Microfluidic device with multiple microcoil NMR detectors...

Details Microfluidic device with multiple microcoil NMR detectors... Microfluidic device with multiple microcoil NMR detectors...

2001-12-03

2004-11-23

Gutierrez, Diego (Department: 2859)

Electricity: measuring and testing

Particle precession resonance

Spectrometer components

C324S306000

Reexamination Certificate

active

06822454

ABSTRACT:

FIELD OF THE INVENTION
The present invention is directed to microfluidic devices having multiple microcoil nuclear magnetic resonance (NMR) detectors and, more particularly to microfluidic devices having improved microcoil NMR detectors for capillary-scale, high resolution NMR spectroscopy probes capable of enhanced sample processing functionality.
BACKGROUND
Nuclear magnetic resonance spectroscopy, or NMR, is a powerful and commonly used method for analysis of the chemical structure of molecules. NMR provides spectral information as a function of the electronic environment of the molecule and is nondestructive to the sample. In addition, reaction rates, coupling constants, bond-lengths, and two- and three-dimensional structure can be obtained with this technique.
Systems for biochemical, chemical, and molecular analysis can be miniaturized as capillary-based systems or substrate-based, i.e., micro-scale, systems with multifunctional capabilities including, for example, chemical, optical, fluidic, electronic, acoustic, and/or mechanical functionality. Miniaturization of these systems offers several advantages, including increased complexity, functionality, and efficiency. Devices can be fabricated from diverse materials including, for example, plastics, polymers, metals, silicon, ceramics, paper, and composites of these and other materials. Mesoscale sample preparation devices for providing microscale test samples are described in U.S. Pat. No. 5,928,880 to Wilding et al. Devices for analyzing a fluid sample, comprising a solid substrate microfabricated to define at least one sample inlet port and a mesoscale flow channel extending from the inlet port within the substrate for transport of a fluid sample are described in U.S. Pat. No. 5,304,487. Currently known miniaturized fluid-handling and detection devices have not met all of the needs of industry.
NMR is one of the most information-rich forms of biochemical, chemical, and molecular detection and analysis, and remains highly utilized in a wide range of health-related industries, including pharmaceutical research and drug discovery. One of the fundamental limitations of NMR for these and other applications involves sample throughput. When compared to other forms of detection (e.g., mass spectrometry), the amount of sample required by NMR is generally orders of magnitude greater, and correspondingly the mass limits of detection are generally orders of magnitude poorer. Conventional NMR spectrometers typically use relatively large RF coils (mm to cm size) and samples in the ml volume range, and significant performance advantages are achieved using NMR microcoils when examining very small samples. Prior to such development of microcoil NMR and NMR flowprobes, NMR remained a test tube-based analytical technique requiring milliliters of sample and often requiring data acquisition times ranging from 10 min. to several hours for informative spectra with sufficient signal to noise ratio (“S/N”).
NMR microcoils are known to those skilled in the art and are shown, for example, in U.S. Pat. No. 5,654,636 to Sweedler et al., and in U.S. Pat. No. 5,684,401 to Peck et al., and in U.S. Pat. No. 6,097,188 to Sweedler et al., all three of which patents are incorporated herein by reference in their entireties for all purposes. A solenoid microcoil detection cell formed from a fused silica capillary wrapped with copper wire has been used for static measurements of sucrose, arginine and other simple compounds. Wu et al. (1994a), J. Am. Chem. Soc. 116:7929-7930; Olson et at. (1995), Science 270:1967-1970, Peck (1995) J. Magn. Reson. 108(B) 114124. Coil diameter has been further reduced by the use of conventional micro-electronic techniques in which planar gold or aluminum R.F. coils having a diameter ranging from 10-200 &mgr;m were etched in silicon dioxide using standard photolithography. Peck 1994 IEEE Trans Biomed Eng 41(7) 706-709, Stocker 1997 IEEE Trans Biomed Eng 44(11)1122-1127, Magin 1997 IEEE Spectrum 34 51-61, which are also incorporated herein by reference in its entirety for all purposes. In Stocker et al. a microcoil was fabricated on a gallium arsenide substrate with an inner diameter of 60 &mgr;m, an outer diameter of 200 &mgr;m, trace width of 10 &mgr;m, trace spacing of 10 &mgr;m, and trace height of Sum. At 5.9T (250 MHz) in 1H-NMR micro spectroscopy experiments using a spectral width of 1 kHz, 4096 sampled data points, and a recovery delay of 1 s, a SNR of 25 (per acquisition) and a spectral line width of less than 2 Hz were obtained from a sample of water.
Miniature total analysis systems (&mgr;-TAS) are discussed in Integrating Microfluidic Systems And NUR Spectroscopy—Preliminary Results, Trumbull et al, Solid-State Sensor and Actuator Workshop, pp. 101-05 (1998), Magin 1997 IEEE Spectrum 34 51-61, and Trumbull 2000 47(1)1-6 incorporated herein by reference in its entirety for all purposes. These groups constructed chip-based capillary electrophoresis (CE) devices equipped with an integrated planar radio frequency detector coil used for nuclear magnetic resonance spectroscopy (NN R). Separations were accomplished in the devices, but satisfactory NMR spectra could only be obtained from samples of high concentration. Two prototype CE-NMR devices are presented that represent complete microanalytical instruments. Further, “The first system, Trident, was designed to be a proof-of-concept fluidic-NMR device to gauge the effectiveness of integrated, single-turn planar NMR coils. The channel network was formed by solvent bonding a photopatterned polyimide coating (on a glass slide) with a cover-glass coated with a thin layer of polyimide. Holes were previously drilled ultrasonically in the glass slide to provide access. A lift-off process was used to create a 1 mm diameter, single-turn coil on the outer surface of the cover glass. The metal was formed from 3 evaporated layers: Cr/Cu/Cr with respective thicknesses of 150, 9700, and 150 angstroms for improved susceptibility matching. The resistance of the coil, pad to pad, was measured to be 5.90. Acrylic wells were then placed over the drilled holes and bonded with epoxy. The second device type created, SpinCollector shown in
FIG. 1
blowups, was made from etched glass channels using methods developed from (D. J. Harrison and N. Chiem, “Immunoassay Flow Systems On-Chip,” TRF, pp. 5-8., 1996). Annealed Pyrex glass wafers (1 mm thick) were etched in HF and HNO3 to a depth of 20 &mgr;m through a Cr/Au mask. Access holes were drilled ultrasonically and, the mask was stripped. The wafers were then cleaned in a 1% HF bath for 1 minute with ultrasonic agitation to remove any loose glass particles. After thorough cleaning, the wafers were thermally bonded to unprocessed pieces forming closed channels. A 5 mm diameter, single-turn coil was then formed through lift-off on the undrilled cover-glass slide over the disk-shaped reservoir, and glass wells were attached using epoxy. The Trumbull et al. device integrated multiple chemical processing steps and the means of analyzing their results on the same miniaturized system. Specifically, Trumbull et al. coupled chip-based capillary electrophoresis (CE) with nuclear magnetic resonance spectroscopy (NMR) in a &mgr;-TAS system.
Capillary-based liquid chromatography and microcoil NMR have compatible flow rates and sample volume requirements. Thus, for example, the combination of the Waters CapLC™ available from Waters Corporation (Milford, Mass., USA) and the MRM CapNMR™ flow probe available from MRM Corporation (Savoy, Ill.), a division of Protasis Corporation (Marlborough, Mass., USA) provides excellent separation capability in addition to UV-VIS and NMR detection for mass-limited samples. The Waters CapLC™ has published flow rates from 0.02 &mgr;L/minute to 40 &mgr;L/minute. A typical CapLC on-column flow rate is 5 &mgr;L/min, the autosampler-injected analyte volume is 0.1 &mgr;L or more, and accurate flow rates are achieved through capillary of typically 50 &mgr;m inner diameter. The NMR flow cell has a typical total volume of 5 &mgr;L with a

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