WO2021077732A1 - 体外模拟和评价血液接触类医疗器械内血小板粘附的方法 - Google Patents

体外模拟和评价血液接触类医疗器械内血小板粘附的方法 Download PDF

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WO2021077732A1
WO2021077732A1 PCT/CN2020/091505 CN2020091505W WO2021077732A1 WO 2021077732 A1 WO2021077732 A1 WO 2021077732A1 CN 2020091505 W CN2020091505 W CN 2020091505W WO 2021077732 A1 WO2021077732 A1 WO 2021077732A1
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blood
fluorescent particles
solution
instrument
platelet adhesion
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PCT/CN2020/091505
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English (en)
French (fr)
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胡盛寿
柳光茂
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中国医学科学院阜外医院深圳医院(深圳市孙逸仙心血管医院)
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Application filed by 中国医学科学院阜外医院深圳医院(深圳市孙逸仙心血管医院) filed Critical 中国医学科学院阜外医院深圳医院(深圳市孙逸仙心血管医院)
Priority to EP20875669.2A priority Critical patent/EP4062872A4/en
Priority to US17/275,203 priority patent/US11925559B2/en
Publication of WO2021077732A1 publication Critical patent/WO2021077732A1/zh

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61F—FILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, e.g. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS
    • A61F2/00—Filters implantable into blood vessels; Prostheses, i.e. artificial substitutes or replacements for parts of the body; Appliances for connecting them with the body; Devices providing patency to, or preventing collapsing of, tubular structures of the body, e.g. stents
    • A61F2/02—Prostheses implantable into the body
    • A61F2/24—Heart valves ; Vascular valves, e.g. venous valves; Heart implants, e.g. passive devices for improving the function of the native valve or the heart muscle; Transmyocardial revascularisation [TMR] devices; Valves implantable in the body
    • A61F2/2472—Devices for testing
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M60/00—Blood pumps; Devices for mechanical circulatory actuation; Balloon pumps for circulatory assistance
    • A61M60/10—Location thereof with respect to the patient's body
    • A61M60/122—Implantable pumps or pumping devices, i.e. the blood being pumped inside the patient's body
    • A61M60/165—Implantable pumps or pumping devices, i.e. the blood being pumped inside the patient's body implantable in, on, or around the heart
    • A61M60/178—Implantable pumps or pumping devices, i.e. the blood being pumped inside the patient's body implantable in, on, or around the heart drawing blood from a ventricle and returning the blood to the arterial system via a cannula external to the ventricle, e.g. left or right ventricular assist devices
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61F—FILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, e.g. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS
    • A61F2/00—Filters implantable into blood vessels; Prostheses, i.e. artificial substitutes or replacements for parts of the body; Appliances for connecting them with the body; Devices providing patency to, or preventing collapsing of, tubular structures of the body, e.g. stents
    • A61F2/82—Devices providing patency to, or preventing collapsing of, tubular structures of the body, e.g. stents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M60/00—Blood pumps; Devices for mechanical circulatory actuation; Balloon pumps for circulatory assistance
    • A61M60/10—Location thereof with respect to the patient's body
    • A61M60/104—Extracorporeal pumps, i.e. the blood being pumped outside the patient's body
    • A61M60/117—Extracorporeal pumps, i.e. the blood being pumped outside the patient's body for assisting the heart, e.g. transcutaneous or external ventricular assist devices
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M60/00—Blood pumps; Devices for mechanical circulatory actuation; Balloon pumps for circulatory assistance
    • A61M60/20—Type thereof
    • A61M60/205—Non-positive displacement blood pumps
    • A61M60/216—Non-positive displacement blood pumps including a rotating member acting on the blood, e.g. impeller
    • A61M60/237—Non-positive displacement blood pumps including a rotating member acting on the blood, e.g. impeller the blood flow through the rotating member having mainly axial components, e.g. axial flow pumps
    • A—HUMAN NECESSITIES
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    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M60/00—Blood pumps; Devices for mechanical circulatory actuation; Balloon pumps for circulatory assistance
    • A61M60/90—Details not provided for in groups A61M60/40, A61M60/50 or A61M60/80
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    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N15/00—Investigating characteristics of particles; Investigating permeability, pore-volume or surface-area of porous materials
    • G01N15/06—Investigating concentration of particle suspensions
    • G01N15/0606—Investigating concentration of particle suspensions by collecting particles on a support
    • G—PHYSICS
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    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N21/00—Investigating or analysing materials by the use of optical means, i.e. using sub-millimetre waves, infrared, visible or ultraviolet light
    • G01N21/62—Systems in which the material investigated is excited whereby it emits light or causes a change in wavelength of the incident light
    • G01N21/63—Systems in which the material investigated is excited whereby it emits light or causes a change in wavelength of the incident light optically excited
    • G01N21/64—Fluorescence; Phosphorescence
    • G01N21/6402—Atomic fluorescence; Laser induced fluorescence
    • G—PHYSICS
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    • G01N21/00—Investigating or analysing materials by the use of optical means, i.e. using sub-millimetre waves, infrared, visible or ultraviolet light
    • G01N21/62—Systems in which the material investigated is excited whereby it emits light or causes a change in wavelength of the incident light
    • G01N21/63—Systems in which the material investigated is excited whereby it emits light or causes a change in wavelength of the incident light optically excited
    • G01N21/64—Fluorescence; Phosphorescence
    • G01N21/6428—Measuring fluorescence of fluorescent products of reactions or of fluorochrome labelled reactive substances, e.g. measuring quenching effects, using measuring "optrodes"
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    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N21/00—Investigating or analysing materials by the use of optical means, i.e. using sub-millimetre waves, infrared, visible or ultraviolet light
    • G01N21/62—Systems in which the material investigated is excited whereby it emits light or causes a change in wavelength of the incident light
    • G01N21/63—Systems in which the material investigated is excited whereby it emits light or causes a change in wavelength of the incident light optically excited
    • G01N21/64—Fluorescence; Phosphorescence
    • G01N21/645—Specially adapted constructive features of fluorimeters
    • G01N21/6456—Spatial resolved fluorescence measurements; Imaging
    • G—PHYSICS
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    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N21/00—Investigating or analysing materials by the use of optical means, i.e. using sub-millimetre waves, infrared, visible or ultraviolet light
    • G01N21/62—Systems in which the material investigated is excited whereby it emits light or causes a change in wavelength of the incident light
    • G01N21/63—Systems in which the material investigated is excited whereby it emits light or causes a change in wavelength of the incident light optically excited
    • G01N21/64—Fluorescence; Phosphorescence
    • G01N21/6486—Measuring fluorescence of biological material, e.g. DNA, RNA, cells
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61F—FILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, e.g. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS
    • A61F2/00—Filters implantable into blood vessels; Prostheses, i.e. artificial substitutes or replacements for parts of the body; Appliances for connecting them with the body; Devices providing patency to, or preventing collapsing of, tubular structures of the body, e.g. stents
    • A61F2/02—Prostheses implantable into the body
    • A61F2/04—Hollow or tubular parts of organs, e.g. bladders, tracheae, bronchi or bile ducts
    • A61F2/06—Blood vessels
    • A61F2002/068—Modifying the blood flow model, e.g. by diffuser or deflector
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61F—FILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, e.g. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS
    • A61F2240/00—Manufacturing or designing of prostheses classified in groups A61F2/00 - A61F2/26 or A61F2/82 or A61F9/00 or A61F11/00 or subgroups thereof
    • A61F2240/001—Designing or manufacturing processes
    • A61F2240/008—Means for testing implantable prostheses
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M2205/00—General characteristics of the apparatus
    • A61M2205/70—General characteristics of the apparatus with testing or calibration facilities
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M2209/00—Ancillary equipment
    • A61M2209/02—Equipment for testing the apparatus
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N15/00—Investigating characteristics of particles; Investigating permeability, pore-volume or surface-area of porous materials
    • G01N15/06—Investigating concentration of particle suspensions
    • G01N15/075—Investigating concentration of particle suspensions by optical means
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N15/00—Investigating characteristics of particles; Investigating permeability, pore-volume or surface-area of porous materials
    • G01N15/01—Investigating characteristics of particles; Investigating permeability, pore-volume or surface-area of porous materials specially adapted for biological cells, e.g. blood cells
    • G01N2015/018—Platelets
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N21/00—Investigating or analysing materials by the use of optical means, i.e. using sub-millimetre waves, infrared, visible or ultraviolet light
    • G01N21/62—Systems in which the material investigated is excited whereby it emits light or causes a change in wavelength of the incident light
    • G01N21/63—Systems in which the material investigated is excited whereby it emits light or causes a change in wavelength of the incident light optically excited
    • G01N21/64—Fluorescence; Phosphorescence
    • G01N21/645—Specially adapted constructive features of fluorimeters
    • G01N21/6456—Spatial resolved fluorescence measurements; Imaging
    • G01N2021/646—Detecting fluorescent inhomogeneities at a position, e.g. for detecting defects
    • G—PHYSICS
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    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/483—Physical analysis of biological material
    • G01N33/487—Physical analysis of biological material of liquid biological material
    • G01N33/49—Blood
    • G01N33/4905—Determining clotting time of blood

Definitions

  • the invention relates to a method for in vitro simulation and evaluation of platelet adhesion in blood contact medical devices, and belongs to the technical field of testing and evaluation of blood contact medical devices.
  • blood contact medical devices such as vascular stents, mechanical valves, artificial hearts, etc.
  • blood contact medical devices When blood flows through blood contact medical devices, it is often caused by non-physiological blood flow shearing forces and low-speed flow.
  • a series of problems such as flow factors such as flow stagnation and non-autologous mechanical structural factors, cause platelets to adhere to the device surface until thrombus formation, which limits the clinical application of blood contact medical devices.
  • the location of platelet adhesion and thrombosis in blood contact medical devices is closely related to the structure of the location. Taking the artificial heart as an example, in the artificial heart that has been clinically used, thrombosis in the pump has always been one of the adverse events.
  • the structure of the flow-through components of blood contact medical devices determines the blood flow field and flow distribution in the device, and eddy current, high shear force, stagnant flow, etc. will cause thrombosis in the device.
  • eddy current, high shear force, stagnant flow, etc. will cause thrombosis in the device.
  • the current blood contact medical devices basically use large-scale animal experiments and clinical trials to calculate the location and incidence of blood contact medical devices thrombosis, that is, first use numerical calculation and flow field display methods to obtain the blood flow in the device Circumstances, by analyzing the blood flow to determine whether the device is prone to platelet adhesion, and then in a large number of expensive animal experiments and clinical trials, the device’s platelet adhesion and thrombosis and high incidence locations are counted, which requires a huge amount of manpower and material resources. To find the flaws in the device design.
  • the purpose of the present invention is to provide a method for in vitro simulation and evaluation of platelet adhesion caused by structural defects or flow factors on blood contact surfaces in blood contact medical devices.
  • This method can locate the position where platelet adhesion and thrombus are easy to form in the device, which is used to analyze the structural defects of the position and improve and optimize it in time.
  • This method can evaluate the defects of the device and whether it can be further improved before clinical application. .
  • a method for in vitro simulation and evaluation of platelet adhesion in blood contact medical devices including the following steps:
  • a glycerin aqueous solution with a concentration of 40% by mass is used to simulate the viscosity and hydrodynamic characteristics of blood, and fluorescent particles with a diameter of 3-5 microns are added to the solution to simulate platelets;
  • the concentration range of the volume percentage of the fluorescent particles in the solution is between 5% and 30%.
  • the experimental device is removed after the test is carried out for 3 days, and it is determined that there is no structural defect in the device that can obviously form platelet adhesion.
  • the artificial organ or medical device is an artificial heart, a vascular stent, a mechanical valve, and the like.
  • non-powered devices such as vascular stents and mechanical valves
  • traditional rotary pumps are used to achieve the flow of solution in the circulation loop; for artificial hearts and other power machinery, they directly rely on their own power to achieve the circulation of solution in the circulation loop.
  • the invention adopts the laser-induced fluorescent particle deposition effect to simulate in vitro the method of platelet adhesion on the inner surface of blood contact medical devices, which can not only locate the position and structural characteristics of platelet adhesion and thrombus easily formed in the device, but also fill platelet adhesion
  • This method can be used to predict the platelet adhesion in the device, evaluate the platelet adhesion and thrombosis risk of a certain local structure in the device. It can not only guide the optimization and improvement of the device structure in the device design optimization stage, but also become a device registration test.
  • the testing method for evaluating the blood compatibility of devices in stages can greatly reduce the development cycle and cost of such devices.
  • Figure 1 is a schematic diagram of the structure of the circulation loop used in the present invention.
  • Fig. 2 is a schematic diagram of the structure of the type 3 axial blood pump model used in the embodiment.
  • Figure 3 is a diagram showing the effect of particle adhesion on the surface of the part observed by taking pictures after the experiment.
  • Figure 4 (a-f) shows the effect of particle adhesion on the surface of the rotor at various angles after laser induction.
  • Fig. 5(a-d) is a diagram showing the effect of particle adhesion on the surface of each angle of the stator of the inlet section after laser induction.
  • Figure 6(a-d) is a diagram showing the effect of particle adhesion on the different angle surfaces of the stator and the wall of the exit section after laser induction.
  • the method of the present invention uses a circulation loop consisting of a liquid storage tank 1 and a silica gel pipe 2.
  • the silica gel pipe 2 is provided with artificial organs or medical equipment 3, and is also provided with a flow meter 4 and Valve 5, and set up a rotary pump to provide power as needed.
  • the liquid storage tank 1 contains a solution that simulates human blood, and the artificial organ or medical device 3 is placed in the solution.
  • the present invention uses a 40% glycerin aqueous solution as a circulating medium.
  • the experimental method of the present invention is: connect the blood contact medical device to the extracorporeal circulation circuit, and then add fluorescent particles with a diameter of 3-5 microns to the solution to simulate platelets, and the concentration of the fluorescent particles in the solution ranges from 5% to 30% between.
  • fluorescent particles with a diameter of 3-5 microns to the solution to simulate platelets, and the concentration of the fluorescent particles in the solution ranges from 5% to 30% between.
  • non-powered devices such as vascular stents and mechanical valves
  • traditional rotary pumps are used to achieve the flow of solution in the circulation loop; for artificial hearts and other power machinery, the flow of the solution in the circulation loop is directly dependent on its own power.
  • the experimental device Observe the fluorescent particle deposition on the blood contact surface of the instrument by naked eyes and photographs. , And then use laser-induced fluorescence technology to slap a laser on the surface of the instrument that is in contact with blood deposited by the fluorescent particles, and observe the aggregation and adhesion of fluorescent particles in the imaging of the charge-coupled device camera through the laser-induced fluorescent particles. If the deposition of fluorescent particles has not occurred, the experimental device shall be dismantled 3 days after the test, and it is determined that there is no structural defect in the device that can form platelet adhesion.
  • the method of the present invention can be used to locate the position and structure in the device where platelet adhesion is most likely to be formed. It can be used to guide the structural improvement of the device, and it can also be used for the registration inspection of the device's performance evaluation before the market. Structural defects can cause platelet adhesion and thrombosis to provide a guiding method, which is of great significance to the development of blood contact medical devices.
  • the type 3 axial blood pump model used in this embodiment is composed of three parts: a front guide 1, a rotor 2 and a rear guide 3.
  • the circulating water pump drives the solution to flow through the blood pump, and the particles will form a deposition effect on the model wall and particle wall; 5) After the solution circulates in the loop for 24 hours, remove the flow-through parts of the instrument under test and observe the instrument with naked eyes and photographs The deposition of fluorescent particles on the inner blood contact surface; 6) In order to show the deposition effect on the wall surface of the model and the surface of the stator rotor, the laser induced fluorescence method is used to irradiate the surface of the model with laser body light to photograph the deposition effect of the particles on the surface of the model. The fluorescent particles attached to the surface are induced by the laser to produce a specific wavelength of light through the fluorescent filter and imaged on the CCD camera, so that the liquid attachment on the rotor surface can be observed.
  • Figure 3 the adhesion of particles on the surface of the component observed by taking pictures after the experiment, it can be seen that the particles have obvious adhesion at positions A, B, and C.
  • Figure 4 (a-f) is the effect of particle adhesion on the surface of the rotor at various angles after laser induction. The adhesion of particles on the surface of the blood pump model rotor is photographed, and the white position is where the particles gather.
  • Figure 5(a-d) is a diagram showing the effect of particle adhesion on the surface of each angle of the inlet section stator after laser induction, where the white position is where the particles gather.
  • Fig. 6(a-d) is a diagram showing the effect of particle adhesion on the different angle surfaces of the stator and the wall of the exit section after laser induction, where the white position is where the particles gather.
  • the method of the present invention can locate the position and structure in the device where platelet adhesion is most likely to form, thereby providing a guiding method for analyzing which local structural defects in the device will cause platelet adhesion and thrombosis.

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Abstract

一种体外模拟和评价血液接触类医疗器械内血小板粘附的方法，包括以下步骤：(1)在体外循环回路中使用质量百分比浓度为40％的甘油水溶液模拟血液的粘度和流体力学特性，在溶液中加入直径3-5微米的荧光粒子模拟血小板；(2)溶液在回路中循环一定时间后将所测人工器官或医疗器械的过流部件拆卸下来通过肉眼及拍照的方式观察器械内血液接触表面上的荧光粒子沉积情况；(3)用激光诱导荧光技术在荧光粒子沉积的、与血液接触的器械表面打上激光，用电荷耦合器件照相机成像的方法拍摄激光诱导荧光粒子聚集和粘附情况。从而能够定位出器械内容易形成血小板粘附和血栓的位置，用于分析器械的结构缺陷并及时加以改进优化。

Description

体外模拟和评价血液接触类医疗器械内血小板粘附的方法 技术领域
本发明涉及一种体外模拟和评价血液接触类医疗器械内血小板粘附的方法，属于血液接触类医疗器械的测试与评价技术领域。
背景技术
血液接触类医疗器械(例如血管支架、机械瓣膜、人工心脏等)研发过程中会面临很多挑战，其中血液流经血液接触类医疗器械时，往往会因为非生理性血流剪切力、低速流、流动滞止等流动因素和非自体的机械结构因素造成的血小板粘附于器械表面直至形成血栓等一系列问题，从而限制了血液接触类医疗器械在临床上的应用。血液接触类医疗器械内的血小板黏附和血栓形成位置与该位置的结构密切相关，以人工心脏为例，在已经临床应用的人工心脏中，泵内血栓一直是不良事件之一。在目前已经临床应用的人工心脏中，几乎所有的人工心脏内血栓都发生于人工心脏内固定的几个位置，研究发现人工心脏内血小板激活是普遍性、全局性的，血小板激活、大量聚集后并不一定粘附于人工心脏内形成血栓，而人工心脏内血小板粘附和血栓形成却是概率性、局部的。
血液接触类医疗器械的过流部件的结构决定了该器械内的血流流场及流动分布情况，而涡流、高剪切力、滞止流动等又会导致器械内血栓形成。目前，在血液接触类医疗器械的设计和测试过程中，缺少直观、有效的办法评价器械内与血液相接触表面上的血小板粘附至形成血栓的缺陷。目前的血液接触类医疗器械基本都是通过大规模的动物实验和临床试验统计血液接触类医疗器械血栓形成位置和发生率，即，首先采用数值计算和流场显示的方法获得器械内的血液流动情况，通过分析血液流动情况判断器械内是否容易产生血小板粘附，然后在大量且昂贵的动物实验和临床试验中统计出器械的血小板粘附形成血栓情况以及高发位置，以致需要花费巨大的人力物力来发现器械设计的缺陷。
因此，通过大规模的动物实验和临床试验统计血液接触类医疗器械血栓形成位置和发生率不仅周期长、代价高昂，会导致器械优化改进的周期过长，而且通过临床试验来获得缺陷的统计数据对患者没有做到最大程度的负责。
发明内容
本发明的目的在于提供一种体外模拟和评价血液接触类医疗器械内血液接触表面上由于结构缺陷或流动因素而引发的血小板粘附的方法。通过该方法能够定位出器械内容易形成血小板粘附和血栓的位置，用于分析该位置的结构缺陷并及时加 以改进优化，通过该方法能够在临床应用前评价出器械的缺陷以及能否进一步改进。
为实现上述目的，本发明采用以下技术方案：
一种体外模拟和评价血液接触类医疗器械内血小板粘附的方法，包括以下步骤：
(1)在体外循环回路中使用质量百分比浓度为40％的甘油水溶液模拟血液的粘度和流体力学特性，在溶液中加入直径3-5微米的荧光粒子模拟血小板；
(2)溶液在回路中循环24小时后将所测器械的过流部件拆卸下来通过肉眼及拍照的方式观察器械内血液接触表面上的荧光粒子沉积情况；
(3)用激光诱导荧光技术在荧光粒子沉积的、与血液接触的器械表面打上激光，用电荷耦合器件(CCD)照相机成像的方法拍摄激光诱导荧光粒子聚集和粘附情况。
其中，在所述步骤(1)中，溶液中荧光粒子的体积百分比浓度范围在5％-30％之间。
在该方法中，如果一直未出现荧光粒子沉积现象则在试验进行3天后拆除实验装置，判定器械内没有可明显形成血小板粘附的结构缺陷。
所述人工器官或医疗器械为人工心脏、血管支架、机械瓣膜等。对于血管支架和机械瓣膜等非动力器械，采用传统的旋转泵来实现循环回路中溶液的流动；对于人工心脏等动力机械直接依靠其自身的动力实现循环回路中溶液的循环流动。
本发明的有益效果是：
本发明采用激光诱导荧光粒子沉积效果来体外模拟血小板在血液接触类医疗器械内表面粘附的方法，既能定位器械内容易形成血小板粘附以及血栓的位置和结构特征，又能填补血小板粘附生成血栓的数值模型与动物实验之间体外测试环节的缺失。该方法可用于预测器械内的血小板粘附情况，评估器械内某个局部结构的血小板粘附和血栓形成风险，既可在器械设计优化阶段指导器械的结构优化和改进，又可成为器械注册检验阶段评价器械血液相容性的检测方法，可极大降低此类器械研发周期并降低研发成本。
附图说明
图1为本发明中所用循环回路的结构示意图。
图2为实施例中所用3型轴流血泵模型的结构示意图。
图3为实验后通过拍照观察到的粒子在部件表面上的粒子附着效果图。
图4(a-f)为激光诱导后转子的各个角度表面上的粒子附着效果图。
图5(a-d)为激光诱导后进口段定子的各个角度表面上的粒子附着效果图。
图6(a-d)为激光诱导后出口段定子和壁面的不同角度表面上的粒子附着效果图。
具体实施方式
以下通过实施例对本发明作进一步说明，但本发明的保护范围并不受这些实施例的限定。
如图1所示，本发明的方法中使用一循环回路，该循环回路由储液槽1和硅胶管道2构成，硅胶管道2上设置有人工器官或医疗器械3，还设有流量计4和阀门5，并根据需要设置提供动力的旋转泵。储液槽1中装有模拟人体血液的溶液，人工器官或医疗器械3置于溶液内，本发明使用浓度为40％的甘油水溶液作为循环介质。
本发明的实验方法是：将血液接触类医疗器械接入体外循环回路中，然后向溶液中加入直径3-5微米的荧光粒子模拟血小板，荧光粒子在溶液中的浓度范围在5％-30％之间。对于血管支架和机械瓣膜等非动力器械，采用传统的旋转泵来实现循环回路中溶液的流动；对于人工心脏等动力机械直接依靠其自身的动力实现循环回路中溶液的流动。溶液在回路中循环一定时间后观察血液接触表面的荧光粒子沉积情况，出现明显沉积现象则将所测器械的过流部件拆卸下来通过肉眼及拍照的方式观察器械内血液接触表面的荧光粒子沉积情况，然后用激光诱导荧光技术在荧光粒子沉积的与血液接触的器械表面打上激光，通过激光诱导荧光粒子观察电荷耦合器件照相机成像中荧光颗粒的聚集和粘附情况。如果一直未出现荧光粒子沉积现象则在试验进行3天后拆除实验装置，判定器械内没有可明显形成血小板粘附的结构缺陷。
在血液接触类医疗器械应用于临床时，在人体内由于器械的某些结构形成的流动因素而产生的血小板粘附现象。而采用本发明的方法可以定位器械内最容易形成血小板粘附的位置和结构，既可用于指导器械的结构改进，也可用于器械上市前对其性能评价的注册检验，为分析器械内哪些局部结构缺陷会导致血小板粘附和血栓形成提供指导性方法，对血液接触类医疗器械的开发有着重要的意义。
实施例
以人工心脏为例，对3型轴流血泵模型进行模拟血液流动实验，评价血泵模型的定子、转子、壳体表面粒子沉积附着效果。如图2所示，本实施例中所使用的3型轴流血泵模型由前导1、转子2及后导3三部分构成。
实验中所使用的设备及材料如下表所示。
Figure PCTCN2020091505-appb-000001
实验过程：1)模拟血液粘度，采用甘油及水按4:6浓度配置溶液；2)在配置的溶液内加入体积比20％的荧光粉，并进行充分搅拌混合至粒子均匀分布；3)连接循环水泵及血泵模型，通电使溶液充分循环，在溶液内循环水泵驱动泵转子转动。4)循环水泵带动溶液流经血泵，粒子会在模型壁面及粒子壁面形成沉积效果；5)溶液在回路中循环24小时后将所测器械的过流部件拆卸下来通过肉眼及拍照的方式观察器械内血液接触表面上的荧光粒子沉积情况；6)为了显示模型壁面及定子转子表面沉积效果，采用激光诱导荧光方法，用激光体光照射模型表面，拍摄粒子在模型表面的沉积效果。表面附着的荧光粒子受激光诱导产生特定波段的光通过荧光滤色片在CCD相机成像，从而观察到转子表面液体附着情况。
实验结果：如图3所示，为实验后通过拍照观察到的粒子在部件表面的粘附情况，可以看出，粒子在位置A、B、C处有明显的附着。图4(a-f)为激光诱导后转子的各个角度表面上的粒子附着效果图，拍摄到粒子在血泵模型转子表面的粘附情况，其中白色位置是粒子聚集的地方。图5(a-d)为激光诱导后进口段定子的各个角度表面上的粒子附着效果图，其中白色位置是粒子聚集的地方。图6(a-d)为激光诱导后出口段定子和壁面的不同角度表面上的粒子附着效果图，其中白色位置是粒子聚集的地方。
从以上结果可以看出，通过本发明的方法能够定位器械内最容易形成血小板粘附的位置和结构，从而为分析器械内哪些局部结构缺陷会导致血小板粘附和血栓形成提供指导性方法。

Claims (5)

  1. 一种体外模拟和评价血液接触类医疗器械内血小板粘附的方法，其特征在于，包括以下步骤：
    (1)在体外循环回路中使用质量百分比浓度为40％的甘油水溶液模拟血液的粘度和流体力学特性，在溶液中加入直径3-5微米的荧光粒子模拟血小板；
    (2)溶液在回路中循环24小时后将所测器械的过流部件拆卸下来通过肉眼及拍照的方式观察器械内血液接触表面上的荧光粒子沉积情况；
    (3)用激光诱导荧光技术在荧光粒子沉积的、与血液接触的器械表面打上激光，用电荷耦合器件照相机成像的方法拍摄激光诱导荧光粒子聚集和粘附情况。
  2. 根据权利要求1所述的方法，其特征在于，所述步骤(1)中，溶液中荧光粒子的体积百分比浓度范围在5％-30％之间。
  3. 根据权利要求1所述的方法，其特征在于，所述血液接触类医疗器械为人工心脏、血管支架或机械瓣膜。
  4. 根据权利要求3所述的方法，其特征在于，对于血管支架和机械瓣膜，采用传统的旋转泵来实现循环回路中溶液的流动；对于人工心脏，直接依靠其自身的动力实现循环回路中溶液的循环流动。
  5. 根据权利要求1所述的方法，其特征在于，如果一直未出现荧光粒子沉积现象则在实验进行3天后拆除实验装置，判定器械内没有可明显形成血小板粘附的结构缺陷。
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