CN107036738A - A kind of blood platelet Micro-force sensor of the elastic film variable capacitance based on nanometer technique - Google Patents
A kind of blood platelet Micro-force sensor of the elastic film variable capacitance based on nanometer technique Download PDFInfo
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- G—PHYSICS
- G01—MEASURING; TESTING
- G01L—MEASURING FORCE, STRESS, TORQUE, WORK, MECHANICAL POWER, MECHANICAL EFFICIENCY, OR FLUID PRESSURE
- G01L1/00—Measuring force or stress, in general
- G01L1/14—Measuring force or stress, in general by measuring variations in capacitance or inductance of electrical elements, e.g. by measuring variations of frequency of electrical oscillators
- G01L1/142—Measuring force or stress, in general by measuring variations in capacitance or inductance of electrical elements, e.g. by measuring variations of frequency of electrical oscillators using capacitors
- G01L1/148—Measuring force or stress, in general by measuring variations in capacitance or inductance of electrical elements, e.g. by measuring variations of frequency of electrical oscillators using capacitors using semiconductive material, e.g. silicon
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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
- A61B5/22—Ergometry; Measuring muscular strength or the force of a muscular blow
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Abstract
The present invention relates to a kind of blood platelet Micro-force sensor of the elastic film variable capacitance based on nanometer technique.The blood platelet Micro-force sensor is parallel plate variable capacitor device, including the positive plate above and underlying minus plate being parallel to each other；Anode golden film and anode of the lateral surface of positive plate provided with tubbiness draw metering contact, and anode working face is provided with silicone intermediate material layer, and the inner bottom surface of the anode golden film of tubbiness is provided with people's fibronectin white；The cathodic work piece of the minus plate draws metering contact composition provided with negative electrode golden film and negative electrode.Inventive sensor can carry out quick and easy and directly measurement to blood platelet convergent force, this global problem is detected to solve blood platelet middle and later periods feature, to be studied deeper into ground hematoblastic physiology and pathological disorders, for early detection platelet function abnormality, instructing blood platelet anticoagulant to develop and illustrate the formation mechenism of relevant disease, there is provided necessary technical equipment.
Description
Technical field
The invention belongs to technical field of medical instruments, it is related to a kind of for the new of fast qualitative detection blood platelet comprehensive function
The micro-nano at-once monitor sensor of type.
Background technology
Blood platelet is as cell minimum in human body, except playing vital make on normal physiological haemostasis
With in pathologic thrombus formation and the role that key is similarly play in Atherosclerosis.As shown in fig. 6, blood is small
The signal that plate is activated after skin injury, wherein：(a) when the endothelial layer on vascular wall breakage does not occur, at blood platelet
In unactivated state；(b) when endothelial layer occurs damaged, blood platelet is quickly activated, and adheres to the cell of damaged part
In epimatrix；(c) blood platelet being activated can increase surface area, the impaired vascular wall of covering by changing own form；(d)
The blood platelet being activated can secrete procoagulant Factor, activate more blood platelets；(e) aggregation of the numerous blood platelets being activated loosely
Tampon is formed, the quick effect temporarily stopped blooding is reached；(f) blood platelet produces convergent force, makes loose tampon become to compact,
So as to play the effect of thorough prolonged hemostasis.If the convergent force produced is not big enough, blood platelet is played in hemostasis
Effect is extremely limited, and the tampon of relaxation easily comes off from impaired vascular wall, not only results in affected part again
Bleeding, can also induce other positions and embolism occur；Opposite, if blood platelet convergent force exceedes normal range (NR), in excessive living
Blood platelet under jump state can generate excessive tampon, trigger thrombus.
Increasing experiment shows that blood platelet convergent force has huge dive in terms of quantitative comprehensive assessment blood platelet work(
Power.But blood platelet progress feature is detected in the world still depend on measurement blood platelet in the sound that stops blooding with research at present
The viscoelasticity characteristic of some mid-early stage indexs and tampon during answering（Such as LTA, VerifyNow P2Y12 Assay,
Platelet function Analyzer of Plateletworks, Impact-R, PFA 100 etc.）, lack and be directed to blood platelet function at the later stage
The assessment of performance, which has limited its application in scientific research and clinical diagnosis, it is difficult to which hematoblastic comprehensive function is provided
Conclusive strong conclusion.And the measurement to blood platelet convergent force depends on the detecting system of closed large scale at this stage, its
Measurement accuracy is low, and can not hematoblastic mechanical interaction phenomenon under the dynamic subcellular fraction yardstick of real-time monitored.
The content of the invention
The expression of middle and later periods platelet function is accurately measured from microcosmic angle in order to realize, the present invention provides a kind of
The blood platelet Micro-force sensor of elastic film variable capacitance based on nanometer technique.
A kind of blood platelet Micro-force sensor of the elastic film variable capacitance based on nanometer technique is that parallel-plate is variable
Capacitor, including the positive plate 1 and minus plate 2 being parallel to each other, positive plate 1 is above, minus plate 2 is located at lower section, and anode
The anode working face of plate 1 correspond to the anode working face of minus plate 2；
The positive plate 1 includes the anode body 11 of tabular, and the anode body 11 is provided with anode hole, the bottom hole of anode hole and
Hole wall constitutes anode material region 15 provided with anode material, the anode material region 15 by tubbiness anode golden film 31 and sun
Pole is drawn metering contact 32 and constituted, and the anode draws the one side that metering contact 32 is located at anode body 11；Anode body 11
Another side be anode working face, anode working face be provided with silicone intermediate material layer；
The bottom surface of anode hole inner anode golden film is provided with people's fibronectin white；
The minus plate 2 includes the cathodic body 21 of tabular, and the one side of cathodic body 21 corresponding with the bottom hole of anode hole is
Cathodic work piece, cathodic work piece is provided with cathode material region 22, and the cathode material region 22 is by negative electrode golden film 41 and the moon
Draw metering contact 42 and constitute in pole；
The material of the anode body 11 and cathodic body 21 is silicon chip；
Spacing between the anode working face and cathodic work piece is 10 microns -1000 microns；
During test, directly platelet suspension to be detected is dropped in the anode golden film 31 of tubbiness in the anode hole of positive plate 1,
Anode is drawn into metering contact 32 simultaneously and negative electrode draws the electric capacity shelves that metering contact 42 connects electric impedance analyzer respectively, according to impedance
The capacitance variation rate that analyzer is measured, converses hematoblastic coagulability.
The technical scheme further limited is as follows：
The thickness of the anode body 11 and the thickness of cathodic body 21 are 400-1000 microns.
The aperture of the anode hole is 50 microns ~ 500 microns.
The bottom surface of the anode golden film 31 of the tubbiness is the arc surface raised up.
The thickness of the anode golden film 31 and the thickness of negative electrode golden film 41 are 100nm.
The thickness of the silicone intermediate material layer 14 is 10nm, and silicone intermediate material is dimethyl siloxane
（PDMS）.
The thickness of people's fibronectin white is 50nm.
10% of the area of negative electrode golden film 41 at least above the bottom area of anode golden film 31 of tubbiness.
Preparing the blood platelet Micro-force sensor of the elastic film variable capacitance based on nanometer technique includes positive plate
The big process of making two with minus plate is made, concrete operation step is as follows：
First, positive plate makes
Step（1）：Use low-pressure chemical vapor deposition（LPVCD）Method, in the two sides of anode body 11 of a piece of twin polishing
The silicon nitride thick upper 50nm of plating respectively（SiN）Silicon nitride film 12 and lower silicon nitride film 13 in film, formation；
Step（2）：Use standard ultraviolet photolithographic technology（UV Photolithography）With reaction equation ion etching technology
（Reactive Ion Etching, RIE）, several a diameter of 2mm anode hole is etched on upper silicon nitride film 12,
Anode body 11 is exposed；
Step（3）：The thick dimethyl-silicons of 10um are plated with spin coating hotplate technology on the lower silicon nitride film 13 of anode body 11
Oxygen alkane material layer（PDMS）14；
Step（4）：Use sodium hydroxide（KOH）Wet etching technique etches away the material of anode body 11 in anode hole；
Step（5）：In order to reduce the probability of breakage of thin film applied, yields is improved, using deep reaction equation ion etching technology（Deep
Reactive Ion Etching, DRIE）Remaining last in the remainder and anode hole of silicon nitride film 12 in removal
Partial silicon nitride 13, still, not insertion dimethyl siloxane material layer（PDMS）14；
Step（6）：By electron beam evaporation deposition technology, the golden film formation anode material of 100nm thickness is plated in anode hole
Region 15, anode material region 15 the anode golden film 31 of tubbiness and anode in anode hole are drawn metering contact 32 and constituted, wherein
Anode draws the anode working face that metering contact 32 is located at anode body 11；
Step（7）：Bioactive process processing is carried out to the lower surface in the anode golden film 31 of tubbiness, people's fibronectin is coated with
White (Human Fibrinogen) 16；Positive plate 1 is completed to make；
2nd, minus plate makes
Step（8）：Electronics evaporation coating techniques are used on the cathodic work piece of cathodic body 21, plating last layer 100nm thickness
Cathode material region 22, cathode material region 22 includes negative electrode golden film 41 and negative electrode is drawn metering contact 42 and constituted；
Step（9）：One layer of photoresist sensitive to UV light is uniformly coated on cathode material region 22 with spin coating hotplate technology
Layer；
Step（10）：With standard ultraviolet photolithographic technology, the predetermined pattern on photoresist layer, on the predetermined pattern and positive plate 1
Anode hole hole shape it is consistent, and spatially in correspondence with each other with aliging；
Step（11）：The gold not being photo-etched beyond the predetermined pattern that glue is protected is removed with chloroazotic acid, the He of negative electrode golden film 41 is retained
Negative electrode draws metering contact 42；
Step（12）：The photoresist that liquid will be covered in lower negative electrode golden film 41 and negative electrode extraction metering contact 42 is removed with photoresist
Remove, complete minus plate 2 and make；
3rd, the assembling of blood platelet Micro-force sensor
By the dimethyl siloxane material layer of positive plate 1（PDMS）14 corresponding matchings are located at the cathode material region 22 of minus plate 2
Top, that is, obtain blood platelet Micro-force sensor.
The advantageous effects of the present invention embody in the following areas：
1st, the research of micro-nano biological Micro-force sensor and blood platelet convergent force is combined by the present invention, it is intended to which fast quantification is assessed
Hematoblastic comprehensive function.
2nd, nowadays to platelet function detection and blood platelet physiology and pathology Journal of Sex Research are all seriously limited by experiment
The precision of detection device, the biological micro- power of the condenser type fexible film produced by micro-nano processing technology proposed by the present invention is passed
Sensor, can realize and carry out quantitative quickly measurement from microcosmic to blood platelet convergent force, be early detection platelet function abnormality,
Blood platelet anticoagulant is instructed to develop and illustrate the formation mechenism of relevant disease there is provided necessary technical equipment and establish certain
Theoretical and experiment basis.
3rd, blood platelet convergent force using to be carried out the new of comprehensive evaluating by smooth development of the invention as to platelet function
Clinical criteria necessary theoretical foundation and experimental result are provided.
Brief description of the drawings
Fig. 1 is inventive sensor structural representation.
Fig. 2 is the manufacturing process schematic diagram of sensor anode.
Fig. 3 is the top view in sensor anode working face.
Fig. 4 is the top view of sensor cathode working face.
The schematic diagram of convergent force when Fig. 5 is present invention measurement coagulating platelets.
Fig. 6 is the schematic diagram that blood platelet is activated after skin injury.
Sequence number in Fig. 1-5：Positive plate 1, minus plate 2, anode body 11, upper silicon nitride film 12, lower silicon nitride film 13,
Dimethyl siloxane material layer 14, anode material region 15, people's fibronectin white 16,17,18, anode golden film 31, anode
Draw metering contact 32, cathodic body 21, cathode material region 22, negative electrode golden film 41, negative electrode extraction metering contact 42.
Embodiment
With reference to embodiment, the present invention is further described.
Referring to Fig. 1, a kind of blood platelet Micro-force sensor of the elastic film variable capacitance based on nanometer technique is flat
Andante variable condenser, including the positive plate 1 and minus plate 2 being parallel to each other, under positive plate 1 is above, minus plate 2 is located at
Side, and the anode working face of positive plate 1 correspond to the anode working face of minus plate 2, between anode working face and cathodic work piece
Spacing be 500 microns.
Referring to Fig. 1 and Fig. 3, positive plate 1 includes the anode body 11 of tabular, and anode body 11 is provided with anode hole, anode
The aperture in hole is 250 microns.The bottom hole and hole wall of anode hole are provided with the anode material region 15 that anode material is constituted；Anode material
Material region 15 is drawn metering contact 32 by the anode golden film 31 and anode of tubbiness and constituted, and the bottom surface of anode golden film 31 is to raise up
Arc surface, the thickness of anode golden film 31 is 100nm.Anode draws the one side that metering contact 32 is located at anode body 11；Sun
The another side of pole body 11 is anode working face, and anode working face is provided with silicone intermediate material layer 14, organosilicon
The thickness of mesosome material layer 14 is 10nm, and silicone intermediate material is dimethyl siloxane（PDMS）.
The bottom surface of anode hole inner anode golden film is provided with people's fibronectin white 16, and the thickness of people's fibronectin white 16 is
50nm。
Referring to Fig. 1 and Fig. 4, minus plate 2 includes the cathodic body 21 of tabular, cathodic body corresponding with the bottom hole of anode hole
21 one side is cathodic work piece, and cathodic work piece is provided with cathode material region 22, and cathode material region 22 is by negative electrode gold
Film 41 and negative electrode are drawn metering contact 42 and constituted, and the thickness of negative electrode golden film 41 is 100nm, the area of negative electrode golden film 41 at least above
The 10% of the bottom area of anode golden film 31 of tubbiness.
The material of anode body 11 and cathodic body 21 is silicon chip, and thickness is 800 microns.
Preparing the blood platelet Micro-force sensor of the elastic film variable capacitance based on nanometer technique includes positive plate
The big process of making two with minus plate is made, concrete operation step is as follows：
First, positive plate makes
Referring to Fig. 2, the operation for making positive plate is as follows：
Step（1）：Use low-pressure chemical vapor deposition（LPVCD）Method, in the two sides of anode body 11 of a piece of twin polishing
The silicon nitride thick upper 50nm of plating respectively（SiN）Silicon nitride film 12 and lower silicon nitride film 13 in film, formation.
Step（2）：Use standard ultraviolet photolithographic technology（UV Photolithography）With reaction equation ion etching technology
（Reactive Ion Etching, RIE）, several a diameter of 250 microns anodes are etched on upper silicon nitride film 12
Hole, is exposed anode body 11.
Step（3）：The thick diformazans of 10um are plated with spin coating hotplate technology on the lower silicon nitride film 13 of anode body 11
Radical siloxane material layer（PDMS）14.
Step（4）：Use sodium hydroxide（KOH）Wet etching technique etches away the material of anode body 11 in anode hole.
Step（5）：In order to reduce the probability of breakage of thin film applied, yields is improved, using deep reaction equation ion etching technology
（Deep Reactive Ion Etching, DRIE）It is remaining in the remainder and anode hole of silicon nitride film 12 in removal
Last part silicon nitride 13, still, not insertion dimethyl siloxane material layer（PDMS）14.
Step（6）：By electron beam evaporation deposition technology, the golden film formation anode of 100nm thickness is plated in anode hole
Material area 15, anode material region 15 the anode golden film 31 of tubbiness and anode in anode hole are drawn metering contact 32 and constituted,
Its Anodic draws the anode working face that metering contact 32 is located at anode body 11.
Step（7）：Bioactive process processing is carried out to the lower surface in the anode golden film 31 of tubbiness, thickness 50nm is coated with
People's fibronectin white (Human Fibrinogen) 16；Positive plate 1 is completed to make.
2nd, minus plate makes
Step（8）：Electronics evaporation coating techniques are used on the cathodic work piece of cathodic body 21, plating last layer 100nm thickness
Cathode material region 22, cathode material region 22 includes negative electrode golden film 41 and negative electrode is drawn metering contact 42 and constituted.
Step（9）：One layer of light sensitive to UV light is uniformly coated on cathode material region 22 with spin coating hotplate technology
Photoresist layer.
Step（10）：With standard ultraviolet photolithographic technology, the predetermined pattern on photoresist layer, the predetermined pattern and positive plate
The hole shape of anode hole on 1 is consistent, and spatially in correspondence with each other with aliging.
Step（11）：The gold not being photo-etched beyond the predetermined pattern that glue is protected is removed with chloroazotic acid, negative electrode golden film is retained
41 and negative electrode draw metering contact 42.
Step（12）：The light that liquid will be covered in lower negative electrode golden film 41 and negative electrode extraction metering contact 42 is removed with photoresist
Photoresist is removed, and is completed minus plate 2 and is made.
3rd, the assembling of blood platelet Micro-force sensor
By the dimethyl siloxane material layer of positive plate 1（PDMS）14 corresponding matchings are located at the cathode material region 22 of minus plate 2
Top, obtains blood platelet Micro-force sensor, and be placed on the support of acrylic material.
Typical case's application of the present invention is as follows
During for detecting, used simultaneously by a pair of blood platelet Micro-force sensors, one measures to biological micro- power, another
Then it is used as reference, influence of the experimental situation noise to biological micro-force measurement precision can be so reduced to greatest extent.Entirely
Experimentation is referring to Fig. 5, the principle of convergent force during blood platelet Micro-force sensor measurement coagulating platelets of the present invention, wherein：Fig. 5
（a）For the schematic diagram of an electric capacity；It is that processing is multiple on a silicon chip due to being micro-nano processing, in practical operation micro-nano to pass
Sensor electric capacity, Fig. 5（b）For the schematic diagram of 2 adjacent sensor capacitances on 1 silicon chip；Fig. 5（c）For platelet suspension
Instill the schematic diagram of a sensor capacitance.
During specific test, first platelet suspension is dropped in people's fibronectin white 16 of anode hole, measurement is now
Capacitance between sensor capacitance anode and negative electrode.Then coagulant is instilled on platelet suspension drop, waits platelet suspension
After drop solidification completely, due to hematoblastic convergent force, the dimethyl siloxane material layer 14 of anode hole bottom can be to enterprising one
Step is raised, and the negative electrode extraction metering contact 42 for now drawing metering contact 32 and minus plate 2 again by the anode of positive plate 1 is surveyed
Capacitance between quantity sensor capacitor anode and negative electrode.The size changed according to the capacitive differential measured twice, can be measured
The size of blood platelet clot retraction ability.
Claims (9)
1. a kind of blood platelet Micro-force sensor of the elastic film variable capacitance based on nanometer technique, it is characterised in that：Institute
Blood platelet Micro-force sensor is stated for parallel plate variable capacitor device, including the anode plate and cathode plate being parallel to each other, positive plate is located at
Top, minus plate are located at lower section, and the anode working face of positive plate correspond to the anode working face of minus plate；
The positive plate includes the anode body of tabular, and the anode body is provided with anode hole, the bottom hole and hole wall of anode hole
Drawn and surveyed by the anode golden film and anode of tubbiness in the anode material region constituted provided with anode material, the anode material region
Contact composition is measured, the anode draws the one side that metering contact is located at anode body；The another side of anode body is anode
Working face, anode working face is provided with silicone intermediate material layer；
The bottom surface of anode hole inner anode golden film is provided with people's fibronectin white；
The minus plate includes the cathodic body of tabular, and the one side of cathodic body corresponding with the bottom hole of anode hole is negative electrode work
Make face, cathodic work piece is provided with cathode material region, and the cathode material region is drawn measurement by negative electrode golden film and negative electrode and touched
Point composition；
The material of the anode body and cathodic body is silicon chip；
Spacing between the anode working face and cathodic work piece is 10 microns -1000 microns；
During test, directly platelet suspension to be detected is dropped in the anode golden film of tubbiness in the anode hole of positive plate, together
When anode drawn into metering contact and negative electrode draw the electric capacity shelves that metering contact connects electric impedance analyzer respectively, according to electric impedance analyzer
The capacitance variation rate measured, converses hematoblastic coagulability.
2. a kind of micro- power of the blood platelet of elastic film variable capacitance based on nanometer technique according to claim 1 is passed
Sensor, it is characterised in that：The thickness of the anode body and the thickness of cathodic body are 400-1000 microns.
3. a kind of micro- power of the blood platelet of elastic film variable capacitance based on nanometer technique according to claim 1 is passed
Sensor, it is characterised in that：The aperture of the anode hole is 50 microns ~ 500 microns.
4. a kind of micro- power of the blood platelet of elastic film variable capacitance based on nanometer technique according to claim 1 is passed
Sensor, it is characterised in that：The bottom surface of the anode golden film of the tubbiness is the arc surface raised up.
5. a kind of micro- power of the blood platelet of elastic film variable capacitance based on nanometer technique according to claim 1 is passed
Sensor, it is characterised in that：The thickness of the anode golden film and the thickness of negative electrode golden film are 100nm.
6. a kind of micro- power of the blood platelet of elastic film variable capacitance based on nanometer technique according to claim 1 is passed
Sensor, it is characterised in that：The thickness of the silicone intermediate material layer is 10nm, and silicone intermediate material is dimethyl-silicon
Oxygen alkane.
7. a kind of micro- power of the blood platelet of elastic film variable capacitance based on nanometer technique according to claim 1 is passed
Sensor, it is characterised in that：The thickness of people's fibronectin white is 50nm.
8. a kind of micro- power of the blood platelet of elastic film variable capacitance based on nanometer technique according to claim 1 is passed
Sensor, it is characterised in that：10% of the area of negative electrode golden film at least above the anode golden film bottom area of tubbiness.
9. prepare the method for the blood platelet Micro-force sensor described in claim any one of 1-8, it is characterised in that：Including positive plate
Making and minus plate the big process of making two, concrete operation step is as follows：
First, positive plate makes
Step（1）：Using low-pressure chemical vapor deposition method, plated respectively on the anode body two sides of a piece of twin polishing
Silicon nitride film and lower silicon nitride film in silicon nitride film thick 50nm, formation；
Step（2）：Using standard ultraviolet photolithographic technology and reaction equation ion etching technology, if being etched on upper silicon nitride film
Dry a diameter of 50 microns ~ 500 microns of anode hole, is exposed anode body；
Step（3）：The thick dimethyl siloxanes of 10um are plated with spin coating hotplate technology on the lower silicon nitride film of anode body
Material layer；
Step（4）：The anode body material in anode hole is etched away with sodium hydroxide wet etching technique；
Step（5）：In order to reduce the probability of breakage of thin film applied, yields is improved, is removed using deep reaction equation ion etching technology
Remaining last part silicon nitride in the remainder and anode hole of silicon nitride film, still, not insertion dimethyl siloxane
Material layer；
Step（6）：By electron beam evaporation deposition technology, the golden film formation anode material of 100nm thickness is plated in anode hole
Region, anode material region the anode golden film of tubbiness and anode in anode hole are drawn metering contact and constituted, and its Anodic is drawn
Metering contact is located at the anode working face of anode body；
Step（7）：Bioactive process processing is carried out to the lower surface in the anode golden film of tubbiness, people's fibronectin is coated with
Layer；Positive plate is completed to make；
2nd, minus plate makes
Step（8）：Electronics evaporation coating techniques are used on the cathodic work piece of cathodic body, the moon of last layer 100nm thickness is plated
Pole material area, cathode material region includes negative electrode golden film and negative electrode draws metering contact composition；
Step（9）：One layer of photoresist layer sensitive to UV light is uniformly coated on cathode material region with spin coating hotplate technology；
Step（10）：With standard ultraviolet photolithographic technology, the predetermined pattern on photoresist layer, on the predetermined pattern and positive plate
The hole shape of anode hole is consistent, and spatially in correspondence with each other with aliging；
Step（11）：The gold not being photo-etched beyond the predetermined pattern that glue is protected is removed with chloroazotic acid, negative electrode golden film and the moon is retained
Draw metering contact in pole；
Step（12）：The photoresist that removing liquid with photoresist will be covered in lower negative electrode golden film and negative electrode extraction metering contact is gone
Remove, complete minus plate and make；
3rd, the assembling of blood platelet Micro-force sensor
The dimethyl siloxane material layer corresponding matching of positive plate is located to the cathode material overlying regions of minus plate, that is, obtains blood
Platelet Micro-force sensor.
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