Patent Grant
7790265
Not Applicable
This invention relates to a surface-energy gradient on a fluid-impervious surface and method of its creation.
Microscopic fluidic devices, ranging from surgical endoscopes and microelectromechanical systems to the commercial ‘lab-on-a-chip’, allow chemical analysis and synthesis on scales unimaginable a few decades ago (Kataoka and Troian, 1999). Advances in microfabrication techniques have led to the ability to manufacture flow channels ranging from a few hundred angstroms to a few hundred microns (Pfahler, et al, 1990). However, due to the microscopic scale of the systems involved, fluid transport and friction losses are problematic. Different methods using temperature, pressure, or electric potential gradients have been developed to transport fluid through these systems. Each of these methods increases the energy required to operate such systems, and none of the methods solve the problem of fluid friction losses.
Friction arises from the adhesive forces between two surfaces in contact In the absence of wear and plastic deformation, as is the case in fluid transport in microscale systems, friction is largely attributable to interfacial effects (Krim, 1996). For laminar flow in channels, fluid friction loss (f) can be estimated as
f=16/Re
where Re=Reynolds Number (ρ v DC/μ)
Therefore, as Dc begins to approach micron and angstrom dimensions, friction loss increases greatly.
Organic thin films have been used to control friction and wear in a variety of machines. As machines get even smaller, and lubricating films approach the monolayer regime, self-assembled monolayer films show great potential for use in such items. SAM films have been shown to reduce the friction between two surfaces. By changing the energy of the surface, the SAM can prevent a fluid such as water from wetting the surface. A reduction in the attraction between the fluid and the tail group of the SAM will result in a reduction in friction.
Several studies have been conducted on the frictional properties of SAMs. These studies have shown how friction varies depending on the structure and composition of the SAM. Most of these studies used Atomic Force Microscopy (AFM) to measure friction. This measurement is performed by passing the AFM probe tip over the SAM surface. The frictional response of the surface is measured by the AFM as the normal force exerted by the probe is varied. In their 1996 paper, Xiao et al determined how the chain length of the SAM affected friction. Their work with mica surfaces showed that longer-chain SAMs reduce friction the most. Longer chain molecules form films that are typically more densely packed and more crystalline in structure than shorter chain molecules do. The enhanced crystalline structure and better packing provide a lower friction surface (Liu and Evans, 1996). Their work with SAM films on gold surfaces led to the same conclusions regarding chain length and crystalline structure.
The effect of the tail group was then studied. Researchers determined that frictional behavior closely followed the variation of the adhesive properties, meaning low-energy surfaces had the lowest friction while high-energy surfaces such as —NH2 produced higher amounts of friction loss (Tsukruk and Bliznyuk, 1998). Kim et al in 1999 found that among low energy surfaces, those with the smallest head group yielded the surface with the lowest friction. Specifically, CF3-terminated films had three times the friction of CH3-terminated films.
In addition to lowering the friction between two surfaces, SAMs can have a dramatic effect on the ability of a fluid to wet a surface. For instance, CH3-terminated SAMs produce low energy, hydrophobic surfaces that are not wet by water while CO2H-terminated SAMs produce high energy, hydrophilic surfaces that are almost completely wet by water. The contact angle that water forms with a surface is a good indication of the surface's hydrophilicity or hydrophobicity. For instance, water forms a contact angle of 115° with CH3 surfaces while it forms a contact angle of<15° with CO2H surfaces. In general, as the contact angle decreases, water has more affinity for the surface and will more easily wet it (Laibinis et al, 1998).
A system that reduced friction losses and improved fluid transport would have a great benefit.
All US patents and applications and all other published documents mentioned anywhere in this application are incorporated herein by reference in their entirety.
Without limiting the scope of the invention a summary of some of the claimed embodiments of the invention is set forth below. Additional details of the summarized embodiments of the invention and/or additional embodiments of the invention may be found in the Detailed Description of the Invention below.
A brief abstract of the technical disclosure in the specification is provided as well only for the purposes of complying with 37 C.F.R. 1.72. The abstract is not intended to be used for interpreting the scope of the claims.
The proposed system uses self-assembled monolayer (SAM) films to modify the surfaces of the channels; a novel design is proposed which modifies the channel using a mixed SAM surface so that fluids are transported with minimal or reduced external forces required. The proposed design will result in microfabricated systems that are smaller and more energy-efficient
In one embodiment a method of derivatizing a fluid-impervious surface with a mixed monolayer to create a surface energy gradient comprises the following steps: a) exposing a base surface having a proximal and a distal portion to a first solution comprising at least one molecule of the formula X-J-M1, wherein X and M1 represent separate functional groups and J represents a spacer moiety that, together, are able to promote formation from solution of a self-assembled monolayer for sufficient time to form a monolayer surface having a uniform surface energy on the base surface.
b) removing a portion of the monolayer of step (a) such that a portion of the base surface is again fully or partially exposed. c) exposing the portion of the base surface from (b) to another molecule including a functional group having a different surface energy from that of the functional group removed in (b) such that a surface energy gradient from a proximal location to a distal location is formed.
In another embodiment, removing a portion of the monolayer is done while the base surface and monolayer surface are immersed in the first solution or a second solution comprising at least one molecule of the formula X-J-M1 as in (a).
In another embodiment, removal of the portion of the monolayer of (a) is performed while at the same time increasing amounts of a third solution comprising a molecule of the formula X-J-M2 where X and J are the same as in (a), but M2 is a functional group with a different surface energy than M1 so that a mixed monolayer surface of M1 and M2 moieties is formed with a molar ratio of M2 to M1 that continually increases from a proximal location to a distal location of the surface of (b) thereby creating a gradient.
In yet another embodiment, the X and J groups of the third solution are different from the X and J groups of the first solution or the X and J groups of the second solution.
In another embodiment, the third solution has a solvent different from that of the first solution or the second solution.
In several other embodiments, the gradient is created on 1) the inside of a tube, 2) the outside of a tube, 3) on a rectangular channel having three walls and one side open, 4) on only 1 face of the channel, 5) on 2 faces of the channel, and 6) on 3 faces of the channel.
In another embodiment, the base surface is a metal oxide comprising a metal oxide from the group comprising silica, alumina, quartz, glass, or the like. In such case, the functional group X is carboxylic acids.
In an additional embodiment, the base surface is a metal selected from the group comprising gold, silver, copper, cadmium, zinc, palladium, platinum, mercury, lead, iron, chromium, manganese, tungsten, and any alloys of the above. In such case, the functional group X is a sulfur-containing functional group (e.g.thiols, sulfides, disulfides, and the like).
In another embodiment, the base surface is doped or undoped silicon. In such case, the functional group X is selected from the group comprising silanes or chlorosilanes.
In another embodiment, the base surface is a metal selected from the group comprising palladium and platinum. In such case, the functional group X is a functional group selected from the group comprising nitrites and isonitriles.
In another embodiment, the base surface is copper. In such case, the functional group X is a hydroxamic acid.
In another embodiment, the base surface is gold. In such case, the functional group X is at least one sulfur-containing functional group selected from the group comprising thiols, sulfides, or disulfides.
In another embodiment, the functional group M is selected from the group comprising ionic, nonionic, polar, nonpolar, halogenated, alkyl, aryl or other functionalities,
In other embodiments, the functional group M can include any one of the following —OH, —CONH—, —CONHCO—, —NH2, —NH—, —COOH, —COOR,—CSNH—, —NO2−, —SO2−, —RCOR—, —RCSR—, —RSR, —ROR—, —PO4−3, —OSO3−2, —SO3−, —NHxR4-x+, —COO−, —SOO−, —RSOR—, —CONR2, —(OCH2CH2)nOH (where n=1-20, preferably 1-8), —CH3, —PO3H−, -2-imidazole, —N(CH.sub.3)2, —NR2, —PO3H2, —CN, —(CF2)nCF3 (where n=1-20, preferably 1-8), CO2CH3, CONHCH3, CH3, CHCH2, OCH2CF2CF3, (CF2)5CF3, (CF2)7CF3, OCH3, CN, Cl, Br, olefins, and the like.
In the above list, R is hydrogen or an organic group such as a hydrocarbon or fluorinated hydrocarbon. As used herein, the term “hydrocarbon” includes alkyl, alkenyl, alkynyl, cycloalkyl, aryl, alkaryl, aralkyl, and the like. The hydrocarbon group may, for example, comprise methyl, propenyl, ethynyl, cyclohexyl, phenyl, tolyl, and benzyl groups. The term “fluorinated hydrocarbon” is meant to refer to fluorinated derivatives of the above-described hydrocarbon groups.
In another embodiment, J is a hydrocarbon chain with the formula —(CH2)n— where n is between 1 and 22, preferably between 2 and 18, more preferably between 2 and 12.
In other embodiment of the invention are 1) a surface that is a surface energy gradient, 2) a surface utilizing a surface energy gradient, 3) a surface that is a surface energy gradient as produced by any of the methods of the claims, and 4) a surface utilizing a surface energy gradient as produced by any of the methods of the claims.
Another embodiment of the invention is a surface as produced by any of the methods of the claims that is used in lab-on-a-chip technology.
In another embodiment, the monolayer surfaces of channels and passages are constructed and arranged such that a single drop or multiple drops of fluid requires less external force to move through channels and passages with the monolayer surface than channels and passages without the monolayer surface.
In another embodiment, the monolayer surfaces are constructed and arranged such that instead of having separate wells where the fluid is delivered and analyzed, the analysis could be done while the fluid moves along the channels. Reactive chemicals can be incorporated into the surface with the surface energy gradient so that the certain chemicals, proteins, etc. could be detected in the drop as it moves along the surface.
In another embodiment, the gradient is created on a standard micromachined array of channels in silicon. Because silicon oxide is a high-energy surface, water will wet it very easily, and friction losses would be high. The high-energy silicon oxide surface can be converted into a low-energy surface by depositing a SAM film on the silicon that will repel water and reduce friction. Based on the details of the experiments discussed in the previous section, the best SAM would be obtained from an alkylsilane-based surfactant with a silane head group and a —CH3 (methyl) tail group. The silane head group will bond with the silicon, resulting in a SAM film with a —CH3 surface. The carbon chain backbone of the SAM should be a single chain and contain at least 12 carbons. This type of SAM will pack very closely, resulting in a lowered friction loss. A molecule with a carbon chain backbone of at least 6 carbons will still pack tightly as well.
In addition to reducing friction, another use for SAMs is in the area of fluid transport. An embodiment of the invention includes a design which gives a means of transporting liquids across a surface without using any external forces in some instances and reduced external forces in other cases. This self-propulsion of liquid drops allows microfabricated systems much more efficient.
An embodiment of the inventive method takes advantages of the ability of SAM films to modify the surface energy of a substrate. By changing the tail group of a SAM from, for example, a —CH3 group to an —OH or —CO2H group, the surface can change from a low-energy surface to a high-energy surface. Water will not wet a low-energy surface, but it will wet a high-energy surface. Therefore, a surface having a surface energy gradient allows water to move across the surface from areas of low energy into areas of higher and higher surface energy. Embodiments of the SAMs of this invention can be used to create such a surface energy gradient.
In an embodiment of the inventive method, a mixed SAM surface is created on a silicon oxide semiconductor surface using two separate SAM surfactant solutions, an AFM tip for nanografting, and a flow controller with picoliter capability for liquid additions. The system is inventive and unique in that it creates a fluid-impervious surface with a gradient in surface energies.
In the first step of this embodiment, the semiconductor surface is exposed to a toluene solution containing an octadecyltrichlorosilane (this is the first SAM surfactant solution) capable of forming a SAM on the surface.
In a specific embodiment, the surface being treated will remain in solution while an AFM tip passes over the surface and begins to remove parts of the original SAM and expose the original semiconductor surface. At the same time the AFM begins to remove the original SAM film, drops of toluene solution containing an organotrichlorosilane surfactant with a high-energy tail group such as —CO2H will be added to the solution The two surfactants (one with the high energy tail group the other with the low energy tail group) will form a mixed SAM on the area where the instrument scraped the previous SAM away. The instrument will continue to scrape along the original surface and remove the original SAM while more of the CO2H-terminated surfactant is added to the solution. This process can continue along the entire length of the channel; as the instrument passes along the surface, the concentration of CO2H-terminated surfactant continually increases in the solution. As the percentage of CO2H-terminated surfactant in solution continually increases, the percentage of CO2H-groups continually increases in the mixed monolayer that forms along the path of the AFM tip. The mixed SAM that forms will have a continuously increasing —CO2H concentration at the surface. Therefore, the surface energy increases along the length of the channel.
octadecyltrichlorosilane (CH3(CH2)17SiCl3) in toluene used as low-energy surfactant
dodecanethiol (CH3(CH2)11SH) in ethanol used as low-energy surfactant
Additional materials and functional groups suitable for use in the present invention can be found in U.S. Pat. No. 5,079,600, issued Jan. 7, 1992, and incorporated herein by reference.
The SAM-forming compound may terminate in a second end, opposite to the end bearing the functional group selected to bind to the surface material, with any of a variety of functionalities. That is, the compound may include a functionality that, when the compound forms a SAM on the surface material, is exposed. Such a functionality may be selected to create a SAM that is hydrophobic, hydrophilic, that selectively binds various biological or other chemical species, or the like. Other groups for M are found in columns 8 and 9 of U.S. Pat. No. 5,776,748.
U.S. Pat. No. 4,690,715 contains good examples of chemicals to use with different surfaces. Other useful patents are U.S. Pat. Nos. 5,620,850, 5,079,600, 5,512,131, 6,235,340. All of the above patents are herein incorporated by reference.
Another embodiment of an inventive method starts with a silicon surface that has a gold, silver, or copper coating on it. With this system embodiment, thiols could be used instead of silanes and ethanol could be used instead of toluene. The process could then take place under ambient conditions. Thiols offer more stability than silanes under many conditions, and ethanol is less hazardous than toluene. Also, the time required to form SAM films on gold, silver, and copper from thiols in solution is often much shorter than the time required to form SAMs from silanes. It can take as little as five minutes to form SAM films on gold surfaces using ethanol solutions containing thiols. It should be noted, that other SAM-forming compounds that work similarly to thiols or those having at least one sulfur-containing functional groups (e.g. sulfide or disulfide) can be selected.
Occasionally, trichlorosilanes or thiols with high-energy tail groups are difficult to synthesize. This method can still be used to create a surface energy gradient by using a trichlorosilane or thiols containing a tail group that has only a slightly higher surface energy than the tail group used in the first step.
The mixed-monolayer film that is formed can be reacted with other reagents to increase the surface energy gradient. For example, a trichlorosilane or thiols with a ═CH2 tail group could be used as the second surfactant in this example. The resulting surface of —CH3 and ═CH2 tail groups could undergo a series of reactions to convert the ═CH2 tail groups into —CO2H groups while leaving the —CH3 groups unreacted. Thus, this process embodiment allows the surface energy gradient to be increased further.
In this embodiment of the invention, the resulting surface could allow for self-propulsion of water or other aqueous fluid or drops thereof. Such a drop of water or other aqueous fluid forms a decreasing contact angle along such a surface and has increasing forces of attraction to such a surface along its length. An organic or oil-bearing fluid could be propelled in a similar manner by starting with a high-energy surface (such as —CO2H) and decreasing the surface energy along the length of the surface or channel using low-energy groups (such as —CH3).
In an embodiment using water, if a drop of water is placed at the beginning of the channel, it will not wet the channel because of the low-energy methyl surface. However, it is attracted to the slightly higher energy surface composed of a mixed methyl and —CO2H surface. As the CO2H concentration of the surface increases, the force of attraction between the water and the surface increases. The contact angle between the advancing drop and the mixed-SAM surface decreases along the length of the channel. Therefore, the drop can propel itself across the surface without the use of any external forces. By changing the surfactant additions so that a surface is created with a surface energy gradient from high-surface energy to low-surface energy, the design would allow for a low-energy nonpolar molecule such as a drop of oil to propel itself across the surface. The design could also be used for systems where one merely wishes to reduce the external energy required to transfer a liquid across a surface.
It should be recognized to one skilled in the art that a multitude of surfaces and surfactants could be used in combinations to form monolayer films. Such combinations are considered covered by this invention. It should also be recognized to those skilled in the art that many different instruments capable of operating at the nanoscale-scale and smaller level can be used with this invention. Such uses are also covered by this invention. Means of optimizing this process by adjusting surfactant concentrations in solution, solutions used, exposure times, instrument speeds, geometries, temperatures, substrates, etc. to fit other systems are covered by this invention.
It should be noted that in another embodiment of the invention, the instrument that removes the original SAM film can also be used to deliver the mixed-SAM solution to the bare surface. For example, a reservoir inside the instrument could contain a mixed-SAM solution. This solution could then be delivered to the surface at an increasing rate of delivery so that the surface energy gradient is created.
In another embodiment, the mixing of the SAM solutions could take place inside the reservoir. The composition of the mixed-SAM solution would change as one SAM solution is gradually added to the original solution inside the reservoir. This solution could then be delivered to the surface at a constant rate of delivery so that the surface energy gradient is created.
In another embodiment, the mixing could take place outside the reservoir and then delivered to the surface by various means, one embodiment of which is through the removal instrument.
In another embodiment, it is not necessary for the reservoir in either example to contain a mixed-SAM solution. It can contain only one SAM in solution. The rate of delivery of this solution could be varied to create the surface energy gradient. In another embodiment, the surface is used for improving fluid flow in diagnostic systems that incorporate chemical, biological, or genomic sensors on the surface. It is also useful in making such systems even smaller and more efficient.
In another embodiment, the surface gradient is applied to DNA microarray slides. Current slides are composed of single strands of DNA attached on a glass slide to form discrete dots in an array pattern. Several hundred or more dots currently can be put on a slide. A solution containing single strands of DNA is poured on top of the slide. The DNA strands in solution eventually match up to the matching stationary strand on the slide. Because the slides are manufactured so that the specific location and composition of the stationary strand is known, one can determine the DNA make-up of the solution by identifying where the DNA coupling reaction occurs.
A further embodiment of this invention, would improve the fluid transport across the slide. Instead of waiting for the DNA strands to diffuse through solution until it finds its matching strand, the fluid is directed across the slide so that it is distributed more efficiently. This would also make the slides much smaller. Rather than having strands in dots, they could be in a series of lines along the surface. As the fluid moves across the surface due to the surface energy gradient, the DNA will react to the matching strand as it passes over it.
Another embodiment is the use of this surface in miniaturized systems that require cooling. The fluid is transported through coolant channels using the surface energy gradient. Reducing the surface tension of a fluid allows it to flow into regions of smaller and smaller dimensions. Any type of semiconductor, electromechanical, or optoelectronic device that requires cooling to operate the most efficiently could use this technology. The invention would also allow such systems to be made even smaller because the size of the device would not face the heat transfer limitations that so many current devices have.
Another embodiment is the use of the surface gradient in medical devices, treatments and artificial organs. Small tubes with a surface energy gradient on the inside surface are able to function as capillaries or other blood vessels. The blood would naturally flow through the tube; surface tension would not prevent it from moving into recesses and other extremely small openings.
Another embodiment is the use of the surface gradient in depositing metal or other components on hard to reach and surfaces in corners or deep recesses. For example, an electroless plating solution could be transported to an inside corner deep within an object using this invention. Metal could then be deposited in an area that was previously unable to be coated.
Another embodiment is the use of the surface gradient in not only just using these systems to merely detect and analyze solutions, this invention can be used in objects and devices that actually treat and/or deliver medical benefits. For instance, a vein or artery surface (either natural or artificial) could be treated so that it has a surface energy gradient that causes plaque or cholesterol particles to be transported to specific areas where they are reacted with a component that destroys them in solution. This would prevent cholesterol from building up on the walls.
Another embodiment is the use of the surface gradient in integration with biopharmaceutical molecules that recognize a certain genetic or protein sequence. When virus or cancer or other disease molecules containing that sequence are transported across the surface, the reactive chemical recognizes the sequence of interest and kills the harmful molecule.
These and other embodiments which characterize the invention are pointed out with particularity in the claims annexed hereto and forming a part hereof. However, for a better understanding of the invention, its advantages and objectives obtained by its use, reference should be made to the drawings which form a further part hereof and the accompanying descriptive matter, in which there is illustrated and described a embodiments of the invention.
While this invention may be embodied in many different forms, there are described in detailed herein specific preferred embodiments of the invention. This description is an exemplification of the principles of the invention and is not intended to limit the invention to the particular embodiments illustrated.
As used herein, the term “tube” is any hollow object open on two sides without limitation by cross-sectional geometries.
Turning now to the drawings,
Unlike prior art examples, the surface energy gradient of this invention is designed to be formed with well-defined dimensions that correspond to the features of the instrument used in the process. The length (L) of the gradient will correspond to the length of the path traced by the instrument while the width (W) of the gradient will correspond to the width of the instrument tip used to expose the base layer. Thus, a very long and thin gradient region can be created with this method with aspect ratios (length divided by width, L/W) that can vary from 2.0, 10.0, to essentially an infinite number. Nanografting using an Atomic Force Microscope (AFM) as the instrument will produce surface energy gradients with the smallest width dimension. As an example, AFM instruments with a tip radius of 20-nm could be used in the invention (Liu and Evans, p. 1236, col. 2). Using this instrument, a surface energy gradient region of 20 nm wide by 1000 nm long could be created; such a region would have an aspect ratio of 50. Gradients with higher aspect ratios (10,000 or greater) can be created by increasing the path length traced by the instrument. High aspect ratio gradient regions could also be made using AFMs with tip radii in the 40-500 nm to produce gradient regions with a larger width W (Tsukruk and Bliznyuk, p.448, col.1). Other instruments such as those commonly used in micromachining applications can be used. Micromachining applications are capable of using manufacturing channels with widths in the 100-1000 micron range while standard machining techniques can produce channels with widths in the 1.0-10.0-mm range.
At least one embodiment of the invention comprises a surface energy gradient that is designed with dimensions that correspond to the features of the instrument used in the process. The length (L) of the gradient can correspond to the length of the path traced by the instrument while the width (W) of the gradient can correspond to the width or radius of the instrument tip used to expose the base layer. Thus, a very long and thin gradient region can be created with this method with aspect ratios (length divided by width, L/W) that can vary from 2.0. 10.0, to essentially an infinite number. Nanografting using an Atomic Force Microscope (AFM) as the instrument will produce surface energy gradients with very small width dimensions. As an example, AFM instruments with a tip radius of 20-nm can be used in the invention (Liu and Evans, p. 1236. col. 2). Using this instrument, a surface energy gradient region of 20 nm wide by 1000 nm long can be created; such a region would have an aspect ratio of 50. Gradients with higher aspect ratios (10,000 or greater) can be created by increasing the path length traced by the instrument. High aspect ratio gradient regions can also be made using AFMs with tip radii in the 40-500 nm to produce gradient regions with a larger width W (Tsukruk and Bliznyuk, p.448, col.1). Other instruments such as those commonly used in micromachining applications can be used. Micromachining applications are capable of using manufacturing channels with widths in the 100-1000 micron range while standard machining techniques can produce channels with widths in the 1.0-10.0-mm range. Although long, narrow gradient regions are described here, shorter and wider gradient regions can also be produced.
In
While this invention may be embodied in many different forms, there are described in detail herein specific preferred embodiments of the invention. This description is an exemplification of the principles of the invention and is not intended to limit the invention to the particular embodiments illustrated.
For the purposes of this disclosure, like reference numerals in the figures shall refer to like features unless otherwise indicated.
The above disclosure is intended to be illustrative and not exhaustive. This description will suggest many variations and alternatives to one of ordinary skill in this art. All these alternatives and variations are intended to be included within the scope of the claims where the term “comprising” means “including, but not limited to”. Those familiar with the art may recognize other equivalents to the specific embodiments described herein which equivalents are also intended to be encompassed by the claims.
Further, the particular features presented in the dependent claims can be combined with each other in other manners within the scope of the invention such that the invention should be recognized as also specifically directed to other embodiments having any other possible combination of the features of the dependent claims. For instance, for purposes of claim publication, any dependent claim which follows should be taken as alternatively written in a multiple dependent form from all prior claims which possess all antecedents referenced in such dependent claim if such multiple dependent format is an accepted format within the jurisdiction (e.g. each claim depending directly from claim 1 should be alternatively taken as depending from all previous claims). In jurisdictions where multiple dependent claim formats are restricted, the following dependent claims should each be also taken as alternatively written in each singly dependent claim format which creates a dependency from a prior antecedent-possessing claim other than the specific claim listed in such dependent claim below.
This completes the description of the preferred and alternate embodiments of the invention. Those skilled in the art may recognize other equivalents to the specific embodiment described herein which equivalents are intended to be encompassed by the claims attached hereto.
Such information as may be found relating to portions of this application include:
This application claims priority from the provisional application 60/335,165 filed Nov. 1, 2001.
| Filing Document | Filing Date | Country | Kind | 371c Date |
|---|---|---|---|---|
| PCT/US02/35134 | 11/1/2002 | WO | 00 | 8/12/2004 |
| Publishing Document | Publishing Date | Country | Kind |
|---|---|---|---|
| WO03/076082 | 9/18/2003 | WO | A |
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| 6770323 | Genzer et al. | Aug 2004 | B2 |
| 20020142453 | Abbott et al. | Oct 2002 | A1 |
| Number | Date | Country | |
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| 20050227232 A1 | Oct 2005 | US |
| Number | Date | Country | |
|---|---|---|---|
| 60335165 | Nov 2001 | US |
