section - research | school of engineering | vanderbilt...

M E M S I N T H E M A R K E T – T E C H N O L O G Y R E P O R T

Appendix A: Nanophysiometer Proposal

Courtesy of Dr. Franz Baudenbacher, VIIBRE, Vanderbilt University:

Optimize and extend sensing capabilities of the NanoPhysiometer

Preliminary Results: With awards from DARPA and NIH we have developed nanophysiometers (NP) with electrochemical and optical sensing capabilities that can monitor the physiological state of a couple of thousand cells to a single cell in a chemically controlled extracellular space. We use soft-lithographic BioMEMS fabrication techniques to create inexpensive silicone-based PDMS (Poly(Dimethylsiloxane)) elastomeric devices to instrument and control a small number of cells in a manner that provides high gain and fast sensor response. The replica molded PDMS NP is sealed against a glass substrate upon which a custom, individually addressable, thin-film platinum interdigitated microsensor electrode (IME) array is deposited.

Figure 1 A shows a cardiac myocyte in the NP sensing system, which allows for continuous pacing, chemical control of the extracellular space, and measuring extracellular and trans-membrane potentials, and intracellular Ca2+ transients (Figure 1 – B). Functionalizing the IME array allows us to conduct electrochemical measurements in our microfluidic cell culture devices. We have demonstrated that we can conduct stable electrochemical measurements in microfluidic devices using thin-film IrOx-coated platinum. Figure 1 C shows a NP with differential pH sensing electrode configuration. The NP has a cell culture volume of 25 nL. Acidification rate measurements of fibroblast cells in the NP using a stop flow protocol are shown in Figure 1 D during hemostasis. We are currently working on oxygen, glucose and lactate sensors using a three-microelectrode configuration (i.e., working, counter, reference) to measure currents related to chemical reactions taking place at the working electrode surface. Our system configuration

- 17 -

Section

7

Figure 1. A - Vanderbilt NanoPhysiometer for confining and studying single cardiac myocytes in a 100 picoliter chemically controlled environment. B – optically recorded cytosolic Ca2+ levels in PLN deficient mice. C – NP with integrated differential pH sensing electrodes in a 25 nL cell culture volume. D – Fibroblast acidification rate measurements in stop flow operation.


places all three electrodes in a very small active volume to increase bandwidth by simultaneously reducing solution resistance (increased accuracy) and diffusion times (increased sensitivity).

Proposed Research: We will expand our electrochemical and optical sensing capabilities and integrate multiple NP systems that provide rapid, high-throughput detection of cellular responses by real-time monitoring of multiple signaling and metabolic variables. Within the scope of this proposal, we will integrate multiple NP systems utilizing the capabilities of microminiaturization and microfluidics in a compact bench top system with disposable cell culture cartridges and sensor arrays. Once during the course of the project we will move towards easier to de-convolute sensor models, higher level of sensor integration and the use microfluidc techniques to vary exposure and cell culture conditions in massively parallel number of cell chambers. The planned approach will proceed on multiple fronts:

Design and fabricate disposable cell culture cartridge with multiple cell chambers and integrated sensor arrays.

Develop and integrate highly sensitive electrochemical and optical sensors Establish and optimize on chip cell culture and sensing techniques

Design and fabricate disposable cell culture cartridge with multiple cell chambers and integrated sensor arrays: The proposed BioMEMS devices and the sensor arrays will be fabricated using soft lithography and thin film deposition techniques in the VIIBRE clean rooms at Vanderbilt University (see Resources). Molds are made by spin-coating photoresist onto silicon wafers, exposing the coated wafer with light transmitted through a patterned photomask. Developed wafers form master molds for repeated casting of a given structure. PDMS is cast onto these masters either by spin coating a thin layer or by pour casting a thick layer. PDMS devices can be stacked to form multi-layer chips with a fluidic and a control layer separated by a thin PDMS membrane2,5. Intersections of fluidic and control layers form valves that can be actuated by pressurizing the control line. Valves placed in series serve as peristaltic pumps. Figure 2 shows the proposed NanoPhysiometer design for trapping and perfusion of cells and recording of multiple physiological parameters. The multilayer device consists of a sensing layer, two fluidics layers and a fluidics control layer. The

- 18 -

Figure 2: Proposed NanoPhysiometer design. A - top view of a cell culture volume with sensor layers.


cell culture is in the second fluidic layer and interfaces through a PDMS membrane with the base fluidic layer. This layer contains the internal electrolyte solution of a miniature Clark-type oxygen or Severinghaus pCO2 sensor. PDMS has an excellent oxygen and CO2 permeability and can be fabricated sufficiently thin for a fast senor response. The glass substrate contains the thin film electrochemical sensing array and the electrolyte containing network of channels patterned using SU-8 photo resist. The thin permeable PDMS membrane, the cell culture layer and the control layer are fabricated as monolithic PDMS structure. Access holes for the microfluidic layers and the control layer are either punched or cast into the individual layer before the final curing, Develop and integrate highly sensitive electrochemical and optical sensors: Within this proposal we plan to assess the state of the cells in the cell culture volume with two real time on chip sensing techniques which complement the proposed off line and off chip techniques. Electrochemical detection methods are used to detect analytes in the extracellular space and conventional fluorescent dyes or advanced quantum dot detection strategies to monitor cellular signaling variables. Initially the electrochemical enzyme electrodes (glucose and lactate) will be similar to the Multianalyte MicroPhysiometer (MMP) and implemented into the NanoPhysiometer using dip coated miniature Pt wires. Nafion or polyurethane layers will be used as protective layers to prevent biofouling of the electrodes. Within the first year we plan to replace the wire electrodes with screen printed miniature enzyme electrodes using a commercial screen printer and ink. Screen printing will lead to a higher integration density and the implementation of large sensor arrays for multiple cell culture volumes. Implementing true Clark-type oxygen and Severinghaus pCO2 sensors underneath the cell culture volume will allow for long term recording and reduces sensor cross talk considerably. In these miniaturized amperometric detection schemes, steady state currents form rapidly at the working electrode because the diffusional flux of analytes to the electrodes is constant. These currents are directly proportional to the concentration of the species being analyzed and are precisely quantifiable. The close placement of the microelectrodes results in a high collection efficiency for analytes produced by the cells. The ultimate limits of detection and resolution for each analyte are determined experimentally but typical concentration limits are in the order of 1-10 micromolar, which corresponds to 10 femtomoles of material in a 10 nL cell culture volume. Calibration of the amperiometric signals will be performed using standard solutions before and after the cells are flushed out of the devices. In addition to the electrochemical sensor array we propose to utilize optical probes and a fiber-optics system inserted into the cell culture volume, which provides high collection efficiency. The fibers are interfaced to high sensitive photodiodes or photomultipliers. Wavelength selection is straight forward using commercial miniature dielectric interference filters, split fibers and monochromators. We routinely monitor absolute cytoplasmic Ca2+ concentration using ratiometric dyes such as fluo-3 or indo-2 . Since the optical detection strategy is very versatile we don’t anticipate difficulties in adapting the system to advanced optical probe or multiplexing strategies. Establish and optimize on chip cell culture arrays and sensing techniques: After having demonstrated the basic functionality we will engineer the Nanophysiometer to create devices for dynamic high-content and high throughput measurements. Using pneumatic pinch valves we will be able adrress each cell culture volume to selectively seed and collect cells after each experiment as well as being able to control the chemical environment of the cells and implementing rapid media switching protocols or collecting and diverting effluent from the cell culture array to secondary analyzers.

- 19 -


Appendix B: Equipment

- 20 -

Appendix B: Figure shows pictures of equipment used throughout fabrication and experimental process. A&B) Spincoater or Polymer Spinner used to spin on SU-8, C) EXFO UV light used to expose SU-8, D) Hotplate used to bake wafers, E) “Q-Imaging Micropublisher” and Zeiss microscope used to image beads and solutions in device,


Appendix C: QFD Diagram

- 21 -


- 22 -


Appendix D: Innovation Workbench (IWB)

Ideation Process

Project Initiation

Project name:MRS Entrepreneurship Challenge/Clark Oxygen Sensor

Project timeline:Timeline (as of 11/16/05)

Date EventSeptember 9, 2005 MRS Competition start dateNovember 3, 2005 Meet with advisor, NCIIA proposal dueNovember 8, 2005 Progress report 1 dueNovember 10, 2005 2:00 PM meeting with advisorNovember 15, 2005 Progress report 2 dueNovember 17, 2005 NCIIA proposal due (web)November 17, 2005 1:00 PM meeting with advisorNovember 29, 2005 Progress report dueDecember 6, 2005 Oral presentation, progress report dueDecember 15, 2005 Team registration deadlineJanuary 23, 2006 Entry postmark deadlineMarch 1, 2006 Semi-finalist notification

Project team:Rachel Weaver, [email protected], 843-260-5860Ryan Dempsey, [email protected], 317-443-3150Peter Shanahan, [email protected], 502-396-2199John Richardson, [email protected], 317-258-4812Charles Bloom, [email protected], 210-269-8758

Innovation Situation Questionnaire

Brief description of the situation

Improve convenienceAvailable for use in any laboratory. A seperate lab station or hood is not neededReduce costsmaller device that takes up less space and requires fewer parts and iterations because it can test so many different things due to the numerous chambersneed less resources because tests are done simultaneously in different chambers

Reduce complexitycan perform multiple tests simultaneouslyrequires less space and partsis transportableeasy to make

- 23 -


Detailed description of the situation If we had a magician I would the magician to miraculously tell me the oxygen concentration in the fluid surrounding or in a cell of interest.The mini problem is to be able to shrink a massive cellular metabolic chamber system into an on-chip micro sized system and to still be able to accurately measure cellular oxygen concentration to determine the metabolic activity of the cells in different situations simulating physiological environments.

Supersystem - System - Subsystems

System nameOn-Chip Clark Oxygen Sensor. The primary useful function of this system is to determine the metabolic activity of cells under different conditions (i.e. with drug perfusion).System structureWe are attempting to create a miniature Clark-type oxygen sensor integrated with a microstructure using a novel fabrication technique. "The oxygen chip consists of a glass substrate with a three-electrode configuration, which is separated and connected by a groove, and a poly(dimethylsiloxane) (PDMS) container with an immobilized PDMS oxygen-permeable membrane."Reference:

Fabrication of miniature Clark oxygen sensor integrated with microstructureChing-Chou Wu, Tomoyuki Yasukawa, Hitoshi Shiku, Tomokazu Matsue

Supersystems and environmentThe main system will be perfused by cellular nutrients and other chemical to be tested on cells of interest. The perfusion channels will in a sense be a subsystem controlled by persfusion input, cellular uptake, cellular output, and perfusion output. This system not only transports chemicals and nutrients to the cells but also simulates an in vitro environment through constant flow. The cells are also a subsystem. The cell take in components from the surrounding fluid, process these components and output waste products. The conditions around the cells within the overall system is what is to be monitored.Systems with similar problemsSimilar systems do exist and have been solved through MEMS applications. Basically MEMS goal is to micro size larger cellular systems in order to minimize cost, increase accuracy, and accomplish many other goals. This solution can clearly be applied to this process also. The basic problem in creating our solution and hence applying the MEMS solution is to be able to create an effective environment for cells to be tested in at such a small size. The underlying problem is to be able to create a sensor small enough in combination with a cellular environment in order to simulate macroscale applications.

Input - Process - Output

Functioning of the systemThe basic focus of the project is to be able to minimize input and output components. These components include cells, drugs, perfusion nutrients, waste products, and any other chemicals to be tested. System inputsThe input is the fluid being perfused to the cells. The cells are the transformers themselves as they transform the input products to output products. System outputsThe output products are unused perfusion components and waste products from cells. There are no harmful effects of the output, we are simply trying to measure the concentration of components in the output. Therefore there is no reason to alter the output whatsoever. The only possible harmful output would be if cells unintentionally penetrated through the boundary and escaped the reaction chamber. This is one problem which we will have to solve in the design of our product.Cause - Problem - Effect

Problem to be resolvedReduce the size of the cellular metabolic chamber from macroscopic to microscopic size.Mechanism causing the problem

- 24 -


The macroscopic testing environement is not quick enough in response, is wasteful of money and inputs, and it can only test one system at a time before resetting and replacing all components.Undesirable consequences if the problem is not resolvedThe major undesirable consequence is the large waste of money that pharmecuetical companies encounter in their wasteful processes.Other problems to be solvedThe other major problem we need to solve is the marketing end of our product. We need to be able to find what it is that companies desire most in their on-chip metabolic chambers.Past - Present - Future

History of the problemThis problem has been encountered since the beginning of cellular biology research. The variable of interest in testing the response of cells exposed to different proteins is their metabolic activity or reactivity to the exposed conditions. One way to test this activity is to determine the oxygen content of the output of the cellular process. Also, determining the pH of certain cellular environments may be of importance, so we proposed to implement pH sensors in our microfluidic chip. Determining pH is one of the most common laboratory procedures. Meters may be too large, and other methods such as litmus paper may be outdated and un-precise.Pre-process timeBefore the cells are exposed to the intended testing environment i.e. drugPost-process timeAfter and during the environmental exposure

Resources, constraints and limitations

Available resourcesSubstance resources:cellsPDMSSU-8glass substrateslight exposure machinephotolithographic mask

Field resources:fluid viscosityBernoulli's law of fluid flowmomentum transfermass transferheat transferfluid flow energyosmotic pressure forceschemical energy

Space resources:space inside devicespace outside device

Time resources:time for cell cultureperfusion timetime to make the MEMs device

Informational resources:Dr. Franz Baudenbaucherhis suggested reading-peer reviewed articles on microfluidic devices and clark oxygen sensors

Functional resourcesflow

Allowable changes to the systemany changes to the device that will allow the simulation of an in vitro environmentany sensor (i.e. pH) can replace the oxygen sensor

Constraints and limitationsmoneytime for multiple iterations

- 25 -


Criteria for selecting solution conceptspositive previous utilization of MEMs devices for cell transport simulationson chip sized sensormultiple applications

Problem Formulation and Brainstorming

Clark Oxygen Sensor Process

4/24/2006 4:53:46 PM.

2 3" silicon wafer substrate cleaned with pressurized nitrogen gas produces wafers coated with SU-8 negative photoresist.

wafers coated with SU-8 negative photoresist produces wafers spun at 500 rpm for 10s and 3000 rpm for 30s is produced by 2 3" silicon wafer substrate cleaned with pressurized nitrogen gas.

wafers spun at 500 rpm for 10s and 3000 rpm for 30s produces spin wafersat 500 rpm again and apply acetone to edges produces bead layer forms around wafer circumferences is produced by wafers coated with SU-8 negative photoresist.

spin wafersat 500 rpm again and apply acetone to edges produces soft bake wafers at 65 C-1 min. & 90 C- 3 min counteracts bead layer forms around wafer circumferences is produced by wafers spun at 500 rpm for 10s and 3000 rpm for 30s.

soft bake wafers at 65 C-1 min. & 90 C- 3 min produces Expose wafers with mask filter to UV light for 30s is produced by spin wafersat 500 rpm again and apply acetone to edges.

Expose wafers with mask filter to UV light for 30s produces Post exposure bake-65C-1min and 90C-5min produces UV light retinal exposure can cause instant blindness is produced by soft bake wafers at 65 C-1 min. & 90 C- 3 min.

bead layer forms around wafer circumferences is produced by wafers spun at 500 rpm for 10s and 3000 rpm for 30s.

UV light retinal exposure can cause instant blindness is produced by Expose wafers with mask filter to UV light for 30s.

Put on UV goggles counteracts UV light retinal exposure can cause instant blindness.

Post exposure bake-65C-1min and 90C-5min produces Remove unexposed soft SU-8 layer with acetone is produced by Expose wafers with mask filter to UV light for 30s.

Remove unexposed soft SU-8 layer with acetone produces Dry wafers by spin at 3000rpm-30s counteracts White residual soft SU-8 remains produces Residual soft SU-8 may remain is produced by Post exposure bake-65C-1min and 90C-5min.

Residual soft SU-8 may remain is produced by Remove unexposed soft SU-8 layer with acetone.

Rinse wafers with methanol counteracts Residual soft SU-8 may remain produces White residual soft SU-8 remains.

White residual soft SU-8 remains is produced by Rinse wafers with methanol.

Dry wafers by spin at 3000rpm-30s produces Cracks occur in SU-8 is produced by Remove unexposed soft SU-8 layer with acetone.

Cracks occur in SU-8 is produced by Dry wafers by spin at 3000rpm-30s.

Hard bake wafers on hot plate until 200C produces Master cell culture and master pneumatic layers made counteracts Cracks occur in SU-8.

Master cell culture and master pneumatic layers made is produced by Hard bake wafers on hot plate until 200C.

15 to 1 Mix PDMS and curing agent for 2min produces Degass PDMS for 3 min.

Degass PDMS for 3 min produces pour PDMS onto cell culture master to create PDMS impressions and pour PDMS onto pneumatic layer for PDMS impression is produced by 15 to 1 Mix PDMS and curing agent for 2min.

pour PDMS onto cell culture master to create PDMS impressions produces Air bubbles occur is produced by Degass PDMS for 3 min.

pour PDMS onto pneumatic layer for PDMS impression produces Air bubbles occur is produced by Degass PDMS for 3 min.

- 26 -


Place master-PDMS forms into vacuum chamber produces partial PDMS curing-Heat at 80C for 1hr counteracts Air bubbles occur.

Air bubbles occur is produced by pour PDMS onto cell culture master to create PDMS impressions and pour PDMS onto pneumatic layer for PDMS impression.

partial PDMS curing-Heat at 80C for 1hr produces place pnematic layer atop cell culture layer is produced by Place master-PDMS forms into vacuum chamber.

place pnematic layer atop cell culture layer produces stacked layers cured for 2hr is produced by partial PDMS curing-Heat at 80C for 1hr .

stacked layers cured for 2hr produces Cured PDMS cut from master is produced by place pnematic layer atop cell culture layer.

Cured PDMS cut from master produces Flow channels created in PDMS-punched with 19 gauge needle is produced by stacked layers cured for 2hr.

Flow channels created in PDMS-punched with 19 gauge needle produces PDMS remnants in channel is produced by Cured PDMS cut from master.

PDMS remnants in channel is produced by Flow channels created in PDMS-punched with 19 gauge needle.

Clean with Nitrogen gas produces PDMS and glass substrate into plasma cleaner-20s with bonding surfaces exposed counteracts PDMS remnants in channel.

PDMS and glass substrate into plasma cleaner-20s with bonding surfaces exposed is produced by Clean with Nitrogen gas.

Create cell culture layer.

Create master cell culture and pneumatic layer.

4/24/2006 4:50:39 PM.

2 3" silicon wafer substrate cleaned with pressurized nitrogen gas produces wafers coated with SU-8 negative photoresist.

Develop Concepts

Evaluate Results

- 27 -


Appendix E: Concept Diagram

- 28 -


Appendix F: Design Safe

- 29 -


- 30 -


- 31 -


- 32 -


- 33 -


- 34 -


Appendix G: Project NotebookTask Details Name Date

1 Met with Dr. Baudenbacher to discuss project All 11/6/052 Preliminary market research Ryan 11/7/053 Completed “Progress Report 1” All 11/8/05

4Met with Dr. Baudenbacher at 2:00 PM to

obtain reference literature & cost estimates All 11/10/055 Added e-mail link to website Ryan 11/10/056 Completed “Progress Report 2” All 11/14/057 Completed NCIIA proposal All 11/16/058 Added reference literature to website Ryan 11/17/059 Met with Dr. Baudenbacher at 1:00 PM All 11/17/0510 Completed “Progress Report 3” All 11/29/0511 Completed preliminary design sketch Peter 11/29/0512 Met with Dr. Baudenbacher John, Peter 11/30/05

13 Completed Innovation Work BenchRachel, Peter 12/1/05

14 Gave first oral presentation All 12/6/0515 Posted “Presentation 12-6-05” on website Ryan 12/8/0516 Attempt (failed) to enter MRS Challenge All 12/9/0517 Completed “Progress Report 4” All 1/17/06

Met with Dr. Baudenbacher to update overall progress All 1/24/06

18 Gave second oral presentation All 1/25/0619 Posted “Presentation 1” on website Ryan 1/26/06

20Changed project name to “MEMS in the

Market” All 1/26/06

21

Met with Dr. Baudenbacher about the deadlines for the mask submissions and the

drawing programs John, Peter 1/26/06

22Compiled list of industry contacts and

distributed to Rachel and Charles Ryan 1/29/06

23Contacted dad’s company about AUTOCAD

drawing Rachel 1/30/06

24Scheduled meeting for 2/1/06 with Dr.

Baudenbacher John 1/31/0625 Completed “Progress Report 5” All 2/1/06

26Met with Dr. Baudenbacher to finalize drawing

for CAD submission John, Peter 2/1/06

27

Performed bioMEMS market research and compiled various literature regarding market

potential Ryan 2/5/06

28Contacted Pfizer, Novartis, and MEMS

Industry Group Ryan 2/5/06

29Finalized the design layout of our bioMEMS

device John, Peter 2/7/06

30 Performed bioMEMS market researchCharles, Rachel 2/7/06

- 35 -


31 Completed “Progress Report 6” All 2/8/06

32Received response from Ellen McDevitt of the

MEMS Industry Group Ryan 2/8/06

33Received response from Pfizer corporate

governance board Ryan 2/8/06

34Contacted Affymetrix, Caliper Life Sciences,

and Cepheid Ryan 2/14/0635 Customized bioMEMS design for our project John, Peter 2/15/0636 Gave third oral presentation All 2/17/06

37Posted “Presentation 2” and pictures on

website Ryan 2/20/0638 Began patent search Charles 2/20/0639 Began writing “Business Strategy Report” Ryan 2/20/0640 Completed “Progress Report 7” All 2/22/0641 Completed preliminary patent search Charles 2/25/0642 Continued writing “Business Strategy Report” Ryan 2/26/0643 Chrome mask fabrication John, Peter 2/28/0644 Completed “Progress Report 8” All 3/1/06

45Met with Rahgav regarding photolithographic

masks John 3/13/0646 Continued writing “Business Strategy Report” Ryan 3/14/0647 Completed the photolithographic masks John, Peter 3/14/0648 Scheduled initial device fabrication for 3/20/06 Peter 3/14/0649 Completed “Progress Report 9” All 3/15/0650 Completed FDA regulatory environment report Charles 3/20/06

51

Completed more photolithographic masks and the PDMS was poured and affixed to the glass

surface.Peter, Rachel 3/21/06

52Took digital photographs of all relevant lab

equipment Rachel 3/21/0653 Completed “Progress Report 10” All 3/22/0654 Gave fourth oral presentation All 3/27/06

55Posted “Presentation 2” and pictures on

website Ryan 4/2/06

56

Group meeting to assign tasks and create schedule to complete project; reviewed

grading criteria All 4/2/06

57Performed food coloring test on first batch of

devices, but they were faulty Peter 4/3/0658 Updated “Business Strategy Report” Ryan 4/3/0659 Documented “brainstorming” methods Ryan 4/3/0660 Contacted Dr. Baudenbacher for help John 4/4/0661 Performed cost savings calculation Ryan 4/5/0662 Completed “Progress Report 11” All 4/5/06

63 Met with Dr. Baudenbacher to update statusPeter, John,

Ryan 4/6/06

64Made 10 new devices with valve cut-off

chamber on the PDMS layer John, Peter 4/7/0665 Researched FDA regulations Ryan 4/8/06

66Researched corporate environment and

current products on the market Ryan 4/10/0667 Completed “Progress Report 12” and updated All 4/12/06

- 36 -


website68 Continued device testing in the lab John, Peter 4/13/0669 Completed “Business Strategy Report” Ryan 4/17/06

70 Completed DesignSafe analysisRyan,

Charles 4/17/0671 Completed patent search documentation Charles 4/18/0672 Completed preliminary design poster Ryan, Peter 4/18/0673 Gave final oral presentation All 4/19/0674 Completed “Technology Report” John 4/22/0675 Completed QFD and other diagrams Rachel 4/22/0676 Submitted design poster for printing Ryan 4/22/0677 Printed copies of final reports All 4/23/06

References1. Materials Research Society. 22 January 2006.

http://www.mrs.org2. Patel, Nelesh. “Emerging Drug Discovery Technologies.”

Business Insights: Healthcare. April 2005.3. Lee, Abraham P. “BioMEMS: Bridging Nano and Micro to Link

Diagnostics to Treatment.” Department of Biomedical Engineering. University of California at Irvine.

4. “Drug Manufacturers and Drug Delivery Industries.” Yahoo! Finance Industry Center. 27 March 2006. http://biz.yahoo.com/ic/index.html

5. Allan, Roger. “BioMEMS Making Huge Inroads Into Medical Market.” Electronic Design. 16 June 2003.

6. Jarvis, Lisa. “Drug Development Costs Soar to Record High Levels.” Chemical Market Reporter. 24 June 2002. Volume 261 Issue 25, p10.

7. Bouchaud, Jeremie. “BioMEMS: high potential but also highly challenging.” Wicht Technology Consulting, Munich. 21 February 2006.

8. Wu, Ching-Chou, Tomoyuki Yasukawa, Hitoshi Shiku, Tomokazu Matsue. “Fabrication of miniature Clark oxygen sensor integrated with microstructure.” Sensors and Actuators B: Chemical, Volume 110, Issue 2, 14 October 2005, Pages 342-349

9. Grayson, Amy C. Richards, et al. “A BioMEMS Review: MEMS Technology for Physiologically Integrated Devices.” IEEE: Institute of Electrical and Electronics. 2004, Volume 92, Part 1, pages 6-21.

10. VIIBRE Microscope Listings. 16 April 2006. http://www.vanderbilt.edu/viibre/VIIBRE_Microscopes.html

- 37 -

Section

8

http://www.vanderbilt.edu/viibre/VIIBRE_Microscopes.html

http://biz.yahoo.com/ic/index.html

http://www.mrs.org/


11. Microfabrication. VIIBRE Lab Facilities. 10 April 2006. http://www.vanderbilt.edu/viibre/av-facilities-microfab.html.

12. Bhakta, V, et al. “BioMEMS-based Nano-Bioreactor: Design and Implementation.” April 2005 Senior Design Project.

13. Hung PJ, Lee PJ, Sabounchi P, et al. Continuous Perfusion Microfluidic Cell Culture Array for High-Throughput Cell-Based Assays. Wiley InterScience. 3 December 2004.

14. Griscom, L, et al. “Techniques for patterning and guidance of primary culture neurons on micro-electrode arrays.” Sensors and Actuators B 2002;83;15-21.

15. Baudenbacher, F., Project Advisor, VIIBRE, Vanderbilt University

16. Wikswo JP. “BioMEMS for Instrumenting and Controlling the Single Cell.” 1 April 2006. http://cswep.org/viibre/documents/TL269_EMBS_2004_BioMEMS_ICSC.pdf

17. Wikswo JP, Baudenbacher F. “Third Year Review of Academic Venture Capital Fund Initiatives.” 1 April 2006. http://www.vanderbilt.edu/htdocs/viibre/documents/VIIBRE_Three_Year_Report_2004.pdf

- 38 -

http://www.vanderbilt.edu/htdocs/viibre/documents/VIIBRE_Three_Year_Report_2004.pdf

http://www.vanderbilt.edu/htdocs/viibre/documents/VIIBRE_Three_Year_Report_2004.pdf

http://cswep.org/viibre/documents/TL269_EMBS_2004_BioMEMS_ICSC.pdf

http://cswep.org/viibre/documents/TL269_EMBS_2004_BioMEMS_ICSC.pdf

http://www.vanderbilt.edu/viibre/av-facilities-microfab.html

section - research | school of engineering | vanderbilt...

Documents