Patent Application
20120208222
1. Field of the Invention
This invention relates to microchemical reactors employing microencapsulated reagents to facilitate chemical reactions and cascades for sensors, analytical systems and other chemical, biochemical and medical applications.
2. Description of the Prior Art
It is the objective of this invention to provide a fast, simple, inexpensive, and convenient way to perform chemical reactions for analytical devices, chemical sensors and detectors, and other applications involving chemical reactions and chemical cascades. This invention uses microencapsulated reagents where the microcapsules are designed such that a chemical reaction, once started, automatically proceeds to its completion. Prior art exists for the technology of microencapsulating chemicals, and this invention makes use of the prior art of microencapsulation. Prior art also exists for handheld, easy to use, tranportable chemical sensors and diagnostic devices for medical and environmental applications. Some examples of devices that are on the market at the time of this writing include blood glucose meters, home cholesterol tests, and point-of-care C-reactive protein tests. There is also a need for devices that can detect potentially harmful chemicals in the environment, such as pesticides and herbicides. This invention provides a new technique for making handheld devices that will allow inexpensive and easy to use chemical analysis systems and devices.
This invention further allows chemical reactions to be incorporated into every day objects. For example, bathroom tissue, cotton swabs, as well as other objects that come into contact with the human body or bodily fluids may now become a medical diagnostic, or environmental measuring device. This would allow individuals to test themselves for diseases, monitor their health, or test their environment for dangerous chemicals.
Prior art exists to incorporate a test for fecal occult blood into toilet paper. U.S. Pat. No. 5,840,584 describes a device where the fecal occult blood test is incorporated into bathroom tissue, allowing people to detect fecal occult blood in their feces. This invention, however, does not use microencapsulated reagents. It describes a sheet of brittle material which houses a plurality of chambers which hold a liquid reagent solution. It also requires absorbent material impregnated with another reagent, guiaiac material. This invention is difficult and expensive to manufacture.
Prior art exists for the mitigation of a chemical or biological compound. For example, if chemical warfare agents or bacterial spores are applied to a surface, the area needs to be decontaminated. In the case of chemical agents and biological spores that have contaminated a building structure and its contents, foams have been devised which are applied to contaminated surfaces. The foams deliver reagents that denature these chemical and biological agents, rendering them non toxic. In current practice water and surfactant are mixed with air to produce a free flowing foam. An active ingredient which denatures the chemical or biological agent is added to the foam. Because of the method by which the active ingredient is entrained in the aqueous foam, much of its effectiveness to mitigate the chemical or biological agent is lost. Another problem of the current technology is short shelf life of the active ingredients.
Prior art exists to encapsulate chemical reagents. A reagent is said to be encapsulated when it is immobilized in microcapsules ranging from a diameter of a less than a micrometer to millimeters. Micro-capsules have shells that can be made of various materials. The encapsulated reagent within the shell is not chemically affected by the encapsulation process. The micro-encapsulation process protects the reagent from the environment.
Prior art techniques exits to control microcapsule sizes and volume of contents. Those skilled in the art of microencapsulation can design porous microcapsule shell walls to allow reagents to enter and exit the microcapsule. This might be useful to allow access to a microencapsulated enzyme or catalyst. Techniques are known to produce friable microcapsules that liberate their contents when mechanically ruptured.
Prior art exists which combines microencapsulated reagents on test swabs. U.S. Pat. No. 5,278,075 describes a swab for detecting the presence of a metal on a solid surface which comprises a microencapsulated reagent that reacts with the metal. However this patent does not claim to colocate multiple microencapsulated reagents such that more than one microencapsulated reagent may partake in a chemical reaction or cascade. Additionally, this patent does not provide a support that serves as a known volume, allowing stoichiometric analytical chemistry and therefore measurements of analyte concentration. This patent also does not provide for microencapsulated process solvent.
U.S. Pat. No. 6,406,876 B1 teaches a method by which an enzyme used for the detection of organophosphate and related materials is covalently attached to a porous support. This invention does not provide a way to automate the timing of release of reagents, nor is the method of covalent attachment used in this patent as effective as microencapsulation at increasing shelf life of biomolecules, such as enzymes.
Prior art exists which automate chemical reactions using mechanical fluidics to control the flow'of reagents in chemical reactions. U.S. Pat. No. 6,861,252 teaches that a sensor for detecting an analyte in the environment can be constructed using reservoirs containing carrier fluids and activators that interact with reagents embedded in polymers. The invention requires mechanical devices, including reservoirs, valves and pumps, which make the invention complicated and cumbersome to operate.
Prior art technology used to automate chemical reactions for chemical sensors includes impregnating various carrier materials by solvent or physical deposition on porous or sponge-like supports. U.S. Pat. No. 7,491,546 teaches a method of water analysis for chlorine in which the chemistry is touch free, utilizing solvent deposited reagents on an insoluble fibrous matrix. This invention does not a provide a way to automate the release of different reagents at specific times, nor does the reagent impregnation method help to protect sensitive molecules from the environment and maximize reagent shelf life.
Briefly described, the present invention relates to methods for making microchemical reactors that are comprised of microencapsulated reagents that can be embedded in or on objects. This invention opens new possibilities for the use of chemistry. It allows both simple and complex chemistry to be portable, automated, simplified, cost effective, and versatile.
It is therefore the primary object of the present invention to provide microencapsulated reagents in stoichiometric ratios which are embedded in objects for the purpose of making microchemical reactors.
Another object of the present invention is to colocate microcapsules containing different reagents that are embedded in objects so that chemical reactions can occur in the same location, which allows many types of easy to use devices to be created. The smallest chemical microreactor consists of two colocated 1 micron diameter microcapsules each containing a different reagent. When these reagents are released from their shells, and react, the smallest microreactor volume is 4.18 attoliters.
A further object of the present invention is to automate chemical reactions by selecting microcapsule shells of microencapsulated reagents that are either friable, solvent specific, porous, or of varying thickness. All of these techniques can be used to release the microcapsule contents at specific times and under specific conditions.
It is still a further object of the present invention to employ chemical logic, if required by the application. This allows chemical reactions in this invention to select a particular chemical pathway from multiple possible chemical pathways, based on conditions that are experienced by the shells of microencapsulated reagents.
Reference is now made to the accompanying drawings, which forms a part of the specification of the present invention.
FIG 3. is a perspective view of the present invention configured as a strip device for detection of pesticides and nerve agents.
FIG 4. is a perspective view of present invention as a sponge tipped swab.
FIG 5. is a perspective view of the present invention as a sponge tipped swab placed into a transparent reaction container.
FIG 6. is a plan view of the present invention configured as a section of bathroom tissue that detects fecal occult blood.
FIG 7. is a side view of the present invention configured as a section of bathroom tissue that detects fecal occult blood.
FIG 8. is block diagram of the present invention configured in a process control system.
Microencapsulation, as used herein, is the process of placing a spherical shell composed of a synthetic or biological polymer completely around another chemical for the purpose of delaying or slowing its release.
A microencapsulated reagent, as used herein, is any chemical that has been microencapsulated.
A microcapsule, as used herein, is a spherically shaped capsule consisting of a shell of varying thickness surrounding a core of liquid or solid chemical. The microcapsule can range in diameter from a micron to several millimeters.
Shell, as used herein, is any synthetic or biological polymer which completely surrounds the core of an encapsulated reagent.
Core, as used herein, is any chemical compound which is surrounded by a spherical shell for the purpose of encapsulation.
Analyte, as used herein, is the specific substance or chemical constituent that is being measured in a chemical analysis.
Working solvent, as used herein, is any liquid which enables the mixing and reaction of reagents to allow chemical reactions.
Foam, as used herein, is an emulsion-like two-phase system where the dispersed phase is gas or air. In the case of rigid insoluble open cell foam the dispersed phase is located within a solid resinous matrix, the cell walls of which are open to the external environment.
A stoichiometric ratio or amount of a reagent, as used herein, is the amount or ratio where, assuming the reaction proceeds to completion, all reagent is consumed, there are no shortfall of reagent and no residues remain.
A surfactant, as used herein, is a soluble compound that reduces the surface tension of liquids or reduces interfacial tension between two liquids or a liquid and a solid.
A microchemical reactor, as used herein, is a device comprised of microencapsulated chemical reagents which are placed in or on an object, which microencapsulated reagents range in size from 1 micron to 2 millimeters, and when combined with an analyte, or each other, produce a desired chemical reaction.
Microchemical reactor, as used herein, is a device that is comprised of microcapsules containing different reagents needed for a desired chemical reaction, combined in correct stoichiometric ratio. The smallest chemical microreactor consists of two colocated 1 micron diameter microcapsules each containing a different reagent. When these reagents are released from their shells, and react, the smallest possible microreactor volume is 4.18 attoliters. If a larger quantity of reaction material is desired, the mixture is extended in length, area, or volume, hence the structure of the reactor is extensible.
The present invention is comprised of microencapsulated reagents. Five different types of shells used in microencapsulation are used to control the reaction sequence and timing. These types are 1) friable shells 2) shells of varying thickness and 3) shells that are solvent specific 4) porous shells and 5) shells that are caused to open by techniques other than mechanical rupture or dissolving, including the absorption of acoustic and electromagnetic energy.
In the present invention, the first method of automating chemical reaction sequence timing is by using a friable microencapsulated reagent, which becomes part of the reaction chain when it is mechanically ruptured. The second method of automating chemical reaction sequence timing is by selecting the thickness of the shell material, whereby, for a specific working solvent, thicker shells take more time to dissolve and release encapsulated contents. The third method of automating chemical reaction sequence timing is by selecting specific shell materials that dissolve at different rates for a specific solvent. The fourth method of automating chemical reaction sequence timing is by selecting shell materials that are porous and allow reactions to occur without releasing the shell contents. Porous shells are useful for some applications wherein it is desirable to re-use a chemical reagent, such as a catalyst or enzyme. The fifth method of automating chemical reaction sequence timing includes using electromagnetic or acoustic energy to open the shell and release the contents. Sensors can be made from microcapsules comprised of material that absorbs either electromagnetic or acoustic energy. This absorption of energy causes the shell of the microcapsule to open, indicating the presence of electromagnetic or acoustic energy. Any combination of these techniques for automating chemical reactions may be used in a system.
The present invention uses microencapsulated reagents in pre-measured quantities so that the chemical reactions are in proper stoichiometric ratios. Some microcapsules may contain more than one reagent. Some microcapsules may be comprised of nested concentric shells which contain different reagents between concentric shells.
The present invention allows two or more chemically distinct microencapsulated reagents to be colocated so that all chemical reactions can occur in the same location, which allows many types of easy to use devices to be created. This allows the reactor to be built onto surfaces or inside structures conducive to their subsequent use. The support can be designed to absorb a predetermined amount of analyte solution or mixture which may be solid, liquid, or gas.
The present invention can utilize chemical logic allowing chemical cascades to be controlled using microencapsulated reagents. Chemical logic allows a chemical pathway to be chosen because of a previously existing condition in the cascade. This is equivalent to an if-then statement in a computer program. For example, if initial condition A is true, then microcapsule 1 dissolves, releasing its reagent and microcapsule 2 does not dissolve. If initial condition B is true, then microcapsule 2 dissolves, releasing its reagent, and microcapsule 1 does not dissolve. This is equivalent to the control logic: if A then release release reagent 1; If B then release reagent 2. To illustrate this automated chemical cascade logic, consider a system where the shell of microencapsulated reagent A will only dissolve in an acidic pH solution. Microencapsulated reagent B will only dissolve in a basic pH solution. This built in intelligence in the automated cascade allows branching of the chemical cascade, meaning decisions are made and paths are followed based on what microencapsulated shells sense.
The present invention can be used for chemical tests which produce a color change, or the change of any quality perceivable by human senses. The present invention can also be configured as an instrument, and detect or measure any physical effect, such as a change of temperature, pressure, volume, voltage, current, capacitance, impedance, or other physical quantity.
The present invention is useful for applications such as chemical synthesis, in which a new chemical product, including a new chemical species or a change of state is desired. For example, the present invention configured as the chemical precursors of a propellent or explosive would make a safe and reliable high energy product.
The present invention is also useful for medical applications intended to produce a therapeutic effect. An example is a bandage which contains microencapsulated reagents which react to release oxygen at a wound site.
The present invention is also useful for applications in which the mitigation of a chemical or biological compound is desired. Mitigation is process by which a harmful chemical or a biological organism, such as nerve agents or anthrax spores, are rendered less harmful, by some chemical called an active ingredient. The active ingredient can be dispersed and delivered in a liquid or free flowing foam. The present invention can be used to deliver a microencapsulated active ingredient that has a long shelf life and can be designed to release gradually. The gradual time release is helpful because it allows all of the active ingredients to be delivered to the chemical or biological target. In the case of foam delivery, an advantage of the present invention is that the active ingredient is dispersed in the foam while in a protected microcapsule and is consequently delivered in its entirety to the target. The present invention thereby provides an effective decontamination tool.
This embodiment mimics the biochemical process by which these inhibitor compounds disrupt nerve transmission in organisms. Acetylcholinesterase (AChE)is an enzyme that is found in nerve synapses. Its function is to break down the neurotransmitter Acetylcholine (AChE) into two smaller molecules. If acetylcholine is not broken down into its constituents, the organism may die. Acetylcholinesterase inhibitors chemically bond to the enzyme so that the enzyme can no longer break down the acetylcholine.
This embodiment of the invention uses microencapsulated acetylcholinesterase (AChE) that interacts with molecules of acetylcholinesterase inhibitor that may be present in the sample solution. An incubation time is necessary to allow the enzyme inhibitor to bind with the enzyme, after which, a second reagent, IPA, is introduced. Indophenyl acetate (IPA) is a compound chemically similar to acetylcholine, because it is hydrolyzed by the enzyme, similar to the way that acetylcholine is broken up into two smaller molecules by the enzyme in nerve synapses. IPA is used because one of its reaction products produces a purple color. If inhibitor is not bound to the enzyme, then the enzyme hydrolyzes the indophenyl acetate, which becomes two smaller molecules, indophenoxide- and acetate. The indophenoxide- is purple colored. If an enzyme molecule is bound with inhibitor, it cannot hydrolyze IPA and no purple color is produced by that enzyme. If the test solution turns purple, this indicates intact acetylcholinesterase enzyme molecules, and therefore the absence of inhibitor. If the test solution does not turn purple, then the enzyme is no longer available, because it is bound up with inhibitor. This indicates the presence of analyte. An estimate of the analyte concentration is determined by observing or instrumentally measuring the relative purple color.
The present invention allows the colocation of microcapsules containing different reagents inside the foam structure, that are released into solution at different times.
An operator uses the device by grasping the handle and swiping the foam tip into an aqueous sample, saturating the foam. The user then waits for an appropriate time and then observes the color change, if any, in the foam. Alternatively in order to sample dry analytes on dry surfaces the present invention can contain microencapsulated working solvent, in friable shells, such as microencapsulated water. The user inserts the foam swab (20) into the transparent reaction container (25). The foam is then reciprocally plunged to release the microencapsulated solvent from friable shells, to mix the contents and develop the color.
The user compares the color of the foam to a printed color gradient. Alternatively, the user could insert the foam swab into a colorimeter that measures the color and displays the concentration of analyte.
In this example, a biosensor which measures the concentration of acetylcholinestase inhibitors found on agricultural produce is described. This device utilizes the Ellman colorimetric method. Ellman's method is a colorimetric process for Acetylcholinesterase activity determination. It uses 5-thio-2nitrobenzoate (TNB-), known as Ellman's Reagent, as a chromogen producing a blue color. However if this reaction proceeds in the presence of AChE inhibitor, the color will shift from blue to yellow depending upon the amount of inhibitor present. It is this gradient in color from blue to yellow that may then be compared to a printed color gradient to indicate the quantity of inhibitor present.
In use, a known volume of analyte, for example, a droplet, is placed onto the exposed reaction zone at the edge of the reagent strip between the plastic outer layers at location (13A). This initiates the chemical cascade. The clear plastic backing encases the reaction products and prevents contamination. The clear backing also allows the operator to easily observe color changes. Each discrete reaction zone is comprised of four encapsulated reagents in stochiometric quantities. Buffer, AChE and TNB, are called the stage one reagents. They are encapsulated in shells that dissolve in water. Acetylcholine (ACh) is called the second stage reagent. It is encapsulated in a friable shell. The open weave of the absorbent material (1) allows wicking of the analyte to the reaction zone where the shells surrounding stage one reagents dissolve and the reagents react.
To make a measurement, the operator places a drop of the analyte at the drop site (13A), advances the strip past the first set of rollers (14) so that the reaction zone is located within the incubation zone (14A). The operator then waits for a predetermined time. Then the operator turns the knob (16), and advances the strip past the crush rollers (15), positioning the reaction zone in front of the viewing screen. At this point a final color is observed. The operator then compares the observed color with a printed color gradient, indicating the concentration of AChE inhibitor.
FIG 8. shows the embodiment of this invention described
These fluid streams are found in boiler and cooling tower water, chemical plant streams, refineries, food processing plants, as well as in other applications. Prior to this invention, many analytes in process streams must be sampled, transported to an analysis laboratory, and then analyzed by laboratory personnel. The need exists for automated real time analysis and control. This invention can be adapted to any process and control stream. The device can be housed in such a way that physical and or chemical parameters, such as but not limited to, temperature, pressure, gaseous environment, electromagnetic radiation, sound, and ionizing radiation could be varied to suit any specific cascade analysis.
In this example a device according to the present invention that detects fecal occult blood is embedded in bathroom tissue. The analyte for this test is called occult blood because the quantities of blood can be so minute that the blood cannot be detected with the naked eye. Stool testing for blood is for the detection of colorectal cancer as well as other conditions such as recent gastrointestinal surgery, gastric (stomach) cancers, ulcers, hemorrhoids, polyps, inflammatory bowel disease, irritations or lesions of the gastrointestinal tract caused by medications (such as nonsteroidal anti-inflammatory drugs), and irritations or lesions of the gastrointestinal tract caused by stomach acid disorders, such as reflux esophagitis.
In the typical fecal occult blood test, feces are applied to a thick piece of paper attached to a thin film coated with guiaiac. A small fecal sample is applied to the film. The fecal sample is obtained either by digital rectal examination or by wiping soiled toilet tissue on the film. Both sides of the test card are peeled open, exposing the inner guaiac paper. One side of the card is marked for application of the stool and the other is for the developer fluid.
After applying the feces, one or two drops of hydrogen peroxide are dripped on to the other side of the film. A rapid blue color change indicates the presence of blood. When the hydrogen peroxide is dripped on to the guaiac paper, it oxidizes the alpha-guaiaconic acid to a blue colored quinone. When there is no blood and no enzymes called peroxidases or catalases, (which are from vegetables) present in the stool sample, the oxidation occurs very slowly. Heme, a component of hemoglobin in blood, catalyzes this reaction, giving a result in about two seconds. Therefore, a quick and intense blue color change of the guaiac paper indicates the presence of blood, a positive test result.
In this embodiment, the present invention is embedded in bathroom tissue.
When the user of this invention wipes the anus after defecating, microencapsulated reagent shells either dissolve or break, releasing reagent to react with blood, if present, in the feces. The bathroom tissue quickly turns blue if there is blood in the feces.
This invention allows individuals to perform their own fecal occult blood test and monitor their health for many life-threatening conditions. The manufacturing process is simple and the present invention automates the chemical reaction for the user.
Thus it will be appreciated by those skilled in the art that the present invention is not restricted to the particular preferred embodiments described with reference to the drawings, and that variations may be made therein without departing from the scope of the present invention as defined in the appended claims and equivalence thereof.
