WO2021247750A1 - Imagerie optique de structures d'hydrogel intelligentes pour des applications de détection - Google Patents

Imagerie optique de structures d'hydrogel intelligentes pour des applications de détection Download PDF

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Publication number
WO2021247750A1
WO2021247750A1 PCT/US2021/035512 US2021035512W WO2021247750A1 WO 2021247750 A1 WO2021247750 A1 WO 2021247750A1 US 2021035512 W US2021035512 W US 2021035512W WO 2021247750 A1 WO2021247750 A1 WO 2021247750A1
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Prior art keywords
microfluidic channel
hydrogel
smart
fluid sample
channel
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PCT/US2021/035512
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English (en)
Inventor
Christopher F. REICHE
Florian Solzbacher
Lars B. Laurentius
Hsuan-Yu Leu
Saeed BOROOMAND
Julia Koerner
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University Of Utah Research Foundation
LEBER, Moritz M.
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Priority to EP21818392.9A priority Critical patent/EP4139679A4/fr
Priority to CA3180053A priority patent/CA3180053A1/fr
Publication of WO2021247750A1 publication Critical patent/WO2021247750A1/fr

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    • G—PHYSICS
    • G01—MEASURING; TESTING
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    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/53—Immunoassay; Biospecific binding assay; Materials therefor
    • G01N33/543—Immunoassay; Biospecific binding assay; Materials therefor with an insoluble carrier for immobilising immunochemicals
    • G01N33/544—Immunoassay; Biospecific binding assay; Materials therefor with an insoluble carrier for immobilising immunochemicals the carrier being organic
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    • B01L3/50—Containers for the purpose of retaining a material to be analysed, e.g. test tubes
    • B01L3/502—Containers for the purpose of retaining a material to be analysed, e.g. test tubes with fluid transport, e.g. in multi-compartment structures
    • 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
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    • B01L3/502715—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 interfacing components, e.g. fluidic, electrical, optical or mechanical interfaces
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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
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    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12M—APPARATUS FOR ENZYMOLOGY OR MICROBIOLOGY; APPARATUS FOR CULTURING MICROORGANISMS FOR PRODUCING BIOMASS, FOR GROWING CELLS OR FOR OBTAINING FERMENTATION OR METABOLIC PRODUCTS, i.e. BIOREACTORS OR FERMENTERS
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    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/53—Immunoassay; Biospecific binding assay; Materials therefor
    • G01N33/543—Immunoassay; Biospecific binding assay; Materials therefor with an insoluble carrier for immobilising immunochemicals
    • G01N33/54366—Apparatus specially adapted for solid-phase testing
    • G01N33/54373—Apparatus specially adapted for solid-phase testing involving physiochemical end-point determination, e.g. wave-guides, FETS, gratings
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    • B01L2200/00—Solutions for specific problems relating to chemical or physical laboratory apparatus
    • B01L2200/02—Adapting objects or devices to another
    • B01L2200/026—Fluid interfacing between devices or objects, e.g. connectors, inlet details
    • B01L2200/027—Fluid interfacing between devices or objects, e.g. connectors, inlet details for microfluidic devices
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    • B01L2300/06—Auxiliary integrated devices, integrated components
    • B01L2300/069—Absorbents; Gels to retain a fluid
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    • B01L2300/0809—Geometry, shape and general structure rectangular shaped
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    • B01L2300/08—Geometry, shape and general structure
    • B01L2300/0861—Configuration of multiple channels and/or chambers in a single devices
    • B01L2300/0877—Flow chambers
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
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    • B—PERFORMING OPERATIONS; TRANSPORTING
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    • B01L2300/16—Surface properties and coatings
    • B01L2300/161—Control and use of surface tension forces, e.g. hydrophobic, hydrophilic
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L2400/00—Moving or stopping fluids
    • B01L2400/08—Regulating or influencing the flow resistance
    • B01L2400/084—Passive control of flow resistance
    • B01L2400/086—Passive control of flow resistance using baffles or other fixed flow obstructions
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    • G01N21/75—Systems in which material is subjected to a chemical reaction, the progress or the result of the reaction being investigated
    • G01N21/77—Systems in which material is subjected to a chemical reaction, the progress or the result of the reaction being investigated by observing the effect on a chemical indicator
    • G01N21/7703—Systems in which material is subjected to a chemical reaction, the progress or the result of the reaction being investigated by observing the effect on a chemical indicator using reagent-clad optical fibres or optical waveguides
    • G01N2021/7706—Reagent provision
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Definitions

  • This disclosure generally relates to methods and systems for detecting a target analyte in a given sample. More specifically, in one particular application, the present disclosure relates to using optical imaging to detect the state of biomarker sensitive hydrogels.
  • One application is directed to medical use, e.g., to detect a medically significant analyte such as glucose, thrombin, fentanyl, other drugs, metabolites, etc. present in a blood sample or another body fluid sample.
  • the present disclosure has broader application so as to be applicable to other fields, e.g., to detect and/or measure the amount of a given target analyte in a given sample taken from any of a wide variety of environments (e.g., using optical imaging to “read” the analyte sensitive hydrogel once it is brought into contact with the sample taken from a given environment).
  • POC point-of-care
  • a smart hydrogel is a crosslinked polymer network that changes volume in response to changes in the environment, such as concentration of an analyte.
  • Smart hydrogels can be obtained by attaching pendant functional groups to the polymer network that bind to the target analyte.
  • Aptamers have recently been explored as analyte-binding moieties to obtain sensitive and selective smart hydrogels.
  • Combining molecular imprinting with target specific aptamers during polymerization can create a sensor that can monitor those analytes with high sensitivity and selectivity.
  • a stand-alone POC device can employ smart hydrogels to detect biological or chemical components in a fluid sample such as blood.
  • the device can include a disposable or reusable microfluidic sample slide with a microfluidic channel, where one or more smart hydrogel structures are positioned in the channel.
  • a sample slide can be inserted into the stand alone device and the device can analyze the swelling state of the hydrogels using a simple optical camera.
  • optical images or data therefrom can be transmitted to a data analysis unit (e.g., a smartphone and associated app) that derives the analyte concentration from such image data.
  • a data analysis unit e.g., a smartphone and associated app
  • the smart hydrogels can be confined to a disposable or reusable microfluidic channel slide that optionally has filters (chemical and/or mechanical filters) to precondition the analyte solution (e.g. to remove red blood cells, other cells, particulates and the like), to enhance the specificity and/or selectivity of the detection of the smart hydrogels.
  • filters chemical and/or mechanical filters
  • the smart hydrogels change volume depending on the environmental concentration of the specific analyte to which they are sensitive, present in the sample.
  • optical components e.g., a zoom lens
  • the device can include an alignment structure for the microfluidic channel slide to ensure that the hydrogels in the channel of such slide are oriented in proper positioning for imaging.
  • the alignment structure may enable the camera with any additional optics to consistently capture images of the same area of the microfluidic channel with its one or more smart hydrogel structures of interest.
  • the sensor device could optionally include a light source for illuminating the one or more smart hydrogel structures in the microfluidic channel.
  • Optional data storage space and either a wired or wireless communication chip can further be provided to electronically tether the device to a data analysis system (e.g., computer or smartphone app).
  • the device can include a pumping system (e.g., a pump plus corresponding electronics for control) to convey (e.g., pull) the fluid sample through the microfluidic channel.
  • a pumping system e.g., a pump plus corresponding electronics for control
  • the microfluidic slide can include a relatively large reservoir to prevent contamination of any pumping system components.
  • the microfluidic channels of the microfluidic slide can be filled with a suitable hydrating solution (e.g., phosphate buffered saline or another appropriate solution) during storage and shipping to ensure the hydrogels in the channels stay hydrated and ready to use.
  • the device can include a light source to ensure sufficient image quality when taking optical photographs of the hydrogel.
  • the device could comprise or consist essentially of an alignment structure for guiding the slide into the device, optional pump system components and optics configured for use with a smartphone camera, along with a wireless (Bluetooth, Wifi) communication unit.
  • the camera of a smartphone, tablet or similar device could replace the camera chip(s) and corresponding electronics, making the device even more cost effective.
  • such a minimalist device may clip or otherwise couple to the smartphone, which is used to take the photos of the hydrogel before and after interaction with the fluid sample.
  • the optical hydrogel sensor devices as contemplated herein can use the volume change of a smart hydrogel that is sensitive to biological or other analytes to detect the presence and/or concentration of such analytes. Furthermore, the sensor devices as contemplated herein can provide a simple optical setup to measure the volume or other dimensional change in the smart hydrogel structures.
  • the optical readout as contemplated herein can include inexpensive off-the-shelf components such as a webcam, CCD/CMOS camera boards, CCD/CMOS camera chips with corresponding electronics, microscope cameras, or other readily available custom miniaturized camera components.
  • An exemplary embodiment of a method for sensing and/or measuring concentration of an analyte of interest may include a step of providing a microfluidics sensor device that includes a microfluidic channel, the channel comprising one or more smart hydrogel structures positioned in the channel.
  • Such structures may be fixed in place relative to the channel (e.g., integrated with a hydrogel or polymer backplane, fixed directly onto a boundary surface of the channel, or the like). Fixation of the smart hydrogel structures in the channel may ensure that the fluid sample flows through and past the hydrogel structures, rather than carrying such structures down the channel.
  • the method may include a step of introducing the fluid sample in which the analyte of interest is to be detected, into the microfluidic channel, where the smart hydrogel structures are specifically configured to shrink or swell in response to contact with the analyte.
  • An optical camera e.g., integrated into a POC sensing device, or included in a smartphone or other device
  • the “before” image provides a baseline of the state of the hydrogel before interaction with analyte
  • the “after” image provides image data that can be used to determine the degree of swelling or shrinking that has occurred, because of such interaction.
  • the degree of shrinking or swelling of the hydrogel structure(s) can be determined, and correlated to the concentration of the analyte in the fluid sample.
  • Such method can provide a simple and effective mechanism to not only detect the presence of the analyte in the fluid sample, but to also determine its concentration in the sample.
  • a microfluidics sensor device comprising a microfluidic channel at least partially defined by a boundary material, the channel comprising one or more smart hydrogel structures positioned in the channel (e.g., fixed as described above), where the smart hydrogel structures are configured to shrink or swell in response to contact with a target analyte to be detected in the fluid sample.
  • a substrate may also be provided on which the boundary material defining the channel is supported (e.g., under the boundary material, where the substrate may potentially also define the bottom of the microfluidic channel).
  • An inlet is provided in fluid communication with the microfluidic channel through which the fluid sample can be introduced into the channel, and an outlet can be provided in fluid communication with the channel through which negative pressure can be applied to the channel, to pull the fluid sample through the channel, into the region of the channel with the smart hydrogel structures.
  • the microfluidic channel and the smart hydrogel structures are configured to allow capture of optical images of the smart hydrogel structures using an optical camera both before and after contact or interaction with the fluid sample. Such imaging allows measurement of the degree of shrinking or swelling of the hydrogel structures due to interaction with the analyte in the fluid sample. Such measurement also allows correlation of this dimensional change with the concentration of the analyte in the fluid sample.
  • the channel, substrate, and hydrogel structures may be part of a microfluidics slide that is received into a POC sensor device, which receives the slide, and conveys the fluid sample through the channel, imaging the hydrogel structure(s) once they have reached equilibrium. Comparison of the “before” and “after” images allows determination of the concentration of the analyte in the fluid sample.
  • Pump components, the camera, optics (e.g., a zoom lens), a light source and the like may be provided within the POC sensor device, separate from the insertable microfluidic slide which is configured for one time, disposable use.
  • Another method according to the present disclosure is directed to manufacture of a microfluidics sensor device (e.g., particularly the insertable slide component thereof).
  • Such manufacturing method may include providing a substrate for supporting a microfluidic channel, and providing a boundary material for defining a microfluidic channel, and forming (e.g., cutting, laser forming, etc.) the channel into the boundary material.
  • the boundary material is positioned onto the substrate (e.g., for support).
  • a fluid and/or pre-gel hydrogel solution is introduced into the microfluidic channel, and a photomask is positioned over the microfluidic channel, where the mask includes one or more apertures.
  • Collimated UV or other curing light wavelengths are directed through the apertures and into the channel, so as to at least partially polymerize portions of the hydrogel solution to form the desired smart hydrogel structures within the channel.
  • the microfluidic channel can then be washed to remove unpolymerized hydrogel solution from the channel.
  • any of the embodiments described herein may further include an optically transparent window material positioned over the boundary material, to protect the channel and hydrogel structures therein, while allowing optical imaging (or UV or other light curing) through the window material.
  • any of the embodiments described herein may further comprise inlet and outlet structures in fluid communication with the microfluidic channel, allowing introduction of the fluid sample, an application of negative pressure to the channel, respectively.
  • any of the embodiments described herein may further comprise a filter structure positioned in the channel, upstream from the smart hydrogel structure(s) to remove red blood cells, particulates, or other components of the fluid sample that may interfere with the ability to obtain a sufficiently transparent sample at the hydrogel structures, to allow effective imaging of the hydrogel structures.
  • a filter structure positioned in the channel, upstream from the smart hydrogel structure(s) to remove red blood cells, particulates, or other components of the fluid sample that may interfere with the ability to obtain a sufficiently transparent sample at the hydrogel structures, to allow effective imaging of the hydrogel structures.
  • Such filter may comprise a polymer, a hydrogel structure that is not configured to shrink or swell in response to contact with a target analyte in the fluid sample, or another filter material.
  • the nature of the filter material may of course depend on the characteristics of the contemplated fluid sample.
  • Light source filtration may also be employed to aid in improving visibility, e.g., red light passes through blood with less absorption than other colors of
  • the smart hydrogel structures may comprise any desired geometry.
  • Non-limiting examples of such shapes include pillars (cylindrical with a circular cross-section, or pillars having other cross-sectional shapes such as rectangular, square, oval, star-shaped, other polygons, etc.), sheets, domes, pyramids, triangular prisms, cubes, other rectangular prisms, etc.).
  • the hydrogel structure may have a thickness from 5 pm to 1000 pm, from 100 pm to 1000 pm, or from 300 pm to 800 pm.
  • pillars or size of other hydrogel structures should be sufficient to be able to optically detect the change in size using simple, inexpensive cameras and optics, but sufficiently small as to allow the microfluidic channel and associated sensor device to be relatively small (e.g., fit into a shirt or pant pocket), and hand-held.
  • a plurality of smart hydrogel structures can be provided inside the channel, which hydrogel structures that are sensitive to different analytes.
  • Such smart hydrogel structures may be positioned in different locations of the channel(s), to allow read out of such either by the same camera chip or by providing a camera chip specific to the location of each hydrogel sample inside the slide structure including the microfluidic channel(s) and hydrogel structures. This way such a device can be used to measure multiple analytes from the same sample.
  • the sensor device can include an alignment structure that enables the camera with any additional optics to consistently capture images of a same area of the microfluidic channel with its one or more smart hydrogel structures.
  • the sensor device can further include a light source for illuminating the one or more smart hydrogel structures in the microfluidic channel.
  • the sensor device can include a plurality of differently configured smart hydrogel structures located in the channel(s), wherein the differently configured smart hydrogel structures provide for sensing of different analytes.
  • the microfluidics channel can be disposable or replaceable, and can be provided as a smart hydrogel microfluidic test slide that is receivable into a receiving analyte device that comprises the optical camera and corresponding electronic components for capturing the optical images of the smart hydrogel structures and measurement of the degree of shrinking or swelling of the smart hydrogel structures, and correlation of the degree of such shrinking or swelling to a concentration of the analyte in the fluid sample.
  • Figure 1 illustrates an exemplary point-of-care sensor device configured to receive a microfluidic slide.
  • Figure 2A shows equilibrium radius for ionic strength sensitive smart hydrogel pillars in a microfluidic channel filled with 1/4X phosphate buffered saline (“PBS”).
  • Figure 2B shows equilibrium radius for glucose sensitive smart hydrogel pillars in a microfluidic channel filled with IX PBS.
  • Figure 3 shows an exemplary microfluidic channel strip or slide.
  • Figure 4 shows an exploded view of a microfluidic channel strip or slide.
  • Figure 5 schematically illustrates an exemplary configuration for polymerizing the hydrogel structures in a microfluidic channel slide or other device.
  • Figure 6A is a graph showing capture/release of thrombin using an aptamer- containing hydrogel that is non-porous, with a thickness of about 800 pm. The shrinking of the hydrogel was detected by a pressure sensor in contact with the gel.
  • Figure 6B is a graph of data obtained measuring the area of a glucose responsive hydrogel disk using an optical imaging approach for different concentrations (5 mM and 0 mM) of glucose.
  • Figure 6C shows the overall change in surface area of the hydrogel as plotted against glucose concentration.
  • Figure 7 is a schematic of a simple micro-channel structure that can be used to fabricate hydrogel pillars reproducibly and inexpensively for optical imaging.
  • Figures 8A-8B show how a standard smartphone camera with a zoom lens accessory can be used to image a small test sample, with good resolution.
  • Figures 9A-9C are images of hydrogel pillars with a diameter of 250 pm and 500 pm inside a microfluidic channel, such images being taken using a standard smartphone zoom lens.
  • Figures 10A-10B show change in surface area of a smart hydrogel as plotted against changing glucose concentration (0 mM to 10 mM) for a particular hydrogel sample.
  • Figure 11 shows change in surface area over time for a smart hydrogel exposed to different glucose concentrations (0 mM and 5 mM).
  • the present invention is directed to microfluidic sensor devices and associated methods for sensing an analyte of interest, using optical imaging of a smart hydrogel that swells or shrinks in response to contact with the analyte of interest.
  • a microfluidics sensor device including a microfluidic channel with one or more smart hydrogel structures disposed in the channel.
  • a fluid sample in which the analyte of interest is to be detected is introduced into the microfluidic channel of the sensor device. Once the hydrogel structure has had sufficient time in contact with the fluid sample to reach an equilibrium state, an optical camera is used to capture an image of the smart hydrogel structure.
  • a reference image of the smart hydrogel can also be captured before contact (or at initial contact, before equilibrium is reached).
  • the degree of shrinking or swelling of the smart hydrogel structure can be measured (e.g., from the captured images), and this change can be correlated to a concentration of the analyte in the fluid sample.
  • a microfluidic sensor device may be configured as a hand-held, small portable device (e.g., sufficiently small to fit into a user’s shirt or pant pocket).
  • a sensor device may include a microfluidic channel defined by a boundary material, the channel comprising one or more smart hydrogel structures located in the channel, where the smart hydrogel structures are configured to shrink or swell in response to contact with a target analyte to be detected in the fluid sample.
  • the microfluidic channel may be a single use, disposable device.
  • the microfluidic channel can be configured to be reusable or replaceable.
  • a substrate can be provided on which the boundary material defining the microfluidic channel is supported.
  • An inlet is provided, in fluid communication with the microfluidic channel through which a fluid sample can be introduced into the channel.
  • An outlet can be provided, also in fluid communication with the microfluidic channel through which negative pressure can be applied to the microfluidic channel to pull the fluid sample through the microfluidic channel.
  • the channel and smart hydrogel structures in the channel are configured to allow capture of optical images of the hydrogel structures using a simple optical camera with appropriate optics (e.g., a simple zoom lens) both before and after interaction of the hydrogel structures with the analyte in the fluid sample. Such images can be used to correlate a measured degree of shrinking or swelling with the concentration of the analyte in the fluid sample.
  • the microfluidic channel and its substrate can be configured as a disposable single use microfluidics channel slide, which is insertable into a point-of- care sensor device, that may include other components of the system (e.g., a pump for pulling the fluid sample through the system, an alignment structure for ensuring proper alignment between the hydrogel structure in the microfluidic channel and the camera to ensure proper imaging that will allow determination of the dimensional change, etc.).
  • a point-of- care sensor device may include other components of the system (e.g., a pump for pulling the fluid sample through the system, an alignment structure for ensuring proper alignment between the hydrogel structure in the microfluidic channel and the camera to ensure proper imaging that will allow determination of the dimensional change, etc.).
  • the device may work in conjunction with a user’s smartphone, using the smartphone and associated optics to capture the needed images.
  • Such a minimalist device may simply include the microfluidic channel with the desired hydrogel structures, that clips or otherwise releasably attaches to a smartphone, providing the needed alignment and imaging of the hydrogel structures. Any needed optics or lens components can be provided with the clip device. Calculations associated with measurement of the shrinking or swelling, and correlation of such change to the analyte concentration can be performed by the smartphone.
  • the microfluidics sensor device may be manufactured by providing a substrate for supporting a microfluidic channel, providing a boundary material for defining the microfluidic channel, and forming the microfluidic channel into the boundary material, positioning the boundary material onto the substrate (e.g., either before or after the channel is formed), and introducing a fluid and/or pre-gel hydrogel solution into the microfluidic channel.
  • a darkfield photomask can be positioned over the microfluidic channel, where the photomask includes one or more apertures, and curing light wavelengths (e.g., collimated UV light) can be directed through the apertures and into the microfluidic channel so as to at least partially polymerize portions of the hydrogel solution to form one or more smart hydrogel structures in-situ within the microfluidic channel.
  • curing light wavelengths e.g., collimated UV light
  • the microfluidic channel can be washed to remove unpolymerized hydrogel solution from the channel.
  • Figure 1 shows an exemplary sensor device 100, including a disposable smart hydrogel microfluidic test slide 102 and a receiving analyte device 104.
  • Test slide 102 may include a substrate 106 that supports a microfluidic channel 108.
  • Channel 108 includes one or more smart hydrogel structures 110 within channel 108. Differently configured smart hydrogel structures 110 may be provided, e.g., each for sensing a different analyte.
  • a filter 112 is shown in channel 108, upstream from the smart hydrogels 110.
  • a sample inlet 114 is provided in fluid communication with channel 108, through which a fluid sample can be introduced into the device 100.
  • Illustrated slide 102 is shown as further including atop cover 109 (e.g., an optically transparent window material) over the material within which the microfluidic channel 108 is defined.
  • atop cover 109 e.g., an optically transparent window material
  • Such a window top cover 109 provides further protection to the channel 108 and the hydrogel structures positioned therein, e.g., from contaminants, etc.
  • Figure 1 further illustrates a connector 116 providing a sealing connection to a pump of the device 104.
  • Device 104 is configured to receive the slide 102, in order to aid in analysis of the fluid sample introduced into the inlet 114 of slide 102.
  • Device 104 is relatively small, e.g., so as to fit in the pocket of a user.
  • Device 104 is shown as including a protective casing 120 with various components housed within such casing 120.
  • apump 122 may be included, e.g., for applying negative pressure to channel 108, to pull the fluid sample through the channel(s) 108 into contact with smart hydrogel structures 110.
  • Alignment structures 124 may be provided, to guide and ensure proper positioning of the test slide 102 within device 104, when a fluid sample is to be analyzed.
  • the alignment structure 124 may enable the camera with any additional optics to consistently capture images of the same area of the microfluidic channel with its one or more smart hydrogel structures of interest.
  • Figure 1 illustrates an optical sensor (i.e., camera), which may include a light source for better illumination during optical imaging of the smart hydrogel structures, at 126. While the light source is shown as positioned in the bottom portion of the housing or device, it will be apparent that the light source could be provided elsewhere (e.g., in the “lid” top portion of the housing or device). For example, illumination could be provided through the microfluidic channel, e.g., where the channel is made from transparent components.
  • PCBs 128 may be provided within device 104, along with corresponding electronic components (e.g., microchips such as microcontrollers and Bluetooth or other communication interfaces mounted to the PCB), e.g., to provide control to pump 122, and to camera 126, its associated light source, etc.
  • electronic components e.g., microchips such as microcontrollers and Bluetooth or other communication interfaces mounted to the PCB
  • Such PCBs and accompanying electronic components may also provide analytics of the images of hydrogel structures 110 captured using camera 126 (e.g., measurement of the degree of shrinking or swelling, and correlation of such change to determine the concentration of analyte in the fluid sample).
  • Figure 1 illustrates an embodiment where the camera is integrated into the device 100
  • the microfluidic test strip 102 may clip to or otherwise couple with a smartphone
  • the smartphone camera and associated optics e.g., a simple zoom lens for use with such a smartphone camera
  • An app installed on the smartphone can perform the analytics (e.g., measurement of the degree of swelling or shrinking) and correlation of such dimensional change to the concentration of the analyte in the fluid sample.
  • FIGs 2A-2B show images of glucose sensitive smart hydrogel pillar structures in different ionic strengths (1/4X PBS in Figure 2A and IX PBS in Figure 2B).
  • the hydrogel structures are glucose sensitive due to their inclusion of phenylboronic acid moieties. In addition to being sensitive to glucose, these hydrogel structures are also sensitive to ionic strength.
  • the same hydrogel pillar structure has a diameter of about 580 pm in Figure 2A (where the ionic strength is 1/4X PBS), but shrinks to about 525 pm in Figure 2B (where the ionic strength is IX PBS).
  • Figure 3 illustrates an exemplary slide similar to slide 102, which was formed, according to the present invention.
  • the microfluidic channel is elongate, e.g., with a width of any desired dimension, e.g. 0.1-5 mm, or 0.1-3 mm, and a length of perhaps 5-100 mm or 5-10 mm.
  • An array of hydrogel pillar structures 110 are seen near the center of the channel 108.
  • An exemplary microfluidic device included channels of 3 mm in width and 65 mm in length, where about 10 mm of channel length was covered with hydrogel pillar structures having a size of about 500 pm.
  • Figure 4 illustrates a more detailed exploded view, of how such a channel device 102' may be configured.
  • device 102' includes a substrate 106, a boundary material layer 107 that at least partially defines the microfluidic channel 108, and a top cover window material 109.
  • An inlet 114 is illustrated, with an accompanying connector 128, and a seal 130 (e.g., double sided tape). As shown, the inlet 114 is configured to provide fluid communication with channel 108.
  • a hole 132 may be provided through top cover 109 to achieve such fluid communication, sealed against leakage by seal 130.
  • Figure 4 shows a similarly configured outlet structure 114' including connector 128', seal 130' and hole 132' at the opposite end of channel 108.
  • Figure 4 further shows a dark field photomask 134 that does not form part of the finished device 102', but which is used to form the smart hydrogel structures within the channel 108.
  • FIG. 5 schematically illustrates a method by which the present microchannel devices may be fabricated.
  • a liquid and/or pregel hydrogel solution may be introduced into channel 108 (e.g., through inlet 114).
  • the desired smart hydrogel structures e.g., pillars
  • Hydrogels are structures that include hydrophilic cross-linked networks of polymer that have both liquid-like and solid-like properties. Smart hydrogels characteristically experience a change in their volume in response to the presence of a specific stimulus or analyte, particularly where the hydrogel incorporates functional groups that can reversibly bind to the target analyte.
  • aptamers e.g., short single strands of nucleic acids such as DNA or RNA
  • a target analyte e.g., glucose, thrombin, proteins, other peptides, viruses or other microbes, opioids, fentanyl, other drugs or drug metabolites to be detected, etc.
  • a target analyte e.g., glucose, thrombin, proteins, other peptides, viruses or other microbes, opioids, fentanyl, other drugs or drug metabolites to be detected, etc.
  • analyte is to be construed broadly, and includes any substance that can itself be identified or measured or of which a chemical or physical property thereof can be identified or measured. Analytes include, for example, nucleic acids, proteins, other peptides, drugs, metabolites, or other compounds.
  • Glucose and thrombin are specific examples of analytes.
  • analytes serve as a physiologic, pathologic, or environmental markers of a known or unknown phenomenon (e.g glucose or insulin levels can serve as a biomarker for diabetes). It should be appreciated that the disclosed embodiments apply generally to smart hydrogels that are responsive to any desired target analyte.
  • Hydrogels can also respond to the presence of an environmental stimulus (e.g., temperature, pH, ionic strength, gas, osmolarity, humidity, etc.) and can additionally serve to indicate particular state data of an aqueous solution, such as pH. That is, hydrogels can change their volume or other dimensions in response to the level of salinity or acidity in an aqueous solution.
  • an environmental stimulus e.g., temperature, pH, ionic strength, gas, osmolarity, humidity, etc.
  • the present systems and methods can be used to detect and measure such.
  • a hydrogel can transition from a collapsed or shrunken state to a swollen state in response to the presence (or absence) of a specific analyte.
  • a change is typically not binary, but the degree of change is gradual, depending on the concentration of analyte present in the environment of interest. In other words, a period of time for equilibration is required.
  • the concentration of the analyte can span any particular concentration along a spectrum of concentration values, from relatively low, to relatively high.
  • the change in volume or other dimension (e.g., diameter of a hydrogel pillar) of the hydrogel due to the presence of the target analyte can be correlated to the concentration of the analyte, and the system can be calibrated to provide such analyte concentration data to a user of the system, based on the changes to the hydrogel detected.
  • the hydrogel is configured to swell or otherwise change volume (e.g., shrink) in response to interaction with the target analyte in response to the concentration of analyte present.
  • the biomarker sensitive hydrogel can be configured to reach an equilibrium within a given time period based on the concentration of analyte available. The particular dimensions selected for a given pillar or other structure can affect the time period needed to reach equilibrium, for a given analyte.
  • the hydrogel structure e.g., such as a pillar having a circular or other cross-sectional shapes such as rectangular, square, oval, star-shaped, other polygons, as well as hydrogel structures configured as domes, pyramids, triangular prisms, cubes, other rectangular prisms, etc.
  • the hydrogel structure can be relatively small.
  • a given portion of the hydrogel structure can have a thickness (e.g., pillar diameter) greater than 5 pm, greater than 10 pm, greater than 20 pm, greater than 30 pm, greater than 40 pm, greater than 50 pm, greater than 70 pm, greater than 80 pm, greater than 90 pm, greater than 100 pm, greater than 150 pm, greater than 200 pm, less than 1000 pm, less than 750 pm, less than 600 pm, less than 500 pm, less than 400 pm, or less than 300 pm.
  • a thickness e.g., pillar diameter
  • exemplary pillars may have any desired height, e.g., from 10 pm to 500 pm, and any desired spacing between pillars, e.g., from 10 pm to 1000 pm, or from 50 pm to 500 pm.
  • the change in dimension observed and measured may be the top planar (or bottom planar) surface area of the hydrogel pillar or other hydrogel structure (e.g., the Jtr 2 calculated surface area of a circular cross-sectioned pillar).
  • Such top planar feature is readily visible through optical imaging as described herein.
  • Smart hydrogels as described herein can be fabricated using various methods resulting in different shapes/structures. While numerous possibilities exist, in an embodiment, the sensor may include one or more hydrogel pillars inside a microfluidic channel. This provides an attractive approach for a POC sensor.
  • Smart hydrogel-based sensing of glucose, pH and ionic strength in vitro or other environments can be provided for.
  • Molecular imprinted hydrogels can be synthesized containing aptamers that selectively bind and release biomarkers (glutathione and the protein thrombin) at low concentrations for sensing applications.
  • biomarkers glutthione and the protein thrombin
  • a molecular imprinting process can be used to synthesize smart hydrogels containing two different types of aptamers conjugated to a polymerizable molecule (e.g., supplied by DNA Technologies (Coralville, IA)) that capture and release thrombin at physiological concentrations (e.g., 10 nM).
  • Such a molecular imprinting process can be configured to leave behind cavities with a stereochemical arrangement of functional groups corresponding to the target analyte structure.
  • the aptamers re-bind thrombin in a sandwich configuration with high selectivity and sensitivity.
  • Figures 6A-6C when the imprinted aptamer hydrogel was exposed to a lOnM increase in thrombin concentration, the re-binding of the thrombin caused the hydrogel to shrink (10-20% change in observed surface area, diameter, or other relevant dimension).
  • Figure 6A records the response as a change in fluid pressure. Response time can be drastically reduced by using relatively thin or porous hydrogel structures.
  • the volume or other dimension of a smart hydrogel structure can be monitored as the analyte level changes. In the present working examples, this was effectively done with a simple smartphone camera, although such could also be achieved with a webcam, microscope camera, custom built solutions, or a wide variety of other cameras. Although the present working examples employed hydrogel pillars, it will be apparent that the smart hydrogel structure can include disks, pillars, pyramids, cubes or other rectangular prism structures, or a wide variety of other structures, where the shrinking or swelling of such structure can be observed optically. In an embodiment, the hydrogel structure is advantageously allowed to expand in three-dimensions, rather than being confined to a single dimension.
  • Figure 6B charts change in hydrogel surface area of the formed smart hydrogel under different concentrations of glucose in IX PBS.
  • the step response i.e., shrinking
  • Figure 6C charts the overall change in the top or bottom planar surface area of the hydrogel pillar as a function of glucose concentration.
  • Figures 10A-10B and Figure 11 show additional results.
  • Figures 10A-10B show change in surface area of a smart hydrogel as plotted against changing glucose concentration for several glucose concentrations ranging from 0 mM to 10 mM.
  • the fluid samples also included a concentration of IX PBS.
  • Figure 11 shows change in surface area over time for a smart hydrogel exposed to 0 mM and 5 mM glucose concentrations, both in IX PBS.
  • a small filter (e.g., 112 in Figure 1) can be incorporated into the microfluidic channel 108 upstream from the location of the smart hydrogel structures 110 to remove red blood cells or similar particulates that might interfere with the needed degree of optical transparency, to be able to image any change in dimensions of the smart hydrogel 110. Such filtration can also aid in minimizing any tendency towards clogging etc.
  • the remaining filtered liquid can be guided to one or more regions populated by smart hydrogels 110 for analysis.
  • Such conveyance of the sample through the hydrogel structures 110 may be dependent on the number of analytes and number of channels used e.g., differently configured hydrogels in different channels as shown in Figure 1, which may be specifically configured for detection of different analytes.
  • the present smart hydrogel analysis as described herein can be provided as a stand-alone optical readout device with wireless or other data transmission, or become part of an accessory for a camera enabled smartphone to use for fast POC analysis of blood, another body fluid or other fluid sample.
  • the microfluidic channel device as described herein can include hydrogels formed according to any desired technique.
  • One non-limiting example of such is Leu et al., Low Cost Microfluidic Sensors with Smart Hydrogel Patterned Arrays Using Electronic Resistive Channel Sensing for Readout, Gels 2018, 4, 84, which is herein incorporated by reference in its entirety.
  • Such a method can be based on use of glass or other material substrate slides, polycarbonate sheets and double-sided vinyl tape.
  • a wide variety of microfluidic fabrication methods can of course be used.
  • the corresponding channel can be flooded with a corresponding liquid or pre-gel hydrogel solution.
  • each chamber branch e.g., such as those seen in Figure 1
  • Fabrication steps may include cutting or otherwise forming the channel into the vinyl tape or other channel boundary material using a knife plotter or the like. Next, the lower side of this tape or other material defining the channel boundary can be placed on the substrate support.
  • the holes for the inlet and the primary and secondary outlets can be cut or otherwise formed at appropriate positions, e.g. using a small biopsy tool, with automated laser cutting equipment, or the like.
  • the polycarbonate sheet or other cover material can then be positioned over the vinyl tape defining the channel, and pressed down to form the microfluidic channels.
  • PDMS Polydimethylsiloxane-based
  • other sealing connector structures can be added on top of the inlet/outlet holes (e.g., seals 130 in Figure 4).
  • Such connectors can aid in ensuring proper connection and a liquid-proof seal is provided to tubes 114 that connect the device to syringes and pumps for processing and later sampling.
  • One or more desired UV light polymerizable pre-gel hydrogel solutions are prepared and sequentially introduced into a respective sample chamber via the secondary outlets. Keeping all other outlets plugged during this time aids in preventing or minimizing flow of any “wrong” pre-gel hydrogel solution into a sample chamber it is not intended to be introduced into.
  • a photomask is positioned over the top cover “window”.
  • a collimated UV light source is used to polymerize the pre-gel hydrogel solution into a smart hydrogel structure (e.g., pillars). Subsequently any remaining pre-gel solution is removed from the sample chamber by washing with PBS.
  • the device can be subjected to varying PBS concentrations to condition the smart hydrogel structures and to remove any residual unreacted materials.
  • the filter structure in the inlet channel can be provided by a hydrogel which is not “smart” (i.e., not sensitive to the target analyte) or can be provided by another polymer capable of filtering out the undesirable components from the sample.
  • a suitable filter material for analysis of a blood sample is VIVID Plasma separation filters available from Pall. Numerous other possible filter materials could also be used, with the particular filter material employed dependent on the nature of the fluid sample being analyzed and the analyte being detected.
  • the device can be filled with PBS to keep the hydrogel structures hydrated until use.
  • a small low-cost accessory can be provided that contains the smart hydrogel structure inside a microfluidic channel.
  • This device can be clipped onto or otherwise used with a camera enabled smartphone such as is readily available.
  • a smartphone camera has the capabilities needed to obtain an image of a smart hydrogel structure before and after sample exposure.
  • An integrated app can be used to process the image data for analysis.
  • the device containing the microfluidic sample channel can have a small footprint and be produced at low cost.
  • Figures 8A-8B are tracings of photographs taken using a Samsung Galaxy smartphone with a simple inexpensive zoom lens adapter, illustrating the capabilities of such for imaging a small test structure (hydrogel structure in a microfluidic channel). The pen seen in Figure 8A is included for size comparison.
  • Figure 8B is a tracing of a photo of the same microdevice, taken with the same Samsung Galaxy smartphone, with an inexpensive zoom lens attachment.
  • a data preprocessing unit e.g., provided by a smartphone or computing device
  • the following components may be used: a microfluidic channel as described herein, a pump or manual suction or capillary forces to pull the sample into the microfluidic channel, a camera chip with corresponding readout electronics and optics to acquire the images of the hydrogel structure, a Bluetooth or other communication chipset or direct interface with an app, and memory to store measurements obtained from the imaged hydrogel structure.
  • the whole device could be powered via a low voltage USB cable or similar connection.
  • an embodiment could be entirely passive, relying on capillary action to draw the sample through the hydrogel pillar(s) or other smart hydrogel structures in the microfluidic channel.
  • An optional microfluidic device holder could include a trigger switch to detect when the microfluidic channel for sample detection has been inserted into the sensor device (e.g., when slide 102 is inserted into sensor 104, as shown in Figure 1).
  • Software components of the described device can be configured to accomplish the following steps: when a microfluidic channel device is inserted a reference image of the hydrogel region of the channel is obtained. Subsequently, capillary action is used, or suction is applied to move the sample from the inlet into the channel(s) of the microfluidic device. After sufficient time has passed to allow the hydrogel to reach equilibrium relative to the sample, another reference image is taken of the hydrogel structure in the fluid sample solution. The disposable microfluidic device can be removed and disposed of. The data can be transferred and analyzed.

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Abstract

L'invention concerne un dispositif autonome de point de traitement qui peut utiliser des structures d'hydrogel intelligentes pour détecter des analytes cibles dans un échantillon de fluide. Le dispositif comprend une lame d'échantillon microfluidique comprenant un canal microfluidique avec une ou plusieurs structures d'hydrogel intelligentes positionnées dans le canal. La lame peut être insérée dans un dispositif d'analyse associé, pour analyser l'état de gonflement des structures d'hydrogel en utilisant un appareil photo optique pour capturer des images de la ou des structures d'hydrogel avant et après l'interaction de cette structure d'hydrogel avec l'échantillon de fluide. Une telle imagerie optique peut être utilisée pour mesurer rapidement et facilement le changement dimensionnel de la structure de l'hydrogel, lequel changement peut être corrélé à la concentration de l'analyte dans l'échantillon de fluide. L'imagerie et l'analyse peuvent être réalisées par un dispositif d'analyse associé (p. ex., destiné à recevoir une lame de microcanal contenant l'échantillon de fluide), ou l'imagerie et l'analyse peuvent être réalisées à l'aide d'un appareil photo de téléphone intelligent et d'une application associée.
PCT/US2021/035512 2020-06-02 2021-06-02 Imagerie optique de structures d'hydrogel intelligentes pour des applications de détection WO2021247750A1 (fr)

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