Bio MEMS

April 20, 2012

INDIAN INSTITUTE OF TECHNOLOGY ROPAR

MEL 419 Mechatronics Term Paper Report on

BIO MEMS
Submitted by

Jyotiraj Thakuria (P2009ME1025) Neeharika Kushwaha (P2009ME1075)

Under the supervision of Dr. Ekta Singla

School of Mechanical, Materials & Energy Engineering

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Abstract
MEMS (microelectromechanical systems) are replacing many components because of its easy fabrication and high accuracy. It is a combination of mechanical and electrical components integrated together on a silicon chip. There are other materials like polymers which can be used as base material but silicon makes the final product cheaper. Application of this technology in biomedical field is BioMEMS. In this term paper after a brief introduction of MEMS and its fabrication, application of MEMS in biomedical field is discussed. A case study was done on drug delivery using BioMEMS and Lab-On-Chip. A chip on which battery, control circuitry, reservoir for drug and biosensor are integrated can be implanted in the body which is controlled from outside using wireless technique. It helps to control timing of drug delivery and quantity of drug to be delivered. Thousands of reservoirs can be fabricated on the chip and all can be filled with different drugs. This technology gives more temporal control. Using MEMS technology makes the products very reliable and decreases the overall cost. Biocompatibilty can be an issue which needs to be resolved.

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Table of Contents
Abstract ......................................................................................................................................................... 2 List Of Figures................................................................................................................................................ 4 Introduction .................................................................................................................................................. 5 What are BioMEMS? ..................................................................................................................................... 6 Microfabrication ........................................................................................................................................... 7 Applications................................................................................................................................................... 8 BIOMEDICAL MICROACTUATORS.............................................................................................................. 8 Micromanipulators ................................................................................................................................... 8 Surgical Microinstruments ............................................................................................................................ 9 Microfilters and Microneedles.................................................................................................................... 10 Microfilters.............................................................................................................................................. 10 Case Study ................................................................................................................................................... 11 Lab-on-a-chip .............................................................................................................................................. 11 History ......................................................................................................................................................... 11 Micro fabrication .................................................................................................................................... 12 Global Challenges........................................................................................................................................ 13 Application .................................................................................................................................................. 13 Microelectromechanical Drug Delivery Systems ........................................................................................ 14 Vivo Devices ............................................................................................................................................ 14 Smart Pills................................................................................................................................................ 16 Biosensors ............................................................................................................................................... 16 Drawbacks ................................................................................................................................................... 17 Conclusion ................................................................................................................................................... 17 References .................................................................................................................................................. 18

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List Of Figures
1) MEMS Fabricated System 2) Bio-Nanorobot 3) Micro Syringe 4) Steps involved in Bio-MEMS Fabrication process. 5) Magnetic microactuator manipulating a single-cell protozoa 6) Surgical microgripper actuated by shape memory- alloy forces 7) Piezoelectrically driven force sensitive scalpel. 8) Micromachined Ultrasonic cutting tool. 9) Smallest conventional needle 10) Microfabricated silicon needle. 11) Silicon micromachined precision filter 12) Schematic of Lab-On Chip 13) Lab On Chip 14) Reservoir Chip 15) Smart Pills

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Introduction
MEMS stand for microelectromechanical systems. Micro-Electro-Mechanical Systems (MEMS) is the integration of mechanical elements, sensors, actuators, and electronics on a common silicon substrate through microfabrication technology. MEMS devices are similar to traditional sensors and actuators although much, much smaller. While the electronics are fabricated using integrated circuit (IC) process sequences, the micromechanical components are fabricated using compatible "micromachining" processes that selectively etch away parts of the silicon wafer or add new structural layers to form the mechanical and electromechanical devices. MEMS are made up of components from 1 to 100 micrometer in size and the final device is from 20micrometer to a millimeter in size. MEMS devices are manufactured using batch fabrication techniques similar to those used for integrated circuits. It uses silicon wafer, which is one of the reason for its low cost. Accelerometer and pressure sensors are one of the most successful MEMS devices and systems. This technology has applications in many different fields of engineering, physical sciences and biomedicines.

http://en.wikipedia.org/wiki/Microelectromechanical_systems

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What are BioMEMS?

Bio Micro Electro Mechanical Systems (BioMEMS) is a multidisciplinary research field that closely integrates engineering with physics, chemistry, and biology. Biomedical or Biological Microelectromechanical Systems (BioMEMS) are now a heavily researched area with a wide variety of important biomedical applications. In addition to components like microchannels, microvalves, micropumps, micromixers and microreactors. This technology is now being used in Lab-on-chip, Drug delivery system, biochip etc. Areas of research and applications in BioMEMS range from diagnostics, such as DNA and protein micro-arrays, to novel materials for BioMEMS, micro-fluidics, tissue engineering, surface modification, implantable BioMEMS, systems for drug delivery, etc. The advantage of this technology is that microvolumes of biological devices or medicines can be handled and tested with more accuracy and human involvement is reduced hence improving the data quality and capabilities. It also reduces time of the measurement and overall cost of the analysis.

Figure 2

Figure 3: Micro-syringe

news.bbc.co.uk/1/hi/Scotland/4192776.st m

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Microfabrication
It is the process of fabrication of miniature structure of micrometer size and smaller. This process is used in integrated circuit fabrication, MEMS fabrication, microsystems and micromachines fabrication. Schematic of the process is-

Figure 4: Microfabrication Process

Basic fabrication steps are same as that of IC fabrication: deposition, patterning, doping and etching. In the following section substrate material and four basic steps are discussed in brief. Substrate material: Silicon is a standard substrate material in microfabrication. It has favorable electrical properties, mechanical properties and it is economically more preferable. The other substrate material that can be used are glass, ceramics and polymers. Thin layer deposition: The most common thin layer deposition methods in microfabrication are CVD (chemical vapor deposition) and PVD (physical vapor deposition) such as sputtering and evaporating. The thickness of layer deposited is around a few micrometers. Other techniques which can be used are electroplating of metal films and spin or spray coating of polymeric films MEL419

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Patterning: The standard process used for patterning is photolithography. A mask with the desired pattern is created on the surface. It is exposed to the UV radiations . Etching: The undesired material is etched away and photoresist is removed from the surface to get the final product.

Applications
BIOMEDICAL MICROACTUATORS
Microactuators are useful in biomedical applications when biological objects or their environment need to be controlled on the microscopic scale. Furthermore, the ability to integrate many microactuators as easily as only one makes it feasible to produce complex microsystems capable of controlling many parameters.

Micromanipulators
To manipulate cells, tissues, and other biological objects, micromanipulators must be driven by a microactuation mechanism capable of operating in a conductive solution.

Figure 5: Magnetic microactuator manipulating single-cell protozoa [7]

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Surgical Microinstruments
For surgery instruments MEMS technology can be implemented like piezoelectrically driven force sensitive scalpel, micromachined ultrasonic cutting tool, microheaters, microsensors etc. The most successful uses of microactuation in surgical devices use high-force small displacement stepper motors or resonant microstructures. MEMS technology can be used to add a variety of capabilities to surgical microinstruments.

Figure 6: Surgical microgripper actuated by shapememory- alloy forces [7]

Figure 7: Piezoelectrically driven force sensitive scalpel [7]

An ultrasonic cutting tool fabricated by bulk micromachining is another good example of using MEMS technology in surgical devices. Again, piezoelectric material is attached to the cutter to resonate the tip of the tool at ultrasonic frequencies. Only when activated the device will easily and rapidly cut through even tough tissues.

Figure 8: Micromachined ultrasonic cutting tool [5]

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Microfilters and Microneedles

Clearly the need to precisely control gas and fluid flow is critical for diagnostic, surgical, and therapeutic biomedical systems. With this as motivation, there have been many efforts to develop viable reliable low-cost high-precision microneedles, microfilters.

Figure 9: Smallest conventional needle (30 gauges).

Figure10: Microfabricated silicon needle. The size scale of both images is the same. [2]

Microfilters
Microfilters are capable of screening micron-scale objects and unacceptably broad statistical distribution of the size of objects can pass.

Figure11: Silicon micromachined precision filter

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Case Study

Lab-on-a-chip
A lab-on-a-chip (LOC) is a device that integrates one or several laboratory functions on a single chip of only millimeters to a few square centimeters in size. LOCs deal with the handling of extremely small fluid volumes down to less than pico liters. Lab-on-a-chip devices are a subset of MEMS devices and often indicated by "Micro Total Analysis Systems" (TAS) as well. Microfluidics is a broader term that describes also mechanical flow control devices like pumps and valves or sensors like flow meters and viscometers. However, strictly regarded "Labon-a-Chip" indicates generally the scaling of single or multiple lab processes down to chipformat, whereas "TAS" is dedicated to the integration of the total sequence of lab processes to perform chemical analysis. The term "Lab-on-a-Chip" was introduced later on when it turned out that TAS technologies were more widely applicable than only for analysis purposes.

Figure 12: Schematic of Lab-On -Chip

History
The first LOC analysis system was a gas chromatograph, developed in 1979 by S.C. Terry at the Stanford University. However, only at the beginning of the 1990s, the LOC research started to seriously grow as a few research groups in Europe developed micropumps, flowsensors and the concepts for integrated fluid treatments for analysis systems. These TAS concepts demonstrated that integration of pre-treatment steps, usually done at lab-scale, could extend the simple sensor functionality towards a complete laboratory analysis. A big boost in research and commercial interest came in the mid 1990s, when TAS technologies turned out to provide interesting tooling for genomics applications, like capillary MEL419

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electrophoresis and DNA microarrays. DARPA (Defense Advanced Research Projects Agency) also supported research in TAS, especially in portable bio/chemical warfare agent detection systems. The added value was not only limited to integration of lab processes for analysis but also the characteristic possibilities of individual components and the application to other, nonanalysis, lab processes. Hence the term "Lab-on-a-Chip" was introduced.

Figure 13: Lab On Chip,Courtesy: Nanogen and Affymetrix Inc.

Micro fabrication
The basis for most LOC fabrication processes is photolithography. Initially most processes were in silicon, as these well-developed technologies were directly derived from semiconductor fabrication. Because of demands for e.g. specific optical characteristics, bio- or chemical compatibility, lower production costs and faster prototyping, new processes have been developed such as glass, ceramics and metal etching, thick-film deposition as well as fast replication methods via electroplating, injection molding. Furthermore the LOC field more and more exceeds the borders between lithography-based microsystem technology, nano technology and precision engineering. LOCs may provide advantages, which are specific to their application. Typical advantages are:

Low fluid volumes consumption (less waste, lower reagents costs and less required sample volumes for diagnostics) Faster analysis and response times due to short diffusion distances, fast heating, high surface to volume ratios, small heat capacities. Better process control because of a faster response of the system (e.g. Thermal control for exothermic chemical reactions) Compactness of the systems due to integration of much functionality and small volumes Massive parallelization due to compactness, which allows high-throughput analysis

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Lower fabrication costs, allowing cost-effective disposable chips, fabricated in mass production Safer platform for chemical, radioactive or biological studies because of integration of functionality, smaller fluid volumes and stored energies

Some of the disadvantages of LOCs are:

Novel technology and therefore not yet fully developed Physical and chemical effectslike capillary forces, surface roughness, chemical interactions of construction materials on reaction processesbecome more dominant on small-scale. This can sometimes make processes in LOCs more complex than in conventional lab equipment Detection principles may not always scale down in a positive way, leading to low signalto-noise ratios Although the absolute geometric accuracies and precision in micro fabrication are high, they are often rather poor in a relative way, compared to precision engineering for instance.

Global Challenges
In developed nations, the most highly valued traits for diagnostic tools include speed, sensitivity, and specificity; but in countries where the healthcare infrastructure is less well developed, attributes such ease of use and shelf life must also be considered. The reagents that come with the chip, for example, must be designed so that they remain effective for months even if the chip is not kept in a climate-controlled environment. Chip designers must also keep cost, scalability, and recyclability in mind as they choose what materials and fabrication techniques to use.

Application
One active area of LOC research involves ways to diagnose and manage HIV infections. Around 90% of people with HIV have never been tested for the disease. Measuring the number of CD4+ T lymphocytes in a persons blood is an accurate way to determine if a person has HIV and to track the progress of an HIV infection. Another research area is in the detection of Tuberculosis in rural areas.

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Bio MEMS Some other interesting LOC applications Genetic analysis Portable devices for pathogen detection High-throughput biology

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Chemical synthesis Metabolite analysis Drug delivery systems

Microelectromechanical Drug Delivery Systems

In pharmaceutical industries drug delivery methods using MEMS technology have significant implication. By using this technology amount of drug delivered and delivery sites can be controlled. Implantable devices can be actuated such that the drug is released continuously, periodically, or selectively by the doctor or patient. A chip is attached on the wrist which wirelessly sends signals to the device implanted in the body. However biocompatibility issues arise. Any device implanted in the body for an extended period of time should not induce toxicity or damage local tissues. Devices can be divided into two groups, vivo devices and transdermal devices. Vivo devices are those which can be found inside the body and Transdermal devices are those which that deliver the drugs through skin.

Vivo Devices
As mentioned above, vivo devices are those which can be found inside the body. These devices can be positioned inside the body either by implantation or by the traditional pill. These devices remain inside the body for extended period of time so biocompatibility can be an issue. These devices contain micro reservoirs which are filled with drugs. The reservoirs are created on the substrate using micro fabrication. The drug is released using different techniques. Different reservoirs can be filled with different drugs. In figure Chip and the reservoir is shown. Reservoir are created on silicon substrate and covered MEL419

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with anode. Cathode is on one part of the chip. When signal is sent to release the drug voltage is applied and reduction-oxidation reaction begins.

Figure 14: Reservoir Chip

One category of these devices utilizes passive delivery techniques. Reservoir membrane is porous which allows a slow diffusion of the drug out of the reservoir. In this technique, biocompatibility issues are limited. Another passive technique involves the use of membranes that slowly deteriorate. The thickness of the membrane determines the time until the drug in the reservoir is released. Another category is active delivery technique which allows much more control over the dosing. An active delivery device requires actuation of the device before the reservoir is opened and the drug delivered. This actuation can be provided in a wide variety of different ways. The MEL419

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advantage of active delivery is the great deal of control it provides over the dosing of the drug. Control elements can be fixed into the device. For example, incorporating integrated circuitry into the device along with chip could allow for highly controlled timed release of the drug, patient or doctor controlled release of the drug (using wireless technology), or even selfadministering devices that detect when further dosing of the drug is required. But in this technique biocompatibility can be an issue. Smart pill is one example for this category.

Smart Pills
A pill can be implanted in the body of the patient. It consists of a battery, biosensor, control circuitry and drug reservoirs. Each pill consists of thousands of reservoir in which different type of drugs can be filled. These reservoirs are sealed with gold cap and wired to power source. The sensor attached to the pill sends the information about surrounding conditions to a chip attached to the wrist. The chip then determines the course of action to take. A signal is sent to the included battery pack, which actuates a membrane. The membrane contracts and just the right amount of the drug is released. Microprocessor and attached sensor can program the time and amount of drug required.

Figure 15: Smart Pills [5]

Biosensors
A biosensor is an analytical device for the detection of an analyte that combines a biological component with a physicochemical detector component [1]. The term 'biosensor' is often used to cover sensor devices used in order to determine the concentration of substances and other parameters of biological interest. For example biosensor can measure insulin in the body, when its level decreases below the required level sensor will send signal to the chip and membrane is actuated to release drug.

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Drawbacks
Biocompatibility is one of the major issues which need to be solved in case of drug delivery systems. An implanted chip in the body can cause infection. For optimizing the performance of MEMS in vivo material which comes in contact with tissues should be biocompatible. A study was carried out for biocompatibility tests and the results indicated that silicon, silicon nitride, silicon dioxide, gold, and SU-8 were biocompatible, and all but silicon and SU-8 had reduced biofouling.

Conclusion
MEMS technologies are powerful tools which makes miniaturization of devices useful in biomedical engineering. MEMS have many characteristics that make them appealing for biological applications, including the ability to control their physical and chemical characteristics on the micrometer scale. Additionally, the control that can be achieved over MEMS operation makes the devices particularly attractive for drug delivery applications where precise dosing is required. The microchip for drug delivery is capable of releasing of drugs by opening various reservoirs on command. The addition of biosensors gives the surrounding information on basis of which, chip gives command to actuate the membrane. The growing interest in combining living cells with micro fabricated devices, and in using micro fabrication technology for drug delivery, may ultimately lead the way to fully integrated, MEMS-based devices that could replace entire biological systems in the human body. MEMS technology has many advantages as it decreases the energy uses. Accuracy of the operation is increased and the processes can be controlled better. But it has some biocompatibility issues in case of drug delivery systems. It is a very complex structure which requires high skilled people to operate. But in recent years this technology has very fast development and it is expected to be developed at a much higher rate.

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References
1) Wanjun Wang and Steven A. Soper, Bio-MEMS Technologies and Applications, CRC Press, 2007. 2) http://en.wikipedia.org/wiki/Lab-on-a-chip 3) http://en.wikipedia.org/wiki/Bio-MEMS 4) Stanford University research on microprobes: http://transducers.stanford.edu/stl/Projects.html 5) Cui, L., Zhang, T., and Morgan, H., Optical particle detection integrated in a dielectrophoretic lab-on-a-chip, J. Micromech. Microeng., 12 ,7, 2002. 6) Nyholm, L., Electrochemical techniques for lab-on-a-chip applications. Analyst 2005, 130(5), 599605. 7) Jack W. Judy, Biomedical applications of MEMS, University of California, Los Angeles.

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