Fig 1: Dolomite PDMS chip interface (Dolomite Microfluidics).

 Particle separator

Fig 40: Lab-on-a-chip microfilter for pathogen separation and up-concentration

 Microarrays

Fig 19: Batch fabrication on common polymeric substrate.

 Identification of hybridisation

Fig 23: Hybridisation is indicated with a white spot in the 500k large array (RHS).
 Tissue Engineering
Printing a 3D-tissue scaffold
(incl. cells) layer by layer.
Integration of BioMEMS units
that monitor organ/tissue
physiology
Early onset warning of tissue
rejection or organ failure
Synthetic Organs:
Heart
Liver
Kidneys
Endocrine glands
Bladder
Blood vessels

Fig 27: 2D layer by layer printing of 3D organ (Heart).

 Microneedles

Fig 29: Silicon microneedles for painless transcutaneous sampling/injection.

 RFID-tags

IDchipsusedinpets
Hermeticallysealed
Sodalimeglasshousing
Diameter:1.25mm
Length:7mm
Readrange:90mm
Containidentificationcode
uniqueforyourpet

Fig 37: ID-100A(1.25) Nano Transponder, Trovan Ltd.

 Camera
Retinal Implants (prior art)

Microcontroller, stimulator, data recovery

and power recovery units

Alireza Zabihian et al. Implantable Biomedical Devices. In: Biomedical Engineering Microelectrode (Utah) Array
Technical Applications in Medicine, ISBN: 9789535107330, 2012, p.420.
Restored vision

Alireza Zabihian et al. Implantable Biomedical Devices.

In: Biomedical Engineering Technical Applications in
Medicine, ISBN: 9789535107330, 2012, p.420.
 Unmanned Aerial Vehicles (UAVs)

Fig 46: The nano hummingbird UAV by Aerovironment (TIMEs 50 best innovations 2011).
 Cyborg beetles

Cyborg beetles
flight control by neural
stimulator
Brain/machine interface
Adult Neural Progenitor
Cells (cell contact and
differentiation)
Microneural interface
direct recording from the
invertebrate eye

Fig 47: Remote controlled Cyborg beetles Michel Maharbiz UC Berkeley.

Cochlear Implant

Fig 48: Cochlear implant hearing aid.

 Neuroscience
Neural recording / brain activity

Fig 48: Recording brain waves by EEG (ElectroEncephaloGraphy)

 Neuroscience
Deep Brain neural recording / stimulation

Fig 48: Deep brain stimulation/recording by implantable electrodes

 Summary
Biomedical Micro Electro-Mechanical Systems
Topics of study (curriculum):
Introduction to BioMEMS
Principles of Biochemistry
Silicon and Soft Fabrication Techniques
Polymer Materials
Microfluidic Principles
Sensor Principles and Microsensors
Microactuators and Drug Delivery
Clinical Laboratory Medicine
Micro-Total-Analysis Systems
Detection and Measurement Methods
Genomics and DNA Microarrays
Proteomics and Protein Microarrays
Emerging BioMEMS technologies
Packaging, Power, Data, and RF Safety
Biocompatibility, FDA and ISO 10993
 Thank you

Erik Johannessen, tel: 31009385, eaj@hbv.no