CN117304539B - Vascular model, preparation method thereof and embolic agent in-vitro simulation test device - Google Patents
Vascular model, preparation method thereof and embolic agent in-vitro simulation test device Download PDFInfo
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- CN117304539B CN117304539B CN202311615450.7A CN202311615450A CN117304539B CN 117304539 B CN117304539 B CN 117304539B CN 202311615450 A CN202311615450 A CN 202311615450A CN 117304539 B CN117304539 B CN 117304539B
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- 238000004088 simulation Methods 0.000 title claims abstract description 30
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- 238000002360 preparation method Methods 0.000 title abstract description 12
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- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08J—WORKING-UP; GENERAL PROCESSES OF COMPOUNDING; AFTER-TREATMENT NOT COVERED BY SUBCLASSES C08B, C08C, C08F, C08G or C08H
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- C08J7/04—Coating
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- B29—WORKING OF PLASTICS; WORKING OF SUBSTANCES IN A PLASTIC STATE IN GENERAL
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- B29C41/00—Shaping by coating a mould, core or other substrate, i.e. by depositing material and stripping-off the shaped article; Apparatus therefor
- B29C41/02—Shaping by coating a mould, core or other substrate, i.e. by depositing material and stripping-off the shaped article; Apparatus therefor for making articles of definite length, i.e. discrete articles
- B29C41/14—Dipping a core
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- B—PERFORMING OPERATIONS; TRANSPORTING
- B29—WORKING OF PLASTICS; WORKING OF SUBSTANCES IN A PLASTIC STATE IN GENERAL
- B29C—SHAPING OR JOINING OF PLASTICS; SHAPING OF MATERIAL IN A PLASTIC STATE, NOT OTHERWISE PROVIDED FOR; AFTER-TREATMENT OF THE SHAPED PRODUCTS, e.g. REPAIRING
- B29C41/00—Shaping by coating a mould, core or other substrate, i.e. by depositing material and stripping-off the shaped article; Apparatus therefor
- B29C41/34—Component parts, details or accessories; Auxiliary operations
- B29C41/42—Removing articles from moulds, cores or other substrates
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- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08F—MACROMOLECULAR COMPOUNDS OBTAINED BY REACTIONS ONLY INVOLVING CARBON-TO-CARBON UNSATURATED BONDS
- C08F220/00—Copolymers of compounds having one or more unsaturated aliphatic radicals, each having only one carbon-to-carbon double bond, and only one being terminated by only one carboxyl radical or a salt, anhydride ester, amide, imide or nitrile thereof
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- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08F—MACROMOLECULAR COMPOUNDS OBTAINED BY REACTIONS ONLY INVOLVING CARBON-TO-CARBON UNSATURATED BONDS
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- C09—DYES; PAINTS; POLISHES; NATURAL RESINS; ADHESIVES; COMPOSITIONS NOT OTHERWISE PROVIDED FOR; APPLICATIONS OF MATERIALS NOT OTHERWISE PROVIDED FOR
- C09D—COATING COMPOSITIONS, e.g. PAINTS, VARNISHES OR LACQUERS; FILLING PASTES; CHEMICAL PAINT OR INK REMOVERS; INKS; CORRECTING FLUIDS; WOODSTAINS; PASTES OR SOLIDS FOR COLOURING OR PRINTING; USE OF MATERIALS THEREFOR
- C09D183/00—Coating compositions based on macromolecular compounds obtained by reactions forming in the main chain of the macromolecule a linkage containing silicon, with or without sulfur, nitrogen, oxygen, or carbon only; Coating compositions based on derivatives of such polymers
- C09D183/04—Polysiloxanes
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- C09D7/62—Additives non-macromolecular inorganic modified by treatment with other compounds
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- G01N33/15—Medicinal preparations ; Physical properties thereof, e.g. dissolubility
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- B29L—INDEXING SCHEME ASSOCIATED WITH SUBCLASS B29C, RELATING TO PARTICULAR ARTICLES
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- C08J2333/00—Characterised by the use of homopolymers or copolymers of compounds having one or more unsaturated aliphatic radicals, each having only one carbon-to-carbon double bond, and only one being terminated by only one carboxyl radical, or of salts, anhydrides, esters, amides, imides, or nitriles thereof; Derivatives of such polymers
- C08J2333/04—Characterised by the use of homopolymers or copolymers of compounds having one or more unsaturated aliphatic radicals, each having only one carbon-to-carbon double bond, and only one being terminated by only one carboxyl radical, or of salts, anhydrides, esters, amides, imides, or nitriles thereof; Derivatives of such polymers esters
- C08J2333/06—Characterised by the use of homopolymers or copolymers of compounds having one or more unsaturated aliphatic radicals, each having only one carbon-to-carbon double bond, and only one being terminated by only one carboxyl radical, or of salts, anhydrides, esters, amides, imides, or nitriles thereof; Derivatives of such polymers esters of esters containing only carbon, hydrogen, and oxygen, the oxygen atom being present only as part of the carboxyl radical
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- C08J2333/00—Characterised by the use of homopolymers or copolymers of compounds having one or more unsaturated aliphatic radicals, each having only one carbon-to-carbon double bond, and only one being terminated by only one carboxyl radical, or of salts, anhydrides, esters, amides, imides, or nitriles thereof; Derivatives of such polymers
- C08J2333/04—Characterised by the use of homopolymers or copolymers of compounds having one or more unsaturated aliphatic radicals, each having only one carbon-to-carbon double bond, and only one being terminated by only one carboxyl radical, or of salts, anhydrides, esters, amides, imides, or nitriles thereof; Derivatives of such polymers esters
- C08J2333/06—Characterised by the use of homopolymers or copolymers of compounds having one or more unsaturated aliphatic radicals, each having only one carbon-to-carbon double bond, and only one being terminated by only one carboxyl radical, or of salts, anhydrides, esters, amides, imides, or nitriles thereof; Derivatives of such polymers esters of esters containing only carbon, hydrogen, and oxygen, the oxygen atom being present only as part of the carboxyl radical
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Abstract
The invention relates to the field of medical injection product testing equipment, in particular to a blood vessel model, a preparation method of the blood vessel model and a device for performing in-vitro simulation testing on an embolic agent by using the blood vessel model. The preparation method of the blood vessel model comprises the following steps: firstly, preparing a blood vessel model solution, slowly immersing a blood vessel model with a blood vessel-like shape into the blood vessel model solution, uniformly wrapping the blood vessel model solution outside the blood vessel model, solidifying, and dissolving the blood vessel model, thereby obtaining the blood vessel model with the same structure as the blood vessel model. The blood vessel model prepared by the method has similar physical properties to the blood vessel of a real organ, can correctly predict the property of the embolic agent in the blood vessel, and can be used for in vitro simulation test of the embolic agent to evaluate the property of the embolic agent.
Description
Technical Field
The invention relates to the field of medical injection product testing equipment, in particular to a blood vessel model, a preparation method of the blood vessel model and a device for performing in-vitro embolic agent simulation test by using the blood vessel model.
Background
In the field of minimally invasive interventions, embolic agents are delivered to organ lesions (liver, kidney, arteriovenous malformation vessels, etc.) for embolization by catheter transarterial super-selection for treatment. However, in practice, there are often problems such as incomplete embolism of the embolic agent and leakage of the embolic agent. Wherein, embolic agent embolization does not completely refer to the incomplete occlusion of the target artery or vein during treatment, which may result in poor treatment or the reoccurrence of blood flow in a short period of time; if the embolic agent does not completely occlude the malformed vessel, further treatment may be required. Embolic agent leakage refers to the fact that embolic agent may sometimes leak from the target site, into surrounding normal blood vessels or organs; this may lead to a reduced effectiveness of the embolism and also to damage of other unaffected tissues.
Thus, evaluating the performance of embolic agents is an important process in product development, testing, and supervision. Various models for evaluating the performance of the embolic agent have been designed, but these models have problems that the environment of the embolic agent in actual use cannot be accurately simulated, and the embolic performance and the passing performance of the embolic agent cannot be quantitatively reflected.
CN115112560B provides an external embolic agent simulation device and a use method thereof, so as to solve the problem of lack of a special external embolic agent simulation device at present. The in vitro simulation device fills the cylindrical housing with glass spheres of different particle sizes, but does not embody the spatial configuration of the blood vessel.
CN116115819a provides a developable in situ cross-linked embolic composition and method of use, in performance testing methods using the renal artery-renal artery model, according to human visceral vessel 1:1, but does not describe a model preparation method, judging from the pictures that the external device is made of hard material, and cannot simulate the elasticity of blood vessels; furthermore, the model does not represent small diameter vessels and therefore does not correctly reflect embolic agent passage performance.
CN111566714B provides a design and method of use of a surgical procedure simulator that can experience the creation of pressure gradients by occluding a blood vessel with a balloon, thereby enabling selective administration of therapeutic agents to specific sites. However, the device only simulates the use environment of the balloon catheter, can not manufacture a corresponding channel structure according to the requirement, and can not perform qualitative evaluation on the embolic agent.
Disclosure of Invention
In order to solve the problems: the invention provides a vascular model imitating vascular morphology and a preparation method thereof, and designs an external simulation test device for the embolic agent based on the vascular model, which can simulate the delivery performance of the vascular environment in vivo to test the embolic agent.
In order to achieve the above object, according to a first aspect of the present invention, there is provided a blood vessel model having a hollow multi-layer structure, wherein an innermost layer is a polyacrylic resin layer a, and a mixed layer of vinyl-terminated dimethyl (siloxane and polysiloxane), dimethylvinylated and trimethylated silica, and dimethylmethylhydrogen (siloxane and polysiloxane) is provided outside the polyacrylic resin layer a.
Preferably, the vascular model is of a hollow three-layer structure, the innermost layer is a polyacrylic resin layer A, the middle layer is a mixed layer of vinyl-terminated dimethyl (siloxane and polysiloxane) (CAS 68083-19-2), dimethyl vinylized and trimethylated silica (CAS 68988-89-6) and dimethyl methyl hydrogen (siloxane and polysiloxane) (CAS 68037-59-2), and the outermost layer is a polyacrylic resin layer B.
Further, in the mixed layer, the mass ratio of the vinyl-terminated dimethyl (siloxane to polysiloxane), the dimethylvinylated and trimethylated silica, and the dimethylmethylhydrogen (siloxane to polysiloxane) is 1: (0.1-0.45): (0.01-0.02).
Furthermore, the blood vessel model is of a hollow three-layer structure imitating a blood vessel shape, preferably a structure imitating a natural blood vessel shape, and comprises multiple stages of branches, the connecting parts among the branches are smoothly connected, and each stage of branch is provided with a gradual change pipe diameter which is changed from large to small.
Preferably, the vessel model has 1 primary branch, 3 secondary branches, each secondary branch connecting 2 tertiary branches; the diameter range of each level of branches of the blood vessel model is changed from 200 μm to 3000 μm, and the diameters of the branches are changed from large to small along with the extension of the trend of the branches.
The second aspect of the present invention provides a method for preparing the blood vessel model, specifically, the method comprises the following steps:
s1: the volume ratio of glycerin, tween 80, triton X100 to water is 1: (0.3-0.5): (0-0.5): (10-20) preparing a solution;
s2: the mass ratio of the solution prepared in the step S1 is 1:1, simultaneously adding potassium persulfate into a mixture of ethyl acrylate and methyl methacrylate, and uniformly stirring after the dripping is finished to obtain polyacrylic resin precursor emulsion;
s3: immersing the vascular mould into the polyacrylic resin precursor emulsion prepared in the step S2, taking out after the vascular mould is immersed completely, standing in the air for standby in a dark place, and wrapping polyacrylic resin on the outer surface of the vascular mould;
s4: the mass ratio is 1: (0.1-0.45): (0.01-0.02) vinyl-terminated dimethyl (siloxane and polysiloxane), dimethylvinylated and trimethylated silica, dimethylmethylhydrogen (siloxane and polysiloxane), and uniformly mixing to obtain a mixed solution;
s5: immersing the vascular mould for standby in the step S3 into the mixed liquid in the step S4 until the vascular mould is completely immersed in the mixed liquid, and wrapping a layer of the mixed liquid outside the vascular mould; curing;
s6: and taking out the solidified blood vessel mould, and completely dissolving the blood vessel mould to obtain the blood vessel model.
Further, in order to prepare a blood vessel model with good thickness uniformity and good observation field of view, the preparation method comprises the following steps:
s1: the volume ratio of glycerin, tween 80, triton X100 to water is 1: (0.3-0.5): (0-0.5): (10-20) preparing a solution;
s2: the mass ratio of the solution prepared in the step S1 is 1:1, simultaneously adding potassium persulfate into a mixture of ethyl acrylate and methyl methacrylate, and uniformly stirring after the dripping is finished to obtain polyacrylic resin precursor emulsion;
s3: immersing the vascular mould into the polyacrylic resin precursor emulsion prepared in the step S2, taking out the vascular mould after the vascular mould is immersed completely, standing the vascular mould in the air for standby in a dark place, and taking out the polyacrylic resin precursor emulsion after the vascular mould for standby;
s4: the mass ratio is 1: (0.1-0.45): (0.01-0.02) vinyl-terminated dimethyl (siloxane and polysiloxane), dimethyl vinyl and trimethyl silicon dioxide and dimethyl methyl hydrogen (siloxane and polysiloxane), uniformly mixing to obtain a mixed solution, adding the mixed solution into the polyacrylic resin precursor emulsion for standby in the step S3, and floating the mixed solution above the polyacrylic resin precursor emulsion to obtain a multiphase solution;
s5: immersing the vascular mould used in the step S3 into the multiphase solution until the mould is completely immersed into the polyacrylic resin precursor emulsion, and solidifying;
s6: and taking out the solidified sample, and completely dissolving the vascular mold to obtain the vascular model.
Further, in the step S2, the dripping speed of the mixture of the ethyl acrylate and the methyl methacrylate is 5-10 mL/min.
Further, in step S2, the time for stirring uniformly after the completion of the dripping is 30-45 min.
Further, in step S2, the potassium persulfate: the mass ratio of (the mixture of ethyl acrylate and methyl methacrylate) is 1:100.
further, the manner of immersing the vascular mold in the polyacrylic resin precursor emulsion in the step S3 is as follows: immersing at a constant speed of 0.5-5 mm/s; the method for taking out the immersed steel pipe after the immersed steel pipe is as follows: taking out at constant speed of 5-10 mm/s.
Further, in step S5, the vascular mold is immersed in the mixed solution in the following manner: immersing at a constant speed of 0.5-5 mm/s; or the vascular mold is immersed in the multiphase solution in the step S5 in the following manner: immersing at a constant speed of 0.5-5 mm/s.
Further, the curing conditions in step S5 are: heating to 70-85 deg.c and curing for 5-10 min.
Further, the vascular mold is a structure imitating a blood vessel shape, preferably imitating a natural blood vessel shape, such as a structure imitating a human liver blood vessel, and comprises multiple branches, such as two or more branches, wherein the connection parts between the branches are smoothly connected, and each branch has a gradual pipe diameter which is gradually changed from large to small.
Preferably, the vascular mould is a three-level branch and is provided with 1 first-level branch and 3 second-level branches, and each second-level branch is connected with 2 third-level branches; the diameter range of each level of branches of the vascular mould is changed from 200 μm to 3000 μm, and the diameters of the branches are changed from large to small along with the extension of the trend of the branches.
The first-stage branch refers to a branch with the largest branch diameter in the vascular mould, the second-stage branch extends from a pipeline of the first-stage branch, and the third-stage branch extends from the tail end of the second-stage branch; if there are more branches, four branches continue to extend from the three branch ends, and so on.
Preferably, the vascular mold material is at least one of ABS, polylactic acid, polycaprolactone and starch-based material, and the common property of such materials is that such materials can be rapidly decomposed under certain conditions, such as being soluble in an organic solvent or being soluble in water for rapid decomposition, and typically the organic solvent is at least one of acetone and dimethyl sulfoxide; the blood vessel mold material can be printed into a structure with a blood vessel-like morphology, namely a blood vessel mold in a 3D printing mode, so that the blood vessel mold material is convenient to quickly decompose to obtain a blood vessel mold after the blood vessel mold is uniformly wrapped with a solution capable of forming the blood vessel mold and solidified.
In a third aspect of the invention, an embolic agent in-vitro simulation test device is provided, comprising a delivery module, a circulation module and the blood vessel model; wherein:
the conveying module is used for pushing and injecting the embolic agent, and pushing and injecting the embolic agent into the blood vessel model;
the circulation module is used for driving physiological simulation liquid to circulate in the blood vessel model so as to simulate the embolism condition of the embolic agent in the blood vessel.
Further, the conveying module comprises a power device, an injection device, a conveying pipeline, a pressure sensing plane, a signal processing component and a signal display component; the signal display part, the signal processing part and the pressure sensing plane are electrically connected in sequence; the pressure sensing plane is positioned between the power device and the injection device, and is in physical connection with the power device, preferably, the physical connection mode is fixed connection, and the fixed connection mode can be bonding or screw fastening; the power device is used for pushing the injection device and pushing and injecting the embolic agent in the injection device into the blood vessel model; the outlet end of the injection device is connected with the blood vessel model through a conveying pipeline; the pressure sensing plane can convert the pushing force from the power device to the injection device on the plane into an electric signal, the signal processing component converts the electric signal into a pressure value, and the signal display component displays the received pressure value, such as a screen;
the circulating module comprises a circulating power device, a circulating pipeline and a liquid storage part; the liquid storage part is communicated with the blood vessel model through a circulating pipeline; the circulation power device is connected to a circulation pipeline between the outlet of the liquid storage part and the inlet of the blood vessel model, so that the physiological simulation liquid in the liquid storage part can flow into the blood vessel model, and then flows back to the liquid storage part from the outlet of the blood vessel model through another section of circulation pipeline, thereby realizing the circulation flow of the physiological simulation liquid in the blood vessel model and simulating the blood flow in the living body. The circulating power device is preferably a peristaltic pump; the physiological simulation solution is a solution such as physiological saline, phosphate buffer saline or artificial blood, and is used for simulating a normal blood flow state.
Preferably, the circulation pipeline is connected with the blood vessel model through a luer connector, and/or the circulation pipeline is connected with the liquid storage part through a luer connector.
Preferably, the power device and the injection device are assembled together through a mechanical structure, for example, the power device can be one of a universal tensile tester (force test LD23 104) or an injection pump; the injection device is an injector, preferably 1-10 mL injector with coaxial injection push rod, injection cylinder and injection port; the embolic agent is placed in the injection device and the power device pushes the embolic agent into the vascular model.
Preferably, the delivery conduit may be a catheter, a silicone hose with a luer connector, or a flexible conduit having a defined inner diameter.
The invention has the following beneficial effects:
(1) The vascular model prepared by the method has similar physical properties to those of a real organ blood vessel, and can correctly predict the property of the embolic agent in the blood vessel.
(2) By adopting the preparation method provided by the invention, a blood vessel model with the diameter below 1mm (such as 200 mu m) and uniform thickness and clear visual field can be prepared according to the requirement, so that the behavior of the embolic agent in small-diameter blood vessels can be studied.
(3) By adopting the preparation method provided by the invention, the vascular model with smooth inner and outer walls can be prepared, so that the embolic agent can smoothly enter each branch of the model, and different distribution behaviors of embolic agents of different types can be accurately reflected and distinguished.
(4) The blood vessel model prepared by the invention is transparent and elastic, so that the embolic agent in-vitro simulation test device provided by the invention has visibility, and can observe the distribution of embolic agent in the blood vessel model in real time; the embolic properties of the embolic agent are quantitatively assessed by measuring the displacement distance of the embolic agent in the vascular model.
(5) The embolic agent in-vitro simulation test device can quantitatively evaluate the conveying performance of embolic agent by testing the pressure of the embolic agent during conveying.
Drawings
FIG. 1 is a schematic diagram of a vascular model according to the present invention;
fig. 2 is a schematic diagram of an in vitro simulation test device for embolic agent provided by the invention.
Detailed Description
The following describes in further detail the embodiments of the present invention with reference to the drawings and examples. The following examples are illustrative of the invention and are not intended to limit the scope of the invention.
Example 1 preparation of vascular model 1 and measurement of Performance
According to the human liver blood vessel image, solidWorks software is used for designing and drawing a structure imitating the human liver blood vessel morphology, and a blood vessel mold is obtained by 3D printing of an ABS material. As shown in fig. 1, the vascular mold has 1 primary branch, 3 secondary branches; the inlet end of each secondary branch is connected with the side wall of the primary branch, and the tail ends of the secondary branches are communicated with the inlet ends of 2 tertiary branches. The primary branch diameter of the vascular mould is gradually changed from 3 mm to 1.8 mm from the inlet end to the tail end, the secondary branch diameter is gradually changed from 600 mu m to 500 mu m from the inlet end to the tail end, and the tertiary branch diameter is gradually changed from 300 mu m to 200 mu m from the inlet end to the tail end; wherein the branch connection portions are passivated using a rounded function so that the connection portions between the branches can be smoothly transitioned.
S1: 80 mL purified water, 4 mL glycerol, 2 mL Tween 80 were added to the beaker and stirred well.
S2: to the solution of S1, a mixture of 5 g ethyl acrylate and 5 g methyl methacrylate was added dropwise at a rate of 5 mL/min, while 0.1 g potassium persulfate was added, and after completion of the addition, the mixture was stirred for 45 minutes to obtain a polyacrylic resin precursor emulsion.
S3: immersing a vascular mould into the polyacrylic resin precursor emulsion prepared in the step S2 at a constant speed of 5 mm/S, taking out at a constant speed of 10 mm/S after the vascular mould is immersed completely, standing in the air in a dark place for standby, and wrapping the outer surface of the vascular mould with polyacrylic resin; the polyacrylic resin precursor emulsion after the vascular mold is taken out continues to be reserved for standby.
S4: weighing 10.0 g of vinyl-terminated dimethyl (siloxane and polysiloxane), 4.5 g of dimethyl vinyl and trimethyl silicon dioxide and 0.1 g of dimethyl methyl hydrogen (siloxane and polysiloxane), uniformly mixing, vacuumizing to remove bubbles to obtain a mixed solution, slowly pouring the mixed solution into the polyacrylic resin precursor emulsion for standby in S3, and floating the mixed solution above the polyacrylic resin precursor emulsion to obtain a multiphase solution.
S5: and (3) immersing the blood vessel mold to be used in the step (S3) into the multiphase solution of the step (S4) at a constant speed of 0.5 mm/S until the blood vessel mold is positioned below the mixed solution, completely immersing the blood vessel mold into the polyacrylic resin precursor emulsion, heating to 85 ℃, and keeping the temperature for five minutes, wherein the polyacrylic resin and the mixed solution wrapped on the outer surface of the blood vessel mold in the step (S3) are completely solidified. In this step, the polyacrylic resin located on the outer surface of the vascular mold from step S3 is solidified into a thin layer, which is called a polyacrylic resin layer a; the mixed solution is solidified into a layer thicker than the polyacrylic resin layer A and covers the surface of the polyacrylic resin layer A, and the layer is called a mixed layer; when the polyacrylic resin and the mixed solution on the outer surface of the vascular mold are solidified, a part of the polyacrylic resin outside the mixed layer is solidified into a thin layer which covers the mixed layer, and the thin layer is called a polyacrylic resin layer B. The polyacrylic resin precursor emulsion is to help form a smooth surface inside and outside the mixed layer. Since the content of the polyacrylic resin precursor emulsion is very low, the strength is very low, and the polyacrylic resin precursor emulsion is heated to 85 ℃ for five minutes, and the polyacrylic resin precursor emulsion in the reaction vessel is still in a liquid state, so that only a very thin polyacrylic resin layer is formed outside the mixing layer except the polyacrylic resin layer and the middle mixing layer which are formed in the innermost layer during heating and curing.
S6: and taking out the solidified sample, placing the sample in acetone, and carrying out ultrasonic treatment for one hour to completely dissolve the mould so as to obtain the transparent and elastic blood vessel model.
The blood vessel model prepared by the steps is of a hollow three-layer structure, wherein the innermost layer is a polyacrylic resin layer A, the middle layer is a mixed layer formed by mixed liquid, and the outermost layer is a polyacrylic resin layer B, and has smooth surfaces inside and outside.
A section of a tube of suitable size was cut from the prepared vessel model, the shore hardness of the samples was measured using a hardness tester, the average was taken six times per group of samples, and the results are recorded in table 1.
From the prepared vessel model, the first, second and third branches were taken separately and cut along the longitudinal axis. The model thickness was measured using a vernier caliper, each branch was marked as a uniform 5-equal-piece, the thickness at 5 was measured, the mean and Relative Standard Deviation (RSD) were calculated, and the results are recorded in table 2.
The roughness of the inner surface of the vascular model was measured using a surface roughness meter, each branch was marked as a uniform 5-equal part, the surface roughness at 5 was measured, the average value was calculated, and the results are recorded in table 3.
Example 2 preparation of vascular model 2 and measurement of Performance
The vascular mold was the same as in example 1.
S1: 100 mL purified water, 10 mL glycerol, 3 mL Tween 80, 5mL of triton X-100 were added to the beaker and stirred well.
S2: to the solution of S1, a mixture of 5 g ethyl acrylate and 5 g methyl methacrylate was added dropwise at a rate of 10 mL/min, while 0.1 g potassium persulfate was added, and after completion of the addition, stirring was carried out for 30 minutes to obtain a polyacrylic resin precursor emulsion.
S3: immersing a blood vessel die into the polyacrylic resin precursor emulsion prepared in the step S3 at a constant speed of 0.5 mm/S, taking out at a constant speed of 5 mm/S after the blood vessel die is immersed completely, standing in the air in a dark place for standby, and wrapping a layer of polyacrylic resin on the outer surface of the blood vessel die; and taking out the polyacrylic resin precursor emulsion after the vascular mold for standby.
S4: the vinyl-terminated dimethyl (siloxane and polysiloxane) 10 g, the dimethylvinylated and trimethylated silica 1.0 g, and the dimethylmethylhydrogen (siloxane and polysiloxane) 0.2 g were weighed, mixed uniformly, and then vacuumed to remove air bubbles to obtain a mixed solution. Slowly pouring the mixed solution into the polyacrylic resin precursor emulsion to be used in the step S3, wherein the mixed solution floats above the polyacrylic resin precursor emulsion to obtain a multiphase solution.
S5: and (3) immersing the vascular mould to be used in the step (S3) into the multiphase solution of the step (S4) at a constant speed of 5 mm/S until the mould is positioned below the mixed solution, immersing the vascular mould in the polyacrylic resin emulsion completely, heating to 70 ℃, and maintaining for ten minutes to form an innermost polyacrylic resin layer A, an intermediate layer mixed layer and an outermost polyacrylic resin layer B, wherein the points similar to those in the embodiment 1 are not repeated.
S6: and taking out the solidified sample, placing the solidified sample in dimethyl sulfoxide, and carrying out ultrasonic treatment for three hours to completely dissolve the mould so as to obtain the transparent and elastic vascular model.
A section of a tube of suitable size was cut from the prepared vessel model, the shore hardness of the samples was measured using a hardness tester, the average was taken six times per group of samples, and the results are recorded in table 1.
Table 1 shore hardness test results
In the hardness test, the Shore hardness of the vascular model tube is 38.6-45.4 HA, and similar to the result 39 HA-46 HA of the known biological sample, the Shore hardness range of the vascular model prepared by the method basically covers the Shore hardness range of the existing biological blood vessel. The method shows that the physical properties of the blood vessel model prepared by the method are consistent with those of the organism blood vessel when the organism blood vessel is extruded and pulled; the final effect of the embolic agent is determined by the performance, so that the vascular model provided by the invention can predict the behavior of the embolic agent in a real vascular environment.
From the prepared vessel model, the first, second and third branches were taken separately and cut along the longitudinal axis. The model thickness was measured using a vernier caliper, each branch was marked as a uniform 5-equal-piece, the thickness at 5 was measured, the mean and Relative Standard Deviation (RSD) were calculated, and the results are recorded in table 2.
Table 2 uniformity test results
From the results, the model is in the same branch, and the RSD of the thickness is within 2.0% under the conditions of different branches and different diameters, so that the model has quite good uniformity. The behavior of the embolic agent in the model needs to be accurately observed and recorded, while the visibility of the model is affected by the thickness and uniformity of the material, and refractive changes due to uneven thickness affect the field of view, and ultimately the observation result. The blood vessel model prepared by the method has uniform thickness and clear visual field.
Example 3 roughness test
The obtained vascular model was subjected to a roughness test, and the results are shown in table 3.
Table 3 roughness test results
The roughness of the internal surface of the vascular model can affect the test performance of the model. From the results, it can be seen that the surface roughness of the inner surface of the model of example 1 in different branches is substantially uniform, and the value is only 0.627-0.633 μm, which is lower than the inner surface roughness of the model of comparative example 3 measured later. The smooth inner surface can reduce friction of the embolic agent therein, and avoid the phenomenon of premature embolism caused by accumulation of the embolic agent due to friction.
Example 4: embolic agent in-vitro simulation testing device
An embolic agent in vitro simulation test device, as shown in FIG. 2, comprises a delivery module, a circulation module, and a vascular model derived from the vascular model made in example 1. Wherein:
the conveying module is used for injecting embolic agent and detecting injection force and comprises a power device, an injection device, a conveying pipeline, a pressure sensing plane, a signal processing component and a signal display component; the power device uses a syringe pump, such as a Boodi wound LSP02-3B syringe pump; the injection device is a syringe, and in the embodiment, a syringe with a luer connector and a capacity of 2.5 and mL is adopted; the pressure sensing plane is fixed on a pushing end of the injection pump, wherein the pushing end refers to one end of the injection pump which can push the injector to inject embolic agent; the signal display part, the signal processing part and the pressure sensing plane are electrically connected in sequence, and specifically, the pressure sensing plane can be a clam-transmitted BCM-H1 model product; the signal processing component and the information display component can be integrated products, such as products adopting mussel XMT808-I model; when the injection pump pushes the injector to inject the embolic agent into the blood vessel model, a pressure sensing plane positioned between the injection end of the injection pump and the injector converts the injection force exerted on the plane into an electric signal, and the mussel transmits XMT808-I to convert the electric signal into a pressure value and display the pressure value on a display screen.
The circulation module is used for simulating blood circulation flow in a blood vessel and comprises a peristaltic pump, a circulation pipeline 1, a circulation pipeline 2 and a liquid storage part; a section of rubber tube with the inner diameter of 5-mm is used as a circulating pipeline 1, one end of the rubber tube is connected with an inlet of a blood vessel model through a luer connector, the middle section of the rubber tube is arranged on a peristaltic pump, and the other end of the rubber tube is placed in a liquid storage part; the vessel model inlet is an inlet of a first-stage branch. Another section of rubber hose with the inner diameter of 5 mm is used as a circulating pipeline 2, one end of the rubber hose is connected with an outlet of the blood vessel model through a luer connector, and the other end of the rubber hose is placed in the liquid storage part, so that physiological simulation liquid circularly flows in the blood vessel model. Specifically, the three-level branch ends of the blood vessel model are all provided with outlets, the blood vessel model can be placed in a container, so that physiological simulation liquid can flow out of the three-level branch ends and then enter the container, the outlets arranged on the container are used as outlets of the blood vessel model, the outlets are connected with one end of a luer connector, and the other end of the luer connector is communicated with the liquid storage part.
The conveying pipeline in the conveying module adopts a catheter with the inner diameter of 0.038 inch, one end of the syringe is connected with one end of the catheter through a luer connector, and the other end of the catheter is inserted into the vascular model; because one end of the circulating pipeline 1 is connected with the inlet of the blood vessel model through the luer connector, the other end of the catheter can be inserted into the circulating pipeline 1 of which the circulating module is positioned at the inlet of the blood vessel model, namely the conveying module is communicated with the blood vessel model through the circulating module, and the embolic agent is injected into the blood vessel model in a pushing way; in other embodiments, a small opening may be formed in the vascular model adjacent to the inlet of the circulatory module, such that the delivery module may access the vascular model through the small opening and bolus the embolic agent.
Example 5 microsphere embolic agent test
Microsphere embolic agent testing was performed using the apparatus of example 4, and model was tested using laboratory-self-made 40-89 μm,90-149 μm,150-299 μm,300-500 μm microsphere samples.
S1: physiological saline is selected as physiological simulation liquid, the physiological saline is added into the liquid storage part, the rotating speed of the peristaltic pump is set to be 10 rpm/min, and the peristaltic pump is started to start circulation.
S2: iodixanol 320 was first mixed with physiological saline 1:1, and then mixing the microsphere embolic agent with the particle size of 150-299 mu m with the mixed solution in a ratio of 1:9, after uniformly mixing the volume ratio, extracting 2.5mL of microsphere mixed solution by using a syringe, fixing the syringe on a syringe pump, setting the injection speed of the syringe pump to be 1 mL/min, and starting the syringe pump.
S3: after all the embolic agent is injected into the vascular model, the injection time is set to 2 min, and the maximum injection force value on the signal display part in the injection process of the embolic agent is read and recorded, and is recorded in table 4 as a conveying performance test result, and is tested for 6 times. The pushing force in the conveying process can reflect the conveying performance of the embolic agent, and the larger the pushing force is, the worse the conveying performance is.
S4: the stagnant position of the embolic agent in the blood vessel model at the end of the bolus injection was recorded, the bolus injection of physiological saline to the embolic site (stagnant position of the embolic agent in the blood vessel model) was continued at a rate of 1 mL/min by means of a syringe pump, a syringe and a catheter, the stagnant position of the embolic agent was recorded, and the maximum distance of movement of the embolic agent under the last bolus injection was measured, and as a result of the embolic performance test, recorded in table 5, 6 times in total. In practical applications, it is desirable that the embolic agent does not migrate under external forces after successful embolization. Therefore, the pushing force is applied again after the embolism is completed, and the displacement generated by the pushing force after the embolism is recorded again as an embolism performance index; the smaller the displacement, the better the embolic performance.
TABLE 4 results of the transport Performance test of microsphere embolic agent with particle size of 150-299 μm
As can be seen from the results of Table 4, in the delivery performance test, the embolic sample used was smoothly delivered in the device, the average value of the measured maximum bolus force was 35.91N, and the relative standard deviation RSD was 1.28%, with good stability.
TABLE 5 embolic Performance test results of microsphere embolic agent with particle size of 150-299 μm
In the embolic performance test, the displacement of the embolic sample used at the point of reaching the embolism was 0.00 mm, reflecting that the embolic sample had good embolic performance.
S5: the distribution position of the embolic agent in the vascular model with the spatial structure is not only related to the matching degree of the particle size and the tube diameter, but also influenced by the space of the bent tube diameter. The behavior of embolic agents of different particle sizes in blood vessels is different, and an excellent vascular model should reflect the difference in the distribution of different particle sizes in blood vessels. The embolic agent (40-89 μm,90-149 μm,150-299 μm,300-500 μm) with different particle size specifications is replaced, and the steps S1-S4 are repeated. The distribution of the embolic agent in the blood vessels of each level after the embolic agent has been reached was observed. After the injection is completed, observing and comparing under a microscope, and when the microspheres accounting for 10% or more of the total injection amount are observed in the pipeline, considering that the microspheres are distributed in the pipeline of the grade; otherwise, the results are recorded in Table 6.
TABLE 6 distribution of embolic agents
Note that: diagonal bars "/" indicate that embolic agent is not distributed in this class of branches.
The results show that the simulation test device can distinguish the differences of the distribution conditions of the embolic agents with different particle size specifications in blood vessels of different levels after the embolic agents reach the embolism, so that the simulation test device can be used for testing the embolic agents, and further can be used for determining the actual blood vessel level of the embolic agents in actual application.
Comparative example 1
Comparative example 1 the same parameters as in example 1, namely, comparative example 1 in which only the vascular mold was immersed in the mixed solution, were identical to those of example 1 except that the contents concerning the polyacrylic resin precursor emulsion in steps S2 to S3 and S4 were omitted. Hardness and uniformity of comparative example 1 were tested according to the method in example 1, and the results are recorded in table 1, table 2.
From the test results, the hardness of comparative example 1 is significantly lower than that of example 1, and the real blood vessel hardness cannot be simulated; this is due to the lack of a critical step to incorporate the polyacrylic resin, which can increase the hardness of the finished product. In addition, comparative example 1 has a uniformity test of RSD of 5.78% at the minimum and 6.20% at the maximum, and is poor in uniformity and uneven in surface, which affects the visual line, due to lack of a polyacrylic resin precursor emulsion that can reduce surface tension and increase the overall fluidity in cooperation with the mixed solution, and the final model cannot exhibit good uniformity.
Comparative example 2
Comparative example 2 the parameters were the same as in example 1 except that the ethyl acrylate portion was removed in step S2. The hardness and uniformity of comparative example 2 were tested according to the method in example 1, and the test results are recorded in table 1, table 2.
From the test results, the hardness of comparative example 2 is significantly lower than that of example 1, and the real blood vessel hardness cannot be simulated; this is because ethyl acrylate is a critical part in the formation of polyacrylic resins, and the lack of this component will not result in the formation of polyacrylic resins, resulting in lower hardness of the finished product. In addition, the RSD of comparative example 2 was 6.73% minimum and 7.01% maximum, uniformity was poor and line-of-sight was not smooth on the surface due to lack of the polyacrylic resin precursor emulsion which could reduce the surface tension of the mixed solution and increase the overall fluidity, and the final model could not exhibit good uniformity.
Comparative example 3
Comparative example 3 the parameters were identical to those of example 1, except that step S3 was omitted. The roughness of comparative example 3 was tested according to the roughness test method in example 1, and the results are recorded in table 3. Embolic agents of different particle sizes (40-89 μm,90-149 μm,150-299 μm,300-500 μm) were tested for embolic agent distribution performance using an in vitro simulated test device according to the method of example 4, the embolic microsphere distribution locations for each particle size were recorded, and the results are recorded in Table 6.
In the roughness test experiment of comparative example 3, the internal surface roughness of the prepared blood vessel model was high because the lack of the polyacrylate precursor emulsion capable of reducing the surface activity formed a thin layer on the internal surface of the blood vessel model after the lack of the S3 step, resulting in a higher roughness of the internal surface of the blood vessel model after curing. In the distribution experiment of comparative example 3, 40-89 μm embolic microspheres were distributed in the primary and secondary blood vessels, and the remaining particle size microspheres were all stagnant in the primary blood vessel. Comparative example 3 was unable to distinguish between 90-149 μm,150-299 μm,300-500 μm particle size embolic agent distribution in blood vessels, reflecting that comparative example 3 was not good in its ability to distinguish between differing particle size embolic agent distribution. The method is characterized in that after the step S3 is lacking, the prepared vascular model is high in inner surface roughness, the embolic agent is blocked in advance in the model under the influence of friction on the inner surface of the model, and cannot be smoothly distributed to more sub-branches, so that the difference of the distribution performance of the embolic agent with different particle diameters cannot be distinguished for the embolic agent by the model finally.
Claims (16)
1. A blood vessel model, which is characterized in that the blood vessel model is of a hollow multilayer structure, the innermost layer is a polyacrylic resin layer A, and the outer layer of the polyacrylic resin layer A is a mixed layer of vinyl-terminated dimethyl (siloxane and polysiloxane), dimethylvinylation and trimethylation silicon dioxide and dimethylmethyl hydrogen (siloxane and polysiloxane); in the mixed layer, the mass ratio of the vinyl-terminated dimethyl (siloxane to polysiloxane), the dimethylvinylated and trimethylated silica and the dimethylmethylhydrogen (siloxane to polysiloxane) is 1: (0.1-0.45): (0.01-0.02); the polyacrylic resin layer A comprises the following components in percentage by mass: 1. is obtained by mixing and polymerizing ethyl acrylate and methyl methacrylate.
2. The vascular model of claim 1, wherein the vascular model is of a hollow three-layer structure, the innermost layer is a polyacrylic resin layer a, the middle layer is a mixed layer of vinyl-terminated dimethyl (siloxane and polysiloxane), dimethylvinylated and trimethylated silica, dimethylmethylhydrogen (siloxane and polysiloxane), and the outermost layer is a polyacrylic resin layer B.
3. Vessel model according to claim 1 or 2, characterized in that the vessel model is a hollow structure imitating vessel morphology, comprising a plurality of branches, the connection parts between the branches are connected smoothly, each branch having a gradual pipe diameter which is changed from large to small.
4. A vessel model according to claim 3, characterized in that the vessel model has 1 primary branch, 3 secondary branches, each secondary branch connecting 2 tertiary branches; the diameter range of each level of branches of the blood vessel model is changed from 200 μm to 3000 μm, and the diameters of the branches are changed from large to small along with the extension of the trend of the branches.
5. A method for preparing a vascular model, comprising the steps of:
s1: the volume ratio of glycerin, tween 80, triton X100 to water is 1: (0.3-0.5): (0-0.5): (10-20) preparing a solution;
s2: the mass ratio of the solution prepared in the step S1 is 1:1, simultaneously adding potassium persulfate into a mixture of ethyl acrylate and methyl methacrylate, and uniformly stirring after the dripping is finished to obtain polyacrylic resin precursor emulsion;
s3: immersing the vascular mould into the polyacrylic resin precursor emulsion prepared in the step S2, taking out after the vascular mould is immersed completely, and standing in the air in a dark place for standby;
s4: the mass ratio is 1: (0.1-0.45): (0.01-0.02) vinyl-terminated dimethyl (siloxane and polysiloxane), dimethylvinylated and trimethylated silica, and dimethylmethylhydrogen (siloxane and polysiloxane), and mixing uniformly to obtain a mixed solution;
s5: immersing the vascular mould for standby in the step S3 into the mixed liquid until the vascular mould is completely immersed into the mixed liquid, and solidifying;
s6: and taking out the solidified sample, and completely dissolving the vascular mold to obtain the vascular model.
6. The method according to claim 5, wherein in the step S3, the polyacrylic resin precursor emulsion after the blood vessel mold is removed is used; in the step S4, adding the mixed solution into the polyacrylic resin precursor emulsion to be used in the step S3, wherein the mixed solution floats above the polyacrylic resin precursor emulsion to obtain a multiphase solution; in step S5, the vascular mold used in S3 is immersed in the multiphase solution until the mold is completely immersed in the polyacrylic resin precursor emulsion, and cured.
7. The method of preparing a vascular model according to claim 5 or 6, wherein in the step S2, the dripping speed of the mixture of ethyl acrylate and methyl methacrylate is 5-10 mL/min; the time for uniformly stirring after the dripping is completed is 30-45 min; the potassium persulfate: the mass ratio of the ethyl acrylate to the methyl methacrylate mixture is 1:100.
8. the method according to claim 5 or 6, wherein in the step S3, the vascular mold is immersed in the following manner: immersing at a constant speed of 0.5-5 mm/s; the mode of taking out after immersing completely is as follows: taking out at constant speed of 5-10 mm/s.
9. The method for preparing a vascular model according to claim 5 or 6, wherein in the step S5, the vascular mold is immersed in the following manner: immersing at a constant speed of 0.5-5 mm/s; the curing conditions in step S5 are: heating to 70-85 deg.c and curing for 5-10 min.
10. The method according to claim 5 or 6, wherein the vascular mold has a structure of a blood vessel-like morphology, comprising a plurality of branches, the connection portions between the branches being smoothly connected, each branch having a gradual pipe diameter which becomes smaller from large to small.
11. The method of preparing a vascular model according to claim 5 or 6, wherein the vascular mold has 1 primary branch, 3 secondary branches, each secondary branch connecting 2 tertiary branches; the diameter range of each level of branches of the vascular mould is changed from 200 μm to 3000 μm, and the diameters of the branches are changed from large to small along with the extension of the trend of the branches.
12. The method of claim 5 or 6, wherein the completely dissolving the blood vessel mold in S6 is dissolving with a solvent that is compatible with the blood vessel mold material; the vascular mold material is at least one of ABS, polylactic acid, polycaprolactone and starch-based material.
13. The method of preparing a vascular model according to claim 5 or 6, wherein the vascular mold is obtained by 3D printing.
14. An embolic agent in vitro simulation test device comprising a delivery module, a circulation module and the vascular model of any one of claims 1-4; wherein:
the conveying module is used for pushing and injecting embolic agent, and pushing and injecting the embolic agent into the blood vessel model;
the circulation module is used for driving the physiological simulation liquid to circulate in the blood vessel model.
15. The embolic agent in vitro simulation test device of claim 14, wherein,
the conveying module comprises a power device, an injection device, a conveying pipeline, a pressure sensing plane, a signal processing component and a signal display component; the signal display part, the signal processing part and the pressure sensing plane are electrically connected in sequence; the power device is used for pushing the injection device and pushing and injecting the embolic agent in the injection device into the blood vessel model; the pressure sensing plane is positioned between the power device and the injection device and is used for converting the injection force from the power device to push the injection device on the plane into an electric signal, the signal processing component converts the electric signal into a pressure value, and the signal display component displays the received pressure value; the outlet end of the injection device is communicated with the blood vessel model through a conveying pipeline;
the circulating module comprises a circulating power device, a circulating pipeline and a liquid storage part; the liquid storage part is communicated with the blood vessel model through a circulating pipeline; the circulating power device is connected to a circulating pipeline between the outlet of the liquid storage part and the inlet of the blood vessel model, so that physiological simulation liquid in the liquid storage part can flow into the blood vessel model; the physiological simulation liquid flows back to the liquid storage part from the outlet of the vascular model through another section of circulating pipeline.
16. The embolic agent in-vitro simulation test device of claim 15, wherein the circulation conduit is connected to the vascular model via a luer fitting, and/or the circulation conduit is connected to the reservoir via a luer fitting; the conveying pipeline is a conduit or a silica gel hose with a luer connector.
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| JP4841663B2 (en) * | 2009-09-30 | 2011-12-21 | 仁夫 岡野 | Vascular model for practicing stent graft insertion or aneurysm and suture surgery for aneurysms |
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