CN102662088A - Method for platelet morphology scan imagery and platelet activation function evaluation - Google Patents
Method for platelet morphology scan imagery and platelet activation function evaluation Download PDFInfo
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- CN102662088A CN102662088A CN2012101568501A CN201210156850A CN102662088A CN 102662088 A CN102662088 A CN 102662088A CN 2012101568501 A CN2012101568501 A CN 2012101568501A CN 201210156850 A CN201210156850 A CN 201210156850A CN 102662088 A CN102662088 A CN 102662088A
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Abstract
The invention discloses a method for platelet morphology scan imagery and platelet activation function evaluation. The method for platelet morphology scan imagery comprises the following steps of: (1) preparing a platelet sample; (2) putting a reference electrode and an exploring electrode connected to a scanning ionic conductance microscope into a cell culture dish obtained by the step (1); and (3) monitoring the change of current flowing into the exploring electrode through the scanning ionic conductance microscope, enabling a setting distance to be kept between the jumping exploring electrode and a platelet through degeneration control, recording a position of the exploring element, and drawing to obtain a three-dimensional topology structure chart of platelet surface morphology through a computer. According to the method, the morphology performances of the platelet before and after adding an activating agent can be intuitively observed in real time, and not only can parameters such as the quantity of platelets and mean platelet volume within a scanning range be measured simply, conveniently, easily and accurately, but also the activation function of the platelet can be evaluated. The method is simple and convenient to operate, and is low in cost.
Description
Technical field
The present invention relates to the method for a kind of blood platelet form scanning imagery and elevated platelet activation assessment.
Background technology
Blood platelet is one of visible component that has in the blood specific morphosis and biochemical composition, and its major physiological function is to participate in blood coagulation and hemostasis.Blood platelet complex structure and individual difference are bigger, because of moving and be out of shape, often show as polymorphic.The blood platelet ovalize or the disc of normal condition in the blood circulation, about 2～4 microns of mean diameter.Blood platelet is subject to machinery, chemical stimulation and activation and cause form to change.When in a single day blood platelet contacts with wound face or activator, can be expanded into disk shape blood platelet, to increase the area of blood coagulation and hemostasis.Fibrin ferment, ADP, adrenaline and collagen etc. all are the activation of platelet agent.Any blood coagulation and hemostasis also all relate to hematoblastic activation, therefore detect the variation of blood platelet form under the activator effect through vitro real time, get final product the physiological function of evaluate platelet directly perceived.The method and the instrument kind that are used to detect the blood platelet form at present are more, and wherein the resolution of ordinary optical microscope and laser confocal microscope only can reach about 200 nanometers, can not satisfy the needs of blood platelet microscopic appearance high resolution observations.ESEM (SEM) is although have sufficiently high resolution; Handle to realize the electric conductivity of sample but need be cured with special blood platelet; This will certainly change even destroy the micromechanism of platelet surface, therefore is not fit to the hematoblastic observation of live body.And study the atomic force microscope (AFM) of strong instrument in the scanning probe microscopy family as the high resolving power bio-imaging; Be used to the three-dimensional topology structural research of blood platelet micromorphology; But because it utilizes the interaction force between probe tip and platelet membrane to carry out negative feedback control to realize scanning imagery; Scanning middle probe and live body hematoblastic slight contact inevitable; Not only can damage hematoblastic surface structure, its mechanicals efforts also can activate blood platelet and cause metamorphosis, therefore can not satisfy the needs of platelet activating agent effect front and back micromorphology imaging.
Need scan-probe to contact and the shortcoming of damaging or activate biological sample in order to overcome atomic force microscope with sample; The Hansma of University of California teaches and has invented contactless scan ion electricity in 1989 and lead microscopy (scanning ion conductance microscopy; SICM); Because the limitation of negative feedback control method at that time and placement technology is with not enough; Very thin glass microspheres pipe probe often all of a sudden contacts with sample when scanning and causes needle point or sample to damage, and a very long time of SICM technology after its invention is only applicable to smooth mylar scanning imagery.The SICM technology has realized under the liquid condition of culture of physiology real-time, contactlessly the detection to living body biological sample surfaces three-dimensional microcosmic structure through improving location and scan control technology in recent years.
Summary of the invention
The objective of the invention is to overcome the deficiency of prior art, a kind of method of blood platelet form scanning imagery is provided.
Second purpose of the present invention provides a kind of elevated platelet activation appraisal procedure.
Technical scheme of the present invention is summarized as follows:
A kind of method of blood platelet form scanning imagery comprises the steps:
(1) preparation of blood platelet sample
Get 2 milliliters of venous blood and put into the sodium citrate anticoagulant tube, obtain platelet rich plasma after centrifugal; Getting the said platelet rich plasma of 200 μ L is positioned over to be coated with in the fibrinogenic 35mm Tissue Culture Dish that 200 μ L concentration are 2mg/mL and hatched 20-30 minute under the room temperature; Do not stick to the blood platelet of said Tissue Culture Dish bottom with the PBS buffer solution elution after, subsequent use after the adding 1.5-2mLPBS damping fluid;
(2) will be connected the scan ion electricity leads microscopical Ag/AgCl contrast electrode and is placed in the Tissue Culture Dish that step (1) obtains; To be connected the scan ion electricity and lead the probe microscope electrode and be placed in the Tissue Culture Dish that step (1) obtains, said exploring electrode is one to be arranged on the Ag/AgCl electrode in the nanopipette that charges the PBS damping fluid;
(3) lead the microscope monitoring with the scan ion electricity and flow into the exploring electrode change in current; Through the distance that keeps between feasible exploring electrode that jumps of negative feedback control and blood platelet setting; Note the position of said exploring electrode, obtain the three-dimensional topology structural drawing of platelet surface pattern through computer drawing.
A kind of elevated platelet activation appraisal procedure comprises the steps:
(1) preparation of blood platelet sample
Get 2 milliliters of venous blood and put into the sodium citrate anticoagulant tube, obtain platelet rich plasma after centrifugal; Get the said platelet rich plasma of 200 μ L and be positioned over that to be coated with 200 μ L concentration be to hatch 20-30 minute under the room temperature in the fibrinogenic 35mm Tissue Culture Dish of 2mg/mL; Do not stick to the blood platelet of said Tissue Culture Dish bottom with the PBS buffer solution elution after, subsequent use after the adding 1.5-2mLPBS damping fluid;
(2) will be connected the scan ion electricity leads microscopical Ag/AgCl contrast electrode and is placed in the Tissue Culture Dish that step (1) obtains; To be connected the scan ion electricity and lead the probe microscope electrode and be placed in the Tissue Culture Dish that step (1) obtains, said exploring electrode is one to be arranged on the Ag/AgCl electrode in the nanopipette that charges the PBS damping fluid;
(3) lead the microscope monitoring with the scan ion electricity and flow into the exploring electrode change in current; Through the distance that keeps between feasible exploring electrode that jumps of negative feedback control and blood platelet setting; Note the position of said exploring electrode, obtain the three-dimensional topology structural drawing of platelet surface pattern through computer drawing;
(4) in Tissue Culture Dish, add activator again, act on 10-20 minute, obtain adding the three-dimensional topology structural drawing of said activator 10-20 minute platelet surface pattern through computer drawing.
Said activator is fibrin ferment or ADP, and the addition of said fibrin ferment is that to make the final concentration of fibrin ferment be 2U/mL, and the addition of said ADP is that to make the final concentration of ADP be 5 μ M.
Activator can also be selected adrenaline or collagen, and its concentration can be regulated according to actual conditions.
The method of a kind of blood platelet form of the present invention scanning imagery and a kind of elevated platelet activation appraisal procedure; Can observe intuitively in real time and add the hematoblastic morphology performance in activator front and back; Not only platelet counts (PLT) and mean platelet volume morphological parameters such as (MPV) in the precise determination sweep limit quickly and easily more can change the mobilizing function that comes evaluate platelet through the activation form of above-mentioned blood platelet behind the interpolation activator.This detection method dispense with dyeing and any special processing more need not expensive reagent, and easy and simple to handle.
Description of drawings
Figure 1A obtains the three-dimensional topology structural drawing of platelet surface pattern for the embodiment 1 of computer drawing.
Figure 1B obtains the three-dimensional topology structural drawing of platelet surface pattern for the embodiment 2 of computer drawing.
Embodiment
Embodiment 1
A kind of method of blood platelet form scanning imagery comprises the steps:
(1) preparation of blood platelet sample
Extract 2 milliliters of venous blood of healthy subjects and put into the sodium citrate anticoagulant tube, 150 * g obtained platelet rich plasma in centrifugal 15 minutes; Getting the said platelet rich plasma of 200 μ L is positioned over to be coated with in the 35mm Tissue Culture Dish that 200 μ L concentration are the 2mg/mL human fibrinogen and hatched 30 minutes under the room temperature; Do not stick to the blood platelet of said Tissue Culture Dish bottom with the PBS buffer solution elution after, subsequent use after the adding 1.5mL PBS damping fluid;
(2) will be connected the scan ion electricity leads microscopical Ag/AgCl contrast electrode and is placed in the Tissue Culture Dish that step (1) obtains; To be connected the scan ion electricity and lead the probe microscope electrode and be placed in the Tissue Culture Dish that step (1) obtains, said exploring electrode is one to be arranged on the Ag/AgCl electrode in the nanopipette that charges the PBS damping fluid;
(3) lead the microscope monitoring with the scan ion electricity and flow into the exploring electrode change in current; Make the constant distance that keeps between the exploring electrode that jumps and blood platelet setting (be exploring electrode any physics does not take place contact) through negative feedback control with blood platelet; Note the position (noting the position of the needle point of exploring electrode when in sweep limit, reaching) of said exploring electrode apart from the platelet surface setpoint distance; Obtain the three-dimensional topology structural drawing of platelet surface pattern through computer drawing; See Figure 1A, and can accurately obtain in the sweep limit platelet counts (PLT) be 20 and mean platelet volume (MPV) to lead the analytical calculation of microscope PaintShop through the scan ion electricity be 9.93fL.
Embodiment 2
A kind of elevated platelet activation appraisal procedure comprises the steps:
(1)-(3) with (1)-(3) of embodiment 1;
(4) in Tissue Culture Dish, add the activator fibrin ferment again; The final concentration that makes fibrin ferment is 2U/mL effect 10 minutes; Utilize the SICM technology to add fibrin ferment after 10 minutes live body platelet surface pattern observe: flow into the exploring electrode change in current with the SICM controller monitoring; Make exploring electrode and blood platelet keep constant distance through negative feedback control; Exploring electrode is at the track of cell surface and adds finite concentration activator hematoblastic surface three dimension topological structure of live body after 10 minutes, and the hematoblastic quantity of disk shape after accurately obtaining to activate; Obtain adding the three-dimensional topology structural drawing of thrombin blood platelet surface topography, (seeing Figure 1B, 50 * 50 μ m) through computer drawing.Be launched into the disk shape behind the platelet activation, comparing before disk shape platelet counts and the activator effect has increased by 2.5 times.）
Utilize the variation of SICM image processing and analyzing software comparison activator effect front and back blood platelet pattern to assess its mobilizing function.
Embodiment 3
A kind of method of blood platelet form scanning imagery comprises the steps:
(1) preparation of blood platelet sample
Get 2 milliliters of venous blood and put into the sodium citrate anticoagulant tube, obtain platelet rich plasma after centrifugal; Getting the said platelet rich plasma of 200 μ L is positioned over to be coated with in the 35mm Tissue Culture Dish that 200 μ L concentration are the 2mg/mL human fibrinogen and hatched 20 minutes under the room temperature; Do not stick to the blood platelet of said Tissue Culture Dish bottom with the PBS buffer solution elution after, subsequent use after the adding 2mL PBS damping fluid;
(2) with (2) of embodiment 1;
(3) lead the microscope monitoring with the scan ion electricity and flow into the exploring electrode change in current; Make the constant distance that keeps between the exploring electrode that jumps and blood platelet setting (be exploring electrode any physics does not take place contact) through negative feedback control with blood platelet; Note the position (noting the position of the needle point of exploring electrode when in sweep limit, reaching) of said exploring electrode apart from the platelet surface setpoint distance; Obtain the three-dimensional topology structural drawing of platelet surface pattern through computer drawing, to obtain the three-dimensional topology structural drawing of platelet surface pattern similar for the computer drawing that passes through of this figure and embodiment 1.
Embodiment 4
A kind of method of blood platelet form scanning imagery comprises the steps:
(1) preparation of blood platelet sample
Get 2 milliliters of venous blood and put into the sodium citrate anticoagulant tube, obtain platelet rich plasma after centrifugal; Getting the said platelet rich plasma of 200 μ L is positioned over to be coated with in the 35mm Tissue Culture Dish that 200 μ L concentration are the 2mg/mL human fibrinogen and hatched 30 minutes under the room temperature; Do not stick to the blood platelet of said Tissue Culture Dish bottom with the PBS buffer solution elution after, subsequent use after the adding 2mL PBS damping fluid;
(2) with (2) of embodiment 1;
(3) lead the microscope monitoring with the scan ion electricity and flow into the exploring electrode change in current; Make the constant distance that keeps between the exploring electrode that jumps and blood platelet setting (be exploring electrode any physics does not take place contact) through negative feedback control with blood platelet; Note the position (noting the position of the needle point of exploring electrode when in sweep limit, reaching) of said exploring electrode apart from the platelet surface setpoint distance; Obtain the three-dimensional topology structural drawing of platelet surface pattern through computer drawing, to obtain the three-dimensional topology structural drawing of platelet surface pattern similar for the computer drawing that passes through of this figure and embodiment 1.
Embodiment 5
A kind of elevated platelet activation appraisal procedure comprises the steps:
(1)-(3) with (1)-(3) of embodiment 1;
(4) in Tissue Culture Dish, add ADP again, the final concentration that makes ADP is 5 μ M effects 20 minutes, obtains adding the three-dimensional topology structural drawing of 20 minutes platelet surface patterns of ADP through computer drawing.The three-dimensional topology structural drawing of said platelet surface pattern is similar with the three-dimensional topology structural drawing of the platelet surface pattern of embodiment 2.
The final concentration that experiment showed, activator fibrin ferment or ADP is done suitably adjustment, also can be used for the present invention.
Experiment showed, and select for use adrenaline or collagen to make activator, also can be used for the present invention.
Measure the resistance 110M Ω of exploring electrode through commercial patch clamp technique.
After configuring sweep parameter through the SICM scanning software; Make exploring electrode move closer to blood platelet through negative feedback control; And finally reach the state that exploring electrode and blood platelet keep constant distance; Should monitor simultaneously and flow into the exploring electrode change in current, to monitor whole stability near process.When exploring electrode reaches in control state, can begin the blood platelet pattern is carried out scanning imagery, its track of passing by is the three-dimensional topology structure (seeing Fig. 2 A, 50 * 50 μ m) of orthoplastocyte.Lead in the three-dimensional topology image of microscope blood platelet pattern at the scan ion electricity, the platelet counts (PLT) that can accurately obtain in sweep limit is 20 (seeing Figure 1A); It is 9.93fL that these hematoblastic mean platelet volumes (MPV) are led the analytical calculation of microscope PaintShop through the scan ion electricity.
After scanning is accomplished, add the platelet activating agent fibrin ferment, its final concentration is 2U/mL, and be 10 minutes action time, scans again, can obtain by the three-dimensional topology structure of blood platelet pattern behind the thrombin activation (seeing Figure 1B, 50 * 50 μ m).Be launched into the disk shape behind the platelet activation, comparing before disk shape platelet counts and the activator effect has increased by 2.5 times.
Scan ion electricity of the present invention is led microscope and is adopted Britain ionscope company scan ion electricity to lead microscope and image processing software.
The scan ion electricity is led microscope and is comprised that the scan ion electricity leads microscope scanner head, scanning monitor and formations such as signal acquisition process device, piezoelectric ceramics power supply and driver, is used for the real time record blood platelet in the variation that adds microscopic appearance before and after the finite concentration activator.
The liquid external scanning circumstance of above-mentioned said physiology is the PBS damping fluid.
The nanopipette of above-mentioned said composition exploring electrode (borosilicate or quartzy microelectrode glass capillary) draws the appearance drawing by microprobe and forms.
Claims (3)
1. the method for a blood platelet form scanning imagery is characterized in that comprising the steps:
(1) preparation of blood platelet sample
Get 2 milliliters of venous blood and put into the sodium citrate anticoagulant tube, obtain platelet rich plasma after centrifugal; Getting the said platelet rich plasma of 200 μ L is positioned over to be coated with in the fibrinogenic 35mm Tissue Culture Dish that 200 μ L concentration are 2mg/mL and hatched 20-30 minute under the room temperature; Do not stick to the blood platelet of said Tissue Culture Dish bottom with the PBS buffer solution elution after, subsequent use after the adding 1.5-2mLPBS damping fluid;
(2) will be connected the scan ion electricity leads microscopical Ag/AgCl contrast electrode and is placed in the Tissue Culture Dish that step (1) obtains; To be connected the scan ion electricity and lead the probe microscope electrode and be placed in the Tissue Culture Dish that step (1) obtains, said exploring electrode is one to be arranged on the Ag/AgCl electrode in the nanopipette that charges the PBS damping fluid;
(3) lead the microscope monitoring with the scan ion electricity and flow into the exploring electrode change in current; Through the distance that keeps between feasible exploring electrode that jumps of negative feedback control and blood platelet setting; Note the position of said exploring electrode, obtain the three-dimensional topology structural drawing of platelet surface pattern through computer drawing.
2. an elevated platelet activation appraisal procedure is characterized in that comprising the steps:
(1) preparation of blood platelet sample
Get 2 milliliters of venous blood and put into the sodium citrate anticoagulant tube, obtain platelet rich plasma after centrifugal; Get the said platelet rich plasma of 200 μ L and be positioned over that to be coated with 200 μ L concentration be to hatch 20-30 minute under the room temperature in the fibrinogenic 35mm Tissue Culture Dish of 2mg/mL; Do not stick to the blood platelet of said Tissue Culture Dish bottom with the PBS buffer solution elution after, subsequent use after the adding 1.5-2mLPBS damping fluid;
(2) will be connected the scan ion electricity leads microscopical Ag/AgCl contrast electrode and is placed in the Tissue Culture Dish that step (1) obtains; To be connected the scan ion electricity and lead the probe microscope electrode and be placed in the Tissue Culture Dish that step (1) obtains, said exploring electrode is one to be arranged on the Ag/AgCl electrode in the nanopipette that charges the PBS damping fluid;
(3) lead the microscope monitoring with the scan ion electricity and flow into the exploring electrode change in current; Through the distance that keeps between feasible exploring electrode that jumps of negative feedback control and blood platelet setting; Note the position of said exploring electrode, obtain the three-dimensional topology structural drawing of platelet surface pattern through computer drawing;
(4) in Tissue Culture Dish, add activator again, act on 10-20 minute, obtain adding the three-dimensional topology structural drawing of said activator 10-20 minute platelet surface pattern through computer drawing.
3. a kind of elevated platelet activation appraisal procedure according to claim 2; It is characterized in that said activator is fibrin ferment or ADP; The addition of said fibrin ferment is that to make the final concentration of fibrin ferment be 2U/mL, and the addition of said ADP is that to make the final concentration of ADP be 5 μ M.
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2000063736A2 (en) * | 1999-04-19 | 2000-10-26 | Imperial College Innovations Limited | Optical microscopy and its use in the study of cells |
| WO2007042776A1 (en) * | 2005-10-07 | 2007-04-19 | Imperial College Innovations Limited | Modulators of the purinergic signalling pathway for treating sodium homeostatsis, hypertension and aldosteronism |
| CN102071135A (en) * | 2009-11-20 | 2011-05-25 | 国家纳米技术与工程研究院 | High resolution patch clamp based on scanning probe microscopy technology and operating method thereof |
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Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2000063736A2 (en) * | 1999-04-19 | 2000-10-26 | Imperial College Innovations Limited | Optical microscopy and its use in the study of cells |
| WO2007042776A1 (en) * | 2005-10-07 | 2007-04-19 | Imperial College Innovations Limited | Modulators of the purinergic signalling pathway for treating sodium homeostatsis, hypertension and aldosteronism |
| CN102071135A (en) * | 2009-11-20 | 2011-05-25 | 国家纳米技术与工程研究院 | High resolution patch clamp based on scanning probe microscopy technology and operating method thereof |
Non-Patent Citations (2)
| Title |
|---|
| YURI E. KORCHEV, ET AL.: "Hybrid Scanning Ion Conductance and Scanning Near-Field Optical Microscopy fort the Study of Living Cells", 《BIOPHYSICAL JOURNAL》 * |
| 纪天容 等: "扫描离子电导显微镜的原理及应用", 《分析化学》 * |
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