CN102353653A - Rapid response hydrogel film glucose optical sensor - Google Patents

Rapid response hydrogel film glucose optical sensor Download PDF

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Publication number
CN102353653A
CN102353653A CN201110177347XA CN201110177347A CN102353653A CN 102353653 A CN102353653 A CN 102353653A CN 201110177347X A CN201110177347X A CN 201110177347XA CN 201110177347 A CN201110177347 A CN 201110177347A CN 102353653 A CN102353653 A CN 102353653A
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glucose
film
fabry
sensitive
perot interference
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张拥军
张曦
关英
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Nankai University
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Nankai University
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Abstract

The invention discloses a rapid response optical glucose sensor based on glucose sensitive hydrogel film. The hydrogel film used for sensing has two properties that on one hand, a swellbility of the hydrogel film in aqueous solution is changed with a glucose concentration in the solution; on the other hand, an absorption spectrum or a reflection spectrum has Fabry-Perot interference fringes. The change of glucose concentration leads to change of hydrogel film swellbility, so as to cause moving of the Fabry-Perot interference fringes; therefore the moving of the Fabry-Perot interference fringes indicates the change of glucose concentration in the solution. The invention utilizes a layer by layer assembly method to prepare the glucose sensitive hydrogel film with a thickness from hundreds nanometers to micrometers, so as to conduct rapid response.

Description

The hydrogel thin film glucose optical sensor that responds fast
Technical field
The present invention relates to a kind of glucose optical sensor, or rather, relate to the Fabry-Perot diffraction fringe of utilizing film and change the hydrogel thin film sensor that moves with concentration of glucose based on the intelligent aqueous gel capable film.This sensor can be applicable to technical fields such as chemistry, food and biological medicine.
Background technology
The swellbility of glucose-sensitive hydrogels in water changes with the change of concentration of glucose, can be used as sensitive element and suitable conversion element cooperation, forms glucose sensor.Especially, if combine to obtain exempting from the mark optical sensor with the optical interference phenomenon.Optical sensor based on glucose-sensitive hydrogels has simply, advantages of being cheap, is expected to be applied to the blood sugar test of technical fields, particularly diabetes patient such as chemistry, food and biological medicine.
People's such as S.A.Asher article (J.H.Holtz and S.A.Asher, Polymerized colloidal crystal hydrogel films as intelligent chemical sensing materials, Nature; 1997,389,829-832) and world patent; Patent No. WO/1998/019787; On May 14 1998 time of disclosure, the name of innovation and creation is called NOVEL POLYMERIZED CRYSTALLINE COLLOIDAL ARRAY SENSORS (Asher, Sanford A.; Holtz; John H.NOVEL POLYMERIZED CRYSTALLINE COLLOIDAL ARRAY SENSORS, WO/1998/019787), United States Patent (USP); Patent No. US Patent 5854078; On Dec 29 1998 time of disclosure, the name of innovation and creation is called Polymerized crystalline colloidal array sensor methods (Asher, Sanford A.; Holtz; John H.Polymerized crystalline colloidal array sensor methods, US Patent 5854078) etc. disclose with the stimulating responsive hydrogel and be sensitive element, be the optical sensing methods of optical conversion component with the colloidal crystal array.People's such as S.A.Asher article (S.A.Asher, V.L.Alexeev, A.V.Goponenko; A.C.Sharma, I.K.Lednev, C.S.Wilcox and D.N.Finegold; Photonic crystal carbohydrate sensors:Low ionic strength sugar sensing, Journal of the American Chemical Society, 2003; 125,3322-3329; V.L.Alexeev, A.C.Sharma, A.V.Goponenko, S.Das; I.K.Lednev, C.S.Wilcox, D.N.Finegold and S.A.Asher; High ionic strength glucose-sensing photonic crystal, Analytical Chemistry, 2003; 75,2316-2323) and United States Patent (USP), patent No. US Patent 7105352; On September 12 2006 time of disclosure, the name of innovation and creation is called Intelligent polymerized crystalline colloidal array carbohydrate sensors (Asher, Sanford A.; Alexeev, Vladimir L.; Lednev, Igor K.; Sharma, Anjal C.; Wilcox, Craig, Intelligent polymerized crystalline colloidal array carbohydrate sensors, US Patent 7105352) method of utilizing similar principles to detect concentration of glucose then disclosed.
United States Patent (USP), patent No. US Patent 6689316, on February 10 2004 time of disclosure, the name of innovation and creation is called Holographic sensors and their production (Blyth, Jeffrey; Lowe, Christopher Robin; Mayes, Andrew Geoffrey; Millington; Roger Bradley.Holographic sensors and their production; US Patent 6689316) and later patents, patent No. US Patent 7443553, October 28 2008 time of disclosure; The name of innovation and creation is called Holographic sensors and their production (Lowe, Christopher Robin; Davidson, Colin Alexander Bennett; Blyth, Jeffrey; Marshall, Alexander James; James; Anthony Peter.Holographic sensors and their production; US Patent 7443553), United States Patent (USP), patent No. US Patent 7402441, October 23 2003 time of disclosure; The name of innovation and creation is called Method of detecting an analyte in a fluid (Lowe, Christopher Robin; Davidson, Colin Alexander Bennett; Blyth, Jeffrey; Kabi lan, Satyamoorthy; Marshall, Alexander James; Gonzalez, Blanca Madrigal; James, Anthony Peter.Method of detecting an analyte in a fluid, US Patent 7402441) then disclose with the stimulating responsive hydrogel and be sensitive element, be the optical sensing methods of optical conversion component with the hologram.People's such as G.J.Worsley article (G.J.Worsley, G.A.Tourniaire, K.Medlock; F.K.Sartain, H.E.Harmer, M.Thatcher; A.M.Horgan and J.Pritchard; Continuous blood glucose monitoring with a thin-film optical sensor, Clin Chem, 2007; 53,1820-1826) to disclose with the glucose-sensitive hydrogels be sensitive element, be the method for the detection concentration of glucose of optical conversion component with the hologram.
Above-mentioned two kinds of optical sensors all use macroscopical hydrogel to be sensitive element.Because the swelling rate of macroscopical hydrogel is slow, causes the sensor response speed very slow.
United States Patent (USP), patent No. US Patent 7440110, on October 18 2002 time of disclosure, the name of innovation and creation is called Optical sensing of measurands (Hjelme, Dag R.; Berg, Arne; Ellingsen, Reinold; Falch, Berit; Astrid;
Figure BSA00000526571700022
Dan; Optical sensing of measurands; US Patent 7440110) and later patents, patent No. US Patent7602498, March 14 2006 time of disclosure; The name of innovation and creation is called Optical sensing of measurands (Hjelme, Dag R.; Berg, Arne; Ellingsen, Reinold; Falch, Berit;
Figure BSA00000526571700023
Astrid;
Figure BSA00000526571700024
Dan; Optical sensing of measurands, US Patent 7602498) disclosing with the semisphere hydrogel is sensitive element, utilizes the Fabry-Perot interference to carry out the optical sensing methods of conversion of signals.Owing to use the less hydrogel of volume, accelerated the sensor response speed, but still remained further to be improved.In addition, two interfaces that Fabry-Perot interferes requirement to form the Fabry-Perot interference cavity are parallel, and the semisphere hydrogel obviously is not desirable Fabry-Perot interference cavity.
Summary of the invention
For overcoming the deficiency of above-mentioned design, the present invention has designed stimulating responsive hydrogel thin film with layer assembly as sensitive element, also is the Fabry-Perot interference cavity simultaneously, utilizes the Fabry-Perot interference to carry out the optical sensing methods of conversion of signals.The hydrogel thin film thickness of the present invention's preparation is between hundreds of nanometers are to several microns, and the hydrogel thin film thickness for preparing than conventional method reduces greatly, therefore can effectively accelerate the swelling rate of hydrogel, thereby realizes quicker response.The film upper and lower surfaces of this law preparation simultaneously is parallel, is better Fabry-Perot interference cavity.
The Fabry-Perot interference fringe is a kind of common Film Optics phenomenon.When a branch of illumination is mapped to a thickness is that θ, refraction index are n eFilm on the time, will repeatedly reflect at two interfaces of film, form a series of reflected light and a series of emergent light.(Fig. 1) these reflected light or emergent light have identical frequency, each other interfere on the absorption spectrum that causes film or the reflectance spectrum and a series of crests and trough, i.e. Fabry-Perot interference fringe occur.The wavelength of adjacent two crests is confirmed by following formula:
1 2 n e θ = 1 λ p - 1 λ p + 1
It is thus clear that the position at peak is only relevant with the thickness and the refraction index of film in the Fabry-Perot striped.When the analyte concentration change, when causing the swellbility change of hydrogel thin film, film thickness and refraction index will change, and cause the Fabry-Perot striped to be moved.Therefore but by the concentration that moves analyte in the directive system of Fabry-Perot striped.(Fig. 2) sensor designed of the present invention promptly realizes the detection to specific analyte based on this principle.
The glucose-sensitive hydrogels film prepares through self-assembling method layer by layer among the present invention.The at first synthetic a pair of macromolecule that can carry out self assembly layer by layer utilizes the interactions such as static, hydrogen bond or covalent bond between the macromolecule, and macromolecule is in layer assembled, and forms polymeric membrane.Through control assembling cycle index, the thickness of control polymeric membrane is between the hundreds of nanometer is to several microns.Fabry-Perot can both take place under dry state and solvent swelling state such film interferes, and can on its absorption spectrum or reflectance spectrum, observe the Fabry-Perot interference fringe.(Fig. 3)
The macromolecule that is used to assemble among the present invention comprises synthetic high polymers such as polyacrylamide, polyacrylate, polymethacrylate; Like polyacrylamide, PHEMA, poly hydroxy ethyl acrylate, poly N-vinyl pyrrolidone, polyvinyl alcohol (PVA) etc., and natural polymer such as glucosan.
Functional groups to glucose-sensitive among the present invention comprises phenyl boric acid, glucose oxidase, concanavalin A etc.These functional groups can react with glucose molecule, and electric charge or parent/hydrophobicity on the macromolecular chain are changed, or change the degree of crosslinking of gel, thereby change the swellbility of aquagel membrane.The swelling of hydrogel thin film causes the variation of film thickness and refraction index, and then causes moving of Fabry-Perot interference fringe, thus the concentration of glucose in the indication solution.These functional groups can be introduced in the film assembling process, also can after assembling is accomplished, introduce through modification.
The sensor that novelty of the present invention embodies in the present invention uses extremely thin hydrogel thin film as response element and acquisition response fast thus.Square being inversely proportional to of the swelling rate of hydrogel and its yardstick, so the hydrogel size is big more, swelling rate is slow more.Because the only hundreds of nanometers of hydrogel thin film thickness that the present invention uses are to several microns, the swelling rate of hydrogel improves greatly under environmental stimuli.Therefore the present invention has had large increase to the response speed of glucose, can be used for the real-time detection of glucose.
Novelty of the present invention also is embodied in through self-assembling method layer by layer and prepares the stimulating responsive hydrogel thin film.The conventional method for preparing aquagel membrane is difficult to prepare the hydrogel thin film of thickness between the hundreds of nanometer is to several microns.In the layer assembly process, thickness progressively increases with the assembling cycle index, and the thickness that at every turn circulates increases to a few nanometer to tens nanometers, therefore is easy to prepare thickness at sub-micron and micron-sized hydrogel thin film.The method of layer assembly simultaneously good reproducibility does not need specific installation, is easy to large-scale production.
In the practical implementation; Can piezoid, silicon chip etc. is substrate preparation glucose-sensitive self assembly hydrogel thin film; The base material of attached water gel film is immersed in the solution, measure the transmitted spectrum or the reflectance spectrum of film, the concentration of glucose from the mobile computing solution of Fabry-Perot interference fringe.Also can glucose-sensitive self assembly hydrogel thin film directly be prepared into the optical fiber head surface, utilize fiber spectrometer to measure the Fabry-Perot interference fringe of film.
Description of drawings
Fig. 1, signal light repeatedly reflect at two interfaces of hydrogel thin film, form a series of reflected light and a series of emergent light.
Moving of the Fabry-Perot interference fringe that the Fabry-Perot interference fringe that occurs in Fig. 2, signal hydrogel thin film absorption spectrum or the reflectance spectrum and the swelling of film cause.
Fig. 3, aquagel membrane in air (dry state) and in water the Fabry-Perot interference fringe of (solvent swelling state).
The reflectance spectrum of hydrogel thin film in the phosphate buffer solution of the 0.050M pH8.5 that contains variable concentrations glucose among Fig. 4, the embodiment 3.Measure down at 25 ℃.
The graph of a relation of concentration of glucose in the light path of hydrogel thin film and the solution among Fig. 5, the embodiment 3.
Among Fig. 6, the embodiment 4 in containing the 0.050M pH8.5 phosphate buffer solution of 2mM glucose the light path of hydrogel thin film variation diagram in time.Measure down at 37 ℃.
The graph of a relation of concentration of glucose in the change in optical path length of hydrogel thin film and the solution among Fig. 7, the embodiment 6.In 25 ℃ of 0.050M pH7.4 phosphate buffer solutions, measure.
The graph of a relation of concentration of glucose in the change in optical path length of hydrogel thin film and the solution among Fig. 8, the embodiment 8.In 25 ℃ of 0.050M pH7.4 phosphate buffer solutions, measure.
Embodiment
Below in conjunction with accompanying drawing and embodiment the present invention is described further.But the present invention is not limited to the following example.
Embodiment 1
0.500g acrylic amide, 0.150g 3-acrylamido phenyl boric acid and 4.0mg azoisobutyronitrile are dissolved in the 40mL dimethyl formamide.Feed nitrogen deoxygenation 30 minutes.Be heated to 70 ℃ under the nitrogen protection, reacted 12 hours.Product precipitates in acetone, filters, and acetone repeatedly washs, and vacuum drying gets acrylic amide-3-acrylamido phenyl boric acid multipolymer.
Clean substrate (quartz, glass or polished silicon slice) soaked 10 minutes in the 0.1wt% poly-vinyl alcohol solution, washed 4 minutes, in 0.1wt% acrylic amide-3-acrylamido phenyl boric acid copolymer solution, soaked 10 minutes then, washed 4 minutes again.Repeat this alternate group process of assembling and promptly obtain polyvinyl alcohol (PVA)/acrylic amide-3-acrylamido phenyl boric acid multipolymer self-assembled film layer by layer.
Embodiment 2
With the reflectance spectrum of the self-assembled film that obtains among the fiber spectrometer mensuration embodiment 1, as shown in Figure 3.The reflectance spectrum of self-assembled film presents a series of crest and trough, i.e. the Fabry-Perot striped.The reason of generation striped as previously mentioned.This self-assembled film is placed deionized water, still can observe Fabry-Perot striped clearly, just the amplitude of striped reduces, and simultaneously owing to the swelling of film in water, fringe density increases.(Fig. 3) these results prove the self-assembled film that obtains among the embodiment 1 can be in water swelling, have hydrogel thin film character.
Embodiment 3
The self assembly aquagel membrane that obtains among the embodiment 1 is immersed in the phosphate buffer solution of 25 ℃ of 0.050M pH8.5 that contain variable concentrations glucose.With the reflectance spectrum of fiber spectrometer mensuration film, as shown in Figure 4.It is thus clear that the reflectance spectrum of self assembly aquagel membrane presents Fabry-Perot interference fringe clearly, and interference fringe moves with the concentration of glucose variation.
By the position of Fabry-Perot interference fringe among Fig. 4, calculate the light path of self assembly aquagel membrane in different concentration of glucose, as shown in Figure 5.It is thus clear that the light path of self assembly aquagel membrane increases and linear increasing with concentration of glucose.Promptly can measure the concentration of glucose in the solution by the mensuration of Fabry-Perot interference fringe.
Embodiment 4
The self assembly aquagel membrane that obtains among the embodiment 1 is immersed in temperature is 37 ℃, contain in the phosphate buffer solution of 0.050M pH8.5 of 2mM glucose.With fiber spectrometer recording sheet reflectance spectrum over time, by the light path of the position calculation self assembly aquagel membrane of Fabry-Perot interference fringe over time, as shown in Figure 6.It is thus clear that the swelling due to concentration of glucose raises promptly reached balance in 1-2 minute, sensor's response is very fast.
Embodiment 5
Replace the 3-acrylamido phenyl boric acid among the embodiment 1 with 2-acrylic amide methyl-5-fluobenzoic acid, use with quadrat method synthesis of acrylamide-2-acrylic amide methyl-5-fluobenzoic acid multipolymer.
Similarly; Clean substrate (quartz, glass or polished silicon slice) was soaked 10 minutes in the 0.1wt% poly-vinyl alcohol solution; Washed 4 minutes, and in 0.1wt% acrylic amide-2-acrylic amide methyl-5-fluobenzoic acid copolymer solution, soaked 10 minutes then, washed again 4 minutes.Repeat this alternate group process of assembling and promptly obtain polyvinyl alcohol (PVA)/acrylic amide-2-acrylic amide methyl-5-fluobenzoic acid self-assembled film layer by layer.
Embodiment 6
The self assembly aquagel membrane that obtains among the embodiment 5 is immersed in the phosphate buffer solution of 25 ℃ of 0.050M pH7.4 that contain variable concentrations glucose.With the reflectance spectrum of fiber spectrometer mensuration film, according to the position of Fabry-Perot interference fringe, calculate the light path of self assembly aquagel membrane in different concentration of glucose, as shown in Figure 7.It is thus clear that the light path of self assembly aquagel membrane increases and linear increasing with concentration of glucose.Show with 2-acrylic amide methyl-5 fluobenzoic acid and replace self assembly aquagel membrane that 3-acrylamido phenyl boric acid obtains can be measured glucose in the solution under the physiological pH condition concentration.
Embodiment 7
In embodiment 1, add the 3rd monomer dimethylamino-propyl acrylic amide, use with quadrat method synthesis of acrylamide-3-acrylamido phenyl boric acid-dimethylamino-propyl acrylamide copolymer.
Similarly; Clean substrate (quartz, glass or polished silicon slice) was soaked 10 minutes in the 0.1wt% poly-vinyl alcohol solution; Washed 4 minutes; In 0.1wt% acrylic amide-3-acrylamido phenyl boric acid-dimethylamino-propyl acrylamide copolymer solution, soaked 10 minutes then, washed again 4 minutes.Repeat this alternate group process of assembling and promptly obtain polyvinyl alcohol (PVA)/acrylic amide-3-acrylamido phenyl boric acid-dimethylamino-propyl acrylamide copolymer self-assembled film layer by layer.
Embodiment 8
The self assembly aquagel membrane that obtains among the embodiment 7 is immersed in the phosphate buffer solution of 25 ℃ of 0.050M pH7.4 that contain variable concentrations glucose.With the reflectance spectrum of fiber spectrometer mensuration film, according to the position of Fabry-Perot interference fringe, calculate the light path of self assembly aquagel membrane in different concentration of glucose, as shown in Figure 8.It is thus clear that the light path of self assembly aquagel membrane increases and linear increasing with concentration of glucose.Show that the self assembly aquagel membrane that adds the 3rd monomer dimethylamino-propyl acrylic amide can measure the concentration of glucose in the solution under the physiological pH condition.

Claims (7)

1. the glucose optical sensor based on the glucose-sensitive hydrogels film that responds fast is characterized in that employed hydrogel thin film has glucose-sensitive property, and its swellbility in water changes with concentration of glucose.
2. the glucose optical sensor based on the glucose-sensitive hydrogels film as claimed in claim 1; It is characterized in that employed hydrogel thin film; Has the Fabry-Perot interference fringe on its absorption spectrum or the reflectance spectrum, through the variation of concentration of glucose in the mobile indication solution of Fabry-Perot interference fringe.
3. glucose-sensitive hydrogels film as claimed in claim 1 is characterized in that its thickness in several white nanometers to several micrometer ranges, therefore can respond rapidly.
4. glucose-sensitive hydrogels film as claimed in claim 1 is characterized in that preparing through the layer assembly method.
5. the macromolecule that is used to assemble in the claim 4 comprises synthetic high polymers such as polyacrylamide, polyacrylate, polymethacrylate; Like polyacrylamide, PHEMA, poly hydroxy ethyl acrylate, poly N-vinyl pyrrolidone, polyvinyl alcohol (PVA) etc., and natural polymer such as glucosan.
6. the described glucose-sensitive hydrogels film of claim 1 is characterized in that containing the functional groups to glucose-sensitive, comprises phenyl boric acid, glucose oxidase, concanavalin A etc.Functional groups can be introduced in the film assembling process, also can after assembling is accomplished, introduce through modification.
7. the described glucose-sensitive hydrogels film of claim 1 can be prepared on the solid substrates such as silicon chip, piezoid, also can directly be prepared on the optical fiber head, becomes Fibre Optical Sensor.
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US10303063B2 (en) 2012-03-29 2019-05-28 Carl Zeiss Smt Gmbh Projection exposure apparatus with at least one manipulator
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CN105044080A (en) * 2015-06-12 2015-11-11 青岛科技大学 Con A measuring method
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CN105651841A (en) * 2016-01-05 2016-06-08 宁夏医科大学 Method for preparing multiple-structure multi-stimuli-responsive hydrogel layer-by-layer assembled film
CN108195821A (en) * 2018-01-30 2018-06-22 上海大学 Conical fiber glucose sensor with phenyl boric acid film and its preparation method and application
CN108467462A (en) * 2018-03-21 2018-08-31 南开大学 A kind of composite hydrogel and preparation method thereof for optical sensing
CN110327056A (en) * 2019-05-24 2019-10-15 武汉大学 A kind of intelligent aqueous gel and preparation method thereof for visualizing blood sugar test
CN110327056B (en) * 2019-05-24 2021-01-01 武汉大学 Intelligent hydrogel for visual blood glucose detection and preparation method thereof
CN110256669A (en) * 2019-06-10 2019-09-20 温州医科大学 Sulfydryl/boronate modified polymer, glucose-sensitive hydrogels composition, glucose-sensitive carry liquid medicine gel and preparation method thereof
CN110256669B (en) * 2019-06-10 2021-05-25 温州医科大学 Sulfydryl/phenylboronic acid group modified polymer, glucose-sensitive hydrogel composition, glucose-sensitive drug-loaded hydrogel and preparation method
CN111849447A (en) * 2020-07-29 2020-10-30 中国海洋石油集团有限公司 Method for modifying xanthan gum and modified xanthan gum oil displacement agent
CN111875737A (en) * 2020-07-29 2020-11-03 中国海洋石油集团有限公司 Phenylboronic acid polymer, preparation method thereof and application thereof in modified xanthan gum
CN111875737B (en) * 2020-07-29 2022-04-12 中国海洋石油集团有限公司 Phenylboronic acid polymer, preparation method thereof and application thereof in modified xanthan gum
CN111849447B (en) * 2020-07-29 2022-04-26 中国海洋石油集团有限公司 Method for modifying xanthan gum and modified xanthan gum oil displacement agent

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Application publication date: 20120215