WO2019104754A1 - 一种确定凝血时间的方法及装置 - Google Patents

一种确定凝血时间的方法及装置 Download PDF

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WO2019104754A1
WO2019104754A1 PCT/CN2017/115866 CN2017115866W WO2019104754A1 WO 2019104754 A1 WO2019104754 A1 WO 2019104754A1 CN 2017115866 W CN2017115866 W CN 2017115866W WO 2019104754 A1 WO2019104754 A1 WO 2019104754A1
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lamb wave
wave sensor
determining
time
blood coagulation
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PCT/CN2017/115866
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English (en)
French (fr)
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周连群
孔慧
李传宇
张威
魏巍
周恒�
郭振
张芷齐
唐玉国
姚佳
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中国科学院苏州生物医学工程技术研究所
苏州国科芯感医疗科技有限公司
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Publication of WO2019104754A1 publication Critical patent/WO2019104754A1/zh

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    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N29/00—Investigating or analysing materials by the use of ultrasonic, sonic or infrasonic waves; Visualisation of the interior of objects by transmitting ultrasonic or sonic waves through the object
    • G01N29/02—Analysing fluids
    • G01N29/036—Analysing fluids by measuring frequency or resonance of acoustic waves
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2291/00—Indexing codes associated with group G01N29/00
    • G01N2291/02—Indexing codes associated with the analysed material
    • G01N2291/025—Change of phase or condition
    • G01N2291/0251—Solidification, icing, curing composites, polymerisation

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  • the invention relates to the technical field of blood coagulation detection, in particular to a method and a device for determining clotting time.
  • Blood Coagulation is a function of the process of changing blood from a flowing state to a non-flowable gel state, essentially the function of transforming soluble fibrinogen in plasma into insoluble fibrin.
  • Coagulation function test can understand the patient's abnormality of coagulation function before operation, and effectively prevent accidents such as bleeding during and after surgery, so as to obtain the best surgical results.
  • Chinese patent document CN 101983338 A discloses a blood coagulation detecting method, which uses a light source to illuminate a blood sample placed in a transparent test tube, obtains the transmitted light intensity in real time before and after the addition of the blood coagulation reagent, and estimates the blood coagulation test result according to the change of the transmitted light intensity.
  • the transmitted light intensity obtained by the above coagulation detecting method is easily affected by ambient light.
  • the coagulation detecting device must be provided with a barrier that blocks ambient light, and the light source and the transparent test tube containing the measuring sample are relatively large in volume.
  • the above-mentioned blood coagulation detecting method obtains the blood coagulation detection result by estimating the transmitted light intensity, and thus the measurement result has an error. If the acquisition of the transmitted light intensity is affected by the ambient light, the detection error is further increased.
  • the embodiment of the invention provides a method and a device for determining the clotting time, so as to solve the problem that the existing coagulation detecting device has a large volume and a large detection error.
  • a first aspect of the present invention provides a method for determining a clotting time, comprising: acquiring a frequency of a Lamb wave sensor output signal in real time when a blood sample to be tested is added to a blood coagulation reagent, wherein the blood sample to be tested is placed in the Lamb wave sensor Interdigitated electrode side surface; judge the phase acquired in real time Whether the difference between the adjacent two Lamb wave frequencies is less than a predetermined value; when the difference between the adjacent two Lamb wave frequencies acquired in real time is less than a predetermined value, the elapsed time is acquired, and the elapsed time As clotting time.
  • the blood coagulation reagent comprises a salt solution containing calcium ions; the blood sample to be tested is added with an agent for removing calcium ions before being added to the blood coagulation reagent.
  • a second aspect of the present invention provides a device for determining a clotting time, comprising: a first acquiring unit, configured to acquire a frequency of a Lamb wave sensor output signal in real time when a blood sample to be tested is added to a blood coagulation reagent, wherein the blood sample to be tested And a judging unit, configured to determine whether a difference between adjacent two Lamb wave frequencies acquired in real time is less than a predetermined value; and a second determining unit, configured to be When the difference between the adjacent two Lamb wave frequencies acquired in real time is less than a predetermined value, the elapsed time is acquired, and the elapsed time is taken as the clotting time.
  • a third aspect of the present invention provides a device for determining a clotting time, comprising: a Lamb wave sensor, wherein a side surface of the fork finger electrode of the Lamb wave sensor is used for placing a blood sample to be tested; a signal processing device, and the Lamb wave sensor An output electrode connection for performing the method of determining clotting time as described in the first aspect or any of the alternative embodiments of the first aspect.
  • the device further includes: a signal generating device connected to the excitation electrode of the Lamb wave sensor for generating an alternating current signal of a predetermined frequency.
  • a side surface of the interdigital electrode of the Lamb wave sensor is coated with a hydrophobic material.
  • the device further includes: a seat body having a test cavity and an inlet connected to the test cavity, wherein the Lamb wave sensor is disposed in the test cavity.
  • the base body comprises: a base, the base is provided with a groove; and the upper seat is detachably fixed above the base to form the test cavity with the groove.
  • the inlet is disposed at a position corresponding to the groove on the upper seat; or the inlet is disposed at a position corresponding to the groove on the base.
  • the signal generating device is connected to the excitation electrode of the Lamb wave sensor through a first probe, the first probe is disposed in a hole opened in the upper seat; and/or
  • the signal processing device is connected to the output electrode of the Lamb wave sensor through a second probe, and the second probe is disposed in a hole opened in the upper seat.
  • the signal processing device comprises a network analyzer.
  • the method and device for determining clotting time provided by the embodiments of the present invention creatively use a Lamb wave sensor to detect clotting time, and the detection result is not easily affected by environmental factors such as illumination, and the detection result is relatively accurate; since the Lamb wave sensor is relatively small, and There is no need to add an auxiliary detection environment to maintain the device (for example, a barrier for shielding ambient light in the prior art), so that the entire clotting time detecting device can also be relatively small and convenient to carry and store.
  • FIG. 1 shows a flow chart of a method of determining clotting time in accordance with an embodiment of the present invention
  • Figure 2 shows a top view of a Lamb wave sensor structure
  • Figure 3 shows a schematic diagram of clotting time detection using a Lamb wave sensor
  • Figure 4 is a graph showing the relationship between the center frequency of the Lamb wave signal and time
  • Figure 5 shows a schematic block diagram of an apparatus for determining clotting time in accordance with the present embodiment
  • FIG. 6 is a schematic structural view of an apparatus for determining a clotting time according to an embodiment of the present invention.
  • Figure 7 shows a side view of a Lamb wave sensor structure
  • Figure 8 shows a top view of yet another Lamb wave sensor structure
  • Figure 9 shows a top view of still another Lamb wave sensor structure
  • Figure 10 is a graph showing the amplitude test of the output signal when the surface of the interdigital electrode is not vapor-deposited parylene C and the parylene C is evaporated;
  • Figure 11 is a block diagram showing another configuration of a device for determining clotting time according to an embodiment of the present invention.
  • Fig. 12 is a view showing another angle of the apparatus for determining the clotting time shown in Fig. 11.
  • FIG. 1 shows a flow chart of a method of determining clotting time, the method comprising the following steps, in accordance with an embodiment of the present invention:
  • Lamb wave sensor is a thin film piezoelectric acoustic wave sensor.
  • the test sensitivity increases with the thickness of the silicon-based substrate film.
  • the modes are first-order antisymmetric mode A 0 and first-order symmetric mode S 0 .
  • the A 0 mode exhibits an evanescent wave when its wave velocity is smaller than the surrounding test medium flow rate, and the acoustic wave loss can be effectively controlled.
  • the embodiment of the present application uses the A 0 mode of the Lamb wave sensor to detect the clotting time.
  • the Lamb wave sensor has interdigital electrodes A1, A2, B1, and B2, in which the vibrators of the interdigital electrodes A1 and A2 are alternately arranged, and the vibrators of the interdigital electrodes B1 and B2 are alternately arranged.
  • Fig. 3 shows a schematic diagram of clotting time detection using a Lamb wave sensor, and the blood sample to be tested is dropped on the vibrator of the interdigital electrode of the Lamb wave sensor.
  • the interdigital electrodes A1 and A2 may respectively be connected to input signals of a predetermined frequency, and the interdigital electrodes B1 and B2 may be used as outputs for outputting Lamb wave signals in real time.
  • the above step S10 starts to acquire the frequency of the Lamb wave sensor output signal (ie, the Lamb wave signal) in real time when the blood coagulation reagent is added to the blood sample to be tested.
  • the frequency of the Lamb wave signal may be the center frequency
  • FIG. 4 shows the corresponding relationship between the center frequency and the time of the Lamb wave signal
  • the position shown by X in the figure is the time at which the blood coagulation reagent is added to the blood sample to be tested.
  • step S20 determining whether the difference between the adjacent two Lamb wave frequencies acquired in real time is less than a pre- Value. When the difference between the adjacent two Lamb wave frequencies acquired in real time is less than a predetermined value, step S30 is performed; otherwise, step S20 is continued.
  • S30 Acquire a time elapsed when a difference between adjacent two Lamb wave frequencies is less than a predetermined value, and take the elapsed time as a clotting time.
  • soluble fibrinogen gradually transforms into insoluble fibrin, which is adsorbed on the Lamb wave sensor, and the frequency of the Lamb wave is gradually reduced.
  • the condition that the difference between the adjacent two Lamb wave frequencies is smaller than a predetermined value is used to determine whether the curve shown in Fig. 4 tends to be stable, that is, whether fibrin is no longer formed in the blood.
  • the Lamb wave frequency reaches a minimum for the first time and remains stable, as indicated by the Y point in FIG.
  • the time elapsed when the difference between the frequencies of the adjacent two Lamb waves is added to the clotting reagent is less than the predetermined value is taken as the clotting time, that is, the time elapsed from the point X to the point Y in FIG.
  • the predetermined value in the step S20 should be 0.
  • the predetermined value can be any value close to 0, which is not limited by the present application, in consideration of the error and other factors in the signal acquisition process.
  • the clotting time in the present application may be prothrombin time (PT), activated partial thromboplastin time (APTT) or thrombin time (TT), and the blood coagulation reagent is selected according to the specific type to be detected when detecting the clotting time.
  • PT prothrombin time
  • APTT activated partial thromboplastin time
  • TT thrombin time
  • Lamb wave sensors are often used to detect temperature, humidity, etc.
  • the above method for determining clotting time creatively uses Lamb wave sensors to detect clotting time, and the detection results are not easily affected by environmental factors such as illumination, and the detection results are more accurate; It is compact and does not require an additional detection environment to maintain the device (such as the barrier used to block ambient light in the prior art), so the entire clotting time detecting device can also be relatively small, easy to carry and store.
  • the blood coagulation reagent includes a salt solution containing calcium ions, such as a calcium chloride solution, and the blood sample to be tested is added with a reagent for removing calcium ions before being added to the blood coagulation reagent to prevent Interference with calcium ions in the blood.
  • a salt solution containing calcium ions such as a calcium chloride solution
  • Figure 5 shows a schematic block diagram of a device for determining clotting time according to the present embodiment, the device for determining clotting time can be used to implement embodiment one or any alternative embodiment thereof The method of determining clotting time.
  • the apparatus includes a first acquisition unit 10, a determination unit 20, and a second determination unit 30.
  • the first obtaining unit 10 is configured to acquire the frequency of the Lamb wave sensor output signal in real time when the blood sample to be tested is added to the blood coagulation reagent, wherein the blood sample to be tested is placed on the side of the interdigital electrode of the Lamb wave sensor.
  • the determining unit 20 is configured to determine whether the difference between the adjacent two Lamb wave frequencies acquired in real time is less than a predetermined value.
  • the second judging unit 30 is configured to acquire the elapsed time when the difference between the adjacent two Lamb wave frequencies acquired in real time is less than a predetermined value, and use the elapsed time as the coagulation time.
  • the above-mentioned device for determining the clotting time has a relatively accurate detection result for the clotting time, and the entire clotting time detecting device can also be relatively small, and is convenient to carry and store. Please refer to
  • An embodiment of the present invention provides a device for determining a clotting time, as shown in FIG. 6, including a Lamb wave sensor 1 and a signal processing device 2.
  • the side surface of the interdigital electrode of the Lamb wave sensor 1 is used to place a blood sample to be measured.
  • the signal processing device 2 is coupled to the output electrode of the Lamb wave sensor for performing the method of determining the clotting time as described in the first embodiment or any alternative embodiment thereof.
  • Lamb wave sensors are often used to detect temperature, humidity, etc.
  • the above-mentioned device for determining clotting time creatively uses Lamb wave sensors to detect clotting time, and the detection results are not easily affected by environmental factors such as illumination, and the detection results are more accurate; It is compact and does not require an additional detection environment to maintain the device (such as the barrier used to block ambient light in the prior art), so the entire device for determining the clotting time can also be relatively small, easy to carry and store.
  • the structure of the Lamb wave sensor is as shown in FIG. 3 and FIG. 7.
  • the Lamb wave sensor sequentially includes an electrode layer 11, a piezoelectric layer 12, and a ground electrode layer 13.
  • the excitation electrode and the output electrode of the Lamb wave sensor are disposed on the electrode layer 11,
  • the ground electrode layer 13 is connected to the ground signal.
  • the Lamb wave sensor further includes a reflective gate, such as G1 and G2 in FIG. 8, disposed on the electrode 11, and the grid of the reflective gate is disposed in parallel with the vibrator of the excitation electrode and the output electrode.
  • the Lamb wave sensor further includes a substrate 14 disposed on a surface of the ground electrode layer 13, and the substrate 14 is provided with a groove, the groove
  • the Lamb wave can be confined within the piezoelectric layer 12 above the film substrate to increase the amplitude of the piezoelectric layer medium during harmonic vibration.
  • the substrate 14 may be the same material or two or more layers of different materials. As shown in FIG. 7, a substrate 15 may be further disposed in the substrate 14.
  • a sandwich 15 is first formed on the substrate 142, and then the substrate 141 is processed on the interlayer 15, and then lining.
  • the electrode layer 13, the piezoelectric layer 12, and the electrode layer 11 are sequentially prepared on the bottom 141, and the surface of the substrate 142 is finally etched.
  • the function of the interlayer 15 is to protect the substrate from etching when the recess is etched, and finally the interlayer 15 at the recess is removed to prepare the apparatus shown in FIG.
  • the material of the substrate 14 is SOI (English name: Silicon On Insulation, Chinese: silicon on an insulating substrate), and the material of the ground electrode layer 13 may be aluminum (Al), tungsten (W), or titanium (Ti). ), one of molybdenum (Mo) and platinum (Pt), and the piezoelectric layer 12 is made of aluminum nitride (AlN) or zinc oxide (ZnO).
  • the electrode layer 30 has a thickness of 100 nm to 250 nm
  • the piezoelectric layer 12 has a thickness of 0.5 ⁇ m to 2.5 ⁇ m
  • the electrode layer 11 has a thickness of 100 nm to 200 nm.
  • the thickness of the substrate under the reflective gate is greater than the thickness of the substrate below the interdigital electrodes.
  • a broken line frame indicates a film substrate region (that is, a region having only the substrate 141 without the substrate 142), and the reflection gates G1 and G2 are respectively disposed on both sides of the excitation electrode and the output electrode, and
  • the reflective gates may be disposed outside the film substrate region as shown in FIG. 8, that is, the thickness of the substrate under the reflective gate is greater than the thickness of the substrate under the transducer; or may be disposed on the film substrate as shown in FIG. within the area.
  • the substrate substrate region has a substrate thickness of from 2 ⁇ m to 20 ⁇ m.
  • the side surface of the interdigital electrode of the Lamb wave sensor 1 is coated with a hydrophobic material 16, such as parylene, to prevent blood from dripping.
  • a hydrophobic material 16 such as parylene
  • Conducting on the interdigital electrodes allows the excitation and output electrodes to be electrically connected directly.
  • the hydrophobic material 16 may be made of parylene C, which has a weak piezoelectric effect, and evaporation on the surface of the interdigital electrode as a waveguide layer does not attenuate the amplitude of the output signal, and FIG. 10 shows that the surface of the interdigital electrode is not steamed.
  • parylene C shown in the Lamb curve in the figure
  • parylene C shown in the P-Lamb curve in the figure
  • Fig. 10 when parylene C is vapor-deposited on one side of the interdigital electrode, the amplitude of the output signal is not attenuated, and the accuracy of the center frequency is not affected.
  • the device for determining the clotting time further includes a seat body 4 having a test cavity and an inlet connected to the test cavity, and the Lamb wave sensor 1 is disposed at Test cavity.
  • the seat body 4 can be integrally provided.
  • the base 4 includes a base 41 and a top seat 42.
  • the base 41 is provided with a recess, and the upper seat 42 is detachably fixed above the base 41, for example, by a fixing pin 43 to be recessed.
  • the grooves form a test chamber.
  • the detachable seat is convenient for cleaning.
  • the injection port may be disposed on the upper seat 42 at a position corresponding to the groove, and is injected from above the seat 4.
  • the injection port may also be disposed on the base 41 at a position corresponding to the groove, and is injected from the bottom of the seat 4.
  • an alternating current signal of a predetermined frequency may be applied to the excitation electrode of the Lamb wave sensor by an external device; or the device may further include a signal generating device 3 connected to the excitation electrode of the Lamb wave sensor 1 for use.
  • An alternating signal that produces a predetermined frequency may be applied to the excitation electrode of the Lamb wave sensor by an external device; or the device may further include a signal generating device 3 connected to the excitation electrode of the Lamb wave sensor 1 for use.
  • the signal generating device 3 and the excitation electrode of the Lamb wave sensor 1 are connected by a first probe 51, and the first probe 51 is disposed in a hole opened in the upper seat 42.
  • the signal processing device 2 and the output electrode of the Lamb wave sensor 1 are connected by a second probe 52, and the second probe 52 is disposed in a hole opened in the upper seat 42.
  • the signal processing device 2 may be a network analyzer; or a circuit board 6 is detachably disposed above the upper seat 42, and the signal processing device 2 is disposed on the circuit board 6.
  • the embodiment of the present invention further provides a non-transitory computer readable storage medium having stored thereon a computer program, which is executed by the processor to implement the determination of blood coagulation as described in Embodiment 1 or any of its optional embodiments. The method of time.

Abstract

一种确定凝血时间的方法及装置，其中方法包括：在待测血样被加入凝血试剂时，实时获取Lamb波传感器输出信号的频率，其中待测血样放置在Lamb波传感器的叉指电极（A1、A2、B1、B2）一侧表面（S10）；判断实时获取的相邻的两个Lamb波频率之间的差值是否小于预定值（S20）；当实时获取的相邻的两个Lamb波频率之间的差值小于预定值时，获取所经过的时间，将所经过的时间作为凝血时间（S30）。确定凝血时间的方法及装置采用Lamb波传感器检测凝血时间，其检测结果不易受光照等环境因素的影响，检测结果较为准确；由于Lamb波传感器较为小巧，并且无需增加辅助的检测环境维持装置，因此整个凝血时间检测装置也可以较为小巧，便于携带和收纳。

Description

一种确定凝血时间的方法及装置 技术领域
本发明涉及凝血检测技术领域，具体涉及一种确定凝血时间的方法及装置。
背景技术
凝血(英文：Blood Coagulation)即血液凝固，是指使血液由流动状态变成不能流动的凝胶状态的过程的一种能力，实质就是血浆中的可溶性纤维蛋白原转变为不溶性的纤维蛋白的功能。凝血功能检测可以在术前了解患者有无凝血功能的异常，有效防止在术中及术后出现出血不止等意外情况，从而获得最佳的手术效果。
中国专利文献CN 101983338 A公开了一种凝血检测方法，其采用光源照射放置在透明试管中的血液样本，在加入凝血试剂前后实时获取透射光强度，根据透射光强的变化情况估算得到凝血检测结果。
然而，上述凝血检测方法获取的透射光强度容易受环境光照的影响，为此凝血检测装置必须设置遮挡环境光线的屏障，加上光源以及盛装测定试样的透明试管，凝血装置的体积相对较大。此外，上述凝血检测方法是通过透射光强度估算得到凝血检测结果的，因此测量结果存在误差，若透射光强度的获取受到环境光线的影响，则会进一步增大检测误差。
发明内容
有鉴于此，本发明实施例提供了一种确定凝血时间的方法及装置，以解决现有凝血检测装置的体积较大及检测误差大的问题。
本发明第一方面提供了一种确定凝血时间的方法，包括：在待测血样被加入凝血试剂时，实时获取Lamb波传感器输出信号的频率，其中所述待测血样放置在所述Lamb波传感器的叉指电极一侧表面；判断实时获取的相 邻的两个Lamb波频率之间的差值是否小于预定值；当实时获取的相邻的两个Lamb波频率之间的差值小于预定值时，获取所经过的时间，将所经过的时间作为凝血时间。
可选地，所述凝血试剂包括含有钙离子的盐溶液；所述待测血样在被加入所述凝血试剂之前，被加入有用于去除钙离子的试剂。
本发明第二方面提供了一种确定凝血时间的装置，包括：第一获取单元，用于在待测血样被加入凝血试剂时，实时获取Lamb波传感器输出信号的频率，其中所述待测血样放置在所述Lamb波传感器的叉指电极一侧表面；判断单元，用于判断实时获取的相邻的两个Lamb波频率之间的差值是否小于预定值；第二判断单元，用于当实时获取的相邻的两个Lamb波频率之间的差值小于预定值时，获取所经过的时间，将所经过的时间作为凝血时间。
本发明第三方面提供了一种确定凝血时间的装置，包括：Lamb波传感器，所述Lamb波传感器的叉指电极一侧表面用于放置待测血样；信号处理装置，与所述Lamb波传感器的输出电极连接，用于执行第一方面或者第一方面任意一种可选实施方式所述的确定凝血时间的方法。
可选地，所述装置还包括：信号发生装置，与所述Lamb波传感器的激励电极连接，用于产生预定频率的交流信号。
可选地，所述Lamb波传感器的所述叉指电极一侧表面涂覆有疏水材料。
可选地，所述装置还包括：座体，所述座体内开设有试验腔体和与所述试验腔体连通的进样口，所述Lamb波传感器设置在所述试验腔体内。
可选地，所述座体包括：底座，所述底座上开设有凹槽；上座，可拆卸地固定在所述底座的上方，以与所述凹槽形成所述试验腔体。
可选地，所述进样口设置在所述上座上对应于所述凹槽的位置；或者，所述进样口设置在所述底座上对应于凹槽的位置。
可选地，所述信号发生装置与所述Lamb波传感器的激励电极之间通过第一探针连接，所述第一探针设置在所述上座上开设的孔中；和/或，所述 信号处理装置与所述Lamb波传感器的输出电极之间通过第二探针连接，所述第二探针设置在所述上座上开设的孔中。
可选地，所述信号处理装置包括网络分析仪。
本发明实施例所提供的确定凝血时间的方法及装置，创造性地采用Lamb波传感器检测凝血时间，其检测结果不易受光照等环境因素的影响，检测结果较为准确；由于Lamb波传感器较为小巧，并且无需增加辅助的检测环境维持装置(例如现有技术中用于遮挡环境光线的屏障)，因此整个凝血时间检测装置也可以较为小巧，便于携带和收纳。
附图说明
通过参考附图会更加清楚的理解本发明的特征和优点，附图是示意性的而不应理解为对本发明进行任何限制，在附图中：
图1示出了根据本发明实施例的一种确定凝血时间的方法的流程图；
图2示出了一种Lamb波传感器结构的俯视图；
图3示出了采用Lamb波传感器进行凝血时间检测的示意图；
图4示出了Lamb波信号的中心频率与时间的对应关系曲线图；
图5示出了根据本实施例的一种确定凝血时间的装置的原理框图；
图6示出了根据本发明实施例的一种确定凝血时间的装置的结构示意图；
图7示出了一种Lamb波传感器结构的侧视图；
图8示出了再一种Lamb波传感器结构的俯视图；
图9示出了再一种Lamb波传感器结构的俯视图；
图10示出了叉指电极表面未蒸镀parylene C和蒸镀有parylene C时输出信号的振幅试验曲线；
图11示出了根据本发明实施例的又一种确定凝血时间的装置的结构示意图；
图12示出了图11所示确定凝血时间的装置的另一角度示意图。
具体实施方式
为使本发明实施例的目的、技术方案和优点更加清楚，下面将结合本发明实施例中的附图，对本发明实施例中的技术方案进行清楚、完整地描述，显然，所描述的实施例是本发明一部分实施例，而不是全部的实施例。基于本发明中的实施例，本领域技术人员在没有作出创造性劳动前提下所获得的所有其他实施例，都属于本发明保护的范围。
实施例一
图1示出了根据本发明实施例的一种确定凝血时间的方法的流程图，该方法包括如下步骤：
S10：在待测血样被加入凝血试剂时，实时获取Lamb波传感器输出信号的频率，其中待测血样放置在Lamb波传感器的叉指电极一侧表面。
Lamb波传感器作为一种薄膜压电声波传感器，测试灵敏度随着硅基衬底薄膜的厚度减小而提高，当薄膜厚度远低于器件叉指换能器的波长时，Lamb波传感器仅存在两种模式，分别为一阶反对称模式A0和一阶对称模式S0。A0模式在其波速小于周围测试介质流速时表现为消逝波，声波损耗能够得到有效控制。本申请实施例采用Lamb波传感器的A0模式进行凝血时间的检测。
如图2所示，Lamb波传感器具有叉指电极A1、A2、B1、B2，其中叉指电极A1和A2的振子交错排布，叉指电极B1和B2的振子交错排布。图3示出了采用Lamb波传感器进行凝血时间检测的示意图，将待测血样滴在Lamb波传感器的叉指电极的振子上。在进行检测时，可以是叉指电极A1和A2分别接预定频率的输入信号，叉指电极B1和B2作为输出端用于实时输出Lamb波信号。上述步骤S10在待测血样中加入凝血试剂时便开始实时获取Lamb波传感器输出信号(即Lamb波信号)的频率。本申请中Lamb波信号的频率可以为中心频率，图4示出了Lamb波信号的中心频率与时间的对应关系曲线图，图中X所示位置为待测血样中加入凝血试剂的时刻。
S20：判断实时获取的相邻的两个Lamb波频率之间的差值是否小于预 定值。当实时获取的相邻的两个Lamb波频率之间的差值小于预定值时，执行步骤S30；否则继续执行步骤S20。
S30：获取相邻的两个Lamb波频率之间的差值小于预定值时所经过的时间，将所经过的时间作为凝血时间。
血液凝固过程中可溶性纤维蛋白原逐渐转变为不可溶的纤维蛋白，吸附在Lamb波传感器上，使得Lamb波的频率逐渐减小。“相邻的两个Lamb波频率之间的差值小于预定值”这一条件用于确定图4所示的曲线是否趋于稳定，也即血液中是否不再生成纤维蛋白。当不再生成纤维蛋白时，Lamb波频率首次达到最小值并保持稳定，如图4中的Y点所示。将加入凝血试剂至相邻的两个Lamb波频率之间的差值小于预定值时所经过的时间作为凝血时间，即图4中X点至Y点所经过的时间。具体地，当Y2点频率与Y1点频率的差值小于预定值时，可以将Y1或Y2作为该Y点。严格地讲，步骤S20中的预定值应该为0，考虑到信号获取过程中会有误差及其他因素影响，该预定值还可以为接近于0的任意数值，本申请对此不做限定。
本申请中的凝血时间可以为凝血酶原时间(PT)、活化部分凝血活酶时间(APTT)或凝血酶时间(TT)，在检测凝血时间时根据需要检测的具体类型选取凝血试剂。
Lamb波传感器往往用于检测温度、湿度等，上述确定凝血时间的方法创造性地采用Lamb波传感器检测凝血时间，其检测结果不易受光照等环境因素的影响，检测结果较为准确；由于Lamb波传感器较为小巧，并且无需增加辅助的检测环境维持装置(例如现有技术中用于遮挡环境光线的屏障)，因此整个凝血时间检测装置也可以较为小巧，便于携带和收纳。
作为本实施例的一种可选实施方式，凝血试剂包括含有钙离子的盐溶液，例如氯化钙溶液，待测血样在被加入凝血试剂之前，被加入有用于去除钙离子的试剂，以防止血液中钙离子的干扰。
实施例二
图5示出了根据本实施例的一种确定凝血时间的装置的原理框图，该确定凝血时间的装置可以用于实现实施例一或者其任意一种可选实施方式 所述的确定凝血时间的方法。如图5所示，该装置包括第一获取单元10、判断单元20和第二判断单元30。
第一获取单元10用于在待测血样被加入凝血试剂时，实时获取Lamb波传感器输出信号的频率，其中待测血样放置在Lamb波传感器的叉指电极一侧表面。
判断单元20用于判断实时获取的相邻的两个Lamb波频率之间的差值是否小于预定值。
第二判断单元30用于当实时获取的相邻的两个Lamb波频率之间的差值小于预定值时，获取所经过的时间，将所经过的时间作为凝血时间。
上述确定凝血时间的装置对于凝血时间的检测结果较为准确，并且使得整个凝血时间检测装置也可以较为小巧，便于携带和收纳。具体请参阅
实施例一。
实施例三
本发明实施例提供了一种确定凝血时间的装置，如图6所示，包括Lamb波传感器1和信号处理装置2。Lamb波传感器1的叉指电极一侧表面用于放置待测血样。信号处理装置2，与Lamb波传感器的输出电极连接，用于执行实施例一或者其任意一种可选实施方式所述的确定凝血时间的方法。
Lamb波传感器往往用于检测温度、湿度等，上述确定凝血时间的装置创造性地采用Lamb波传感器检测凝血时间，其检测结果不易受光照等环境因素的影响，检测结果较为准确；由于Lamb波传感器较为小巧，并且无需增加辅助的检测环境维持装置(例如现有技术中用于遮挡环境光线的屏障)，因此整个确定凝血时间的装置也可以较为小巧，便于携带和收纳。
Lamb波传感器的结构如图3和图7所示，Lamb波传感器顺次包括电极层11、压电层12、地电极层13，Lamb波传感器的激励电极和输出电极设置在电极层11上，地电极层13连接地信号。可选地，Lamb波传感器还包括反射栅，如图8中的G1和G2，设置在电极11上，并且反射栅的栅格与激励电极和输出电极的振子平行设置。可选地，该Lamb波传感器还包括衬底14，设置在地电极层13的表面，并且衬底14上设置有凹槽，该凹槽 可以将Lamb波限制于薄膜衬底上方的压电层12内，增大压电层介质在简谐振动时的振幅。
该衬底14可以为同一材质，也可以不同材质的两层或两层以上。如图7所示，衬底14中还可以设置有夹层15，在该Lamb波传感器的制备过程中，先在衬底142上制备夹层15，然后在夹层15上加工衬底141，进而在衬底141上依次制备地电极层13、压电层12、电极层11，最后衬底142表面刻蚀出凹槽。夹层15的作用是保护刻蚀凹槽时衬底141不被刻蚀，最后将凹槽处的夹层15去除掉即可制备得到图7所示的装置。可选地，衬底14的材质为SOI(英文全称：Silicon On Insulation，中文：绝缘衬底上的硅)，地电极层13的材质可选铝(Al)、钨(W)、钛(Ti)、钼(Mo)、铂(Pt)之一，压电层12的材质为氮化铝(AlN)或氧化锌(ZnO)。可选地，电极层30的厚度为100nm至250nm，压电层12的厚度为0.5μm至2.5μm，电极层11的厚度为100nm至200nm。进一步地，反射栅下方的衬底厚度大于叉指电极下方的衬底厚度。如图8和图9中，虚线框表示薄膜衬底区域(也即仅有衬底141而无衬底142的区域)，反射栅G1和G2分别设置在激励电极和输出电极的两侧，并且反射栅可以如图8所示均设置在薄膜衬底区域外，也即反射栅下方的衬底厚度大于换能器下方的衬底厚度；或者也可以如图9所示均设置在薄膜衬底区域内。可选地，薄膜衬底区域的衬底厚度为2μm至20μm。
作为本实施例的一种可选实施方式，如图3和图7所示，Lamb波传感器1的叉指电极一侧表面涂覆有疏水材料16，例如派瑞林parylene，以防止血液滴在叉指电极上时导电，使得激励电极和输出电极直接电连接。更进一步地，疏水材料16可以采用parylene C，其具有微弱的压电效应，蒸镀在叉指电极表面作为波导层不会使得输出信号的振幅衰减，图10示出了叉指电极表面未蒸镀parylene C(图中Lamb曲线所示)和蒸镀有parylene C(图中P-Lamb曲线所示)时输出信号的振幅试验曲线。从图10中可以看出，叉指电极一侧表面蒸镀有parylene C时，输出信号的振幅不衰减，不会影响中心频率的准确性。
作为本实施例的一种可选实施方式，该确定凝血时间的装置还包括座体4，座体4内开设有试验腔体和与试验腔体连通的进样口，Lamb波传感器1设置在试验腔体内。该座体4可以为一体设置的。或者如图11和图12所示，座体4包括底座41和上座42，底座41上开设有凹槽，上座42可拆卸地固定在底座41的上方，例如通过固定销43固定，以与凹槽形成试验腔体。可拆卸的座体在清洗时较为便捷。
如图11所示，进样口可以设置在上座42上对应于凹槽的位置，从座体4的上方进样。或者，如图12所示，进样口也可以设置在底座41上对应于凹槽的位置，从座体4的底部进样。
上述确定凝血时间的装置中，可以通过外接的装置给Lamb波传感器的激励电极施加预定频率的交流信号；或者，该装置也可以包括信号发生装置3，与Lamb波传感器1的激励电极连接，用于产生预定频率的交流信号。
如图11和图12所示，信号发生装置3与Lamb波传感器1的激励电极之间通过第一探针51连接，第一探针51设置在上座42上开设的孔中。类似地，信号处理装置2与Lamb波传感器1的输出电极之间通过第二探针52连接，第二探针52设置在上座42上开设的孔中。
上述信号处理装置2可以为网络分析仪；或者上座42上方可拆卸地设置有电路板6，信号处理装置2设置在电路板6上。
本发明实施例还提供一种非暂态计算机可读存储介质，其上存储有计算机程序，该计算机程序被处理器执行时实现实施例一或者其任意一种可选实施方式所述的确定凝血时间的方法。
虽然结合附图描述了本发明的实施例，但是本领域技术人员可以在不脱离本发明的精神和范围的情况下作出各种修改和变型，这样的修改和变型均落入由所附权利要求所限定的范围之内。

Claims (10)

  1. 一种确定凝血时间的方法，其特征在于，包括：
    在待测血样被加入凝血试剂时，实时获取Lamb波传感器输出信号的频率，其中所述待测血样放置在所述Lamb波传感器的叉指电极一侧表面；
    判断实时获取的相邻的两个Lamb波频率之间的差值是否小于预定值；
    当实时获取的相邻的两个Lamb波频率之间的差值小于预定值时，获取所经过的时间，将所经过的时间作为凝血时间。
  2. 根据权利要求1所述的方法，其特征在于，所述凝血试剂包括含有钙离子的盐溶液；所述待测血样在被加入所述凝血试剂之前，被加入有用于去除钙离子的试剂。
  3. 一种确定凝血时间的装置，其特征在于，包括：
    第一获取单元，用于在待测血样被加入凝血试剂时，实时获取Lamb波传感器输出信号的频率，其中所述待测血样放置在所述Lamb波传感器的叉指电极一侧表面；
    判断单元，用于判断实时获取的相邻的两个Lamb波频率之间的差值是否小于预定值；
    第二判断单元，用于当实时获取的相邻的两个Lamb波频率之间的差值小于预定值时，获取所经过的时间，将所经过的时间作为凝血时间。
  4. 一种确定凝血时间的装置，其特征在于，包括：
    Lamb波传感器，所述Lamb波传感器的叉指电极一侧表面用于放置待测血样；
    信号处理装置，与所述Lamb波传感器的输出电极连接，用于执行权利要求1至3任一项所述的确定凝血时间的方法。
  5. 根据权利要求4所述的确定凝血时间的装置，其特征在于，还包括：
    信号发生装置，与所述Lamb波传感器的激励电极连接，用于产生预定频率的交流信号。
  6. 根据权利要求4所述的确定凝血时间的装置，其特征在于，所述Lamb波传感器的所述叉指电极一侧表面涂覆有疏水材料。
  7. 根据权利要求5所述的确定凝血时间的装置，其特征在于，还包括：
    座体，所述座体内开设有试验腔体和与所述试验腔体连通的进样口，所述Lamb波传感器设置在所述试验腔体内。
  8. 根据权利要求7所述的确定凝血时间的装置，其特征在于，所述座体包括：
    底座，所述底座上开设有凹槽；
    上座，可拆卸地固定在所述底座的上方，以与所述凹槽形成所述试验腔体。
  9. 根据权利要求4所述的凝血检测系统，其特征在于，所述信号处理装置包括网络分析仪。
  10. 一种非暂态计算机可读存储介质，其上存储有计算机程序，其特征在于，所述计算机程序被处理器执行时实现权利要求1或2所述的确定凝血时间的方法。
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