DOW-UAP-D136, AAWSAP DIRD, Biosensors and BioMEMS: A Survey of the Present Field, March 2010

This document is a Defense Intelligence Reference Document (DIRD), a technical reference format used by the Defense Intelligence Agency (DIA) to capture baseline knowledge on a specific topic for later analytic use. DIRDs are best understood as reference and synthesis products rather than as original research. It is one of 38 DIRDs produced under the Advanced Aerospace Weapon System Applications Program (AAWSAP) between 2009 and 2011. Because AAWSAP’s scope permitted a broad range of supporting topics, not every DIRD in the series directly concerns aerospace systems or future threat assessment. The following summary reflects the DIRD’s scope and framing at the time of writing and should not be read as implying current validation of the concepts discussed. This DIRD surveys biosensors and BioMEMS, a broad class of miniature biomedical devices that combine microscale engineering with sensing, fluid handling, stimulation, or drug-delivery functions. The report reviews major application areas including implantable blood-chemistry sensors, neural interfaces, neurostimulation, drug-delivery pumps, microfluidic systems, and emerging nanoscale extensions of the field, while emphasizing that miniaturization can improve sensitivity and enable functions that are difficult or impossible at larger scales. However, it also makes clear that practical development is constrained by biocompatibility, long-term stability, sensor drift, device degradation inside the body, and the high regulatory burden associated with implantable medical systems. The document presents BioMEMS as a rapidly growing and productive field whose future advances are likely to come through continued improvements in fabrication, materials, and reliability.

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Defense
Intelligence
Reference
Document
Acquisition Threat Support
31 March 2010
ICOD: 1 December 2009
DIA-08-1003-020
Biosensors and BioMEMS: A
Survey of the Present Field
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Biosensors and BioMEMS: A Survey of the Present Field
Prepared by:
Acquisition Support Division (DW0-3)
Defense Warning Office
Directorate for Analysis
Defense Intelligence Agency
Author:
AAP Person 65
Administrative Note
COPYRIGHT WARNING: Further dissemination of the photographs in this publication is not authorized.
This product is one in a series of advanced technology reports produced in FY 2009
under t he Defense Intelligence Agency, Defense Warning Office's Advanced Aerospace
1
Weapon System Applications (AAWSA) Program. Comments or uestions pertaining to
this document should be addressed to!AAP Person 1 , AAWSA Program
Manager, Defense Intelligence Agency, ATTN: CLAR/DWO-3, Bldg 6000, Washington,
DC 20340-5 100.
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Contents
Introduction ........................................................................................................... vi
What is BioMEMS? .................................................................................................. 1
Characteristics of BioMEMS ................................................................................ 2
Categories of BioMEMS ....................................................................................... 3
BioMEMS Micromachines ........................................................................................ 3
Brain-Implanted BioMEMS Micromachine Neuroelectrodes ................................ 4
Fluidic BioMEMS ..................................................................................................... 6
Drug-Delivery Pumps ......................................................................................... 7
What is a Biosensor? .............................................................................................. 9
BioMEMS Implantable Sensors ............................................................................. 10
MEMS Blood Glucose Sensors ............................................................................... 13
Commercial Blood Glucose Sensors .................................................................. 14
Enzyme-Based Biosensors................................................................................ 14
Thermopile Implantable Glucose Sensors ........................................................ 15
Neuroengineering by BioMEMS............................................................................. 20
Bioelectric Events............................................................................................. 20
Bionics and Neurointerfaces................................................................................. 22
Bioelectrodes and BioMEMS ............................................................................. 22
Microelectrode Array Fabrication ..................................................................... 24
Brain-Machine Interfaces ................................................................................. 25
Polymer BioMEMS Electrodes ........................................................................... 26
Retinal Devices Using BioMEMS........................................................................ 27
Microscale in Therapeutic Neurostimulation..................................................... 30
MEMS in Microfluidics........................................................................................... 32
Lab Chips ......................................................................................................... 33
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NASA Space Applications for Microfluidic Systems ........................................... 34
Microcantilever MEMs Sensors ............................................................................. 36
Conclusion............................................................................................................ 39
Figures
Figure 1. Varieties of BioMEMS and Sensors........................................................... 2
Figure 2. Functional MEMS Micromachines Attached to Sensing Bioelectrodes....... 5
Figure 3. Schematic Diagram of a MEMS Motor Complete With a Method of
Converting Oscillatory Motion to Linear Motion ....................................... 5
Figure 4. Illustration of the Basic Physical Principle of the BioMEMS Motor ........... 6
Figure 5. Close-up Views of the Micro-Motor Gear .................................................. 6
Figure 6. An Insulin MEMS Pump............................................................................ 8
Figure 7. An ISFET (Ion Sensitive Field Effect Transistor) Needle-Type pH Sensor
for Monitoring Tissue Physiologic Status ............................................... 11
Figure 8. A Fiber Optical Oxygen Sensor .............................................................. 12
Figure 9. Control of an Insulin-Delivery System by an Implantable Glucose
Sensor ................................................................................................... 13
Figure 10. Glucose Oxidase .................................................................................. 14
Figure 11. An Experimental MEMS Blood Glucose Sensor ..................................... 15
Figure 12. Photomicrograph ................................................................................. 16
Figure 13. A MEMS Thermopile Glucose Sensor .................................................... 17
Figure 14. Illustration of the Thermocouple Principle .......................................... 18
Figure 15. Thermopile Glucose Sensor (left) With Functional Illustration (right)
are Made Using Photolithographic Techniques .................................... 19
Figure 16. Photograph and Illustration of the Thermopile Glucose Sensor in a
Catheter .............................................................................................. 19
Figure 17. A MEMS Biopotential Electrode System................................................ 20
Figure 18. A Neural Cell Showing Dendritic Inter-Connections That are Electrically
Active With Other Cells........................................................................ 21
Figure 19. A Neuroprosthetic Interface ................................................................ 22
Figure 20. Scanning Electron Micrograph of a Brain Electrode Array Manufactured
From Titanium and Produced by a Process of Electrodischarge
Machining............................................................................................ 23
Figure 21. Scanning Electron Micrograph of a 1141 Electrode Array Made to Be
Inserted Into the Surface of the Human Brain .................................... 25
Figure 22. Polymer Based Cortical Penetrating Neuroelectrodes Made by Processes
of Thin Film Deposition and RF Etching ............................................... 26
Figure 23. A MEMS Microelectrode Array Implanted Into the Cortex of a Rat Brain
............................................................................................................ 27
Figure 24. A Representation of the Retinal Prosthesis ......................................... 28
Figure 25. A BioMEMS Fabricated 4x4 Microelectrode Retinal Array..................... 28
Figure 26. An Illustration of the Retinal Neuroprosthesis Created by the Boston
Implant Project ................................................................................... 29
Figure 27. Power Transfer by Magnetic Induction to an Implanted BioMEMS Retinal
Prosthesis ........................................................................................... 30
Figure 28. A New Generation of Implantable Neurostimulation Devices Can Pass
Through the Lumen of a Syringe Needle.............................................. 31
Figure 29. Illustration of the Internal Construction of the Ultrasound Powered
Neurostimulator Developed at ASU ..................................................... 32
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Figure 30. Microfluidics in Glass........................................................................... 32
Figure 31. Commercial Lab-Chip Devices That Allow Analysis for Biomarkers of
Various Diseases Using On-Chip Electrophoresis in Microscale........... 34
Figure 32. Design of an Automated Cell Culture System for NASA Space
Applications Incorporating Microfluidics and Integrated Optical
Components ........................................................................................ 35
Figure 33. NASA Space Application of Microfluidic Cell Culture System Made by
Micromachining................................................................................... 36
Figure 34. Principle of a Microcantilever That Bends When It is Loaded With an
Adherent Mass .................................................................................... 37
Figure 35. Scanning Electron Micrograph Showing a Cantilever Beam With a Single
Vaccinia Virus Particle ......................................................................... 38
Figure 36. Antibodies Attached to a Cantilever Array Create Different Specificities
to Substances in Blood That are Indicative of Cancer.......................... 38
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Biosensors and BioMEMS: A Survey of the Present Field
Introduction
Biomedical sensors and implantable devices employing micro­
electromechanical technology will be important to the future of biomedicine.
Once just science fiction, the notion of a bionic man is now becoming a reality
through the application of microscale technologies. Today it is not unusual to
have a friend or family member who has an implantable device, such as a
pacemaker, defibrillator, cochlear implant, biosensor, neurostimulator, or
insulin pump.
We have only seen the beginning of this technology development, and today's
state-of-the-art implantable devices will be seen as crude and cumbersome
tomorrow. With the rapid pace of development, it is probable that within the
next two decades we will have as many medical treatments based on
microdevices as there are pharmaceutical solutions today. This paper
examines some of the most recent advances in the field, as well as the
technologies that are likely to appear in the next few years.
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What is BioM EMS?
BioMEMS stands for biomedical micro-_glectro-mechanical ~ystems. It is a name applied
to biological and medical devices that are created using advanced fabrication processes
that allow the devices to be very small relative to comparable devices produced by
traditional techniques. BioMEMS devices can also exploit the microscale to provide new
functions that are not practical or possible in large-scale devices.
The name applies to an exceptionally wide variety of engineered devices that derive
from electrical, mechanical, chemical, and molecular engineering. The name
distinguishes these from nanoMEMS which are submicron in scale such as carbon
nanotube structures.
Recently BioMEMS has become something of a misnomer as many of the latest
technologies are being designed and developed based on nanoscale technologies which
are many times smaller than microscale technologies. While current devices are
manufactured mostly on the microscale, many of the functioning parts and the
materials they operate on are at the nanoscale level.
NanoMEMS for biomedical applications are mostly carbon-based materials that have
emerged as prime materials because of their favorable mechanical and electrical
properties. Carbon-based nanostructures such as graphene exhibit a high Young's
modulus (stiffness), high strength, low density, low friction and large surface area. The
low friction of a carbon nanotube allows production of practically frictionless bearings
and has thus been a huge motivation towards applications such as nanomotors. Carbon
nanostructures are much stronger than steel, which allows carbon-based materials to
meet high-stress demands in biomedical applications such as weight-bearing
prosthetics (like hip-joint or bone replacements), where other materials would fail.
The field of BioMEMS encompasses micro devices that are often but not exclusively
made by the same photolithographic techniques used to make computer chips. Their
applications include neuroprosthetics, sensors and actuators, and microchemistry
systems. A microchemistry system, often called a lab on a chip, can analyze chemical
properties of a very small quantity of material such as a tiny blood sample. Advanced
systems can perform several tests on the sample at one time.
There are also drug-delivery systems, miniature hearing aids, artificial retinas, DNA
analysis systems, cancer diagnostics, and an amazing variety of devices which support
the function of the human body. Figure 1 shows some devices that were developed by
the faculty of Biomedical Engineering at Arizona State University.
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Varieties of BioMEMs and Sensors
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Figure 1. Varietie.s of BioMEMS and Sensors. These BioMEMS devices were made at Arizona State University
(ASU). They represent many of the areas of BioMEMS research.
CHARACTERISTICS OF BIOMEMS
Conceiving and designing BioMEMS devices requires a different perspective of the
physical world. These devices can operate on principles such as capillary force, van der
Waals forces, and electric-field forces. These forces become relatively strong when the
size scale reaches very small dimensions. In the realm of the very small, the force of
gravity is far less important than electrical charge and viscosity.
From the perspective of microscale devices, engineers need to think about
accomplishing tasks on an extremely subtle scale but with an exceptionally effective
result. BioMEMS employs engineering sciences in ways that are more than just scaling
down familiar devices used in biomedical applications. Rather, employment of new
structures and new materials including polymers and biological components is
necessary. In addition we need to be concerned about things like biocompatibility (the
effect of the device on body tissue) as well as the degradation effects of tissues and
body fluids on the device itself.
Development of a new product that is targeted for implantation into the human body is
particularly expensive due to federal regulation of medical devices. Devices must be
shown to be effective for their intended use, and above all