Bioengineering, Research

Major Research Interest:
Microfabricated Bioanalysis Systems, Bioanalytical Chemistry and Genomics
more opportunities

Project Type		Funding
Rotation	Yes	NIH	Yes
Summer	Yes	Private Foundation
Thesis	Yes	Other	Yes

Abstract: We are working on the development of new analysis technologies that will advance genome sequencing, polymorphism characterization, proteomics and health care diagnostics. Toward this end we developed the first Capillary Array Electrophoresis instruments and the energy transfer dye label concepts that were used in the sequencing of the Human Genome. Our approach is to exploit miniaturization of chemical and biochemical analysis along with high-sensitivity fluorescence detection to produce integrated microfabricated lab-on-a-chip microanalysis systems. We are now going beyond the traditional lab-on-a-chip concept to the development of chemical and biochemical microprocessors. We have developed microphotolithographic methods for fabricating capillary electrophoresis systems on glass substrates or chips and the development of methods for DNA sample preparation on these devices. The advantages of these devices are that very small amounts of sample are needed, the electrophoretic separations are 10-100 times faster than conventional techniques, and miniaturization permits the fabrication of massively parallel analysis devices. Photolithographic CE systems have been fabricated and used to perform high speed DNA fragment analyses, PCR fragment sizing and DNA sequencing. Methods have also been developed for fabricating CAE chips with from 96 to 384 capillaries that are capable of analyzing large numbers of samples in parallel. We have also developed methods for integrating PCR-based sample preparation on these chips to make the first miniaturized DNA analysis bioprocessors. Future work will focus on the fabrication and operation of more complex DNA sample preparation and analysis systems including valves, vents, reactors, pumps etc. to perform nanoliter chemistries that would not be feasible or practical in a conventional macroscopic laboratory. Examples include the development of chips to automatically evolve selected RNA populations, the development of ultra-high gain cascaded PCR reactors, chips to perform analysis of single cell genetics and expression, the development of chip-based logic circuits using DNA as the information carrier in microfluidic channel "wires", and the development of microchemical and biochemical analysis devices to explore for chemical signs of extraterrestrial life, and the development of portable clinical health care monitors.

References:

1. Simpson, P. C., Woolley, A. T. and Mathies, R. A. Microfabrication Technology for the Production of Capillary Array Electrophoresis Chips, Biomedical Microdevices 1, 7-25 (1998).

2. Kheterpal, I., Li, L., Speed, T. P. and Mathies, R. A. A Three-Color Labeling Approach for DNA Sequencing Using Energy Transfer Primers and Capillary Electrophoresis, Electrophoresis 19, 1403-1414 (1998).

3. Woolley, A. T., Lao, K., Glazer, A. N. and Mathies, R. A. Capillary Electrophoresis Chips with Integrated Electrochemical Detection, Analytical Chemistry 70, 684-688 (1998).

4. Simpson, P. C., Roach, D., Woolley, A. T., Thorsen, T., Johnston, R., Sensabaugh, G. F. and Mathies, R. A. High Throughput Genetic Analysis using Microfabricated 96 Sample Capillary Array Electrophoresis Micro-Plates, Proceedings of the National Academy of Sciences U.S.A.95, 2256-2261 (1998).

5. Simpson, P. C. and Mathies, R. A. High-Performance Microfabricated Capillary Array Electrophoresis Systems for DNA Analysis, Proceedings of the International Society for Optical Engineering-SPIE, Micro- and Nanofabricated Structures and Devices for Biomedical Environmental Applications, Volume 3258, 170-180 (1998).

6. Haab, B. B. and Mathies, R. A. Single Molecule DNA Detection in Microfabricated Capillary Electrophoresis chips, Proceedings of the International Society for Optical Engineering-SPIE, Progress in Biomedical Optics, Volume 3259, 104-111 (1998).

7. Mathies, R. A., Simpson, P. C. and Woolley, A. T. DNA Analysis with Capillary Array Electrophoresis Microplates, Micro Total Analysis Systems '98, Proceedings of the Micro-TAS '98 Workshop, Banff Canada, October 13-16, 1998, Kluwer Academic Publishers, eds. D. Jed Harrison and A. van den Berg, pp.1-7 (1998).

8. Collins, F. S., Patrinos, A., Jordan, E., Chakravarti, A., Gesteland, R., Walters, L. and the members of the DOE and NIH Planning Groups, New Goals for the U.S. Human Genome Project: 1998-2003, Science 282, 682-689 (1998).

9. Liu, S., Shi, Y., Ja, W. W., and Mathies, R. A. Optimization of High-Speed DNA Sequencing on Microfabricated Capillary Electrophoresis Channels, Anal. Chem. 71, 566-573 (1999).

10. Kheterpal, I. and Mathies, R. A. Capillary Array Electrophoresis DNA Sequencing, Analytical Chemistry, 71, 31A-37A (1999).

11. Scherer, J. R., Kheterpal, I., Radhakrishnan, A., Ja, W. W. and Mathies, R. A. Ultra-High Throughput Rotary Capillary Array Electrophoresis Scanner for Fluorescent DNA Sequencing and Analysis, Electrophoresis 20, 1508-1517 (1999).

12. Hutt, L. D., Glavin, D. P., Bada, J. L. and Mathies, R. A. Microfabricated Capillary Electrophoresis Amino Acid Chirality Analyzer for Extraterrestrial Exploration, Analytical Chemistry 71, 4000-4006 (1999).

13. Shi, Y., Simpson, P., Scherer, J. R., Wexler, D., Skibola, C., Smith, M. T. and Mathies, R. A. Radial Capillary Array Electrophoresis Microplate and Scanner for High-Performance Nucleic Acid Analysis, Analytical Chemistry 71, 5354-5361 (1999).

14. Haab, B. B., and Mathies, R. A. Single Molecule Detection of DNA Separations in Microfabricated Capillary Electrophoresis Chips Employing Focused Molecular Streams, Analytical Chemistry 71, 5137-5145 (1999).

15. Xie, J., Hung, S.-C., Glazer, A. N., and Mathies, R. A. Energy Transfer Fluorescent Labels for DNA Sequencing and Analysis, in Topics in Fluorescence Spectroscopy, Volume 7: ANA Technology, in press (1999).

16. Lagally, E., Simpson, P. C. and Mathies, R. A. Monolithic Integrated Microfluidic DNA Amplification and Capillary Electrophoresis System, Sensors and Actuators B 63, 138-146 (2000).

17. Medintz, I. L., Lee, C.-C. R., Wong, W. W., Pirkola, K., Sidransky, D. and Mathies, R. A. Loss of Heterozygosity Assay for Molecular Detection of Cancer using Energy-Transfer Primers and Capillary Array Electrophoresis, Genome Research, 10, 1211-1218 (2000).

18. Paegel, B. M., Hutt, L. D., Simpson, P. C. and Mathies, R. A. Turn Geometries for Minimizing Band Broadening in Microfabricated Capillary Electrophoresis Channels, Analytical Chemistry 72, 3030-3037 (2000).

19. Lagally, E. T., Paegel, B. M. and Mathies, R. A. Microfabrication Technology for Chemical and Biochemical Microprocessors, in Micro Total Analysis Systems 2000, eds. A. van den Berg, W. Olthuis and P. Bergveld, Kluwer Academic Publishers, Dordrecht, The Netherlands, pp. 217-220 (2000).

20. Medintz, I., Wong, W. W., Sensabaugh, G. and Mathies, R. A. High Speed Single Nucleotide Polymorphism Typing of a Hereditary Haemochromatosis Mutation with Capillary Array Electrophoresis, Electrophoresis 21, 2352-2358 (2000).

21. Wedemayer, G., Medintz, I., Wong, W. W., Scherer, J. R. and Mathies, R. A. Conversion of Capillary Electrophoresis Microchip Data for Analysis with Genetic Profiler Software, BioTechniques 30, 122-128 (2001).

22. Lagally, E. T., Medintz, I. and Mathies, R. A. Single Molecule DNA Amplification and Analysis in an Integrated Microfluidic Device, Anal. Chem. 73, 565-570 (2001).

23. Medintz, I., Wong, W. W., Berti, L., Shiow, L., Tom, J., Scherer, J. R., Sensabaugh, G. and Mathies, R. A. High Performance Multiplex SNP Analysis of 3 Haemochromatosis Related Mutations with Capillary Array Electrophoresis Microplates, Genome Research 11, 413-421 (2001).

24. Medintz, I., Wong, W. W. and Mathies, R. A. Fluorescence Labeling Methods for Microchannel Plate Capillary Electrophoresis DNA Sizing, Journal of Capillary Electrophoresis and Microchip Technology 7, 40-46 (2002).

25. Berti, L., Xie, J., Medintz, I. L., Glazer, A. N. and Mathies, R. A. Energy Transfer Cassettes for Facile Labeling of Sequencing and PCR Primers, Analytical Biochemistry 292, 188-197 (2001).

26. Berti, L., Medintz, I., Tom, J. and Mathies, R. A. Energy Transfer Cassette Labeling for Capillary Array Electrophoresis Short Tandem Repeat DNA Fragment Sizing, Bioconjugate Chemistry 12, 493-500 (2001).

27. Medintz, I. L., Paegel, B. M. and Mathies, R. A. Microfabricated Capillary Array Electrophoresis DNA Analysis Systems, J. Chromatography A 924, 265-270 (2001).

28. Medintz, I. L., Berti, L., Emrich, C. A., Tom, J., Scherer, J. R. and Mathies, R. A. Genotyping Energy-Transfer Cassette Labeled Short Tandem Repeat Amplicons with Capillary Electrophoresis Microchannel Plates, Clinical Chemistry 47, 1614-1621 (2001).

29. Scherer, J. R., Paegel, B., Wedemayer, G. J., Medintz, I. L., and Mathies, R. A. High Pressure Gel-Loader for Capillary Array Electrophoresis Microchannel Plates, BioTechniques 31(5), 1150-1155 (2001)

30. Medintz, I. L., Paegel, B. M., Blazej, R. G., Emrich, C. A., Berti, L., Scherer, J. R. and Mathies, R. A. High-Performance Genetic Analysis Using Microfabricated Capillary Array Electrophoresis Microplates, Electrophoresis, 22, 3845-3856 (2001).

31. Mathies, R. A., Smaller, Faster and More Sensitive: Electrophoretic DNA Analysis for the 21st Century, , in Molecular Testing in Laboratory Medicine, eds. D. E. Bruns, Y. M. D. Lo and C. T. Wittwer (AACC Press, Washington, DC), pp. 127-128 (2002).

32. Emrich, C. A., Medintz, I. L., Tian, H., Berti, L. and Mathies, R. A. (Ultra)2-High-throughput Genetic Analysis Using Microfabricated Capillary Array Devices, Micro Total Analysis Systems 2001, eds. J. M. Ramsey and A. van den Berg, Kluwer Academic (Dordrecht, The Netherlands), pp. 13-15.

33. Lagally, E. T. and Mathies, R. A. Integrated PCR-CE System for DNA Analysis to the Single Molecule Limit. Micro Total Analysis Systems 2001, eds. J. M. Ramsey and A. van den Berg, Kluwer Academic (Dordrecht, The Netherlands), pp. 117-118.

34. Paegel, B. M., Emrich, C. A., Blazej, R. G., Elkin, C. J., Scherer, J. R. and Mathies, R. A. Microfabricated Capillary Array Electrophoresis: High-throughput DNA Sequencing and Polymorphism Analysis, Micro Total Analysis Systems 2001, eds. J. M. Ramsey and A. van den Berg, Kluwer Academic (Dordrecht, The Netherlands), pp. 462-464.

35. Paegel, B. M., Emrich, C. A., Wedemayer, G. J., Scherer, J. R. and Mathies, R. A. High-Throughput DNA Sequencing with a 96-Lane Capillary Array Electrophoresis Bioprocessor, Proc. Natl. Acad. Sci. U.S.A., 99, 574-579 (2002).

36. Lagally, E. T., Emrich, C. A. and Mathies, R. A. Fully Integrated PCR-Capillary Electrophoresis Microsystem for DNA Analysis. Lab-on-A-Chip, 1 (2) 102-107 (2001).

37. Medintz, I. L., Berti, L. and Mathies, R. A. Novel Energy Transfer Fluorescence Labeling Cassette, BioTechniques 32, 270 (2002).

38. Emrich, C. A., Tian, H., Medintz, I. and Mathies, R. A. Microfabricated 384-Lane Capillary Array Electrophoresis Bioanalyzer for Ultra High-Throughput Genetic Analysis, Analytical Chemistry, 74, 5076-5083 (2002).

39. Mathies, R. A., Lagally, E. T., Kamei, T., Grover, W. H., Liu, C. N., Scherer, J. R. and Street, R. A. Capillary Array Electrophoresis Bioprocessors, Technical Digest of the 2002 Hilton Head Workshop on Solid-State Sensors, Actuators, and Microsystems, Hilton Head Island, SC, Transducers Research Foundation publishers, June 2-6, 2002, pp. 112-117.

40. Paegel, B. M., Yeung, S. H. I. and Mathies, R. A. Microchip Bioprocessor for
Integrated Nanovolume Sample Purification and DNA Sequencing, Anal. Chem. 74,
5092-5098 (2002).

41. Blazej, R. G., Paegel, B. M. and Mathies, R. A. SNP Discovery and Genotyping by Polymorphism Ratio Sequencing, Genome Research, 13, 287-293 (2003).

42. Grover, W. H., Skelley, A. M., Liu, C. N., Lagally, E. T., and Mathies, R. A. Monolithic Membrane Valves and Diaphragm Pumps for Practical Large-Scale Integration into Microfluidic Devices, Sensors & Actuators B, in press (2002).

43. Skelley, A. M., Grunthaner, F. J., Bada, J. L., and Mathies, R. A. Mars Organic Detector III: A Versatile Instrument for Detection of Bio-organic Signatures on Mars, SPIE Proceedings of the In-Situ Instrument Technologies Meeting, June 11-13, 2002, Pasadena, CA, in press (2003).

44. Grover, W. H., Skelley, A. M., Liu, C. N., Lagally, E. T., and Mathies, R. A. Practical Valves and Pumps for Large-Scale Integration in Microfluidic Devices, Micro Total Analysis Systems 2002, Volume 1, eds. Y. Baba, S. Shoji and A. van den Berg, Kluwer Academic (Dordrecht, The Netherlands), pp 136-138.

45. Paegel, B. M., Yeung, S. H. I., Scherer, J. R., and Mathies, R. A. Microfluidic Circuit for Integrated DNA Sequencing Product Purification and Analysis, Micro Total Analysis Systems 2002, Volume 2, eds. Y. Baba, S. Shoji and A. van den Berg, Kluwer Academic (Dordrecht, The Netherlands), pp 940-942.

46. Kamei, T., Scherer, J. R., Paegel, B.M., Skelley, A. M., Street, R. A., and Mathies, R. A. Integrated Amorphous Silicon Photodiode Detector for Microfabricated Capillary Electrophoresis Devices, Micro Total Analysis Systems 2002, Volume 1, eds. Y. Baba, S. Shoji and A. van den Berg, Kluwer Academic (Dordrecht, The Netherlands), pp 257-259.
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47. Emrich, C. A., and Mathies, R. A. The Õ-Injector: A new Electrokinetic Dispensing Element for Microdevice Separations, Micro Total Analysis Systems 2002, Volume 2, eds. Y. Baba, S. Shoji and A. van den Berg, Kluwer Academic (Dordrecht, The Netherlands), pp 748-749.

48. Paegel, B. M., Blazej, R. G., and Mathies, R. A. Microfabricated DNA Sequencing Devices, in Analytical Techniques in DNA Sequencing, eds. B. Nunnally and M. Kekker.

49. Lagally, E. T., and Mathies, R. A. Monolithic Integrated PCR Reactor-CE System for DNA Amplification and Analysis to the Single Molecule Limit, Proceedings of the 2nd Annual Int. IEEE-EEMBS Special Topic Conference on Microtechnologies in Medicine & Biology, eds. A. Dittmar and D. Beebe, pp. 437-441 (2002).

50. Blazej, R., Paegel, B. M., Emrich, C. A., and Mathies, R. A. Microfabricated capillary array electrophoresis: implementation and applications, In Lab-on-a-Chip/mTAS, ed. by A. Van den Berg, Elsevier, submitted.

51. Paegel, B. M., Blazej, R. G., and Mathies, R. A. Microfluidic Devices for DNA Sequencing Sample Preparation and Electrophoresis Analysis, Current Opinions in Biotechnology,14, 42-50 (2003).

52. Bromberg, A, and Mathies, R. A. Homogeneous Immunoassay for Detection of TNT and its Analogs on a Microfabricated Capillary Electrophoresis Chip, Anal. Chem., in press.

53. Chan, E.M., Mathies, R.A. and Alivisatos, A. P. Size-Controlled Growth of CdSe
Nanocrystals in Microfluidic Reactors, Nano Letters, in press.

More Opportunities:

For First-Year Graduate Students:

The Mathies group has outstanding opportunities for graduate research projects developing novel lab-on-a-chip microfabricated chemical and biochemical analysis systems. These devices are focused on genomic sequencing, genotyping, point-of-care analysis devices, forensics, DNA computing, space exploration, etc.

Current new research projects include:

1. Ultrahigh throughput microfabricated genetic and proteomic analyzers for medical diagnostics and health care monitoring

2. Development of miniaturized microfabricated chemical and biochemical analyzers for detection of extraterrestrial life signatures on Mars and Europa in collaboration with NASA.

3. Development of point-of-care and portable microanalysis devices for cancer diagnosis, infectious disease diagnosis and biothreat detection.

We are located in spacious new laboratory facilities in Lewis Hall and have a very active group of 15 scientists that includes lots of bioengineers. Rotation opportunities are currently available.

Please go to our web site http://www.cchem.berkeley.edu/ramgrp/alpha/ for a more detailed description of all the exciting projects being carried out.