CA2380075C - Microfabricated devices and method of manufacturing the same using polymer gel - Google Patents

Microfabricated devices and method of manufacturing the same using polymer gel Download PDF

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Publication number
CA2380075C
CA2380075C CA2380075A CA2380075A CA2380075C CA 2380075 C CA2380075 C CA 2380075C CA 2380075 A CA2380075 A CA 2380075A CA 2380075 A CA2380075 A CA 2380075A CA 2380075 C CA2380075 C CA 2380075C
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microscale
channel
polymerizable mixture
polymer gel
polymer
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CA2380075A
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French (fr)
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CA2380075A1 (en
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David J. Beebe
Jeffrey S. Moore
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University of Illinois
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University of Illinois
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    • G—PHYSICS
    • G03—PHOTOGRAPHY; CINEMATOGRAPHY; ANALOGOUS TECHNIQUES USING WAVES OTHER THAN OPTICAL WAVES; ELECTROGRAPHY; HOLOGRAPHY
    • G03F—PHOTOMECHANICAL PRODUCTION OF TEXTURED OR PATTERNED SURFACES, e.g. FOR PRINTING, FOR PROCESSING OF SEMICONDUCTOR DEVICES; MATERIALS THEREFOR; ORIGINALS THEREFOR; APPARATUS SPECIALLY ADAPTED THEREFOR
    • G03F7/00—Photomechanical, e.g. photolithographic, production of textured or patterned surfaces, e.g. printing surfaces; Materials therefor, e.g. comprising photoresists; Apparatus specially adapted therefor
    • G—PHYSICS
    • G03—PHOTOGRAPHY; CINEMATOGRAPHY; ANALOGOUS TECHNIQUES USING WAVES OTHER THAN OPTICAL WAVES; ELECTROGRAPHY; HOLOGRAPHY
    • G03F—PHOTOMECHANICAL PRODUCTION OF TEXTURED OR PATTERNED SURFACES, e.g. FOR PRINTING, FOR PROCESSING OF SEMICONDUCTOR DEVICES; MATERIALS THEREFOR; ORIGINALS THEREFOR; APPARATUS SPECIALLY ADAPTED THEREFOR
    • G03F7/00—Photomechanical, e.g. photolithographic, production of textured or patterned surfaces, e.g. printing surfaces; Materials therefor, e.g. comprising photoresists; Apparatus specially adapted therefor
    • G03F7/0002—Lithographic processes using patterning methods other than those involving the exposure to radiation, e.g. by stamping
    • B—PERFORMING OPERATIONS; TRANSPORTING
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    • B01J19/0093—Microreactors, e.g. miniaturised or microfabricated reactors
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    • B01L3/5027—Containers for the purpose of retaining a material to be analysed, e.g. test tubes with fluid transport, e.g. in multi-compartment structures by integrated microfluidic structures, i.e. dimensions of channels and chambers are such that surface tension forces are important, e.g. lab-on-a-chip
    • B01L3/502707—Containers for the purpose of retaining a material to be analysed, e.g. test tubes with fluid transport, e.g. in multi-compartment structures by integrated microfluidic structures, i.e. dimensions of channels and chambers are such that surface tension forces are important, e.g. lab-on-a-chip characterised by the manufacture of the container or its components
    • B—PERFORMING OPERATIONS; TRANSPORTING
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    • G03—PHOTOGRAPHY; CINEMATOGRAPHY; ANALOGOUS TECHNIQUES USING WAVES OTHER THAN OPTICAL WAVES; ELECTROGRAPHY; HOLOGRAPHY
    • G03F—PHOTOMECHANICAL PRODUCTION OF TEXTURED OR PATTERNED SURFACES, e.g. FOR PRINTING, FOR PROCESSING OF SEMICONDUCTOR DEVICES; MATERIALS THEREFOR; ORIGINALS THEREFOR; APPARATUS SPECIALLY ADAPTED THEREFOR
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    • G03F7/004—Photosensitive materials
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    • G03F7/032—Non-macromolecular photopolymerisable compounds having carbon-to-carbon double bonds, e.g. ethylenic compounds with binders
    • G03F7/033—Non-macromolecular photopolymerisable compounds having carbon-to-carbon double bonds, e.g. ethylenic compounds with binders the binders being polymers obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. vinyl polymers
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    • G03—PHOTOGRAPHY; CINEMATOGRAPHY; ANALOGOUS TECHNIQUES USING WAVES OTHER THAN OPTICAL WAVES; ELECTROGRAPHY; HOLOGRAPHY
    • G03F—PHOTOMECHANICAL PRODUCTION OF TEXTURED OR PATTERNED SURFACES, e.g. FOR PRINTING, FOR PROCESSING OF SEMICONDUCTOR DEVICES; MATERIALS THEREFOR; ORIGINALS THEREFOR; APPARATUS SPECIALLY ADAPTED THEREFOR
    • G03F9/00—Registration or positioning of originals, masks, frames, photographic sheets or textured or patterned surfaces, e.g. automatically
    • G03F9/70—Registration or positioning of originals, masks, frames, photographic sheets or textured or patterned surfaces, e.g. automatically for microlithography
    • H—ELECTRICITY
    • H01—ELECTRIC ELEMENTS
    • H01L—SEMICONDUCTOR DEVICES NOT COVERED BY CLASS H10
    • H01L21/00—Processes or apparatus adapted for the manufacture or treatment of semiconductor or solid state devices or of parts thereof
    • H01L21/02—Manufacture or treatment of semiconductor devices or of parts thereof
    • H01L21/027—Making masks on semiconductor bodies for further photolithographic processing not provided for in group H01L21/18 or H01L21/34
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
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    • B01J2219/00824—Ceramic
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    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
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    • B01J2219/00781—Aspects relating to microreactors
    • B01J2219/00819—Materials of construction
    • B01J2219/00833—Plastic
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
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    • B01J2219/00891—Feeding or evacuation
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    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
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    • B01L2200/00—Solutions for specific problems relating to chemical or physical laboratory apparatus
    • B01L2200/12—Specific details about manufacturing devices
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    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
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    • B01L2300/08—Geometry, shape and general structure
    • B01L2300/0809—Geometry, shape and general structure rectangular shaped
    • B01L2300/0816—Cards, e.g. flat sample carriers usually with flow in two horizontal directions
    • B—PERFORMING OPERATIONS; TRANSPORTING
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    • B01L2300/161—Control and use of surface tension forces, e.g. hydrophobic, hydrophilic
    • B—PERFORMING OPERATIONS; TRANSPORTING
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    • B—PERFORMING OPERATIONS; TRANSPORTING
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    • G03F—PHOTOMECHANICAL PRODUCTION OF TEXTURED OR PATTERNED SURFACES, e.g. FOR PRINTING, FOR PROCESSING OF SEMICONDUCTOR DEVICES; MATERIALS THEREFOR; ORIGINALS THEREFOR; APPARATUS SPECIALLY ADAPTED THEREFOR
    • G03F7/00—Photomechanical, e.g. photolithographic, production of textured or patterned surfaces, e.g. printing surfaces; Materials therefor, e.g. comprising photoresists; Apparatus specially adapted therefor
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Abstract

Microfabricated devices and methods of manufacturing the devices are disclosed. The devices are manufactured from a substrate having microscale fluid channels, and polymerizing a polymerizable mixture in the channels to form stimuliresponsive operating components of the device. The operating components can be functional or structural components. The method of manufacture obviates the traditional assembly of microscale components to form a device because the microscale components are formed in situ or within the device. The microscale components are constructed from polymer gels and said polymer gels are utilized in the method to provide the microscale components.

Description

MICROFABRICATED DEVICES AND
METHOD OF MANUFACTURING THE SAME
USING POLYMER GEL
FIELD OF THE INVENTION
The present invention is directed to microfabricated devices, to methods of manufacturing the microscale devices, and to methods of detecting a chemical change, a physical change, a chemical agent, or a biological agent using the microscale devices. In particular, the devices are manufac-tured from a substrate having microscale fluid chan-nels, and polymerizing one or more polymerizable mixtures in the channels to form the operating com-ponents of the device. The method of manufacture eliminates the traditional assembly of individual microscale components to form the device.

BACKGROUND OF THE INVENTION

Current methods of manufacturing micro-scale devices, like microfluidic devices such as valves, pumps, and actuators, typically parallel, and are extensions of, macroscale design, manufac-ture, and assembly processes. For example, litho-graphic processes are used to add material to, or subtract material from, a substrate. The parallel approach to manufacturing microscale devices has retarded the development of complex microscale de-vices, especially because of difficulties in micro-scale device assembly, long development time, and high cost.
Presently, two approaches typically are used in the manufacture of microscale devices. The first is a true integrative approach in which litho-graphic processes are used to fabricate all required device components using a single process, e.g., polysilicon surface micromachining. In the second approach, fabrication of individual components is followed by component assembly to form the device.
In this approach, assembly of the microscale device is identical to the assembly of a macroscale device, except uncommon methods are required to assemble microsized components. For example, slurry assembly is one method of assembling microscale components to form a microscale device.
Research in the area of microelectro-mechanical (MEM) systems has provided many examples of microfluidic devices and components, like minia-turized pumps and valves. Many types of microscale valves have been manufactured, including passive and active valves. However, the integration of micro-scale valves and other microscale components into microfluidic devices has proved difficult because a manufacturing process that provides a useful valve often is different from a manufacturing process that provides a useful pump or sensor. In other words, different device components often require different materials of construction and different types of manufacturing steps, thereby making integration of several microscale components into a single device difficult.
As stated above, two general methods of manufacturing microscale devices currently are used.
Either the components are built separately, and then assembled to form the microscale device, much like assembly of a macroscale device, or traditional lithographic techniques are used to manufacture all the components of the device. The assembly approach is difficult at the microscale range for readily apparent reasons (e.g., the micron range size of the components makes handling and assembly difficult).
In addition, electrostatic and other surface forces become dominant at the small size of the microscale components, thereby making manipulation of the com-ponents difficult. Lithographic processes overcome some of the problems associated with the assembly process, but integration of multiple components into a single device is hindered by the several disparate materials of construction and manufacturing methods often required to manufacture the different individ-ual microscale components of the device.
Investigators have studied other micro-scale fabrication methods including fabrication of metal wires in channels, folding conductive polymer boxes, microstamping and micromolding, and two pho-ton polymerization, but many of the above-mentioned problems associated with the manufacture of micro-scale devices have not been overcome. For example, T Breen et al., Science, 284, pp. 948-951 (1999) discloses in-channel fabrication techniques that utilize laminar flow to create textured walls and to position metal traces within microchannels. Smela et al., Science, 268, pp. 1735-1738 (1995) discloses conductive microscale actuators built by lithograph-ically patterning conductive polymers on flat sub-strates. Two-photon polymerization has been used to provide three-dimensional structures from a polymer gel precursor (see S. Maruo, J. Microelectromechan-ical Systems, 7, pp. 411-415 (1998), and B.H.
Cumpston et al., Nature, 398, pp. 51-54 (1999)).
The present invention is directed to a new method of manufacturing microscale devices that overcomes problems associated with traditional as-sembly, lithographic, and other methods. The pres-ent method permits the integration of several dif-ferent microscale components, which can be manufac-tured from different materials of construction, into a single microscale device, without the need to assemble individual microscale components to form the device.

SiTNIIMARY OF THE INVENTION

The present invention relates to methods of manufacturing microscale devices, to the micro-scale devices made by the method, and to methods of detecting a chemical or physical change, or a chemi-cal or biological agent, using the microscale de-vices. More particularly, the present invention relates to a method of manufacturing microscale devices that is fundamentally different from prior manufacturing methods, solves problems and disadvan-tages associated with prior manufacturing methods, and retains advantages associated with prior manu-facturing methods. In particular, the present WO 01/07506 PCT/[JS00/20042 -method retains an advantage of a lithographic pro-cess (which avoids assembly) and retains an advan-tage of an assembly process (which permits integra-tion of device components made from different mate-5 rials of construction). The present manufacturing method also provides the ability to expand the func-tionality of microscale devices, and thereby expand the scope of microscale devices, both in types of devices and practical applications, beyond present-day limits.
Accordingly, one aspect of the present invention is to provide a method of manufacturing microscale components of a microscale device, i.e., a method of manufacturing individual microscale device components on or within a substrate to pro-vide the completed microscale device. The micro-scale component can be a structural component of the device (i.e., a wall or channel of the device), or the microscale component can be a functional compo-nent of the device (i.e., a valve, a pump, an opto-electronic component, or a sensor, for example). A
structural component is nonresponsive to physical and chemical changes, and to chemical and biological agents. A functional component can be responsive either to a biological agent (i.e., is biorespon-sive) or to a physical or chemical change or a nonbiological chemical agent (i.e., is physio/-chemoresponsive).
Another aspect of the present invention is to provide a method of manufacturing a microscale device utilizing a substrate having one or more microscale channels, the properties of laminar fluid flow in a microscale channel, and polymerization of a polymerizable mixture at a preselected location within a channel. The substrate can have preformed channels, for example, channels prepared by litho-graphic techniques. Alternatively, the present method can be used to form the microscale channels in the substrate. In either embodiment, the present method is repeated as necessary to fabricate indi-vidual microscale components in the channels, from the same or different materials of construction, until manufacture of the microscale device is com-plete.
Yet another aspect of the present inven-tion is to provide a method of manufacturing a microscale device wherein no manipulative assembly steps are required to form the microscale device from microscale components.
Still another aspect of the present in-vention is to provide a method of manufacturing a microscale device having a plurality of functional microscale components, wherein individual components can be manufactured from different materials of construction. Accordingly, microscale devices manu-factured by the present method can be specifically designed for any of a variety of specific end use applications. The present method, therefore, greatly expands the number of practical applications for microscale devices.
Another aspect of the present invention is to provide a method of manufacturing microscale devices wherein development and manufacturing times are short, and the resulting devices are cost effec-tive.
It also is an aspect of the present inven-tion to provide microscale devices that perform as sensors, actuators, or detectors, and that provide a fast and accurate response to a preselected stimulus of interest, such as a chemical or biological com-pound, or a physical or chemical change, like a temperature or pH change. This aspect of the inven-tion is achieved by manufacturing a microscale com-ponent having the appropriate functionality to re-spond to the stimulus of interest.
Another aspect of the present invention is to provide a microscale device capable of converting a microscale physical or chemical change, or a microscale amount of a chemical or biological agent, directly to a macroscale detectable response without the need for an external power source or other ex-ternal means of converting a microscale event to a macroscale response. The microscale devices, there-fore, are useful as portable detectors and sensors for physical or chemical changes, or for chemical and biological agents, for example, to detect or monitor environmental and food contaminants, changes in a chemical process, or disease treatment regi-mens.
Another aspect of the present invention is to solve a longstanding problem of bridging the gap between microscale and macroscale environments.

- 7a -According to one aspect of the present invention, there is provided a method of manufacturing a microscale component of a microscale device comprising: (a) providing a substrate; (b) forming one or more microscale channels in the substrate; (c) introducing a liquid polymerizable mixture into the channel; (d) optically masking the channel to permit exposure of the polymerizable mixture to a polymerization-initiating energy source at a preselected location along the channel; (e) exposing the channel to the energy source for a sufficient time to polymerize the polymerizable mixture at the preselected location of the channel to form a polymer gel; and (f) removing residual unreacted polymerizable mixture from the channel to provide the microscale component in the channel as the polymer gel.

According to another aspect of the present invention, there is provided the method described herein wherein the substrate is transparent.

According to still another aspect of the present invention, there is provided the method described herein wherein the substrate comprises glass, a plastic, silicon, or a transparent mineral.

According to yet another aspect of the present invention, there is provided the method described herein wherein the channel is formed by a lithographic process.

According to a further aspect of the present invention, there is provided the method described herein wherein the substrate has a cross-section diameter of about 1 micron to about 1 millimeter.

According to yet a further aspect of the present invention, there is provided the method described herein - 7b -wherein polymerizable mixture has a Reynold's number of about 1 to about 2000.

According to still a further aspect of the present invention, there is provided the method described herein wherein a plurality of liquid polymerizable mixtures are simultaneously or sequentially introduced into the channel in a laminar array.

According to another aspect of the present invention, there is provided the method described herein wherein one or more liquid polymerizable mixtures and one or more inert liquids, each with a Reynold's number of about 1 to about 2000, are simultaneously or sequentially introduced into the channel in a laminar array.

According to yet another aspect of the present invention, there is provided the method described herein wherein one or more liquid polymerizable mixtures and one or more inert liquids, each with a Reynold's number of about 1 to about 2000, are simultaneously or sequentially introduced into the channel in a choatic flow stream.

According to another aspect of the present invention, there is provided the method described herein wherein the polymerizable mixture comprises a monofunctional monomer, a polyfunctional crosslinking monomer, or a mixture thereof.

According to still another aspect of the present invention, there is provided the method described herein wherein the polymerizable mixture further comprises a photoinitiator, an optional surfactant, or a mixture thereof.

- 7c -According to yet another aspect of the present invention, there is provided the method described herein wherein the microscale component has a diameter-to-height ratio of about 10 to 1 to about 0.5 to 1.

According to a further aspect of the present invention, there is provided the method described herein wherein the polymerization-initiating energy source comprises light, heat, vibration, an electrical field, or a magnetic field.

According to yet a further aspect of the present invention, there is provided the method described herein wherein the energy source comprises ultraviolet light.

According to still a further aspect of the present invention, there is provided the method described herein wherein an anchoring material is positioned at the preselected location of the channel.

According to another aspect of the present invention, there is provided the method described herein wherein the anchoring material comprises a chemical anchor.

According to yet another aspect of the present invention, there is provided the method described herein wherein the anchoring material comprises a metal film, a photo-initiator, a monomer, or a mixture thereof.

According to another aspect of the present invention, there is provided the method described herein further comprising a step of derivatizing the polymer gel by attaching a biomolecule to the polymer gel.

According to still another aspect of the present invention, there is provided the method described herein - 7d -further comprising the step of derivatizing the polymer gel by coating the polymer gel with a fatty acid or a lipid.
According to yet another aspect of the present invention, there is provided the method described herein wherein the polymer gel is capable of undergoing a volume change in response to a predetermined stimulus.

According to a further aspect of the present invention, there is provided the method described herein wherein the stimulus is a physical change in a medium contacting the gel.

According to yet a further aspect of the present invention, there is provided the method described herein wherein the physical change is a temperature change, an electric field change, a change in light, or a pressure change.

According to still a further aspect of the present invention, there is provided the method described herein wherein the stimulus is a chemical change in a medium contacting the gel.

According to another aspect of the present invention, there is provided the method described herein wherein the chemical change is a pH change or an ionic strength change.

According to yet another aspect of the present invention, there is provided the method described herein wherein the stimulus is a chemical compound in a medium contacting the gel.

According to another aspect of the present invention, there is provided the method described herein - 7e -wherein the stimulus is a biological agent in a medium contacting the gel.

According to still another aspect of the present invention, there is provided the method described herein wherein the biological agent is a toxin, a pathogen, or an antigen.

According to yet another aspect of the present invention, there is provided the method described herein wherein the biological agent is botulinum toxin, anthrax, or Ebola.

According to a further aspect of the present invention, there is provided a method of manufacturing a functional microscale component of a microscale device comprising: (a) providing a transparent cell having a cavity; (b) introducing a blend of structural monomers into the cavity said blend comprising a first polymerizable mixture; (c) optically masking the cavity to define one or more channels in the cell and to permit exposure of the unmasked structural monomer blend to a polymerization-initiating energy source; (d) exposing the cell to the energy source for a sufficient time to polymerize the structural monomer blend at unmasked locations in the cell to form microchannels in a resultant substrate; (e) removing residual unreacted monomer blend from the substrate to provide the channels in the cell; (f) introducing a second liquid polymerizable mixture comprising functional monomers into the channels; (g) optically masking the channels to permit exposure of the second polymerizable mixture to the polymerization-initiating energy source at a preselected location along the channel; (h) exposing the channel to the energy source for a sufficient time to polymerize the second polymerizable mixture at the preselected location of the - 7f -channel to form a polymer gel; and (i) removing residual unreacted second polymerizable mixture from the channel to provide the functional microscale component in the channel as the polymer gel.

According to yet a further aspect of the present invention, there is provided the method described herein, wherein the cavity in the cell is about 50 to about 250 m in height and, independently, about 500 to about 25,000 m in width and length.

These and other aspects and advantages of the present invention will become apparent from the following detailed description of the preferred embodiments taken in conjunction with the figures.
BRIEF DESCRIPTION OF THE DRAWINGS

Fig. 1 is a schematic of a device of the invention illustrating sensing of an analyte and activation of the device in response to the analyte;
Fig. 2 is a schematic of a polymer-based pH sensor/actuator prepared by the method of the present invention;
Fig. 3 illustrates the volume change of a microscale component in response to a change in pH;
Figs. 4 and 6 illustrate a method of manu-facturing a microscale device of the present inven-tion.
Fig. 5 illustrates examples of micro-channel shapes for a microscale device of the pres-ent invention;
Fig. 7 illustrates the formation of func-tional hydrogels on the walls of a microchannel utilizing laminar flow;
Fig. 8 illustrates a bioresponsive hydrogel that can be used as a microscale component of a microscale device;
Fig. 9 illustrates volume changes of a microscale hydrogel component in response to pH
changes;
Fig. 10 illustrates a flow router prepared by the method of the present invention;
Fig. 11 illustrates pH-sensitive beads of the present invention, and the reproducible response of the beads to a pH change;
Figs. 12 and 13 show different complex geometries of microscale components;
Figs. 14 and 15 show different shapes of polymer hydrogels prepared within a microscale chan-nel;
Fig. 16 shows microscale detection devices of the present invention;
Fig. 17 shows a biomimetric valve prepared by the present method; and Fig. 18 is a schematic showing the use of choatic fluid flow in the method of the present invention.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
Existing methods of manufacturing micro-scale fluidic systems, and microscale devices in general, largely are extensions of macroscale manu-facturing and assembly techniques. Current methods of microfabrication have tremendous value, but also have limitations. In particular, the ability to quickly manufacture complex microscale devices is very difficult. As importantly, the ability to integrate functional components, including sensing and detection components, into a microscale device is difficult. Lengthy design and fabrication pro-cesses typically are required. For example, the development of complex microscale devices using current approaches requires a time frame of months to years. Such long development and manufacturing times negate the use of microscale devices in appli-cations that require design, development, and manu-facture of a complex device in a time frame of hours to days.
A microscale device manufactured by the present method often utilizes the conversion of chemical energy into mechanical work, which is the basis of movement in living systems. The essence of such a process is captured by a variety of natural and synthetic polymer gels that undergo volume changes in response to a chemical or physical stimu-lus in their surrounding environment. Such polymer gels have been investigated for a variety of appli-cations, such as actuators, sensors, controllable membranes for separations, and modulators for drug delivery.
A disadvantage encountered in all of these applications is the slow response time exhibited by such chemomechanical materials, together with a lack of response specificity to a particular stimulus.
For example, for macroscale polymer structures, response times often are measured in days because diffusion of the surrounding medium into the poly-meric network is the rate-limiting factor governing polymer expansion. As with any diffusion limited process, increasing the surface area to volume ratio significantly increases the speed of the process.
For example, it has been found that polymer hydrogel volume changes scale with the square of the dimen-sion. Thus, scaling hydrogels to the microscale results in substantially improved response times.
Accordingly, microscale devices comprising a stimuli-responsive polymer gel positioned within a microfluidic channel achieve fast response times attributed to the microscale size of the device.
For example, simplicity of fabrication and the large force generated by expansion make polymer gels ideal functional materials to regulate fluid flow in microscale systems.
Conventional actuators, e.g., electromag-netic, electrostatic, and thermopneumatic, require relatively complex assembly and an external power source for operation, which limits their use in practical applications. In contrast, stimuli-re-sponsive hydrogels have a significant advantage over conventional microfluidic actuators because of an ability to undergo abrupt volume changes in response to the surrounding environment without the require-ment of an external power source. In addition, stimuli-responsive hydrogels can respond to a vari-ety of stimuli, such as pH, temperature, electric field, light, chemical compounds (e.g., carbohy-drates), and biological agents (e.g., antigens).
Because expansion of the polymeric hydrogel into the surrounding medium is the rate-limiting factor gov-erning the swelling process, scaling the size of the hydrogel down to a micron dimension enables a fast volumetric transition that is necessary to achieve practical macroscale detection of a microscale event.
The present invention, therefore, provides a method that allows for the rapid development and manufacture of complex microscale devices that are simple to build. The method utilizes traditional and nontraditional fabrication processes (e.g., lithography/micromolding), physics of the microscale (e.g., laminar flow, short diffusion paths), and synthetic organic chemistry (e.g., functional poly-mers) to provide a new method of manufacturing com-plex microscale devices.
The present invention provides a new method of manufacturing microscale components and microscale devices, which utilizes the property of laminar fluid flow in microscale channels and the polymerization of a polymerizable mixture. The present method has many advantages over prior meth-ods of manufacturing microscale components and microscale devices. For example, the present method eliminates manipulative assembly of individual microscale components to form a microscale device.
In particular, the microscale devices are manufac-tured solely by the appropriate application of one or more of laminar fluid flow, substrate surface treatment, polymer chemistries, and polymerization initiation. Accordingly, the present method greatly simplifies manufacture of complex microscale de-vices.
The microscale devices of the present invention are useful, for example, in the detection of chemical compounds and biological agents. The present microscale devices exhibit the advantages of simple device fabrication, integration of device functionality through "in situ" component fabrica-tion, simple operation, no external power require-ments, and simple operation, but complex functional-ity. The microscale devices can be used to detect physical changes (like temperature changes), chemi-cal changes (like pH changes), chemical compounds, biological agents (like pathogens or toxins), or host defense responses to biological agents. The devices also can be used in applications associated with environmental toxicology, clinical detection and diagnoses, and chemical process streams.
In the following description of the pres-ent invention, a detailed explanation of nonlimiting embodiments is presented first to broadly set forth the invention. Then, various features of the inven-tion are explained individually and specifically.
One envisioned microscale device is illus-trated in Fig. 1. The device of Fig. 1 is a detec-tion device for a component in a biological fluid (e.g., saliva, sweat, blood, or urine) or other liquid media (e.g., a process stream or a water flow). In Fig. 1, a device 100 contains a respon-sive hydrogel 102 in a microchannel 104. Responsive hydrogel 102 contracts upon exposure to an analyte of interest, thereby allowing component A in a microchannel 108 to flow to a chamber 106 and mix with a component B and produce detectable change, for example, a color change in chamber 106. The color change provides a macroscale response to a microscale event, i.e., contact of the analyte of interest with responsive hydrogel 102. Device 100 requires no electrical power supply, utilizes no electronics, and contains no complex microfabricated component. The responsive hydrogel 102 acts as both a sensor and an actuator to provide a direct link from a molecular event to a macroscale detection.
Hydrogel 102 also can contract in response to a physical change or a chemical change in microchannel 104 to provide a macroscale response to a microscale event.
Another device prepared by the method of the present invention is a microscale device, as illustrated in Fig. 2, that provides self-regulation of pH. In particular, pH is a critical parameter in several biofluidic systems (e.g., capillary electro-phoresis and single cell/embryo analysis). In the transport, manipulation, and analysis of single animal embryos, it is important to closely regulate pH in an analysis chamber in order to facilitate analysis over the long time period of embryo devel-opment. In the case of embryos, pH regulation within a 0.3 pH range is required. The method of the present invention permits the manufacture of a microscale fluidic device that incorporates a polymer-based actuator/sensor device capable of sensing and rapidly responding to a change in pH.
The microscale device does not utilize individual sensor, actuator, and control processes, but rather a single "smart," or responsive, polymer gel that senses and controls pH by porting an appropriate fluid from a reservoir in response to changes in pH.
In general, the polymer-based pH actua-tor/sensor is, at least in part, manufactured using a substrate having the basic structure of the micro-scale fluidic device and a spatially controlled polymerization within channels of the substrate. In this spatially controlled polymerization, if desired or required, an optional anchoring material can be patterned in a microscale channel formed in the substrate. The optional anchoring material, zirco-nium, for example, has a high affinity for the poly-mer gel comprising the pH actuator/sensor and an-chors the polymer gel to a surface of channel.
The polymer gel is positioned in the chan-nel using fluid transport through the channel, that is, a polymerizable mixture comprising the monomers that form the polymer gel and an initiator are flowed through the microscale channel, and the poly-merization is effected at a previously spatially defined region in the channel by the selective ap-plication of light or other suitable energy source to that region. Regions in the channel that are to be free of the polymer gel are masked from the poly-merization trigger, e.g., incident light. Polymer-ization, therefore, is confined to the desired spa-tially defined region, and any unreacted polymeriza-tion mixture is rinsed from the channel.
Polymerization can be initiated by a vari-ety of energy sources, for example, light, heat, vibrational, electrical, or magnetic. The preferred energy source is light. The remainder of the de-tailed disclosure predominantly refers to light-initiated polymerizations, i.e., photopolymeriza-tion, for simplification of the disclosure. How-ever, the invention is not limited to photopolymer-izations, and other forms of polymerization initia-tion known persons skilled in the art can be used.
The resulting device is capable of self-regulating the pH of an analysis chamber, as illus-trated in Fig. 2. In operation, the pH responsive polymer-based sensor/actuator comprises a polymer gel that undergoes a rapid and substantial volume contraction at high pH. Contraction of the polymer gel allows additional hydrogen ions to flow from a reservoir into the analysis chamber, and thereby lower the pH. In response to the drop in pH, the polymer gel expands and reduces flow from the hydro-gen ion reservoir to provide a self-regulation of pH.
A microscale pH sensor/actuator 10 illus-trated in Fig. 2 is manufactured as follows. Stan-dard etching techniques can be used to form a cham-ber 12 and channels 14. A layer transfer process is used to form a flexible membrane 16 that is deformed by the volume contractions and expansions of a polymer-based sensor/actuator 22. Thus, device 10 is formed from channels 14 and chambers 12 etched in two separate substrates 18 and 20 (e.g., glass or silicon) with flexible membrane 16 transferred to one substrate, e.g., substrate 18, and a polymer gel 22 is patterned and formed prior to bonding sub-strates 18 and 20 together.
The polymeric sensor/actuator 22 is a swellable, three-dimensional polymer gel that main-tains contact with a fluid in channels 14 at all times. Polymeric sensor/actuator 22 is covalently bound to membrane 16 and the walls of channel 14, and uniformly fills the space in the channel 14.
Although polymeric sensor/actuator 22 restricts fluid flow, fluid can be transported through the porous polymer gel to provide a continuous sensing of fluid pH.
Polymeric sensor/actuator 22 typically comprises at least three components (1) an optional anchoring material, e.g., either an initiator or a monomer, adhered to a film on a surface of channel 14, or a physical or mechanical anchor, like a post, (2) a polymerizable monomer, and (3) a polymerizable crosslinker. If an optional anchoring material is used, the monomer or initiator adhered to a surface of channel 14 can be selectively deposited onto a preselected region of channel 14. For example, phosphate groups present on a surface-bound initia-tor or monomer direct adsorption of these molecules onto surfaces patterned with zirconium by utilizing a known zirconium phosphonate/phosphate interaction (see, G. Cao et al., Acc. Chem. Res., 25, p. 420 (1992), and H. Katz et al., Science, 254, p. 1485 (1991).
Formation of polymeric sensor/actuator 22 at a preselected location in chamber 14 is achieved by microfluidic delivery of a polymerizable mixture containing an appropriate monomer/crosslinker mix-ture (e.g., a mixture of vinyl imidazole, N-iso-propyl acrylamide, and ethylene glycol dimethacryl-ate crosslinker). Polymerization of the polymer-izable mixture can be initiated by applying incident light, or other suitable energy source, to the pre-selected location of polymer formation. If an op-tional anchoring monomer is adhered to a surface of channel 14, the anchoring monomer is threaded into the polymer gel network as polymerization of the anchoring monomer with the polymerizable mixture proceeds.
Polymerization at locations in channels 14 outside the desired location of polymer gel forma-tion is avoided by masking such locations from the incident light or other energy source. After poly-merization, excess unreacted polymerizable mixture is flushed from channels 14 to position polymeric sensor/actuator 22 in channels 14, as shown in Fig.
2. The resulting polymer gel preferably fills the gap between flexible membrane 16 and the wall of channel 14, and is strongly adhered to these sur-faces. The polymeric gel contracts at high pH, and expands (e.g., swells) at a pH below 6.8. The vol-ume change of the polymer gel between the expanded and contracted states is a factor of about 10, and is rapid because of the small size of polymeric sensor-actuator 22. The speed and degree of con-traction and expansion is sufficient to provide an adequate self-regulation of pH. Polymer gel 22 functions as both sensor and actuator to regulate fluid flow without the need for external monitoring and control. The sensing and actuation functions are attributed to the use of a polymeric material that exhibits discontinuous volume changes in re-sponse to the chemical environment, i.e., pH, of the fluid stream. The change in volume of the polymer gel is illustrated in Fig. 3.
The pH sensor/actuator illustrated in Fig.
2 demonstrates one microscale device utilizing a functional polymer gel and one method of microfabri-cating the microscale device. However, the present invention is not limited to the above-described pH
sensor/actuator. The method of the present inven-tion is generic for the preparation of numerous other microscale devices having a preselected array of one or more microscale channels that can contain one or more polymer gels designed to perform a spe-cific function, e.g., detect an analyte or a change in a physical property, or act as a valve or a pump.
In general, a microscale device of the present invention comprises (a) nonresponsive con-struction materials and (b) responsive materials.
The responsive material can be a bioresponsive mate-rial and/or a physico/chemoresponsive material. The responsive material typically is a polymeric hydro-gel. The responsive materials are prepared from monomers, and typically photopolymerizable monomers, and are integrated directly into the device as de-scribed above. The responsive materials typically are polymers prepared from multifunctional acryl-ates, hydroxyethylmethacrylate (HEMA), elastomeric acrylates, and related monomers. The nonresponsive materials are used to define the walls of channels and form the structural components of permeable, semipermeable, and impermeable flexible barriers.
Nonresponsive materials typically are prepared from hydrocarbon monomers, like dicyclopentadiene.
Physico/chemoresponsive materials are hydrogels that exhibit fast and substantial changes in volume as a function of various stimuli and are used to fabricate microscale components that regu-late and/or monitor temperature, pH, ionic strength, the presence of a particular compound, and other environmental variables. Physico/chemoresponsive materials also are the basic building block for the preparation of a microscale component containing a bioresponsive material.
Bioresponsive materials typically comprise a synthetic hydrogel and a biomolecule. Biorespon-sive materials are capable of exhibiting a volume change in the presence of toxins or pathogens, for example, and either can undergo volume changes mul-tiple times in a reversible and repeatable fashion, or can be "one-shot" materials that undergo an irre-versible volume change, depending upon the composi-tional makeup of the bioresponsive material.
The manufacture of a microscale device of the present invention, i.e.,a hydrogel jacket valve in a T-channel, is illustrated in Figs. 4 and 6. In general, micromolding techniques are used to provide wide, shallow cartridges. Polymer components, both functional and structural, are created inside a cartridge via direct photopatterning of a liquid phase polymerizable mixture. Through the applica-tion of liquid phase polymerization, lithography, and laminar flow, all components of the device, including the nonresponsive microchannels, are eas-ily constructed.
In a typical procedure illustrated in Fig.
4, a cartridge 200, for example, about 100 to 250 }1m deep, and, independently, about 500 to 25,000 um wide and long, is filled with a polymerizable mix-ture comprising monomers and a photoinitiator. The mixture is allowed to reach a quiescent state, then is exposed to UV light. A photomask 204 positioned on a top surface of cartridge 200 determines the geometry of the structural components of the device and of the microchannels. The polymerizable mixture that is not protected by photomask 204 polymerizes to form the nonfunctional structural material of the microscale device. Polymerization times are about 5 seconds to 10 minutes depending on the photoiniti-ator, monomer mixture, and light intensity. A con-venient light source is a filtered light source from a standard fluorescence microscope.
When polymerization is complete, residual, unpolymerized polymerizable mixture is flushed from cartridge 200 to provide a channel 202. The unpoly-merized mixture is flushed from the cartridge with a suitable solvent (e.g., water or methanol) to remove the unpolymerized mixture under the photomask.
Multiple structures can be created simultaneously by using a photomask with a multistructure pattern, or by refilling the cartridge with another the portion of same, or a different, polymerizable mixture and repeating the polymerization in a sequential fash-ion. Fig. 4 shows a microscale device 210 having a microscale component 212 positioned in microchannel 202.
Structures that are close together (i.e., <300 }.im) typically are not fabricated simultaneously because of a partial polymerization occurring be-tween the objects, but sequential polymerization can be used to avoid this problem. This method allows polymer materials of different shapes and sizes, and of different chemical identity, to be integrated directly into microfluidic systems, as illustrated in Fig. S.
Fig. 5 contains examples of various geome-tries of microchannels of a microscale device of the present invention. The structural material used to construct the microchannels illustrated in Fig. 5 was a mixture of isobornyl acrylate (IBA), 2,2-bis[p-21-hydroxy-31-methacryloxypropoxy)phenylene]-propane, or tetraethyleneglycol dimethacrylate TM
(TeEGDMA), and IRGACURE 651 as the photoinitiator.
These and similar monomers are preferred because they have a low degree of shrinkage during polymer-ization, exhibit fast polymerization kinetics, and are excellent structural materials that are nonfunc-tional and nonresponsive to stimuli of interest.
Typical polymerization times were about 5 to about seconds.
After UV exposure, the liquid polymer-izable mixture is converted into a clear, rigid structural material. By a suitable selection of components in the polymerizable mixture, micro-channels resistant to a variety of common solvents (e.g., water, ethanol, and acetone) can be prepared.
In particular, Fig. 5a-c illustrate the basic steps in the preparation of a microchannel: (a) a photo-mask positioned on a top of the channel surface of a cartridge which determines the shape of the channel;
(b) the microchannel after photopolymerization, (c) the channel after flushing with methanol to remove the unpolymerized monomer mixture. Fig. Sd-f illus-trate a variety of microchannel geometries with the corresponding photomask shown at a reduced size in the upper right corner of each figure. Scale bars are 500 pm.
The present method allows the construction of all device structures and components, and, there-fore, allows the total fabrication of a microscale device. For example, a predetermined array of microscale fluid channels in a substrate can be fab-ricated using any technique known to persons skilled in the art, e.g., etching or bonding of glass, or micromodeling or bonding of a polydimethylsiloxane.
Next, a suitable polymerizable mixture is introduced into the channels. For example, the first step can be building the "walls" of the device on a sub-strate. In particular, the channels are filled with the appropriate polymerizable mixture, then the areas designated as walls are exposed to light, or other suitable energy source, to polymerize the monomers in the polymerizable mixture. The other areas of the channels are masked to prevent poly-merization of the polymerizable mixture. Next, the remaining unreacted polymerizable mixture (i.e., the mixture under the mask) is rinsed from the channels.
Then, a different polymerizable mixture can be in-troduced to the channels, and exposure of a prese-lected area to light, for example, forms a device component (e.g., a valve). The walls are prepared from a structural polymer, whereas a component is prepared from a functional polymer gel, i.e., a polymer that undergoes a change in response to a stimuli (e.g., heat, light, pH, or a biomolecule).
This process can be repeated one or more times to manufacture additional device components comprising different functional polymer gels. Accordingly, an apparatus is envisioned wherein a substrate having a predetermined array of channels is introduced into the apparatus, then the apparatus is programmed to fabricate a customized microscale device. The pres-ent invention, therefore, provides a new process for manufacturing microscale devices useful in a variety of practical applications for microsystems. Addi-tional embodiments of the present invention are described below.
In another embodiment, a complex two-di-mensional microscale device is manufactured using a large hele-shaw flow cell, which is a wide, shallow flow chamber, is provided. Next, the flow chamber is filled with a first polymerizable mixture. Typi-cally, the first polymerizable mixture is nonfunc-tional structural material to manufacture device walls, for example. An optical mask is used to selectively expose preselected areas of the flow chamber to incident energy, like light, and polymer-ize the polymerizable mixture present at those ar-eas. The remaining unreacted polymerizable mixture then is rinsed from the flow chamber. This process is repeated to add functional components (e.g., valves, sensors, and displays) to the device, as desired, using different polymerizable mixtures polymerized at different preselected areas in the flow chamber, as illustrated in Fig. 6a.
As discussed in more detail hereafter, fluid flow into the channels is laminar because of the microscale size of the fluid channels. Accord-ingly, three-dimensional functional devices can be prepared using the present method. In particular, rather than using a wide, shallow flow chamber, a flow channel having a relatively equal height-to-width ratio (e.g., an order of 1, or a square) is used. When using such a microscale channel, two or more different polymerizable mixtures can be intro-duced into a channel simultaneously or sequentially because fluid flow is laminar as opposed to turbu-lent. Alternatively, a polymerizable mixture and an inert liquid can be introduced into the chamber simultaneously or sequentially.
As used here and hereafter, the term "in-ert liquid" refers to a liquid that does not undergo a polymerization reaction when subjected to light or other polymerization-initiating energy source. The inert liquid, therefore, can be a solvent or car-rier, like glycerin, or can be a liquid that carries a component to assist polymerization, like a poly-merization catalyst, such as a transition metal - "'S -G

metathesis-active catalyst for performing ring-open metathesis polymerization.
Laminar fluid flow at microscale combined with photopolymerization techniques allows the prep-aration of three-dimensional structures within microchannels. Fig. 6 illustrates a variety of geometric constructs made entirely by using laminar flow and photopolymerization, as illustrated in Fig.
6a. The device shown in Fig. 6a allows three fluid streams to be mixed. Two fluid streams 302 and 304 are controlled externally, while a third stream 306 is controlled automatically by a functional valve 308.
A device 300 illustrated in Fig. 6a is constructed from a substrate, e.g., a simple hele-shaw flow cell (i.e., a wide, shallow microfluidic channel). First, a nonfunctional (i.e., structural) polymerizable mixture is flowed into the cell and selective regions are exposed to ultraviolet light to form the channel walls and the unexposed regions are flushed to form channels 302, 304, and 306.
Next, a second polymerizable mixture is flowed into the newly formed channels. This mixture, which provides a pH sensitive hydrogel 308 after polymer-ization, is exposed only where a pH sensitive valve is desired, and the unexposed polymerizable mixture is flushed from the channels. Finally, a passive chaotic advection mixer 310 is prepared downstream in channel 302.
To create the three-dimensional geometry of mixer 310, laminar flow is used to define the dimensions in the plane perpendicular to flow and lithographic processes are used to define the dimen-sions in the direction of flow.
Fig. 6b illustrates a cross section of a microscale channel divided into four equal quad-rants. A different polymerizable mixture or an inert liquid compound is introduced into each quad-rant by laminar flow. The polymerizable mixtures polymerize in response to an exposure to a different wavelength of light, for example. Using an appro-priate energy source, a filter, and a mask, it is possible selectively polymerize the mixtures in the different quadrants. The y-z plane defines the walls of the device and fluid interfaces between fluid streams, and the x dimension is defined by the masking. Alternatively, the device can be formed sequentially with only one quadrant containing the polymerizable mixture and others containing an inert liquid, e.g., glycerin. One example of a device fabricated by this method is a passive micromixer 310 of Fig. 6(a) in which each channel contains an obstacle fabricated from a different functional polymer, such that the mixing characteristics change in response to the temperature or pH of the solu-tions to be mixed. See R.H. Liu, Journal of Micro-electromechanical Systems, submitted for publica-tion, April 1, 1999.
To construct mixer 310, a first polymer-izable mixture fluidized in stream 1 (Fig. 6b) to-gether with an inert fluid in streams 2, 3, and 4.
This procedure is repeated to form a three-dimen-sional serpentine-like channel. The channel struc-ture is functional (i.e., it expands and contracts in response to changes in pH) and is capable of adjusting the mixing performance in response to changes in the streams to be mixed (i.e., pH).
Alternatively, the mixer structure can be formed by simultaneously using different polymerizable mixture that polymerize upon exposure to light of different wavelengths.
Another embodiment of the present inven-tion uses hydrodynamic focusing to continuously manufacture small diameter polymeric threads. In this embodiment, a polymerizable mixture and an inert liquid are introduced into a microscale chan-nel utilizing laminar flow. In particular, the laminar fluid stream has a cross section such that the polymerizable mixture is surrounded by the inert liquid, i.e., so-called "sheath flow" because the inert liquid forms a sheath around a core of the polymerizable mixture, for example. Through a suit-able design of the fluid streams, a wide variety of threads of different cross section geometries can be formed, such as hollow, solid, multilayer, finned, and ribboned, for example. In addition, spheres or any particle shape that can be carried within a fluid stream can be positioned within the thread during manufacture. Either the thread and/or the bead can be manufactured from functional polymers.
In forming a thread, the polymerizable mixture, typically containing dicyclopentadiene or norborene, and inert liquid are allowed to continu-ously flow through the channel. Polymerization is effected at a preselected area of the channel, and a thread emerges from the channel. The process is adaptable to any material than can be carried in solution and solidified via some external stimuli (e.g., heat or light). The placement of objects in the thread can be controlled through the use of serial hydrodynamic focusing elements and the appro-priate choice of fluid properties, such as density and viscosity, for example, and fluid velocities.
The result of such a sheath flow is the preparation of a functional thread that can be woven into a fabric that responds to an external stimuli, i.e., a thread that expands or contracts in response to a pH
change or a change in temperature.
Laminar flow, without photomasks, can be used to control microscale component geometry during fabrication microscale device, as illustrated in Fig. 7. In Fig. 7a, three fluid streams are pumped through a microchannel. The two outer streams con-tain functional polymerizable mixtures, while the middle stream comprises an inert fluid (Fig. 7a).
For example, the outer streams of the polymerizable mixtures comprise, for example, acrylic acid, ethyl-ene glycol dimethacrylate, water, and a photoiniti-ator. The middle inert stream can comprise glyc-erin. After a steady laminar flow is established using syringe pumps, the flow rates are gradually reduced to zero (Fig. 7b), followed by UV irradia-tion at the desired area to initiate polymerization.
The result of polymerization is the formation of pH-sensitive hydrogels along the walls of the micro-channels while the channel remains open (Fig. 5c).
The functionalized walls can be used to regulate flow based on the pH of the fluid passing through the channel. When exposed to a basic solution (Fig.
7d), the pH-sensitive hydrogels expand to seal off the channel. Scale bars in Fig. 7 are 500 pm.

Functional components made of different functional materials that are otherwise incompatible can be fabricated simultaneously using this method because the inert stream eliminates the necessity of direct contact between the two outer streams.
The preceding general discussion demon-strates the ability to utilize laminar flow in microscale channels, followed by photoinitiated polymerization at a preselected location in the channel, to provide functional microscale devices, like a pH sensor/actuator described above. In par-ticular, Fig. 3 illustrates a circular polymer gel fabricated in a microscale channel via photoiniti-ated polymerization. In Fig. 3a, the polymer gel is expanded in acid, while in Fig. 3b, the polymer gel has contracted in a basic solution, thereby demon-strating pH sensitivity. Because of the small size of the pH sensor, the response to changes in pH, i.e., contraction and expansion, is rapid. The response also is reproducible.
An additional embodiment of the present invention includes writing with beam of light, wherein arbitrary two-dimensional shapes are formed by simply slowly moving a beam of light at an appro-priate wavelength over a channel containing a poly-merizable mixture, as illustrated in Fig. 6c. An-other embodiment utilizes a selective surface treat-ment, wherein selectively patterning an initiator on a channel surface can be used to define polymeriza-tion patterns. The inventive method can be utilized to manufacture both the structural components, like walls and channels, and the functional components, like sensors, valves, and pumps, of a microscale device, without the need to assemble individual device components.
The following describes various features of the present invention in more detail and provides further specific examples of the present invention.
The substrate used in the present method is not limited, and can be any material of construc-tion. If the substrate is monolithic, i.e., is a single component, the substrate is transparent to permit light to pass through the substrate and con-tact a polymerizable mixture in a microscale channel to effect polymerization. If the substrate com-prises two or more substrate components secured together to form the substrate, at least one sub-strate component is transparent to permit photo-initiated polymerization to occur in the microscale channels. Nonlimiting examples of substrates in-clude glass, a plastic, a transparent mineral, and similar substrates.
For example, the substrate can be silicon.
When using such a substrate, silicon planar proces-sing can be used for positioning electronic compo-nents, and the present invention can be used to position polymer gels over the electronic components to interface with the electronic components.
The channels present in the substrate are microscale in size. The substrate can contain one or a plurality of microscale channels depending upon the final end use application of the microscale device. The channels can be preformed in the sub-strate by methods well known in the art, such as lithography. Alternatively, the channels can be manufactured using the present invention. In this method, structural polymers are selectively produced at preselected locations on the substrate to provide the channel array of interest. Structural polymers typically are prepared from hydrocarbon monomers.
The channels are of microscale size such that fluid flow through the channels is laminar.
This permits two or more liquids to flow through the channel simultaneously without mixing. Accordingly, the channels have a cross-section diameter of about 1 micron to about 1 millimeter, and preferably about 2 microns to about 500 microns. To achieve the full advantage of the present invention, the channels have a cross section diameter of about 5 microns to about 250 microns.
The polymerizable mixture introduced into the microscale channels is a liquid. In addition, the liquid has properties which permit flow in a laminar fashion. Liquids that flow in a laminar fashion, i.e., without turbulent mixing, allow mul-tiple liquid streams to flow through the chamber simultaneously without mixing. Fluids flowing at microscale dimensions exhibit several differences from macroscale fluid flow. At a microscale channel size, turbulence does not exist and fluid flow is laminar. In laminar flow, it is possible to pre-cisely control the simultaneous introduction of multiple fluid streams into a single channel. An example of laminar flow is sheath flow in a flow cytometry system where hydrodynamic focusing is used to precisely align cells in solution. Laminar flow also is discussed in P.J. Kenis et al., Science, 285 pp. 83-85 (1999).

Liquids capable of exhibiting laminar flow have a low Reynold's number (Re). The Reynold's number is related to the tendency of a flowing liq-uid to develop turbulence. The Reynold's number is defined as follows:

Re = vlo p wherein the lower the velocity (v, in ml/s) of the liquid flow, the channel diameter (1, in m), and liquid density (p, in kg/m3), and the higher the liquid viscosity (,u, in kg/ms), the lower the Re.
In general, laminar flow occurs in fluids having an Re less than about 2000. Turbulent flow occurs in fluids having an Re greater than 2000.
Accordingly, a fluid used in the present invention, and introduced into a microscale channel, has a Reynolds number of about 1 to about 2000, and pref-erably about 2 to about 1000. To achieve the full advantage of the present invention, the fluid has an Re of about 5 to less than about 500, and especially less than about 100. Two or more different fluid streams simultaneously flowing in the same micro-sized channel, and having a low Re, do not develop turbulence, and the only method of mixing the fluid streams is diffusion at the fluid interface. Ac-cordingly, separate flowing layers of low Re fluids can flow through a microscale channel simulta-neously.
The fluid, or fluids, introduced into a microscale channel can be a polymerizable mixture or can be an inert liquid. A single fluid can be in-troduced into a channel, or more than one fluid can be introduced into a channel in a laminar flow. For example, two to five separate fluids can be intro-duced into the channel using laminar flow. When more than one fluid is introduced into a channel, at least one of the fluids is a polymerizable mixture.
Any other combination of inert liquid and polymer-izable mixture can be introduced into chamber.
Typically, a polymerizable mixture is introduced such that the mixture contacts a surface of the channel, and the resulting polymer gel is adhered to the surface. However, in the manufacture of a thread, the polymerizable mixture can be introduced such that the mixture does not contact channel sur-faces, i.e., is the core of a core/sheath flow.
An inert liquid flowing into the channel requires a low Re to provide laminar flow. The inert liquid also is incapable of being polymerized during a polymerization step. An inert liquid is introduced into the channel, for example, to act as a"spacer," i.e., to permit introduction of a de-sired thickness or cross section geometry of a polymerizable mixture in embodiments wherein the polymer gel thickness is less than the cross sec-tional dimension of the channel. After the polymer-ization step, the inert liquid is rinsed from the chamber. A nonlimiting example of an inert liquid is glycerin.
The polymerizable mixture flowing into the microscale channel is a liquid and also requires a low Re to provide laminar flow. The polymerizable mixture contains monomers capable of being polymer-ized when exposed to light or other polymer-initiat-ing energy sources. The polymerizable mixture pref-erably contains a high percentage of monomers capa-ble of photoinitiated polymerization. The mixture also can contain a photoinitiator. Most preferably, the polymerizable mixture is a neat mixture of mono-mers and photoinitiator, i.e., is free of a solvent.
However, if a solvent is necessary to solubilize or disperse a solid monomer or photoinitiator, or to adjust a physical property of the polymerizable mixture, a solvent can be included in the polymer-izable mixture. Typically, a solvent is present, if at all, in an amount of about 1% to about 25%, and preferably about 1% to about 10%, by weight, of the polymerizable mixture.
The solvent is not reactive when subjected to a polymerization-initiating energy source, and typically has a low molecular weight and a low boil-ing point. Nonlimiting examples of solvents in-clude, but are not limited to, alcohols, like metha-nol and ethanol, ethers, aliphatic and aromatic hydrocarbons, ketones, like acetone, and water.
The monomers present in the polymerizable mixture typically include: (a) one or more mono-functional monomers, like monounsaturated ethylenic monomers, to provide the basic polymer structure, and (b) one or more polyunsaturated monomers which act as crosslinking agents. The polymerizable mix-ture can contain only polyunsaturated monomers as the monomer. The monomers are selected to provide a polymer gel having the desired physical and chemical properties to perform the end use for which the device is designed. The monomers, therefore, can possess one or more functional groups to impart functionality to the polymer gel, or the monomers can be nonfunctional to provide structures within the device, for example, in the preparation of chan-nel walls, for example.
In particular, the monomers used to fabri-cate the functional polymer gel components typically exhibit a larae physical change in response to min-ute chemical or biological stimuli. The gels bridge the macro-to-micro size gap to provide a large am-plification of chemical/biological signals by di-rectly coupling the signals to the physical macro-sized world. This feature eliminates the need for many typical system components (i.e., detection, spotting, separation), and can eliminate the need for many preparation steps to separate, isolate, purify analyte.
The monounsaturated ethylenic monomers can be substituted in order to provide a polymer having pendant acid groups or pendant basic groups. Like-wise, the monomers can contain other types of sub-stituents, like silicone groups, epoxy groups, hy-droxy groups, amino groups, or a hydrolyzable group, like cyano groups. The polymerizable mixture can contain one monounsaturated monomer, or a plurality of comonomers, in order to provide a polymer gel having the desired chemical and physical properties to perform its intended function.
A polymer containing pendant acid groups can be either strongly or weakly acidic. The poly-mer can be a homopolymer or a copolymer. The acidic polymer typically is a lightly crosslinked acrylic-type polymer, such as lightly crosslinked poly-acrylic acid. The lightly crosslinked acidic resin typically is prepared by polymerizing an acidic monomer containing an acyl moiety, e.g., acrylic acid or a salt thereof, or a moiety capable of pro-viding an acid group, i.e., acrylonitrile, in the presence of a crosslinker, i.e., a polyunsaturated monomer. The acidic polymer can contain other co-polymerizable units, i.e., other monoethylenically unsaturated comonomers free of an acidic substit-uent. An acidic polymer typically contains at least 10%, and more preferably, at least 25%, and up to 100%, acidic monomer units. The other copolymeriz-able units can, for example, help improve the hydro-philicity or hydrophobicity of the polymer gel. The acidic polymer can be neutralized from 0 to 100 mole % with a base, like sodium hydroxide, to provide a neutralized acidic polymer.
Generally, acidic polymers have pendant carboxyl, sulfonate, sulfate, or phosphate groups present along the polymer chain. Polymers contain-ing such acidic moieties are synthesized from mono-mers previously substituted with one or more acidic substituents or by incorporating the acidic substit-uent into the polymer after synthesis. To incorpo-rate carboxyl groups into a polymer, any of a number of ethylenically unsaturated carboxylic acids can be homopolymerized or copolymerized. Carboxyl groups also can be incorporated into the polymer chain indirectly by hydrolyzing homopolymers and copoly-mers of monomers such as acrylamide, acrylonitrile, methacrylamide, and alkyl (meth)acrylates.
Ethylenically unsaturated carboxylic acid and carboxylic acid anhydride monomers include, for example, acrylic acid, methacrylic acid, ethacrylic acid, a-chloroacrylic acid, a-cyanoacrylic acid, ~3-methylacrylic acid (crotonic acid), a-phenylacrylic acid, ~3-acryloxypropionic acid, sorbic acid, a-chlorosorbic acid, angelic acid, cinnamic acid, p-chlorocinnamic acid, ~3-stearylacrylic acid, itaconic acid, citraconic acid, mesaconic acid, glutaconic acid, aconitic acid, maleic acid, fumaric acid, tri-carboxy ethylene, 2-methyl-2-butene dicarboxylic acid, maleamic acid, melamide, N-phenylmaleamide, maleic anhydride, fumaric anhydride, itaconic anhy-dride, citraconic anhydride, mesaconic anhydride, methyl itaconic anhydride, ethyl maleic anhydride, diethyl maleate, methyl maleate, maleic anhydride, and mixtures thereof.
Ethylenically unsaturated sulfonic acid monomers include aliphatic and aromatic vinyl sulfonic acids, such as vinyl sulfonic acid, allyl sulfonic acid, vinyl toluene sulfonic acid, styrene sulfonic acid, acrylic and methacrylic sulfonic acids, such as sulfoethyl acrylate, sulfoethyl meth-acrylate, sulfopropyl acrylate, sulfopropyl meth-acrylate, 2-hydroxy-3-methacryloxypropyl sulfonic acid, and 2-acrylamide-2-methylpropane sulfonic acid. A sulfonate-containing acidic polymer also can be prepared from monomers containing functional groups hydrolyzable to the sulfonic acid form, for example, alkenyl sulfonic acid compounds and sulfo-alkylacrylate compounds.
Sulfate-containing acidic polymers are prepared by reacting homopolymers or copolymers containing hydroxyl groups or residual ethylenic unsaturation with sulfuric acid or sulfur trioxide.
Examples of such treated polymers include sulfated polyvinyl alcohol, sulfated hydroxyethyl acrylate, and sulfated hydroxypropyl methacrylate. Phosphate-containing acidic resins are prepared by homopoly-merizing or copolymerizing ethylenically unsaturated monomers containing a phosphoric acid moiety, such as methacryloxy ethyl phosphate.
Copolymerizable monomers for introduction into the acidic polymer include, but are not limited to, ethylene, propylene, isobutylene, C1_16alkyl acrylates and methacrylates, vinyl acetate, methyl vinyl ether, and styrenic compounds having the for-mula R-C=CH 2 a wherein R represents hydrogen or a C1_6alkyl group, and wherein the phenyl ring is optionally substi-tuted with one to four C,alkyl or hydroxy groups.
Suitable alkyl acrylates and methacrylates include, but are not limited to, methyl (meth)-acrylate, ethyl (meth)acrylate, isopropyl (meth)-acrylate, n-propyl (meth)acrylate, n-butyl (meth)-acrylate, and the like, and mixtures thereof. Addi-tional examples of the alkyl (meth)acrylates in-clude, but are not limited to, isobutyl, pentyl, isoamyl, hexyl, 2-ethylhexyl, cyclohexyl, decyl, isodecyl, benzyl, lauryl, isobornyl, octyl, and nonyl (meth)acrylates. Suitable sytrenic and vinyl compounds include, but are not limited to, styrene, a-methylstyrene, B-methylstyrene, p-methylstyrene, t-butylstyrene, vinyl benzoate, isopropenyl acetate, a halostyrene, isoprene, vinyl toluene, vinyl naph-thalene, acrylonitrile, acrylamide, methacrylamide, methacrylonitrile, vinyl acetate, vinyl propionate, vinyl butyrate, vinyl stearate, isobutoxymethyl acrylamide, vinyl chloride, and the like, and mix-tures thereof.
Analogous to the acidic polymer gel, a basic polymer gel can be strongly or weakly basic.
The basic polymer can be a homopolymer or a copoly-mer. The strongly basic polymers typically are present in the hydroxide (OH) or bicarbonate (HCO3) form.
A basic polymer gel typically is a lightly crosslinked acrylic-type resin, such as a poly-(vinylamine). The basic polymer also can be a poly-ethylenimine, a poly(allylamine), a poly(allylguani-dine), a poly(dimethyldiallylammonium hydroxide), a quaternized polystyrene derivative, such as q N+Me3 -OH

a guanidine-modified polystyrene, such as q NH
,N~ NH2 H

a quaternized poly((meth)acrylamide) or ester ana-log, such as q O
NH (CH 2) nN+Me 3 OH
or Rl q O
O( CH 2) nN+Me 3- OH

wherein Me is methyl, R1 is hydrogen or methyl, n is a number 1 to 8, and q is a number 10 to about 100,000, or a poly(vinylguanidine), i.e., poly(VG), a strong basic polymer having the general structural formula H-N
R~NH
2\N
/

wherein q is a number 10 to about 100,000, and R2 and R3, independently, are selected from the group con-sisting of hydrogen, C1-C4 alkyl, C3-C6 cycloalkyl, benzyl, phenyl, alkyl-substituted phenyl, naphthyl, and similar aliphatic and aromatic groups. Like an acidic polymer gel, the basic polymer gel can con-tain other copolymerizable units and is crosslinked using a polyunsaturated monomer.
The monosaturated ethylenic monomer also can be a functionalized monomer, for example, a hydroxyalkyl (meth)acrylate, an aminoalkyl (meth)-acrylate, or a glycidyl (meth)acrylate. Such mono-mers can be photopolymerized to provide polymers having functional pendant groups useful as is, or that can be derivatized by subsequent reactions to provide polymers that respond to a specific stimuli.
For example, the polymer can be derivatized by at-taching an antibody or a chemical or physical label-ing group to the polymer.
An example of a class of functional mono-mers is a monomer containing a glycidyl group, like glycidyl (meth)acrylate. A monomer in this class can be any monomer having a carbon-carbon double bond and a glycidyl group. Typically, the monomer is a glycidyl ester of an aõ3-unsaturated acid, or anhydride thereof. The a,6-unsaturated acid can be a monocarboxylic acid or a dicarboxylic acid. Exam-ples of such carboxylic acids include, but are not limited to, acrylic acid, methacrylic acid, eth-acrylic acid, a-chloroacrylic acid, a-cyanoacrylic acid, 8-methylacrylic acid (crotonic acid), a-phenylacrylic acid, /3-acryloxypropionic acid, sorbic acid, a-chlorosorbic acid, angelic acid, cinnamic acid, p-chlorocinnamic acid, /3-stearylacrylic acid, itaconic acid, citraconic acid, mesaconic acid, glutaconic acid, aconitic acid, maleic acid, fumaric acid, tricarboxy ethylene, maleic anhydride, and mixtures thereof. Specific examples of monomers containing a glycidyl group are glycidyl (meth)-acrylates (i.e., glycidyl methacrylate and glycidyl acrylate), mono- and di-glycidyl itaconate, mono-and di-glycidyl maleate, and mono- and di-glycidyl formate. Allyl glycidyl ether and vinyl glycidyl ether also can be used as a monounsaturated monomer in the method of the present invention.
In addition, the polymer gel can initially be a copolymer of an a,,3-unsaturated acid and an alkyl (meth)acrylate, which then is reacted with a glycidyl halide or tosylate, e.g., glycidyl chlo-ride, to position pendant glycidyl groups on the polymer gel. The aõ~3-unsaturated carboxylic acid can be an acid listed above, for example.
In an alternative embodiment, a polymer gel having pendant hydroxyl groups first is formed.
The polymer then is reacted to position pendant glycidyl groups on the polymer. The polymer having pendant hydroxyl groups can be prepared by incorpo-rating a monomer, like 2-hydroxyethyl methacrylate or 3-hydroxypropyl methacrylate, into the polymer gel.
A preferred monounsaturated monomer con-taining a glycidyl group is glycidyl (meth)acrylate having the following structure:

/O\
CH2=i-C-OCH2-CH CHZ

wherein R4 is hydrogen or methyl.
Another example of a class of monomers containing a functional group are the hydroxy(C1-C;)alkyl (meth)acrylates, e.g., 2-hydroxyethyl meth-acrylate, 2-hydroxyethyl acrylate, 2-hydroxypropyl methacrylate, and 3-hydroxypropyl methacrylate.
The polymer gel initially can be a copoly-mer of an alkyl (meth)acrylate, which then is re-acted with a glycol or polyol, e.g., ethylene glycol or propylene glycol, to position pendant hydroxy groups on the acrylate copolymer.
In an alternative embodiment, a polymer gel having pendant glycidyl groups first is formed.
The polymer gel then is reacted with a reagent to open the glycidyl epoxy ring and position pendant hydroxy groups on the acrylate polymer. The acrylate copolymer having pendant glycidyl groups can be prepared by incorporating a monomer like glycidyl acrylate, glycidyl methacrylate, allyl glycidyl ether, or vinyl glycidyl ether into the polymer gel.

A preferred monounsaturated monomer con-taining a hydroxy group is a hydroxyalkyl (meth)-acrylate having the following structure:

CH2=i-C-O-R'-OH

wherein R4 is hydrogen or methyl, and R5 is a C, to C.
alkylene group or an arylene group. For example, RS
can be, but is not limited to (-CH2-),,, wherein n is 1 to 6, -iH-CH2--iH-CH2-CH2-any other structural isomer of an alkylene group containing three to six carbon atoms, or a cyclic C3-C6 alkylene group. R5 also can be an arylene group, like phenylene ( i. e., C6H4 ) or naphthylene ( i. e., Cl,H,) . R5 optionally can be substituted with sub-stituents, like C1-C6 alkyl, halo, (i.e., Cl, Br, F, and I), phenyl, alkoxy, and aryloxy (i.e., an ORZ
substituent), for example.

An additional functional monomer has the structure:

CH2=C-C1-OR 6 wherein Ra is hydrogen or methyl, and R6 is a substi-tuted alkyl group containing one to sixteen carbon atoms. The R6 group is substituted with one or more, and typically one to three, moieties such as halo, amino, phenyl, and alkoxy, for example. The struc-ture, therefore, encompasses aminoalkyl (meth)-acrylates. Most preferably, R1 is methyl and R' is an amino-substituted alkyl group having two to four carbon atoms.
Additional functional monomers include the alkylated alkylol acrylamide monomers, which are derivatives of acrylamide, methacrylamide, methylol acrylamide, or similar alkyl modified acrylamide monomer as disclosed, for example, in U.S. Patent Nos. 3,991,216; 4,097,438; and 4,305,859.
The acrylamide monomers preferably are alkylated with an alkyl group, such as methyl, ethyl, propyl, n-butyl, or isobutyl, and similar alkylated alkylol acrylamide monomers.
The monomers useful in the present method are not limited to acrylate or vinyl-type monomers, but can include any other monounsaturated or polyun-saturated monomer that is photopolymerizable. Exam-ples of other types of photopolymerizable monomers include, for example, an epoxy compound, including an epoxy functional silicone compound.

A wide variety of photopolymerizable mono-mers are known in the art, and include, for example, the various acrylic compounds and vinyl compounds disclosed above. Nonlimiting examples of other suitable classes of photopolymerizable monomers, used either alone or in monomer mixtures, include epoxysilicone compounds, epoxy compounds, polymer-izable ether compounds, and polyhydroxy organic compounds.
Numerous photopolymerizable epoxysilicone compounds are available commercially. For example, epoxysilicones sold under the trade designations UV9400 and UV500A are available from the GE Sili-cones, Waterford, New York. UV9400 contains 80-99%
by weight of dimethyl, methyl, 2-(7-oxabicyclo-(4.1.0) hept-3-yl)ethyl silicone having (dimethyl (2-(7-oxabicyclo(4.1.0)hept-3-yl)ethylsilyl)-oxy) terminal groups. UV500A contains about 10-30 per-cent by weight dimethyl, methyl, 2-(7-oxabicyclo-(4.1.0)hept-3-yl)ethyl silicone having (dimethyl (2-(7-oxabicyclo(4.1.0) hept-3-yl) ethylsilyl)-oxy) terminal groups. The epoxysilicone in UV9400 and UV500A has a CAS No. 150678-61-8. W9300 is another suitable epoxysilicone (containing 80-99% by weight dimethyl, methyl, 2-(7-oxabicyclo(4.1.0) hept-3-yl)-ethyl) silicone (CAS No. 67762-95-2), also available from General Electric.
Additional epoxy-functional silicone com-pounds are available from the General Electric Co.
under the trade designations UV9315 and UV9320.

UV9315 contains 80-99% by weight dimethyl, methyl, 2-(7-oxabicyclo(4.1.0)hept-3-yl)ethyl silicone hav-ing dimethyl (2-(7-oxabicyclo(4.1.0)hept-3-yl)-ethylsilyl)-oxy terminal groups (CAS No. 150678-61-8). UV9320 contains 80-99% by weight (2-hydroxy-phenyl)propyl, trimethyl-heptyl-3-yl)ethyl, methyl-3-methyl-2-(7-oxabicyclo(4.1.0)hept-3-yl)ethyl-silyl)-oxy) silicone having dimethyl siloxy terminal groups (CAS No. 130885-21-1).
Other photopolymerizable silicone com-pounds are available from Genesee Polymers Corpora-tion of Flint, Michigan. For example, photopolymer-izable silicone compounds are sold under the trade designations EXP-29 and EXP-32 silicone fluids.
EXP-29 is an epoxy-functional dimethylpolysiloxane copolymer having a molecular weight of about 5700 and the structure:

(CH3) 3SiO i i0 Si0 Si (CH3) 3 CH3 57 i3H6 O

CH ~
( / O

EXP-32 also is an epoxy functional dimethylpoly-siloxane copolymer fluid having a molecular weight of about 8300 and the structure:

I
(CH3) 3SiO i iO Si0 Si (CH3) ~
1 3 ~ ~
96 . 5 C3H6 O

CH
/ O

5.5 Additional epoxysilicone compounds are described in Koshar et al. U.S. Patent No. 4,313,988.

Further photopolymerizable monomers in-clude a product available from Union Carbide under the trade designation UVR-6110. UVR-6110 contains the difunctional epoxy compound, 3,4-epoxycyclo-hexylmethyl-3,4-epoxycyclohexane carboxylate. Other epoxy compounds that can be included in the polymer-izable mixture are, for example, bis(3,4-epoxycyclo-hexylmethyl)adipate, 2-(3,4-epoxycyclohexyl-5.5-spiro-3,4-epoxy)cyclohexane-metal-dioxane, a digly-cidyl ether of phthalic acid, a diglycidyl ether of hexahydrophthalic acid, a diglycidyl ether of bis-phenol A, a cresol-novolac epoxy resin, other di-functional and multifunctional epoxy compounds, and mixtures thereof. Monoepoxy compounds, like a Ce-C1, alkylglycidyl ether, also can be used in the poly-merizable mixture.

Preferred monomers for use in a pH sen-sor/actuator include, but are not limited to, acrylic acid, butyl methacrylate, 2-(dimethyl-amino)ethyl methacrylate, 2-hydroxyethyl meth-acrylate, hydroxypropyl methacrylate, methacrylic acid, methyl methacrylate, and ethylene glycol dimethacrylate.
Polymerization of the unsaturated ethyl-enic monomers, including acidic or basic monomers, or other functional monomers, and optional copoly-merizable monomers, typically is performed by free radical processes in the presence of a polymeriz-able crosslinker, conventionally a polyunsaturated organic compound. The polymers are crosslinked to a sufficient extent such that the polymer is an insoluble gel. For use in many applications, a polymer gel is lightly crosslinked, i.e., has a crosslinking density of less than about 20%, pref-erably less than about 10%, and most preferably about 0.01% to about 7%, which allows the polymer gel to expand and contract.
A polymerizable crosslinker most prefera-bly is used in an amount of less than about 7 wt%, and typically about 0.1 wt% to about 5 wt%, based on the total weight of monomers. Examples of crosslinking polyvinyl monomers include, but are not limited to, polyacrylic (or polymethacrylic) acid esters represented by the following formula (I); and bisacrylamides, represented by the follow-ing formula (II).

CH2=CH HC=CH2 I ( 0=C-O-X O-C=0 k (I) , wherein X is ethylene, propylene, trimethylene, cyclohexyl, hexamethylene, 2-hydroxypropylene, - ( CH2CH2O ) PCH2CH2 - , or I I
-(CHz-CH-O)rCH2 CH

p and r are each an integer 5 to 40, and k is 1 or 2;

CH2=CH
I /HC=CH 2 0=C-NH (CH 2CH2NH) 1C=0 (II) wherein 1 is 2 or 3.
The compounds of formula (I) are prepared by reacting polyols, such as ethylene glycol, pro-pylene glycol, trimethylolpropane, 1,6-hexanediol, glycerin, pentaerythritol, polyethylene glycol, or polypropylene glycol, with acrylic acid or meth-acrylic acid. The compounds of formula (II) are obtained by reacting polyalkylene polyamines, such as diethylenetriamine and triethylenetetramine, with acrylic acid.
Specific crosslinking monomers include, but are not limited to, 1,4-butanediol diacrylate, 1,4-butanediol dimethacrylate, 1,3-butylene glycol diacrylate, 1,3-butylene glycol dimethacrylate, di-ethylene glycol diacrylate, diethylene glycol di-methacrylate, ethoxylated bisphenol A diacrylate, ethoxylated bisphenol A dimethacrylate, ethylene glycol dimethacrylate, 1,6-hexanediol diacrylate, 1,6-hexanediol dimethacrylate, neopentyl glycol di-methacrylate, polyethylene glycol diacrylate, poly-ethylene glycol dimethacrylate, triethylene glycol diacrylate, triethylene glycol dimethacrylate, tri-propylene glycol diacrylate, tetraethylene glycol diacrylate, tetraethylene glycol dimethacrylate, dipentaerythritol pentaacrylate, pentaerythritol tetraacrylate, pentaerythritol triacrylate, tri-methylolpropane triacrylate, trimethylolpropane trimethacrylate, tris(2-hydroxyethyl)isocyanurate triacrylate, tris(2-hydroxyethy)isocyanurate tri-methacrylate, divinyl esters of a polycarboxylic acid, diallyl esters or a polycarboxylic acid, triallyl terephthalate, diallyl maleate, diallyl fumarate, hexamethylenebismaleimide, trivinyl trimellitate, divinyl adipate, diallyl succinate, a divinyl ether of ethylene glycol, cyclopentadiene diacrylate, tetraallyl ammonium halides, or mix-tures thereof. Compounds such as divinylbenzene and divinyl ether also can be used to crosslink the poly(dialkylaminoalkyl acrylamides). Especially preferred crosslinking agents are N,N'-methylene-bisacrylamide, N,N'-methylenebismethacrylamide, ethylene glycol dimethacrylate, and trimethylol-propane triacrylate.
In addition to the polymerizable mono-mers, the polymerizable mixture contains a photo-initiator, which facilitates polymerization when the polymerizable mixture is exposed to light.
Alternatively, the photoinitiator can be adhered to a surface of a microscale channel at the position preselected for forming the polymer gel.
The photoinitiator is not limited, except that the initiator must be functional at the wave-length used to effect polymerization. The photo-initiator can be organic or inorganic in nature, and can be useful in aqueous or organic solvent-based polymerization mixtures. The photoinitiator is present in the polymerizable mixture in a suffi-cient amount to facilitate light or radiant energy-induced polymerization, i.e., about 0.1% to about 5%, by weight, based on the total weight of mono-mers in the polymerizable mixture.
A photoinitiator is a compound that ab-sorbs energy, either directly or indirectly, from a photon and subsequently initiates polymerization.
In particular, photoinitiators absorb light in the UV-visible spectral range (i.e., 250 to 450 nm) and convert this light energy into chemical energy in the form of reactive intermediates, such as free radicals or reactive cations, which subsequently initiate polymerization of monomers.
Photoinitiators for free radical UV cur-ing are divided into two classes, namely Type I and Type II initiators. Upon irradiation, Type I ini-tiators undergo fragmentation to yield initiating radicals. The majority of Type I initiators are aromatic carbonyl compounds containing suitable substituents that facilitate direct photofragmenta-tion. Type II initiators mainly undergo two reac-tion pathways, hydrogen abstraction by the excited initiator, and photoinduced electron transfer, followed by fragmentation.
Type I photoinitiators include benzoin derivatives, notably benzoin ethers; benzil deriva-tives, like benzilketals, including 2,2-dimethoxy-2-phenylacetophenone (DMPA), a-hydroxyalkylphe-nones, like 2-hydroxy-2-methyl-l-phenylpropan-l-one (HMPP) and 1-hydroxy-cyclohexyl-phenylketone (HCPK); a-aminoalkylphenones; and acylphosphin-oxides. Type II photoinitiators include aromatic ketones (e.g., benzophenone, substituted benzo-phenones, benzils, fluorenone, xanthone, thioxan-thones), with performance being enhanced by the use of a tertiary amine synergists, like alkanolamines (e.g., triethanolamine, N,N-dimethylethanolamine, and N-methyldiethanolamine), and derivatives of a p-N,N-dimethylaminobenzoic acid. One class of amines is aliphatic amines and the other class is aromatic amines. Aliphatic amines are transparent down to 260 nm and consequently an amine can use light from the UV lamp down to 260 nm. The aro-matic amines display strong absorption around 300 nm and consequently screen much of the UV light.
Examples of Type II photoinitiators are the benzo-phenone-amines and thioxanthone-amines.
Specific examples of Type I photoiniti-ators include, but are not limited to, a-alkoxy-deoxybenzoins, a,a-dialkyloxydeoxybenzoins, a,a-dialkoxyacetophenones, a,a-hydroxyalkylphenones, 0-acyl a-oximinoketones, dibenzoyl disulphide, S-phenyl thiobenzoates, acylphosphine oxides, di-benzoylmethanes, phenylazo-4-diphenylsulphone, 4-morpholino-a-dialkylaminoacetophenones, and mix-tures thereof. Specific examples of Type II photo-initiators include, but are not limited to, benzo-phenones, camphorquinone, fluorenones, xanthones, benzils, a-ketocoumarins, anthraquinones, tere-phthalophenones, and mixtures thereof.
Water-soluble photoinitiators utilized in the polymerization of vinyl-type monomers include unimolecular photoinitiators, such as peroxides, which show absorption in the 200-300 nm region, like hydrogen peroxide, peroxydisulphate, and peroxydiphosphate; alkylazo compounds, like azoiso-butyramide, a,a'-azobis(2-amidino)propane hydro-chloride, and 4,41-azobis(4-cyanovaleric); carbonyl compounds, like alkylphenones, such as 4-substi-tuted (2-hydroxy-2-propyl)phenyl ketones and benzoylmethyl thiosulphates; a-dicarbonyl com-pounds, like solvated 2,3-butanedione; phosphines, like acylphosphine oxides and acylphosphonates, such as lithium and magnesium phenyl-2,4,6-tri-methylbenzoylphosphinates; and copper (II) com-plexes, like copper(II)-bis(aminoacid)chelates with various amino acids (e.g., glutamic acid, serine, or valine).
Bimolecular water-soluble photoinitiators include coordination complexes, like iron (III), cobalt (III), and chromium (VI) complexes, such as trinuclear transition metal complexes; carbonyl compounds, like aromatic carbonyl compounds, such as benzophenone or thioxanthone derivatives in the presence of aliphatic amines as hydrogen donors, which have been made water soluble by attaching ionic groups, such as trimethylammonium or sulphon-ates; aromatic hydrocarbons, like pyrene; and dye-sensitized systems, which comprise a dye and a reducing agent such as an amine, sulphinate, phos-phine, enolate, a-aminosulfone, or carboxylte.
Another class of photoinitiators is cat-ionic initiators, which are compounds that under the influence of UV or visible radiation lead to the release of an acid, which in turn catalyzes the desired polymerization process. Cationic photo-initiators include diazonium salts, iodonium salts, and sulfonium salts.
Specific examples of photoinitiators include, but are not limited to benzophenone; 4,4'-bis(N,N'-dimethylamino)benzophenone (Michler's ketone); a,a-dimethyl-a-hydroxyacetophenone; 1-phenyl-1,2-propanedione, 2-(O-benzoyl)oxime; 4-phenylbenzophenone; benzil; (1-hydroxycyclohexyl)-phenylmethanone; diphenyl(2,4,6-trimethylbenzoyl)-phosphine oxide; xanthone; thioxanthone; 2-chloro-thioxanthone; 9,10-phenanthraquinone; benzoin ethers (e.g., methyl, ethyl, or isobtyl); a-di-methylamino-a-ethyl-a-benzyl-3,5-dimethyl-4-morpho-linoacetophenone; a,a-dimethoxy-a-phenylacetophe-none; 9,10-anthraquinone; and a,a-diethoxyaceto-phenone.
Additional examples of photoinitiators include, but are not limited to, iodonium salts and sulfonium salts. The anion of these salts is not limited, but preferably is a complex anion contain-ing Group Va or VIa elements. Exemplary, but non-limiting, elements present in the anions are, for example: boron, phosphorus, antimony, arsenic, and tin. Nonlimiting examples of suitable nonbasic, nonnucleophilic anions include, but are not limited to: BF4 , PF6 , AsF6-, SbF6 , SnCl6 , SbCl6 , BiCl, ', C10, , HSO4 1 ZrF6-2, GaC14 , InF. , TiFS z, A1F, ' and FeCl4 ' .
Nonlimiting examples of particular sul-fonium salt photoinitiators include the triaryl sulfonium complex salts, such as phenoxyphenyl sul-fonium hexafluorophosphate; trifluoromethyl diphen-yl sulfonium tetrafluoroborate; triphenyl sulfonium tetrafluoroborate, methyl diphenyl sulfonium tetra-fluoroborate, dimethyl phenyl sulfonium hexafluoro-borate, triphenyl sulfonium hexafluorophosphate, triphenyl sulfonium hexafluoroantimonate, diphenyl naphthyl sulfonium hexafluoroarsenate, tritolyl sulfonium hexafluorophosphate, anisyl diphenyl sul-fonium hexafluoroantimonate, 4-butoxyphenyl diphen-yl sulfonium tetrafluoroborate, 4-chlorophenyl diphenyl sulfonium hexafluorophosphate, tri(4-phenoxyphenyl) sulfonium hexafluorophosphate, di(4-ethoxyphenyl) methyl sulfonium hexafluoroarsenate, 4-acetonylphenyl diphenyl sulfonium tetrafluoro-borate, 4-thiomethoxyphenyl diphenyl sulfonium hexafluorophosphate, di(methoxysulfonylphenyl) methyl sulfonium hexafluoroantimonate, di(nitro-phenyl) phenyl sulfonium hexafluoroantimonate, di(carbomethoxyphenyl) methyl sulfonium hexafluoro-phosphate, 4-acetamidophenyl diphenyl sulfonium tetrafluoroborate, p-(phenylthiophenyl) diphenyl sulfonium hexafluoroantimonate, l0-methylphenox-athiinium hexafluorophosphate, 5-methylthianthren-ium hexafluorophosphate, 10-phenyl-9,9-dimethyl-thioxanthenium hexafluorophosphate, 10-phenyl-9-oxothioxanthenium tetrafluoroborate, 5-methyl-10-oxothianthrenium tetrafluoroborate, 5-methyl-10,10-dioxothianthrenium hexafluorophosphate, dimethvl naphthyl sulfonium hexafluorophosphate, and mix-tures thereof. Bis-type sulfonium salt photo-initiators, such as bis-(4-(diphenylsulfonio) phenyl)sulfide bis-hexafluorophosphate, for exam-ple, also can be used.
Many sulfonium salt photoinitiators are available commercially. For example, a preferred sulfonium salt initiator is available under the trade name CYRACURE UVI-6974 from Union Carbide Corporation of Danbury, Connecticut. CYRACUREMUVI-6974 contains a mixture of triaryl sulfonium hexa-fluoroantimonate salts having CAS Nos. 89452-37-9 and 71449-78-0, and is sold as a 50 wt.% solution in propylene carbonate. CAS No_ 89452-37-9 is (thiodi-4,1-phenylene) bis(diphenyl-sulfonium) hexafluoroantimonate. CAS No. 71449-78-0 is diphenyl(4-phenylthiophenyl) sulfonium hexafluoro-antimonate. Another suitable sulfonium photoiniti-ator available from Union Carbide Corporation is TM
CYRACURE WI-6990. UVI-6990 contains triaryl sul-fonium hexafluorophosphate salts having CAS Nos.
74227-35-3 and 68156-13-8, and is sold as a 50%
solution in propylene carbonate. CAS No. 74227-35-3 is bis(4-(diphenylsulfonio)phenyl) sulfide bis-(hexafluorophosphate). CAS Nos. 68156-13-8 is diphenyl phenylthiophenyl sulfonium hexafluoro-phosphate.

Nonlimiting examples of useful iodonium salt initiators include the aryl iodonium salts, such as diphenyliodonium tetrafluoroborate, di(2,4-dichlorophenyl)iodonium hexafluorophosphate, di-phenyliodonium hexafluorophosphate, diphenyliodon-ium hexafluoroarsenate, diphenyliodonium iodide, diphenyliodonium hexafluoroantimonate, 4-chloro-phenylphenyliodonium tetrafluoroborate, di(4-chlor-ophenyl)iodonium hexafluoroantimonate diphenyl-iodonium hexafluorophosphate, diphenyliodonium trifluoroacetate, 4-trifluoromethylphenylphenyl-iodonium tetrafluoroborate, ditolyliodonium hexa-fluorophosphate, di(4-methoxyphenyl) iodonium hexafluoroantimonate, di(4-methoxyphenyl)-iodonium chloride, (4-methylphenyl)phenyliodonium tetra-fluoroborate, di-(2,4-dimethylphenyl)iodonium hexafluoroantimonate, di-(4-t-butylphenyl)iodonium hexafluoroantimonate, 2,21-diphenyliodonium hexa-fluorophosphate, di(4-methylphenyl)iodonium tetra-fluoroborate, di(4-heptylphenyl)iodonium tetra-fluoroborate, di(3-nitrophenyl)iodonium hexafluoro-phosphate, di(4-chlorophenyl)iodonium hexafluoro-phosphate, di(naphthyl)iodonium tetrafluoroborate, di(4-trifluoromethylphenyl)iodonium tetrafluoro-borate, di(4-methylphenyl)iodonium hexafluorophos-phate, diphenyliodonium hexafluoroarsenate, di(4-phenoxyphenyl)iodonium tetrafluoroborate, diphenyl-iodonium hexachlorostannate, phenyl-2-thienyl-iodonium hexafluorophosphate, diphenyliodonium hexafluorostannate, 2,21-diphenyliodonium tetra-fluoroborate, di(2,4-dichlorophenyl)iodonium hexa-fluorophosphate, di(4-bromophenyl)iodonium hexa-fluorophosphate, di(4-methoxyphenyl)iodonium hexa-fluorophosphate, di(3-carboxyphenyl)iodonium hexa-fluorophosphate, di(3-methoxycarbonylphenyl)-iodonium hexafluorophosphate, di(3-methoxysulfonyl-phenyl)iodonium hexafluoroohosphate, di(4-aceta-midophenyl)iodonium hexafluorophosphate, di(2-benzothienyl)iodonium hexafluorophosphate, bis(4-dodecylphenyl)iodonium hexafluoroantimonate, bis(4-dodecylphenyl) iodonium hexafluoroarsenate, and mixtures thereof.
Many iodonium salt initiators are also available commercially. An iodonium salt is avail-able from the General Electric Co., New York under the trade designation UV9380C. UV9380C contains about 30% to about 60% by weight bis(4-dodecyl-phenyl)iodonium hexafluoroantimonate (CAS No.
71786-70-4). Other components of UV9380C are 2-isopropyl thioxanthone, C12 and C14 alkyl glycidyl ethers (about 30% to about 60% by weight), and linear alkylate dodecylbenzene. The C12 and C14 alkyl glycidyl ethers are monoepoxy compounds and can be considered photopolymerizable monomers.
Another iodonium salt is available from the General Electric Co. under the trade designa-tion UV9310C. The active initiator component of UV9310C is about 30 to about 60 weight percent bis(4-dodecylphenyl)iodonium hexafluoroantimonate (CAS No. 71786-70-4). Other components of UV9310C
are 2-ethyl-l,3-hexanediol (about 30-60 weight percent) and a linear alkylate dodecylbenzene (about 5-10 weight percent). The 2-ethyl-1,3-hexanediol present in UV9310C is a polyhydroxy com-pound capable of reacting with the epoxy function-alities and can be considered as a photopolymeriz-able monomer.
Other examples of sulfonium salt and iodonium salt photoinitiators are found, for exam-ple, in Guarnery et al. U.S. Patent No. 4,250,006;
Schlesinger U.S. Patent No. 4,287,228; and Smith U.S. Patent No. 4,250,053.

The polymerizable mixture, and the poly-mer gels prepared therefrom, can, if desired, in-clude optional additives, such as dyes, fillers, pigments, flow agents, thickeners, thixotropic agents, surface active agents, viscosity modifiers, plasticizers, and similar additives known to per-sons skilled in the art to modify a physical or functional property of the polymerizable mixture or polymer gel. These optional ingredients are in-cluded in the polymerizable mixture in an amount sufficient to perform their intended purpose, typi-cally in amounts of 0.01 part to 5 parts, by weight, per 100 weight parts of the polymerizable mixture.
The polymerizable mixture is introduced into a microscale channel utilizing laminar flow such that, if desired, more than one fluid stream can be introduced into the channel simultaneously or sequentially, without mixing of the fluid streams. The channel is optically masked except for the preselected location of the channel where polymerization is desired. Sufficient energy to effect polymerization, like light of the proper wavelength, is directed at the preselected location for a sufficient time to polymerize the monomers in the mixture, typically about 20 seconds to about 5 minutes. The unreacted polymerizable mixture pres-ent at the masked locations of the channel then are flushed from the channel, leaving a polymer gel at the preselected location in the channel. The poly-mer gel can occupy the entire cross section of the channel, or a fraction of the cross section.
Microchannel surfaces can vary in polar-ity from hydrophobic to hydrophilic. Surface modi-fication is important for wetting, adhesion, bio-logical response, and for the constructions of hydrophobic vents. This can be easily accom-plished, for example, by using various substituted acrylates (e.g., perfluoroacrylates). For devices that require spatially varying surface chemistries, in situ methods to surface graft hydrogels can be used.
For example, a polymer is adhered to a surface of the channel by applying an anchoring material to the surface of the channel at a prese-lected location in the channel. The optional an-choring material serves to position the polymer gel at the preselected location in the channel, and helps ensure that the polymer gel is not moved by a flowing fluid during subsequent manufacturing steps, or during use of the device.
The optional anchoring material can be in the form of a thin layer of a material on a channel surface that adheres to the polymer gel and main-tains the polymer gel at the preselected location in the channel. In another embodiment, the anchor-ing material is in the form of a post manufactured from a structural material, and positioned in the microscale channel at the preselected location for the polymer gel. The post typically is a hard, nonfunctional plastic or metal material, and the functional, responsive polymeric hydrogel is pre-pared to surround the post. Another method of anchoring the polymer gel is to provide a micro-scale channel having a reduced cross sectional diameter at the preselected location for the poly-mer gel. In this embodiment, the walls of the channel physically hold the polymer gel at the desired preselected location. Persons skilled in the art are capable of selecting other anchoring materials and designing channels to inhibit move-ment of microscale components in the device during manufacture or use.
A microscale component prepared in a channel has a diameter-to-height ratio, i.e., an aspect ratio, of about 10 to 1 to about 0.5 to 1, and preferably at 5 to 1 to about 0.5 to 1. To achieve the full advantage of the present inven-tion, the polymer gel, or microscale component, has an aspect ratio of about 2 to 1 to about 0.5 to 1.
Components having a low aspect ratio, coupled with the small size of the component, provide a rapid component response to a stimulus.
In addition to modifying the geometry of the hydrogel objects, porosity can be introduced to the hydrogel structure to increase the rate of fluid diffusion and hydrogel expansion or contrac-tion. The introduction of porosity is achieved by adding surfactant and water to the polymerizable mixture. It has been theorized that surfactant micelle formation leads to the porous hydrogel structure during polymerization. It is observed that by introducing porosity, the response time for both hydrogel expansion and contraction improves more than ten-fold.
In addition, the polymer gel, or the microscale component, in the channel can be used as is to perform its intended function, or the polymer gel can be derivatized to perform a desired func-tion. For example, antibodies can be bound to the surface of the polymer gel to perform immunological assays. In addition, functional groups on the polymer gel can be altered chemically such that the polymer can selectively detect or measure an analyte or physical property of interest.
For example, a hydrogel can be deriv-itized to provide a bioresponsive microscale de-vice. Many extremely sensitive and elegant natural mechanisms detect and respond to a variety of dif-ferent foreign or damaging substances in the body.
While cell and tissue biosensing approaches are being investigated, interfacing between a cell/-tissue response and a macroscale detection is nontrivial and involves the development of complex analytical techniques. A microscale device of the present invention that utilizes a bioresponsive hydrogel provides a new and effective cell/tissue biosensor, while avoiding many of the disadvantages inherent in current approaches. By integrating biomolecules into or onto the surface of a hydro-gel, selective and sensitive sensors that directly bridge the nano-to-macro scale can be produced.
The bioresponsive hydrogels are capable of a highly sensitive detection of a variety of toxins and pathogens, for example.
In general, hydrogels forming a micro-scale device are three-dimensional networks of hydrophilic polymers capable of absorbing large amounts of a fluid to form a swollen elastic gel.
To maintain the three-dimensional structures, the polymer chains of hydrogels are crosslinked, either chemically through covalent bonds or physically through noncovalent interactions, such as hydrogen-bonding and ionic interactions. The hydrogels of interest are those that possess, in addition to expansion and contraction properties, the ability to respond in a defined manner to an external stim-ulus, like pH, temperature, electric field, ionic strength, light, pressure, or an antigen or other chemical agent.
Such stimuli-responsive hydrogels have been termed smart, or intelligent, hydrogels, and have wide applications in controlled drug delivery, biomedical diagnostic devices, and separation and purification technology. However, a slow time response has limited their use in many applica-tions. By scaling the hydrogel to the microscale, this disadvantage is overcome, thereby making hydrogels ideal for use in microfluidic devices for detecting biological and chemical agents. The ability of a microscale stimulus to trigger a large physical change eliminates several problems that limit the utility of other detection devices. For example, bioresponsive hydrogels can be developed using known biomolecular mechanisms of pathogen and toxin response to create a class of smart hydrogels having biorecognition coupled to a fast and detect-able volume change.
By incorporating a suitable biomolecule into a hydrogel, specificity for a particular bio-logical or chemical agent is achieved. To illus-trate this approach, hydrogels responding by three different modes of biological and chemical action have been developed. In particular, the current strong interest in the estrogen receptor (ER) in medical and environmental health research derives from the role of the receptor as a central point for signal transduction. Numerous naturally occur-ring and synthetic chemicals can bind to the large hydrophobic ligand binding pocket of the ER, and elicit estrogenic and/or antiestrogenic effects.
These ligands, including antagonists, can operate by an active mechanism, not only blocking binding of the natural hormone estradiol (Ez), but also changing ER conformation, resulting in different downstream events. Studies confirm that ligand induced changes in ER conformation modulate ER
interactions with coactivator proteins, which ulti-mately lead to altered gene transcription. A
hydrogel responsive to endocrine disrupting chemi-cals (EDC) can be developed to demonstrate the ability to detect a specific class of toxins. One design utilizes receptor-ligand interactions and involves conjugating the estrogen receptor (ER) and its natural ligand, estradiol, to a hydrogel net-work. Noncovalent crosslinks can be formed by the interaction of estradiol with the ER, shifting the hydrogel into a contracted state. Above a thresh-old concentration of a competitive ligand (i.e., any EDC), the noncovalent crosslinks are disassem-bled, causing the hydrogel to revert to its ex-panded state.
Another example of microscale detection of a toxin is botulinum toxin (BoNT). Botulinum toxin is one of the most poisonous toxins known, and causes human poisoning at exceedingly low con-centrations. The extraordinary potency of botuli-num neurotoxin is attributed to its extreme neuro-specificity and the catalytic cleavage of neuronal substrates involved in exocytosis at an extremely low toxin concentration. Upon aerosol exposure, intestinal ingestion, or wound infection, the vari-ous serotypes of botulinum toxin bind rapidly (within a few hours) to nerve terminals. Thus, a very narrow window of opportunity exists for con-ventional intervention approaches, such as parenteral administration of antitoxins. Conse-quently, it would be extremely valuable to have a device that can rapidly detect poisonous levels of botulinum toxin.
BoNT also has emerged as an extremely important pharmaceutical for the treatment of a myriad of neuromuscular disorders, including focal dystonias, spasticity, tremors, migraine and ten-sion headaches, and other maladies. A disadvantage of BoNT therapy is the observation that certain individuals gain immunity to the toxin and become refractory to treatment. Thus, a sensitive method of detecting antibodies in the serum of BoNT-treated individuals could aid the physician in prescribing dosing regimens. Such an assay could also be used to rapidly and sensitively assess the immune status of individuals. A rapid and sensi-tive assay for botulinum toxin also could be used to detect diffusion of the toxin from the injection site in pharmaceutical applications, thus avoiding undesired secondary tissue effects or systemic poisoning. A rapid and accurate assay for BoNT, therefore, could be of considerable value in en-hancing the medical applications of BoNT.
The most sensitive test currently avail-able for BoNT is the mouse bioassay test (sensitiv-ity of one mouse unit or about 10 pg; femtomolar range). However, the mice assay has many draw-backs, such as practicality of maintaining mouse colonies, the long time for detection (up to two days), and the need for immunologic confirmation.
Current in vitro assays, such as ELISA, are rela-tively insensitive, and under best case conditions detect about 10-100 mouse units (about 100-1000 pg) per ml of solution. Problems also exist in sam-pling and concentrating the toxins from biological specimens and other sources, such as aerosols, powders, soils, and other matrices.
The microscale devices of the present invention provide a rapid detection of protein toxins by use of a hydrogel having crosslinks that are specific peptide sequences cleaved by BoNT. In addition, a single BoNT molecule can cleave multi-ple crosslinks because of its catalytic mode of activity. Consequently, such a microscale device can detect a very low level of BoNT. Furthermore, the microscale device can contain a hydrogel that reversibly responds to BoNT, or is in the form of a "bio-fuse," wherein the toxin irreversibly changes the crosslinked hydrogel.
A hydrogel useful in a present microscale device for the detection of BoNT is illustrated in Fig. 8. In particular, Fig. 8a illustrates a hydrogel for detection of host response, thereby providing a method of determining which individuals are infected by the toxin, and to what degree. In particular, Fig. 8a illustrates a hydrogel network conjugated to an antigen that is known to activate a human immune response against BoNT. Antibodies from serum of an individual infected with BoNT
further crosslinks, and, therefore, collapses, the hydrogel as illustrated in Fig. 8a. In particular, upon exposure to infected sera, antigen-antibody pairs form noncovalent crosslinks causing the hydrogel to contract. Antigens suitable for conju-gation to hydrogel include the c-terminus of the BoNT heavy chain.
Fig. 8b illustrates a hydrogel "bio-fuse"
in which the crosslinks are a specific peptide sequence recognized and cleaved by BoNT. Cleavage of the crosslinks results in expansion of the hydrogel which is coupled to a macroscale detection of the volume change.
As illustrated in Fig. 8, the degree of crosslinking changes upon exposure to the stimulus.
The degree of swelling of a polymer network is inversely proportional to the degree of crosslink-ing, especially in a region of low crosslink den-sity. By attaching responsive segments to the polymer network that form or break crosslinks upon exposure to the stimulus, the hydrogel can undergo dramatic changes in volume, provided the initial crosslink density is sufficiently low, i.e., has a crosslink density of less than 15, preferably less than 10, and most preferably less than 7. The crosslink density, however, is sufficient to pre-vent solubilization of the polymer comprising the hydrogel. This allows a microscale event to create a macroscale detection of an antigen.
Accordingly, microscale devices respon-sive to different chemical and biological stimuli can be prepared. The microscale devices can de-tect, for example, environmental toxins specific to endocrine disrupting chemicals; a host-defense response specific to BoNT; and bacterial protein toxins. Examples of toxins other than BoNT that can be detected include, but are not limited to, anthrax and Ebola. Hydrogels conjugated with biomolecules specific to a particular chemical or biological agent can be prepared utilizing a judi-cious device of hydrogel and biomolecule. Such a choice can be readily determined by persons skilled in the art.
In another embodiment, a hydrogel can be derivatized or modified to provide a biological response microscale component. For example, a hydrogel can be coated with a lipid or fatty acid to provide a pH-sensitive hydrogel matrix surface modified with a lipid bilayer that contains channel proteins or receptors to form a"gel cell." Be-cause the lipid coating is impermeable to ions, a pH different from the pH of the surrounding medium can be maintained within the hydrogel interior, allowing the hydrogel to remain contracted while surrounded in a pH environment that normally causes volume expansion. Upon exposure of the surface to a specific stimulus, the lipid bilayer is dis-rupted, causing the hydrogel to swell, and thereby signal the presence of the stimulus.
To illustrate a gel cell, a pH-sensitive hydrogel having terminal hydroxy groups and con-taining a pH indicator (e.g., phenolphthalein) is prepared in a microchannel using the above-de-scribed technique. The hydrogel has a diameter of 400 um. The hydrogel then is immersed in benzene and modified by covalently bonding fatty acids to the surface of the hydrogel via the hydrogel hydroxy groups. The modified hydrogel then is exposed to an alkaline solution (which normally causes the hydrogel to swell) and the hydrogel diameter is measured at timed increments to test the efficiency of the fatty acid layer as a bar-rier. Hydrogels modified with a fatty acid coating remain stable for several days without an observ-able change in color or volume. In contrast, un-modified hydrogels that contain the pH indicator are fully expanded in the alkaline solution within 40 minutes together with a color range from clear to pink. When exposed to an alkaline buffer solu-tion (pH 12), a fatty acid modified hydrogel showed no volume or color change until the fatty acid layer was physically disrupted by piercing the gel with a micropipette tip, which caused the gel to rapidly swell and change color. The modified hydrogels, therefore, are capable of swelling and changing color after the fatty acid layer is dis-rupted, and can be used to detect a microscale event.
The photopolymerization of a polymeriz-able mixture in the fabrication of microelectronic devices was further demonstrated, with high resolu-tion, by flowing a polymerizable mixture into pre-fabricated microchannels. In a typical procedure, a glass channel, about 500 to about 2000 ~.rm wide and about 50 to about 180 ,um deep, was filled with a polymerizable mixture containing acrylic acid and 2-hydroxyethyl methacrylate (HEMA) (in a 1:4 mol ratio), ethylene glycol dimethacrylate (EGDMA) (1 wt %), and a light-sensitive initiator (3 wt %).
The polymerizable mixture was allowed to reach a quiescent state, and then exposed to ultraviolet light through a photomask placed on top of the channels. When the polymerization was completed, the channel was flushed with deionized water to remove the unreacted polymerizable mixture. Poly-merization time varied depending on light intensity and initiator, but is as fast as 20 seconds using a photoinitiator and an unfiltered light source from a standard fluorescence microscope. The resulting polymer gel can be used as a pH sensor/actuator.
The pattern of the photomask provided a polymer gel having the shape of the pattern, with good resolution and high fidelity. A polymer gel with features as small as 25 /.tm have been fabri-cated, and gel size is limited only by mask resolu-tion. The fabrication of multiple microscale com-ponents can be achieved either sequentially or simultaneously with multiple microscale components defined on a single mask. Components made of dif-ferent polymers can be made sequentially.

With further reference to the Figures, various embodiments disclosed above are illus-trated.
Fig. 9 illustrates the response of a pH-sensitive polymer gel positioned in a microscale channel. The polymer gel was polymerized in the channel to provide a spatially defined structure that varies in size from 380 ~zm in 1 M hydrochloric acid to 680 ,um in 1 M sodium hydroxide (Fig. 9a-c).
Fig. 9 also illustrates that the pH-sensitive poly-mer gel reversibly and reproducibly changes in size as fluid flow in the channel varies from acid to base, then back to acid (Fig. 9d-f).
Polymer gels of the appropriate composi-tion and geometry, therefore, reversibly expand and contract, but are otherwise stable in the micro-fluidic stream. For example, polymer gels compris-ing poly(HEMA) can undergo many cycles of volume transition without fatigue. Preferably, the lat-eral dimension of the gel is equal to or larger than the height to reduce folding or buckling of the polymer gel due to volume changes. Such dimen-sions also help anchor the gel, and prevent the gel from migrating downstream during fluid flow. Some gel sizes and shapes, especially gels having a large aspect ratio, tend to fatigue from repeated volume transitions due to the development of high internal stress concentrations. The time response of the volume change roughly follows the square of the dimension. A response of less than 10 seconds was observed for a polymer gel 100 ,um in diameter in a 50 ,um deep channel.

Fig. 10 illustrates a microscale flow routing device containing two different polymer gels. The function of the flow routing device, for example, is to control flow of a fluid flowing in the direction of the arrow. The two polymer gels positioned in the microchannel respond differently to the presence of an acid and base, for example.
In particular, gel A swells in the presence of a base, and contracts in the presence of an acid.
Gel B, in contrast, contracts in the presence of a base and swells in the presence of an acid. Ac-cordingly, an acidic fluid flowing in the direction of the arrow is routed to the left. An alkaline fluid flowing in the direction of the arrow is routed to the right. The pH responsive microscale device illustrated in Fig. 10, therefore, performs the sensor and actuation functions normally per-formed by discrete device components (e.g., valve, sensors, and electronics) in a traditional system.
The two different polymer gels of Fig. 10 are sequentially positioned in the channel. First, a polymerizable mixture A is introduced in the channel, then photopolymerized at location A while masking the remainder of the channel. Residual, unreacted polymerizable mixture A is flushed from the channel. A polymerizable mixture B then is introduced into the channel, followed by polymeriz-ing mixture B by masking the channel except for location B and photopolymerizing at location B.
Unreacted, residual polymerizable mixture B from the channel then is flushed to provide the flow routing device illustrated in Fig. 10.

In general, flow in a channel can be regulated by a volume change of the polymer gels.
Flow regulation was demonstrated by measuring the pressure drop at constant flow rate over a channel containing polymer gels. In this test, 1 x 9 array of oval components, each 300 x 700 /.im, were poly-merized along the length of 1000 7rm wide glass channel. Pressure drop measurements were taken at a constant flow rate of 0.15 ml/min, while the polymer gels were allowed to contract and expand by changing the pH. At a pH of 1.8, the gels were in a contracted state and produced a pressure drop of 0.09 psi. After raising the pH to 12.9, the gels were fully expanded to cause the pressure drop to increase almost eight-fold. The present invention, therefore, provides a simple-to-fabricate micro-scale device that functions as a pH-sensitive throttle valve for microfluidics.
Fig. 11 further illustrates a pH-sensi-tive polymer gel manufactured in a microscale chan-nel. The pH-sensitive polymer gel comprises a polystyrene core having a pH-responsive hydrogel on the core surface. Fig. 11 also illustrates the reproducible response of the pH sensor to changes in pH.
The following reaction schemes illustrate various specific polymerizable mixtures used in the microfabrication method of the present invention.
The reaction schemes illustrate that the pH-sensi-tive polymer gels prepared at a predetermined loca-tion in a microscale channel can be water based or organic based. The reaction schemes also illus-trate a rigid, highly crosslinked polymer that can be used structurally as opposed to functionally, e.g., to manufacture walls of the microscale chan-nels.

a) Water-based pH-sensitive polymers + +
Ho O O O

N

0 +CH3 light crosslinked N-CH3 polymer \ q S CH3 Cl aCH3 b) Organic-based pH-sensitive polymer + +
HO O O O co H I

I light crosslinked polymer O~~O +

c) Rigid, impermeable, highly crosslinked networks P
/ , + Cl~u l ,H

DCE, RT
Fig. 12 illustrates that various differ-ently shaped polymer gels can be synthesized within the microscale channel. A polymer corresponding to each shape has been prepared by using the appropri-ately shaped mask. This is further illustrated in Fig. 13, which illustrates a curved mask and the curved polymer gel resulting from the mask. Fig.
13 further illustrates that the polymer gel pre-pared in the channel has a geometry that is dimensionally sharp and is essentially identical to the shape of the mask.
The photoinitiated polymerization, there-fore, is essentially limited to the location of the channel that is exposed to the incident radiation.
It was observed that the polymerization reaction does not extend radially under the mask to any substantial degree. It is theorized, but not re-lied upon herein, that polymerization is limited to exposed locations in the channel because the exo-therm in such a microscale reaction is sufficiently low such that heat initiated polymerization does not occur radially under the mask.

Figs. 14-15 illustrate various shapes of polymer gels prepared within a microscale channel by photoinitiated polymerization. Fig. 14 illus-trates that a relatively complex geometry can be prepared and can reproducibly respond to stimuli, e.g., pH, and thereby act as a sensor. Fig. 15 illustrates that more than one polymer gel can be positioned at a preselected location within a microscale channel. Fig. 15 further illustrates that the individual polymer gels can be manufac-tured in sequence by adjusting the position of the mask. If the three polymer gels in Fig. 15 are identical, microfabrication of the polymer gel is achieved by introducing a single polymerizable mixture into the channel and performing a single or sequential photoinitiated polymerization wherein either a single mask allows all polymer gels to be manufactured simultaneously, or a mask is adjusted to allow a different location of the channel (and the polymerizable mixture) to be exposed to inci-dent radiation.
In embodiments where it is desirable to have different polymer gels fabricated in a channel to take advantage of different types of responses, or different response times or volumes, for exam-ple, different polymerizable mixtures are intro-duced into the chamber sequentially after each photoinitiated polymerization and rinsing of the chamber, followed by a proper adjustment of the mask. Alternatively, three separate polymerizable mixtures can be introduced into a microscale chan-nel by utilizing laminar flow. The three polymer gels then can be prepared simultaneously by utiliz-ing a suitably configured mask and exposing the channel to suitable incident radiation. The proper or ideal wavelength to effect polymerization of each polymerizable mixture can be achieved by using filters, for example. Fig. 15 further illustrates that an array of polymer gels in a channel can be used to regulate flow in response to a pH change.
Fig. 16 illustrates macroscale detection methods for a microscale event. Fig. 16a contains a top and side view of a sensor for more than one chemical or biological agent. In the absence of a stimulus, the hydrogel is in a contracted state and the device appears colored from the top view. The hydrogel sensor expands (right bottom) in response to a stimulus and it presses against the top inter-nal surface of the device to change the optical properties by excluding dye from that region. Each hydrogel component responds to a different stimuli giving rise to unique patterns for different chemi-cal and biological agents.
In Fig. 16b an elastic membrane and ser.-sor/actuator are both made by the present method.
The elastic membrane is formed first, then hydrogel sensor/actuator is fabricated. Hydrophobic vents are used to flush and fill the chambers and a hy-drophobic valve is used to keep the two solutions separated. When a sample is introduced and detec-tion occurs, the hydrogel expands pushing a first solution into second solution to produce a colored product.
Fig. 17 illustrates a biomimetric valve prepared by the present method. In a typical pro-cedure, two pH-sensitive strips are prepared simul-taneously (Fig. 17a). Then, non-pH-sensitive strips prepared from HEMA, EGDMA (1.0 wt %) and IRGACURE TM 651 (3.0 wt %) (Fig. 17b) formed the bi-strip hydrogel valve with anchor. When exposed to a basic solution, the bi-strip hydrogel expands and curves to form a normally closed valve (Fig. 17c).
The bi-strip valve can be pushed open (Fig. 17d) to allow flow in one direction (from left to right) while restricting flow in the opposite direction (Fig. 17e) . When exposed to acidic solutions (Fig.
17f), the valve is deactivated, returning to the permanently open state. Scale bars in Fig. 17 are 500 um. The non-pH-sensitive hydrogel strip also has an anchor that fixes one end of the bi-strip hydrogel to the channel top and bottom at the de-sired location. The non-pH-sensitive strip remains the same volume, causing the bi-strip gel to curve towards the non-pH-sensitive strip. The microscale valve operates like the passive valves found in veins, allowing the fluid flow in only one direc-tion. The pH-sensitive strip serves as a spring to provide a restoring force for the valve. When contacted in acidic solution, the valve becomes deactivated and remains permanently open (Fig.
17d). In this example, the valve responds to the local chemical environment in addition to the local fluid flow characteristics.
The previous discussion illustrates posi-tioning and anchoring of a polymeric gel within a microscale channel by the use of a polymerizable mixture, laminar flow, and optical masks. However, a polymerizable mixture also can be properly posi-tioned in a microscale channel utilizing choatic flow. In choatic flow, two liquids appear to be in a mixed state, but the mixed state is constant.
For example, a theoretical video of choatic flow shows no change and the video is essentially a still photograph. In contrast, a theoretical video of turbulent flow shows constant change, i.e., is not a still photograph, but is a motion picture.
Fig. 18 illustrates a blend of a polymer-izable mixture and an inert liquid in chaotic flow.
The choatic flow positions the polymerizable mix-ture at preselected positions continuously across the length of the channel. Subsequent photo-in-duced polymerization provides a continuous polymer gel having a preselected pattern along the length of the channel, as shown in Fig. 18. Such pattern-ing greatly expands design capabilities of a micro-scale device, and expands the scope of useful ap-plications for such microscale devices.
In accordance with an important feature of the present invention, a polymer gel can be fabricated within a microchannel, wherein the poly-mer gel has a functionality that can respond to a thermal, physical, chemical, or biological stimu-lus. This functionality can be achieved by a proper selection of the monomers comprising the polymer gel, or by appropriately derivitizing the polymer gel after microfabrication in the channel, for example, by incorporating a cell or a biologi-cal molecule into the polymer gel. The present method provides a fast method of preparinc such polymeric functional components for a microscale device. The polymerization times are short, e.g., about 20 seconds, and the polymer gel reproducibly responds to an external stimuli regardless of shape or geometry. The gels respond quickly and accu-rately to the external stimuli, in part because of the small size of the polymer gel.
The present disclosure therefore is di-rected to a new method of fabricating microscale devices having functional polymer gels synthesized within microscale fluid channels. The simple and fast microscale fabrication of functional struc-tures having a variety of geometries and sizes within microscale fluid channels has been demon-strated. In one embodiment, the functional struc-ture, i.e., a polymer gel, is a pH-sensitive poly-mer that expands and contracts in response to changes in pH. In accordance with the present method, polymerizations are used to define polymer gel geometries via masking, and the resulting poly-mer gel structures are sharply defined and can be used as functional components within microfluidic devices. A pH-responsive throttle valve has been specifically demonstrated. Microscale components containing polymer gels responsive to temperature, electric fields, ionic strength, light, pressure, carbohydrates, and proteins also have been demon-strated.
The present method permits the fabrica-tion of complex microsize fluid flow devices having a plurality of functional components, including sensors, valves, pumps, and optoelectronic compo-nents, without traditional assembly processes, because the microscale components are formed in situ within the channels. The present method also can be used to fabricate the microscale channels on a substrate.
In addition, because the resulting poly-mer gel components are functional (e.g., pH sensi-tive), the need for power sources, electronics, and sensors for actuation, control, and feedback is eliminated, thereby greatly simplifying the design and manufacture of the device. The present method also utilizes the feature of laminar flow to allow manufacture of polymer gels of preselected chemical identity and dimensions, thereby increasing the functional flexibility of the devices and providing devices having a fast response time.
Obviously, many modifications and varia-tions of the invention as hereinbefore set forth can be made without departing from the spirit and scope thereof.

Claims (31)

CLAIMS:
1. A method of manufacturing a micro-scale component of a microscale device comprising:

(a) providing a substrate;

(b) forming one or more microscale channels in the substrate, wherein each of the one or more microchannels has a cross-sectional diameter of 1 micron to 1 millimeter;

(c) introducing a liquid polymerizable mixture into the channel, wherein the polymerizable mixture has a Reynold's number of less than 2000;

(d) optically masking the channel to permit exposure of the polymerizable mixture to a polymerization-initiating energy source at a preselected location along the channel;

(e) exposing the channel to the energy source for a sufficient time to polymerize the polymerizable mixture at the preselected location of the channel to form a polymer gel; and (f) removing residual unreacted polymerizable mixture from the channel to provide the microscale component in the channel as the polymer gel.
2. The method of claim 1 wherein the substrate is transparent.
3. The method of claim 1 wherein the substrate comprises glass, a plastic, silicon, or a transparent mineral.
4. The method of claim 1 wherein the channel is formed by a lithographic process.
5. The method of claim 1 wherein polymerizable mixture has a Reynold's number of 1 to 2000.
6. The method of claim 1 wherein a plurality of liquid polymerizable mixtures are simultaneously or sequentially introduced into the channel in a laminar array.
7. The method of claim 1 wherein one or more liquid polymerizable mixtures and one or more inert liquids, each with a Reynold's number of 1 to 2000, are simultaneously or sequentially introduced into the channel in a laminar array.
8. The method of claim 1 wherein one or more liquid polymerizable mixtures and one or more inert liquids, each with a Reynold's number of 1 to 2000, are simultaneously or sequentially introduced into the channel in a choatic flow stream.
9. The method of claim 1 wherein the polymerizable mixture comprises a monofunctional monomer, a polyfunctional crosslinking monomer, or a mixture thereof.
10. The method of claim 9 wherein the polymerizable mixture further comprises a photoinitiator, an optional surfactant, or a mixture thereof.
11. The method of claim 1 wherein the microscale component has a diameter-to-height ratio of 10 to 1 to 0.5 to 1.
12. The method of claim 1 wherein the polymerization-initiating energy source comprises light, heat, vibration, an electrical field, or a magnetic field.
13. The method of claim 12 wherein the energy source comprises ultraviolet light.
14. The method of claim 1 wherein an anchoring material is positioned at the preselected location of the channel.
15. The method of claim 14 wherein the anchoring material comprises a chemical anchor.
16. The method of claim 15 wherein the anchoring material comprises a metal film, a photo-initiator, a monomer, or a mixture thereof.
17. The method of claim 1 further comprising a step of derivatising the polymer gel by attaching a biomolecule to the polymer gel.
18. The method of claim 1 further comprising the step of derivatizing the polymer gel by coating the polymer gel with a fatty acid or a lipid.
19. The method of claim 1 wherein the polymer gel is capable of undergoing a volume change in response to a predetermined stimulus.
20. The method of claim 19 wherein the stimulus is a physical change in a medium contacting the gel.
21. The method of claim 20 wherein the physical change is a temperature change, an electric field change, a change in light, or a pressure change.
22. The method of claim 20 wherein the stimulus is a chemical change in a medium contacting the gel.
23. The method of claim 22 wherein the chemical change is a pH change or an ionic strength change.
24. The method of claim 20 wherein the stimulus is a chemical compound in a medium contacting the gel.
25. The method of claim 20 wherein the stimulus is a biological agent in a medium contacting the gel.
26. The method of claim 25 wherein the biological agent is a toxin, a pathogen, or an antigen.
27. The method of claim 26 wherein the biological agent is botulinum toxin, anthrax, or Ebola.
28. A microscale component selected from the group consisting of a pump, a valve, a sensor, a flow router, an actuator, an optoelectronic component, and an analyte detector, wherein the microscale component is manufactured by the method of any one of claims 1 to 27.
29. A microscale component manufactured by the method of any one of claims 1 to 27, wherein the component is a pH
sensor/actuator.
30. A method of manufacturing a functional microscale component of a microscale device comprising:

(a) providing a transparent cell having a cavity;
(b) introducing a blend of structural monomers into the cavity said blend comprising a first polymerizable mixture, wherein the first polymerizable mixture has a Reynold's number of less than 2000;

(c) optically masking the cavity to define one or more channels in the cell and to permit exposure of the unmasked structural monomer blend to a polymerization-initiating energy source, wherein each of the one or more channels has a cross-sectional diameter of from 1 micron to 1 millimeter;

(d) exposing the cell to the energy source for a sufficient time to polymerize the structural monomer blend at unmasked locations in the cell to form microchannels in a resultant substrate;

(e) removing residual unreacted monomer blend from the substrate to provide the channels in the cell;

(f) introducing a second liquid polymerizable mixture comprising functional monomers into the channels, wherein the second polymerizable mixture has a Reynold's number of less than 2500;

(g) optically masking the channels to permit exposure of the second polymerizable mixture to the polymerization-initiating energy source at a preselected location along the channel;

(h) exposing the channel to the energy source for a sufficient time to polymerize the second polymerizable mixture at the preselected location of the channel to form a polymer gel; and (i) removing residual unreacted second polymerizable mixture from the channel to provide the functional microscale component in the channel as the polymer gel.
31. The method of claim 30, wherein the cavity in the cell is about 50 to about 250 µm in height and, independently, about 500 to about 25,000 µm in width and length.
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