CN107007287A - Biomolecule detection devices and method - Google Patents
Biomolecule detection devices and method Download PDFInfo
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- CN107007287A CN107007287A CN201710371402.6A CN201710371402A CN107007287A CN 107007287 A CN107007287 A CN 107007287A CN 201710371402 A CN201710371402 A CN 201710371402A CN 107007287 A CN107007287 A CN 107007287A
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
- A61B5/00—Measuring for diagnostic purposes; Identification of persons
- A61B5/145—Measuring characteristics of blood in vivo, e.g. gas concentration, pH value; Measuring characteristics of body fluids or tissues, e.g. interstitial fluid, cerebral tissue
- A61B5/14507—Measuring characteristics of blood in vivo, e.g. gas concentration, pH value; Measuring characteristics of body fluids or tissues, e.g. interstitial fluid, cerebral tissue specially adapted for measuring characteristics of body fluids other than blood
- A61B5/1451—Measuring characteristics of blood in vivo, e.g. gas concentration, pH value; Measuring characteristics of body fluids or tissues, e.g. interstitial fluid, cerebral tissue specially adapted for measuring characteristics of body fluids other than blood for interstitial fluid
- A61B5/14514—Measuring characteristics of blood in vivo, e.g. gas concentration, pH value; Measuring characteristics of body fluids or tissues, e.g. interstitial fluid, cerebral tissue specially adapted for measuring characteristics of body fluids other than blood for interstitial fluid using means for aiding extraction of interstitial fluid, e.g. microneedles or suction
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
- A61B5/00—Measuring for diagnostic purposes; Identification of persons
- A61B5/145—Measuring characteristics of blood in vivo, e.g. gas concentration, pH value; Measuring characteristics of body fluids or tissues, e.g. interstitial fluid, cerebral tissue
- A61B5/14546—Measuring characteristics of blood in vivo, e.g. gas concentration, pH value; Measuring characteristics of body fluids or tissues, e.g. interstitial fluid, cerebral tissue for measuring analytes not otherwise provided for, e.g. ions, cytochromes
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Abstract
A kind of biomolecule detection devices and method, wherein device includes being integrated in the detection unit being isolated on same substrate and reference cell, include the piezoelectric membrane, sensitive layer and the gel layer that are sequentially stacked, wherein gel layer is stored with the tissue fluid containing biomolecule to be detected；The sensitive layer energy specific recognition biomolecule to be detected for differing only in detection unit of the sensitive layer of two units, the distribution of the biomolecule to be detected for changing detection unit storage；Piezoelectric membrane is used to obtain frequency signal in response to the distribution of biomolecule to be detected；The difference for the frequency signal that biomolecule detection devices are obtained according to detection unit and reference cell, analysis obtains the concentration of biomolecule to be detected in tissue fluid.Influence of the noise that the detection process that apparatus and method proposed by the present invention reduce complexity is introduced to testing result, greatly improves accuracy of detection；And because detection unit and reference cell are integrated on same substrate, realize the overall miniaturization of chip.
Description
Technical field
The invention belongs to field of biological detection, relate more specifically to a kind of biomolecule detection devices and method.
Background technology
The traditional detection method of physical signs includes blood count and implantation biochip etc., but this little the common of methods presence lacks
Point is invasive, for being difficult to bear for needing to repeat the patient of detection for a long time.
In current a variety of Non-invasive detection modes, it is the degree of accuracy and correlation highest and relatively easy that tissue fluid, which extracts detection,
The detection method of realization.Because tissue fluid is the important component of human body fluid, tissue fluid is provided newly for human body cell
Old metabolism environment, its composition also most directly reflects the health status of human body cell, while tissue fluid is carried out in real time with blood
Mass exchange, so certain ratio is presented in corresponding biomolecule content in the content and blood of the biomolecule of certain in tissue fluid
Relation.By taking glucose as an example, by detecting the glucose in tissue fluid, blood glucose value can be indirectly corresponded to out.
The extracting method to tissue fluid is mainly that Reverse iontophoresis is saturating at present, but the tissue fluid extraction efficiency of the method
Tissue liquid hold-up that is low, extracting is few, and the concentration of the biological molecules detected wherein contained can be lower, so wanting to reach noninvasive
And accurate purpose is detected, it is necessary to a kind of extremely sensitive detection mode.
And the detection mode to tissue fluid mainly includes at present：Electrochemical sensor and SAW device, wherein, electrification
Learn sensor and detected that and enzyme is in the nature protein using enzyme, thus use electrochemical sensor progress detect presence with
Lower problem：1st, the activity of enzyme is easily affected by environment, and sensitivity and life-span are unstable, and testing result is easily by tissue fluid
The influence of the materials such as middle uric acid and ascorbic acid；2nd, detection process is related to catalysis oxidation, electrochemical reaction, electro transfer of enzyme etc.
Multiple roundabout processes, therefore accuracy, robustness, response time and test limit are all easily impacted.SAW device is utilized
Polymer is detected as sensitive layer material, but it equally exists the problem of existing when electrochemical sensor is detected, and it is examined
Survey system is only applicable to the detection of liquid environment, and the sensitivity of SAW device is relatively low.
The content of the invention
Based on problem above, it is a primary object of the present invention to propose a kind of biomolecule detection devices and method, it is used for
Solve at least one of above technical problem.
To achieve these goals, as one aspect of the present invention, the present invention proposes a kind of biomolecule detection devices,
Including being integrated in the detection unit being isolated on same substrate and reference cell, detection unit and reference cell include folding successively
Piezoelectric membrane, sensitive layer and the gel layer put, wherein：
Gel layer, for storing the tissue fluid containing biomolecule to be detected；
The sensitive layer of detection unit and reference cell is differed only in, and the sensitive layer energy specific recognition of detection unit treats
Biomolecule is detected, the distribution of biomolecule to be detected in the tissue fluid for changing detection unit storage；
Piezoelectric membrane, for the distribution in response to biomolecule to be detected, obtains a frequency signal；
The difference for the frequency signal that biomolecule detection devices are obtained according to detection unit and reference cell, analysis obtains group
Knit the concentration of biomolecule to be detected in liquid.
In some embodiments of the invention, above-mentioned detection unit and reference cell also include：
Top electrode between piezoelectric membrane and sensitive layer；
Ion reverse electro-osmotic is carried out by applying DC voltage to top electrode, the group containing biomolecule to be detected is extracted
Liquid is knitted, the obtained tissue fluid containing biomolecule to be detected is extracted and is stored in gel layer.
In some embodiments of the invention, above-mentioned detection unit and reference cell also include：
Hearth electrode between substrate and piezoelectric membrane；
Cause piezoelectric membrane resonance by applying alternating voltage to top electrode and hearth electrode, piezoelectric membrane is in response to tissue fluid
In biomolecule to be detected distribution, obtain frequency signal.
In some embodiments of the invention, above-mentioned detection device is by drawing negative electrode and drawing positive electrode and external electrical
Road carries out wire bonding connection, and the extraction positive electrode and extraction negative electrode are structure as a whole with top electrode and hearth electrode respectively.
In some embodiments of the invention, above-mentioned detection device also includes the thin substrates being located between substrate and hearth electrode
Film, for supporting detection unit and reference cell.
In some embodiments of the invention, the sensitive layer of above-mentioned detection unit matches with biomolecule to be detected, bag
Include molecular imprinting film, biological enzyme membrane, antigen-antibody film or the film containing specific DNA.
In some embodiments of the invention, above-mentioned substrate is hollow in the detection unit position corresponding with reference cell
Structure.
In some embodiments of the invention, above-mentioned substrate is formed with the detection unit position corresponding with reference cell
Sound wave reflecting grating structure；The sound wave reflecting grating is Bragg reflection grid.
In some embodiments of the invention, the material of above-mentioned gel layer includes synthesis macromolecule hydrogel or natural polymer
Sub- hydrogel.
In some embodiments of the invention, the material of above-mentioned piezoelectric membrane includes inorganic piezoelectric material and organic piezoresistive material
Material.
To achieve these goals, as another aspect of the present invention, the present invention also proposes a kind of biomolecule detection
Method, using above-mentioned biomolecule detection devices, comprises the following steps：
Step 1, the tissue fluid containing biomolecule to be detected extracted in advance is stored in gel layer；
Biomolecule to be detected in step 2, the sensitive layer specific recognition tissue fluid of detection unit, and change to be detected
The distribution of biomolecule；
The frequency signal of step 3, the frequency signal to detection unit and reference cell seeks difference, and analysis is obtained in tissue fluid
The concentration of biomolecule to be detected.
In some embodiments of the invention, above-mentioned detection unit and reference cell, which have, is located at piezoelectric membrane and sensitive layer
Between top electrode；
Biomolecule detecting method also includes before step 1：Pretreatment goal skin area, detection unit and reference list
Member is while contact target skin area, the extraction of ion reverse electro-osmotic is carried out containing to be checked by applying DC voltage to top electrode
Survey the tissue fluid of biomolecule.
Biomolecule detection devices proposed by the present invention and method, have the advantages that：
1st, sensitive layer is differed only in due to detection unit and reference cell, and whether differing only in for sensitive layer can
Specific recognition biomolecule to be detected, therefore the difference of final frequency signal that two units are obtained only is by life to be detected
Caused by thing molecule, therefore the dense of biomolecule to be detected in tissue fluid is obtained by asking two frequency signals difference to analyze
Degree, influence of the noise that the detection process that this apparatus and method reduces complexity is introduced to testing result, so as to greatly improve
Accuracy of detection；And because detection unit and reference cell are integrated on same substrate, it is achieved that chip entirety is small-sized
Change；
2nd, the present invention characterizes the concentration of biomolecule to be detected using the knots modification of the frequency signal of piezoelectric membrane response,
Therefore only need to extract micro tissue fluid, can both ensure human-body safety, specific recognition biomolecule to be detected can be enabled again
Sensitive layer be difficult saturation, so as to realize exempt from desorption, be used repeatedly；Again due to be detected using energy specific recognition
The sensitive layer of biomolecule substitutes the biology enzyme in electrochemical means, therefore can provide higher selectivity, and can strengthen inspection
The robustness of device is surveyed, is increased the service life；
3rd, because the detection means and its detection method of the present invention only need to two up and down vertical opposite electrodes, with tradition
The electrochemical method of differential configuration compare, planar spatially save the position of two electrodes, it is necessary to ion it is reverse
The tissue fluid of electro-osmosis also saves one times；
4th, due to the particular design of detection means of the present invention, Reverse iontophoresis is applied to the noninvasive inspection of biomolecule thoroughly
In survey technology, the Reverse iontophoresis noninvasive advantage for extracting tissue fluid, and because detection means is thin-film body sound thoroughly can be played
Wave resonator, it can make up Reverse iontophoresis extraction group thoroughly to mechanics physical quantity such as pressure, viscous force etc. very strong sensitiveness
The poor efficiency of liquid is knitted, so as to effectively shorten the response time；
5th, biomolecule detection devices of the invention, can be single in detection according to detection environment and desired different choice substrate
The member position corresponding with reference cell is the detection means of hollow structure, then because hollow structure therein is substantially equivalent to
Resonance chamber, thus accuracy and sensitivity easily reach it is more excellent；
6th, biomolecule detection devices of the invention, can be single in detection according to detection environment and desired different choice substrate
The member position corresponding with reference cell is formed with the detection means of sound wave reflecting grating structure, therefore real equivalent to sound wave reflecting layer
Core structure, thus stability and repeatability easily reach it is more excellent.
Brief description of the drawings
Fig. 1 is the view in transverse section for the biomolecule detection devices that one embodiment of the invention is proposed；
Fig. 2 is the structural representation for the biomolecule detection devices that one embodiment of the invention is proposed；
Fig. 3 is the view in transverse section for the biomolecule detection devices that another embodiment of the present invention is proposed；
Fig. 4 is the structural representation for the biomolecule detection devices that another embodiment of the present invention is proposed.
Embodiment
For the object, technical solutions and advantages of the present invention are more clearly understood, below in conjunction with specific embodiment, and reference
Accompanying drawing, the present invention is described in further detail.
In order to avoid influence of multiple roundabout processes to testing result accuracy as far as possible, differential configuration can be used, i.e.,
SAW device of the application distribution on two chips is operated as detection group and reference group.But SAW device
Mechanical wave is mainly what is propagated by the surface of piezoelectric membrane, and it is integrated that this also results in that two SAW devices can not be close
In a Si substrate, otherwise it can be interfered during two SAW devices work of differential configuration, and this can be to last
Difference frequency processing and testing result are brought and had a strong impact on, therefore the differential configuration of multiple SAW devices is not easy of integration.
And FBAR (Film Bulk Acoustic Resonator, FBAR) be it is a kind of using film and
The high-frequency reonsator of micro-nano technology fabrication techniques, converts electric energy to sound wave by the inverse piezoelectric effect of piezoelectric membrane and forms humorous
Shake, when the physical quantitys such as the quality in membrane resonant regional environment, density, viscosity change, FBAR resonant frequency can be sent out
Raw skew, recycles peripheral radio frequency (RF) oscillating circuit to can detect that this skew to realize to environmental quality, density, viscosity
Etc. the detection of physical quantity.FBAR is because small volume, cost are low, quality factor (Q) are high, frequency high (up to 1-10GHz), to be measured
The features such as thing sensitivity height and integrated circuit (IC) technical compatibility, gas sensor and bio-sensing are had been applied in recent years
The various fields such as device.
The invention discloses a kind of biomolecule detection devices, including it is integrated in the detection unit being isolated on same substrate
And reference cell, detection unit and reference cell include piezoelectric membrane, sensitive layer and the gel layer being sequentially stacked, wherein：
Gel layer, for storing the tissue fluid containing biomolecule to be detected；
The sensitive layer of detection unit and reference cell is differed only in, and the sensitive layer energy specific recognition of detection unit treats
Biomolecule is detected, the distribution of biomolecule to be detected in the tissue fluid for changing detection unit storage；
Piezoelectric membrane, for the distribution in response to biomolecule to be detected, obtains a frequency signal；
The difference for the frequency signal that biomolecule detection devices are obtained according to detection unit and reference cell, analysis obtains group
Knit the concentration of biomolecule to be detected in liquid.
Wherein, detection unit is identical with the environment to be detected that reference cell is contacted.
Due to the sensitive layer that differs only in of detection unit in the present invention and reference cell, and sensitive layer is differed only in
Whether can specific recognition biomolecule to be detected, therefore the difference of final frequency signal that two units are obtained only is by treating
Detect caused by biomolecule, therefore biomolecule to be detected in tissue fluid is obtained by asking difference to analyze two frequency signals
Concentration, this apparatus and method reduces influence of the noise to testing result that the detection process of complexity is introduced, so that greatly
Improve accuracy of detection；And because detection unit and reference cell are integrated on same substrate film, it is achieved that chip is whole
The miniaturization of body.Again because the sensitive layer using energy specific recognition biomolecule to be detected substitutes the biology in electrochemical means
Enzyme, therefore higher selectivity can be provided, and the robustness of detection means can be strengthened, increase the service life.
In some embodiments of the invention, substrate film is silica or silicon nitride or oxidation nitridation mix insulation layer.
In some embodiments of the invention, above-mentioned detection unit and reference cell also include：
Top electrode between piezoelectric membrane and sensitive layer；
Group of the ion reverse electro-osmotic extraction containing biomolecule to be detected is carried out by applying DC voltage to top electrode
Liquid is knitted, the obtained tissue fluid containing biomolecule to be detected is extracted and is stored in gel layer.
Gel layer can not only provide good adhesive force but also can store the tissue fluid extracted.In two iontophoresis electricity
The direct current of the sizes such as extremely upper alternately application etc. duration, such as be that negative pole applies direct current in first half cycle using a as positive pole b,
Then reversion electrode by negative pole of a by positive pole of b within the later half cycle apply etc. size direct current, so repeat it is lasting one timing
Between positive and negative alternate square wave current is provided, can so improve the efficiency of ion reverse electro-osmotic while ensure that iontophoresis
Same amount of tissue fluid is extracted on two electrodes.
Top electrode is the metallic film sputtered on piezoelectric membrane, and the metal material can be the metallic conduction materials such as gold or platinum
Material, can also be made up of the material of carbon nano-tube film or other high conduction performances, top electrode can also be it is above-mentioned a kind of or
Person's multiple material is composited.
In some embodiments of the invention, the material of above-mentioned gel layer includes synthesis macromolecule hydrogel or natural polymer
Sub- hydrogel.
In some embodiments of the invention, above-mentioned detection unit and reference cell also include：
Hearth electrode between substrate and piezoelectric membrane；
Cause piezoelectric membrane resonance by applying alternating voltage to top electrode and hearth electrode, piezoelectric membrane is in response to tissue fluid
In biomolecule to be detected distribution, obtain final frequency signal.
The material of above-mentioned hearth electrode is high conductivity metal material.
Therefore, because the knots modification for the frequency signal that the present embodiment is responded using piezoelectric membrane divides to characterize biology to be detected
The concentration of son, therefore only need to extract micro tissue fluid, it can both ensure human-body safety, it is to be detected to enable specific recognition again
The sensitive layer of biomolecule is difficult to saturation, exempts from desorption so can realize, is used repeatedly.
In some embodiments of the invention, the material of above-mentioned piezoelectric membrane includes inorganic piezoelectric material and organic piezoresistive material
Material, the piezoelectric such as can be ZnO or AlN, by sputtering, either depositing operation is grown on hearth electrode or grown
It is orientated along c-axis or forms certain slanted angle with c-axis.
In some embodiments of the invention, above-mentioned detection device also includes the thin substrates being located between substrate and hearth electrode
Film, for supporting detection unit and reference cell.
In some embodiments of the invention, above-mentioned detection device is by drawing negative electrode and drawing positive electrode and external electrical
Road carries out wire bonding connection, and the extraction positive electrode and extraction negative electrode are structure as a whole with top electrode and hearth electrode respectively.
In some embodiments of the invention, the substrate in above-mentioned detection device is corresponding with reference cell in detection unit
Position be hollow structure；The hollow structure is resonance chamber, and the presence of the resonance chamber can make accuracy and sensitivity more
Easily it is optimal.Wherein, substrate can be monocrystalline silicon piece.
In some embodiments of the invention, the substrate in above-mentioned detection device is corresponding with reference cell in detection unit
Position be formed with sound wave reflecting grating structure；The sound wave reflecting grating is Bragg reflection grid.By that acoustic impedance mismatch degree is big
Specular layer and the overlapping growth of silicon layer, can make resonance concentrate on piezoelectric membrane region as far as possible, so as to reduce acoustic loss, carry
High q-factor.
In some embodiments of the invention, the sensitive layer of above-mentioned detection unit matches with biomolecule to be detected.I.e.
The sensitive layer of different energy specific recognition biomolecule to be detected can be used according to the different choice of biomolecule to be detected, should
Sensitive layer is the thin polymer film that evident characteristics are selected with biomolecule, as molecule engram film.Using microsphere with
Polymer monomer polymerization process produces molecular memory, after microsphere is removed, is formd and microsphere space in polymer
The hole for the multiple action point that configuration matches.Molecule engram film possesses high sensitivity, selectivity, robustness and relatively
Long service life.Glucose molecule imprinted polymer films are selected by taking glucose molecule as an example, using the mode of plating by Portugal
Grape sugar imprinting micella is deposited on top electrode, by adjusting the parameters such as electroplating voltage, electric current, time on nanoscale
Accurately control the thickness and quality of sensitive layer.Molecular imprinting film can selectively be changed according to the heterogeneity of testing molecule
For biological enzyme membrane, antigen-antibody film, containing the single-minded Sexual behavior mode identification capture film such as specific DNA films.
To achieve these goals, as another aspect of the present invention, the present invention proposes a kind of biomolecule detection side
Method, using above-mentioned biomolecule detection devices, comprises the following steps：
Step 1, the tissue fluid containing biomolecule to be detected extracted in advance is stored in gel layer；
Biomolecule to be detected in step 2, the sensitive layer specific recognition tissue fluid of detection unit, and change to be detected
The distribution of biomolecule；
The frequency signal of step 3, the frequency signal to detection unit and reference cell seeks difference, and analysis is obtained in tissue fluid
The concentration of biomolecule to be detected.
In some embodiments of the invention, above-mentioned detection unit and reference cell, which have, is located at piezoelectric membrane and sensitive layer
Between top electrode；
Also include before step 1：Pretreatment goal skin area, detection unit and reference cell are while contact target skin
Region, tissue of the ion reverse electro-osmotic extraction containing biomolecule to be detected is carried out by applying DC voltage to top electrode
Liquid.
In some embodiments of the invention, a kind of biomolecule detecting method is proposed, is specially：Pass through pretreatment first
To improve the permeability of skin, the gel layer in above-mentioned biomolecule detection devices is then attached to pretreating skin region,
Apply appropriately sized DC voltage on the top electrode of two units and carry out Reverse iontophoresis thoroughly, it is noninvasive in certain time to carry
Tissue fluid is taken, then the tissue fluid extracted is stored in gel layer, and biomolecule detection devices then are departed from into skin.It is single in detection
The top electrode and hearth electrode of member and reference cell apply alternating voltage and cause piezoelectric membrane resonance.Tissue fluid is each in overall process
Into branch in gel layer free diffusing.Can be by molecule engram film (energy selectivity during molecules detected diffusion motion
Recognize the sensitive layer of biomolecule to be detected) recognize and fixation be finally reached balance, cause resonance range (piezoelectric membrane) mechanics
The change of physical quantity, and with it to load mechanical quantity linear for resonant frequency knots modification, so that indirect using frequency shift amount
Ground quantitative expression goes out the concentration information of molecules detected.Finally according to detection unit and the frequency-splitting of reference cell, ring is excluded
The disturbing factor change that temperature, water etc. are unrelated with molecules detected in border causes detection noise, obtains more accurately to be detected
Information.Biomolecule detection devices can continuously be used when molecule engram film is not reaching to saturation, with frequency shift amount
Information correspondence biomolecule concentration.
In some embodiments of the invention, need to locate target skin area in advance before noninvasive extraction tissue fluid
Reason, by target skin area chemical enhancement method, phonophoresis, electroporation, vacuum suction method through certain time etc. wherein
A kind of method effect or two kinds and two or more method collaboration processing, to improve skin in tissue fluid and tissue fluid
The permeability of testing molecule, to promote subsequent ion reverse electro-osmotic to extract tissue liquid with efficient in the short time.
In some embodiments of the invention, it can be attached to what is pre-processed using the gel layer on electrode when extracting tissue fluid
On skin area, gel layer can not only provide good adhesive force but also can store the tissue fluid extracted.In two iontophoresis
Replace the direct current of the sizes such as the durations such as application on transflective electrode, be such as that negative pole applies direct current in first half cycle using a as positive pole b
Electricity, then invert electrode by negative pole of a by positive pole of b within the later half cycle apply etc. size direct current, so repeat lasting one
Fix time to provide positive and negative alternate square wave current, can so improve the efficiency of ion reverse electro-osmotic while ensure that ion-conductance
Same amount of tissue fluid is extracted on two electrodes of infiltration.(ion reverse electro-osmotic) is needed after ion reverse electro-osmotic certain time
Gel layer is departed from into skin, now the various biomolecule in gel layer tissue fluid, for example glucose, antigen-antibody, DNA and certain
A little protein etc. can carry out free diffusing with hydrone in gel layer, and biomolecule free diffusing reaches within a certain period of time
Static balancing, so the biomolecule distribution now in gel layer is uniform in theory.
Biomolecule detection devices proposed by the present invention and method, its Cleaning Principle is：Due to the sensitive layer of detection unit
Function with energy specific recognition biomolecule to be detected, therefore understand molecules detected along concentration according to diffusion theory derivation
Diffusion is simultaneously enriched with sensitive layer.The piezoelectric membrane of specific recognition, when no biological molecule concentration is in sensitive layer,
It possesses certain definite value resonant frequency, when hydrone and molecules detected absorption in sensitive layer when, piezoelectric membrane mechanical quantity hair
It is raw to change, such as pressure, viscous force or Media density.Therefore the resonant frequency of piezoelectric membrane can shift, this frequency displacement
The load that value corresponds to piezoelectric membrane changes.This is also referred to as FBAR responses.
Using the identical detection unit of parameter and reference cell, modification can selectivity on the top electrode of detection unit
The sensitive layer of biomolecule to be detected is recognized, modification is unable to biological point to be detected of specific recognition on the top electrode of reference cell
The sensitive layer of the phase same material of son, allows two sensitive layers to contact the gel layer of the tissue fluid containing equal amount, two under identical environment
The resonant frequency of the piezoelectric membrane of unit can all shift, but their offset size can difference, this measures of dispersion
The concentration of molecules detected is only dependent upon, therefore can be dense come quantitatively characterizing molecules detected using the two offset differences
Degree.
Biomolecule detection devices proposed by the present invention and method are described in detail below by way of specific embodiment.
Embodiment 1
As shown in Fig. 1~2, the present embodiment proposes a kind of biomolecule detection devices 10, including detection unit 100 and reference
What unit 200, the detection unit 100 and reference cell 200 were isolated is integrated on same substrate 11 and same substrate film 12,
As shown in figure 1, wherein,
Substrate 11 has two resonance chambers 13 and 14 in detection unit 100 and the corresponding position of reference cell 200；
Detection unit 100 include be sequentially stacked the first hearth electrode 101, the first piezoelectric membrane 102, the first top electrode 103,
Sensitive layer 104, the first gel layer 105, first of energy specific recognition biomolecule to be detected are drawn top electrode 106 and first and drawn
Go out hearth electrode 107；
Reference cell 200 include be sequentially stacked the second hearth electrode 201, the second piezoelectric membrane 202, the second top electrode 203,
It is unable to the sensitive layer 204 of specific recognition biomolecule to be detected, the second gel layer 205, second and draws top electrode 206 and second
Draw hearth electrode 207.
Wherein the first gel layer 105 mutually combines together with the second gel layer 205.
The biomolecule detection devices 10 are a FBAR, as shown in Fig. 2 drawing top electricity by first
Draw the extraction extraction hearth electrode 207 of top electrode 206 and second of hearth electrode 107, second and drawn with external circuit in pole 106 and first
Line bonding is connected.And first draw top electrode 106 and first top electrode 103, the second extraction top electrode of top electrode 206 and second
203rd, first the hearth electrode 101, second of hearth electrode 107 and first extraction hearth electrode 207 and second hearth electrode 201 respectively one is drawn
Body structure.
By the pretreated skin of the laminating of gel layer 105 and 205 of biomolecule detection devices 10, to the first top electrode
103 and second top electrode 203 apply appropriately sized DC voltage and carry out Reverse iontophoresis thoroughly, it is noninvasive in certain time to extract
Tissue fluid, the tissue fluid of extraction is stored in gel layer 105 and 205, and biomolecule detection devices 10 then are departed from into skin, completes
The extraction of tissue fluid.
Apply alternating voltage to top electrode 103,203 and hearth electrode 101,201 so that the first piezoelectric membrane 102 and second
The resonance of piezoelectric membrane 202, then tissue fluid free diffusing in gel layer 105 and 205, understands by energy in free diffusing motion process
The sensitive layer 104 of specific recognition biomolecule to be detected is recognized and fixed, so that the mechanics thing of the first piezoelectric membrane 102
Reason amount changes, further such that the resonant frequency of the first piezoelectric membrane 102 changes, then according to the first piezoelectric membrane
102 and the difference of the resonant frequency of the second piezoelectric membrane 202, you can indirect quantitative expression goes out the dense of molecules detected in tissue fluid
Spend information.
Embodiment 2
As shown in figs. 34, the present embodiment proposes a kind of biomolecule detection devices, its structure and the biology in embodiment 1
Molecular detector arrangement is essentially identical, differs only in, and the basalis 11 in the present embodiment is in detection unit 100 and reference cell
200 corresponding positions have two Bragg-grating structures 15 and 16, so that resonance concentrates on FBAR resonance as far as possible
Area, reduces acoustic loss, so as to put forward high q-factor.
Particular embodiments described above, has been carried out further in detail to the purpose of the present invention, technical scheme and beneficial effect
Describe in detail bright, it should be understood that the foregoing is only the present invention specific embodiment, be not intended to limit the invention, it is all
Within the spirit and principles in the present invention, any modification, equivalent substitution and improvements done etc. should be included in the protection of the present invention
Within the scope of.
Claims (10)
1. a kind of biomolecule detection devices, including it is integrated in the detection unit being isolated on same substrate and reference cell, institute
Piezoelectric membrane, sensitive layer and gel layer that detection unit and reference cell include being sequentially stacked are stated, wherein：
Gel layer, for storing the tissue fluid containing biomolecule to be detected；
The sensitive layer of detection unit and reference cell is differed only in, the sensitive layer energy specific recognition institute of the detection unit
Biomolecule to be detected is stated, the distribution of biomolecule to be detected in the tissue fluid for changing the detection unit storage；
Piezoelectric membrane, for the distribution in response to the biomolecule to be detected, obtains a frequency signal；
The difference for the frequency signal that the biomolecule detection devices are obtained according to the detection unit and reference cell, is analyzed
The concentration of biomolecule to be detected into the tissue fluid.
2. biomolecule detection devices as claimed in claim 1, wherein, the detection unit and reference cell also include：
Top electrode between the piezoelectric membrane and sensitive layer；
Ion reverse electro-osmotic is carried out by applying DC voltage to the top electrode, extraction is described to contain biomolecule to be detected
Tissue fluid, extract the obtained tissue fluid containing biomolecule to be detected and be stored in the gel layer.
3. biomolecule detection devices as claimed in claim 2, wherein, the detection unit and reference cell also include：
Hearth electrode between the substrate and piezoelectric membrane；
Cause the piezoelectric membrane resonance, the piezoelectric membrane response by applying alternating voltage to the top electrode and hearth electrode
The distribution of biomolecule to be detected, obtains frequency signal in the tissue fluid.
4. biomolecule detection devices as claimed in claim 3, wherein：
The detection means is connected by drawing negative electrode and drawing positive electrode with external circuit progress wire bonding, the extraction
Positive electrode and extraction negative electrode are structure as a whole with the top electrode and hearth electrode respectively；
The detection means also includes the substrate film being located between the substrate and hearth electrode, for supporting the detection unit
And reference cell.
5. biomolecule detection devices as claimed in claim 1, wherein, the sensitive layer of the detection unit with it is described to be detected
Biomolecule matches, including molecular imprinting film, biological enzyme membrane, antigen-antibody film or the film containing specific DNA.
6. biomolecule detection devices as claimed in claim 1, wherein, the substrate is in the detection unit and reference cell
Corresponding position is hollow structure.
7. biomolecule detection devices as claimed in claim 1, wherein, the substrate is in the detection unit and reference cell
Corresponding position is formed with sound wave reflecting grating structure；The sound wave reflecting grating is Bragg reflection grid.
8. biomolecule detection devices as claimed in claim 1, wherein, the material of the gel layer includes synthesis macromolecule water
Gel or natural polymer hydrogel；The material of the piezoelectric membrane includes inorganic piezoelectric material and organic piezoelectric materials.
9. a kind of biomolecule detecting method, using the biomolecule detection devices as any one of claim 1 to 8,
Comprise the following steps：
Step 1, the tissue fluid containing biomolecule to be detected extracted in advance is stored in the gel layer；
The piezoelectric membrane of step 2, detection unit and reference cell in response to biomolecule to be detected in the tissue fluid distribution,
The frequency signal of detection unit and the frequency signal of reference cell are exported respectively；
The frequency signal of step 3, the frequency signal to the detection unit and reference cell seeks difference, and analysis obtains the tissue
The concentration of biomolecule to be detected in liquid.
10. biomolecule detecting method as claimed in claim 9, wherein, the detection unit and reference cell, which have, to be located at
Top electrode between the piezoelectric membrane and sensitive layer；
The detection method also includes before step 1：Pretreatment goal skin area, the detection unit and reference cell are same
When contact the target skin area, carrying out ion reverse electro-osmotic by applying DC voltage to the top electrode extracts described
Tissue fluid containing biomolecule to be detected.
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