KR20210015523A - An artificial medical tube having multi-layered structure and a method of preparing the same - Google Patents

Abstract

The present invention provides a multi-layered medical artificial tube structure, and a method of producing the same. According to the present invention, the multi-layered medical artificial tube structure comprises: a porous inner wall layer which forms an inner wall of a medical artificial tube structure and is made of a first biocompatible water-insoluble polymer; an intermediate layer which is applied onto an outer surface of the porous inner layer and made of a water-insoluble polymer having high flexibility and resilience; and an outer wall layer which is applied onto an outer surface of the intermediate layer and made of a second biocompatible water-insoluble polymer. The multi-layered medical artificial tube structure according to the present invention has biocompatibility that is less irritating to the body and does not cause immune rejection as well as mechanical properties similar to those of the vascular tissue of the human body, such as the blood vessel, thereby being usefully used as a medical artificial tube that can replace the phloem of the human body, such as a blood vessel, a neural tube, a bile duct, and a small intestine tube.

Description

An artificial medical tube having multi-layered structure and a method of preparing the same}

The present invention relates to a medical artificial tube that can replace various phloems of the human body, such as blood vessels, neural tubes, bile ducts, and small intestine ducts, and a method of manufacturing the same.

Model experiments that can reliably represent diseases to replace human body ducts such as blood vessels, neural ducts, bile ducts, and small intestines according to diseases or aging of animals including humans, or for the prevention, diagnosis, and treatment of phloem-related diseases To do this, medical artificial tubes are being developed. For example, artificial blood vessels representing tubes are used to replace damaged blood vessels or connect blood vessels to blood vessels for smooth supply of blood to organs due to blood vessel damage, obstruction, and fistula.

As a method of manufacturing such a medical artificial tube, a method of weaving fibers such as polyester or extruding/drawing a polymer such as polytetrafluoroethylene was used, but in order to provide an artificial tube closer to the actual blood vessel Various manufacturing methods have been proposed.

For example, Korean Patent Publication No. 10-1728773 (Patent Document 1) is produced as a substrate for artificial blood vessels by spinning polytetrafluoroethylene in a tube shape, and pores are removed by removing the lubricant contained in the spinning solution. Disclosed is a method of manufacturing an artificial blood vessel in which is formed.

Republic of Korea Patent Laid-Open Publication No. 10-2013-0088231 (Patent Document 2) uses polyvinyl alcohol to form a tube-shaped polyvinyl alcohol model in which the lower end of the tube body is branched with a molding mold, and the tube-shaped polymer model Disclosed is a method of manufacturing a nanofiber tube for artificial blood vessels in which a tube-like polyvinyl alcohol model is eluted after a nanofiber layer is laminated through electrospinning.

Republic of Korea Patent Publication No. 10-0205360 (Patent Document 3) describes a vascular circular shaping process for shaping a molded product into a blood vessel shape according to accurate vascular shape statistics, a silicone application process for applying silicone to the outer surface of the model, and Disclosed is a method of manufacturing a model blood vessel comprising a process of removing a molding material to remove a molding material inside which silicone is applied.

Republic of Korea Patent Publication No. 10-1686437 (Patent Document 4) is a step of using a 3D printer to produce a soluble or decomposable structure that is a support having the same or similar shape as a medical artificial tube; Coating a polymer solution having different physical or chemical properties from the structure on the surface of the soluble or degradable structure; It provides a method for manufacturing a medical artificial tube using a three-dimensional printing structure including; dissolving or decomposing the structure while allowing the coated polymer solution to remain in a solid form to obtain a medical artificial tube.

However, the medical artificial tube manufactured in this way is insufficient in biocompatibility or does not have the mechanical properties that an actual phloem has to have, such as ductility, and thus it is necessary to develop a medical artificial tube having properties similar to the actual phloem.

Patent Document 1: Korean Registered Patent Publication No. 10-1728773 Patent Document 2: Korean Patent Application Publication No. 10-2013-0088231 Patent Document 3: Korean Patent Publication No. 10-0205360 Patent Document 4: Korean Patent Publication No. 10-1686437

An object according to an aspect of the present invention is to provide a medical artificial tube that has biocompatibility and has mechanical properties similar to the vascular tissues of the human body such as blood vessels, as invented in consideration of the above problems.

Another object of the present invention is to provide a manufacturing method for effectively manufacturing the aforementioned medical artificial tube.

In order to achieve the above object, the present invention,

A hollow porous inner wall layer made of a first biocompatible water-insoluble polymer and constituting the inner wall of the medical artificial tube structure;

An intermediate layer coated on the outer surface of the hollow porous inner wall layer and made of a water-insoluble polymer having high flexibility and resilience; And

It is coated on the outer surface of the intermediate layer, and the outer wall layer made of a second biocompatible water-insoluble polymer; providing a medical artificial tube multilayer structure.

In the medical artificial tube multilayer structure of the present invention, the first biocompatible water-insoluble polymer and the second biocompatible water-insoluble polymer are independently of each other, respectively, polycaprolactone, polyethylene, polypropylene, polyamide, polymethylmethacrylate, and chloride. Polyvinyl, polyglycolic acid, polylactic acid, polylactic-glycolic acid copolymer, etc. can be used at least one kind, and the water-insoluble polymer having high flexibility and resilience is polyurethane such as thermoplastic polyurethane, natural rubber, At least one kind of synthetic rubber, silicone elastomer, etc. may be used.

In the medical artificial tube multilayer structure of the present invention, the first biocompatible water-insoluble polymer and the second biocompatible water-insoluble polymer are polycaprolactone, respectively, and the water-insoluble polymer having high flexibility and resilience is a thermoplastic polyurethane. It is more preferable.

In the medical artificial tube multilayer structure of the present invention, the hollow porous inner wall layer, the intermediate layer and the outer wall layer may each independently have a multilayer structure of two or more layers, for example, the total thickness of the hollow porous inner wall layer is 10 to 1000 μm, The total thickness of the intermediate layer may be 10 to 1000 μm, and the total thickness of the outer wall layer may be 10 to 1000 μm.

In the medical artificial tube multilayer structure of the present invention, it is preferable that the hollow porous inner wall layer further contains an antithrombotic agent.

In addition, the present invention in order to achieve the above object,

(S1) preparing a hollow medical artificial tube template formed of a water-soluble polymer;

(S2) A coating solution in which water-soluble powders are dispersed and a first biocompatible non-aqueous polymer is dissolved in a solvent is coated on the outer surface of the medical artificial tube template, the solvent is removed, and the water-soluble powders are dissolved in water, and the medical artificial tube template Forming a porous inner wall layer on the outer surface of the;

(S3) forming an intermediate layer on the outer surface of the porous inner wall layer by coating an outer surface of the porous inner wall layer with a coating solution in which a water-insoluble polymer having high flexibility and resilience is dissolved in a solvent and removing the solvent;

(S4) coating an outer surface of the intermediate layer with a coating solution in which a second biocompatible non-aqueous polymer is dissolved in a solvent, and removing the solvent to form an outer wall layer; And

(S5) dissolving and removing the medical artificial tube template with water; including, a method of manufacturing a medical artificial tube multilayer structure.

In the method of manufacturing a medical artificial tube multilayer structure of the present invention, the water-soluble polymers that can be used include polyvinyl alcohol, maltitol, gelatin, etc., and the first biocompatible non-water-soluble polymer, the second biocompatible non-water-soluble polymer And the water-insoluble polymer having high flexibility and resilience is as described above. The water-soluble powder is preferably a salt, and the water-soluble powder may have an average particle diameter of 10 to 50 μm, but is not limited thereto. In addition, the thickness of the porous inner wall layer formed in the step (S2) may be 1 to 2 times the average particle diameter of the water-soluble powder.

In the method of manufacturing a medical artificial tube multilayer structure of the present invention, the step of (S3) may be repeated two or more times, or the steps of (S2) and (S4) may be repeated two or more times independently of each other. have. In addition, it is preferable to further add an antithrombotic agent to the coating solution of (S2).

The medical artificial tube multilayer structure of the present invention has a hollow inner wall layer and an outer wall layer made of biocompatible polymers in contact with biological tissues such as blood, so that there is little stimulation in the body and does not cause an immune rejection reaction. In addition, since the inner wall layer has porosity similar to that of human vascular tissue, stiffness can be reduced and a good strain rate is shown.

In addition, the intermediate layer of the medical artificial tube multilayer structure of the present invention is made of a polymer having high flexibility and resilience, has low stiffness, and exhibits good resilience due to excellent elastic behavior even when stretched at a high strain rate.

Therefore, the medical artificial tube multilayer structure of the present invention has good biocompatibility and can exhibit mechanical properties similar to vascular tissues of the human body such as blood vessels, and thus, a medical artificial tube that replaces the phloem of the human body such as blood vessels, neural tubes, bile ducts, and small intestine ducts. It can be used very usefully.

On the other hand, according to the method of manufacturing a medical artificial tube multilayer structure of the present invention, an artificial tube multilayer structure having a porous inner wall layer in which the pore network is well dispersed is formed by forming an inner wall layer including water-soluble powders and dissolving it. If necessary, by performing multi-stage coating in each coating step to form two or more layers, a medical artificial tube multilayer structure having a desired thickness can be effectively manufactured.

The following drawings attached to the present specification illustrate preferred embodiments of the present invention, and serve to further understand the technical idea of the present invention together with the detailed description of the present invention, which will be described later. It is limited to and should not be interpreted.
1 is a schematic exploded perspective view of a cross section of a medical artificial tube multilayer structure according to an embodiment of the present invention.
2 is a process chart explaining the manufacturing process of the 3D soft tube.
3 is a photograph of a tubular structure manufactured by FDM-based 3D printing, a tubular structure manufactured by a dip coating method, a photograph of a cross section thereof, and a photograph of the mechanical compliance thereof.
4 is a graph comparing mechanical properties after coating PCL and TPU on a PVA template, respectively.
5 is a schematic diagram of a process of performing dip coating using a polymer solution in which salt powder is dispersed, and a SEM photograph showing the result thereof.
6 schematically illustrates a case in which a plurality of dip coatings is performed, and a salt particle elution process is performed after a plurality of dip coatings are performed, and a salt particle dissolution process is performed at each step after each dip coating step is finished. It is a schematic diagram and a SEM photograph showing the result and a graph on the mechanical properties.
7 is a graph showing mechanical properties of porous and non-porous samples according to the type of polymer material.
8 is a table showing the numerical values of the mechanical properties of representative natural living tissues.
9 is a perspective cross-sectional view schematically showing a multilayered artificial tube structure, and a SEM photograph of a sample implementing the same and a graph showing mechanical properties.
10 is a photograph showing the results of needle punching and suture tension test of the artificial tube structure.

Hereinafter, preferred embodiments of the present invention will be described in detail with reference to the accompanying drawings. Prior to this, terms or words used in the specification and claims should not be construed as being limited to their usual or dictionary meanings, and the inventors appropriately explain the concept of terms in order to explain their own invention in the best way. Based on the principle that it can be defined, it should be interpreted as a meaning and concept consistent with the technical idea of the present invention. Accordingly, the embodiments described in the present specification and the configurations shown in the drawings are only the most preferred embodiment of the present invention, and do not represent all the technical spirit of the present invention, and thus various alternatives that can be substituted for them at the time of application It should be understood that there may be equivalents and variations.

1 is a schematic exploded perspective view of a cross section of a medical artificial tube multilayer structure according to an embodiment of the present invention.

Referring to FIG. 1, the medical artificial tube multilayer structure 10 constitutes an inner wall of the medical artificial tube structure, and includes a hollow porous inner wall layer 1 made of a first biocompatible non-water-soluble polymer. In the medical artificial tube multilayer structure 10 of the present invention, since the hollow porous inner wall layer 1 comes into contact with a living body tissue such as blood through the hollow portion 2, it is formed of a non-aqueous polymer having biocompatibility. As the first biocompatible non-aqueous polymer, any polymer material that does not stimulate the body and does not cause an immune rejection reaction can be used.For example, polyethylene and polypropylene in addition to polycaprolactone, a material already approved by FDA as a biocompatible polymer , Polyamide, polymethyl methacrylate, polyvinyl chloride, polyglycolic acid, polylactic acid, polylactic-glycolic acid copolymer, and the like may be used at least one or more.

In addition, the hollow porous inner wall layer 1 has a porosity similar to that of a human vascular tissue, and the porosity can be adjusted equally or similarly according to the required phloem of the human body. As the coating layer becomes porous, stiffness of the inner wall layer 1 is lowered and a good strain rate can be exhibited, and when an antithrombotic agent is further included, good antithrombosis retention power can be secured.

In the medical artificial tube multilayer structure 10 of the present invention, an intermediate layer 3 made of a water-insoluble polymer having high flexibility and resilience is coated on the outer surface of the hollow porous inner wall layer 1. The hollow porous inner wall layer 1 made of a conventional biocompatible water-insoluble polymer such as polycaprolactone has a higher modulus of elasticity than soft tissues such as blood vessels of the human body despite being porous, so the elastic deformation rate is not high. Accordingly, by forming the intermediate layer 3 of a polymer having high flexibility and resilience on the outside of the hollow porous inner wall layer 1, the medical artificial tube multilayer structure 10 has low stiffness and high strain rate. Even when it is stretched, it has a high resilience by supplementing it so that its elastic behavior is excellent.

Polyurethane such as thermoplastic polyurethane is typically known as a water-insoluble polymer having such high flexibility and resilience. At least one or more types of natural rubber, synthetic rubber, and silicone elastomer can be used.

In the medical artificial tube multilayer structure 10 of the present invention, the outer wall layer 5 made of a second biocompatible water-insoluble polymer is coated on the outer surface of the intermediate layer 3. Since the outer wall layer 5 also comes into contact with biological tissues such as blood, it is formed of a non-aqueous polymer having biocompatibility, as described above, like the first biocompatible non-aqueous polymer.

In the medical artificial tube multilayer structure 10 of the present invention, the first biocompatible water-insoluble polymer and the second biocompatible water-insoluble polymer are polycaprolactone, respectively, and the water-insoluble polymer having high flexibility and resilience is thermoplastic. It is more preferable that it is polyurethane.

Meanwhile, in the medical artificial tube multilayer structure 10 of the present invention, the thickness and mechanical properties of each layer can be adjusted by forming a multilayered structure of two or more layers independently of each other as needed. . The total thickness of the porous inner wall layer may be 10 to 1000 μm, the total thickness of the intermediate layer may be 10 to 1000 μm, and the total thickness of the outer wall layer may be 10 to 1000 μm, but are not limited thereto.

As described above, the medical artificial tube multilayer structure 10 of the present invention is a multilayer structure having a hollow inner wall layer/intermediate layer/outer wall layer, and has good biocompatibility and can exhibit mechanical properties similar to the vascular tissues of the human body such as blood vessels, It can be very useful as a medical artificial tube that replaces the body tube of the human body such as blood vessels, neural tubes, bile ducts, and small intestines.

The medical artificial tube multilayer structure 10 having the above-described structure can be manufactured by the following method.

First, a hollow medical artificial tube template formed of a water-soluble polymer is prepared (step S1).

The method of preparing a hollow medical artificial tube template using a water-soluble polymer is preferably manufactured using a three-dimensional printer as disclosed in Patent Document 4 (Korean Patent Publication) of the present applicant. In other words, after specifying the internal tube structure of the patient needed through various means for imaging the body such as ultrasound, computed tomography, magnetic resonance imaging, or through surgery (can be omitted if individual customization is not required) , Using this data, a medical artificial tube template can be prepared by 3D printing the material. The interior of the medical artificial tube template manufactured according to step (S1) is a hollow type with an empty inside, such as human tubular tissues such as blood vessels. Preferably, the interior of the manufactured medical artificial tube template is preferably formed by sealing end portions so that external fluid does not penetrate.

The material for the medical artificial tube template is a water-soluble polymer that can be dissolved in water, which is the most common solvent. For example, one or more water-soluble polymers such as polyvinyl alcohol, maltitol, and gelatin may be used.

Next, a coating solution in which water-soluble powders are dispersed and a first biocompatible non-aqueous polymer is dissolved in a solvent is coated on the outer surface of the medical artificial tube template, the solvent is removed, and the water-soluble powders are dissolved in water, A porous inner wall layer is formed on the outer surface (step S2).

The water-soluble powder is used to make the porous inner wall layer have porosity similar to human vascular tissue. The polymer coating solution in which water-soluble powders are dispersed as a solid component is coated on the outer surface of a medical artificial tube template and then the solvent is removed by a hot air dryer or the like to form a solid inner wall layer. Then, water-soluble powders are dissolved in water by treating the surface of the artificial tube template on which the inner wall layer is formed with water using a method such as immersion. Accordingly, the water-soluble powders dispersed in the inner wall layer are eluted, and the inner wall layer is made porous (the treated water is dried and removed). The porosity of the inner wall layer can be adjusted equally or similarly by adjusting the size of the water-soluble powder and the dispersion concentration in the coating liquid according to the required characteristics of the body duct of the human body. As the coating layer becomes porous, the inner wall layer not only lowers stiffness and can exhibit a good strain rate, but also has good antithrombosis retention ability by retaining antithrombotic agents in the pores when an antithrombotic agent is further included in the coating solution. Can be secured.

The water-soluble powder is preferably a salt such as salt, and the water-soluble powder may have an average particle diameter of 10 to 50 μm, but is not limited thereto. In addition, if the water-soluble powder remains, it is preferable to completely elute the water-soluble powder, since it may cause side effects to the human body and may not have the desired porosity. If the thickness of the inner wall layer formed according to the step (S2) is too thick than the average particle diameter of the water-soluble powder, the water-soluble powder located inside the inner wall layer will not be eluted by water, so it is coated once according to step (S2). The thickness of the resulting porous inner wall layer is preferably adjusted to about 1 to 2 times the average particle diameter of the water-soluble powder to prevent residual water-soluble powder. In order to form an inner wall layer having a desired thickness, the above-described step (S2) may be repeated two or more times to form a porous inner wall layer having a multilayer structure. When the porous inner wall layer is multilayered, only the innermost wall layer can be porous.

As the first biocompatible non-aqueous polymer, the aforementioned polymer may be used, and the solvent is not limited as long as it is a solvent capable of dissolving the first biocompatible non-aqueous polymer such as DMF.

Then, a coating solution in which a water-insoluble polymer having high flexibility and resilience is dissolved in a solvent is coated on the outer surface of the porous inner wall layer and the solvent is removed to form an intermediate layer on the outer surface of the porous inner wall layer (step S3). .

The water-insoluble polymer having high flexibility and resilience is as described above, and the solvent is not limited as long as it is a solvent capable of dissolving the used polymer such as DMF. By forming an intermediate layer (3) made of a polymer having these characteristics on the outside of the porous inner wall layer, the medical artificial tube multilayer structure has low stiffness and is complemented to have excellent elastic behavior even when stretched at a high strain rate. You will be equipped with gilliance.

If the intermediate layer also needs to be porous, the above-described water-soluble powder can be dispersed in the coating solution of step (S3) to make the intermediate layer porous through the same process, and in order to form an intermediate layer having a desired thickness, the ( The intermediate layer having a multilayer structure may be formed by repeating the step S3) two or more times. When the intermediate layer is multilayered, it goes without saying that only the intermediate layer directly coated on the inner wall layer can be porous.

Subsequently, a coating solution in which a second biocompatible non-aqueous polymer is dissolved in a solvent is coated on the outer surface of the intermediate layer and the solvent is removed to form an outer wall layer (step S4). The second biocompatible water-insoluble polymer is as described above, and the solvent is not limited as long as it is a solvent capable of dissolving the used polymer such as DMF. Step S4 may be substantially the same as the step S2 except that the water-soluble powder is not used, and if necessary, the water-soluble powder may be dispersed in the coating solution and performed in the same manner as the step S2. The above-described step (S4) may be repeated two or more times to form an outer wall layer having a multilayer structure. When the outer wall layer is multi-layered, it goes without saying that only the outer wall layer directly coated on the intermediate layer can be porous.

After sequentially forming a porous inner wall layer/intermediate layer/outer wall layer on the outer surface of the hollow medical artificial tube template according to steps (S1) to (S4) described above, the medical artificial tube template is dissolved in water and removed (S5). step).

Since the medical artificial tube template is of a hollow type, for example, if water is injected into the inside of the template by cutting the distal end of the sealed template and immersing the template in water, the water-soluble template is dissolved and removed. A medical artificial tube with a multi-layered structure of inner wall layer, middle layer, and outer wall layer is completed.

Hereinafter, examples will be described in detail to illustrate the present invention in detail. Papers published through Journal of the Mechanical Behavior of Biomedical Meterialx 91 (2019) 193-201 are incorporated herein as a reference. However, the embodiments according to the present invention may be modified in various forms, and the scope of the present invention should not be construed as being limited to the embodiments described below. Embodiments of the present invention are provided to more completely describe the present invention to those of ordinary skill in the art.

Medical artificial tube Preparation of the template

Since the template must be removed without leaving any harmful residue in the last step, a representative water-soluble polymer, polyvinyl alcohol (PVA) was used. For 3D printing of PVA, a polymer in the form of a filament having a diameter of 1.75mm (PVA, ESUN, China) was used. The 3D printer was a custom-made system operated by the mechanism of ME (Material Extrusion) or FDM (Fused Deposition Molding). The nozzle temperature was set at 180 °C, the bed temperature was 50 °C, and the nozzle movement speed was set to 20mm/s. A 400 μm diameter dispensing nozzle was mounted on the extruder and the layering thickness was 0.15 mm. Thereafter, the product was subjected to ultrasonic treatment in water at 50 °C to planarize the surface.

Fabrication of tubular structure

The prepared PVA artificial tube template was immersed in the polymer solution. To compare the properties of the materials used, polycaprolactone (PCL, MW 80k, Sigma-Aldrich, US) and thermoplastic polyurethane (TPU, Daelim cemical, Korea) were used as materials for the dip coating comolecular solution. Both types were dissolved in DMF at a concentration of 15% (w/v), and after coating, the solvent was volatilized to coat the solid polymer film on the PVA template core. A tubular structure was fabricated by removing the PVA template from the core by immersing in sonicated water at 50 °C for 30 minutes after making an incision at the end of the coating so that water can penetrate into the tube.

In addition, a polymer solution containing salt was used in the dip coating step in order to have a porous morphology of the tube wall. Salt particles (MW 0.44 Sigma-Aldrich) were pulverized, filtered through a 45 μm mesh, and mixed with a polymer solution at a concentration of 400% (w/w). After coating and drying the salt slurry, the coated part was immersed in sonicated water for 2 minutes to leach out the salt particles. The process for removing the PVA mold is as described above.

Evaluation of mechanical properties

Uniaxial tensile tests were performed using a uniaxial testing machine (E300LT, Instron, UK). As the sample, a tube (tube) prepared above was used, and the cylindrical PVA template was manufactured with a diameter of 10 mm and a height of 20 mm. After preparing specimens (three pieces each) with a height of 15 mm and a width of 5 mm, a tensile strength test was performed at a rate of 10 mm/min, and the data was displayed as an average value for three specimens at a 10 mm gauge length.

3D custom production of tubular structures

2 is a view explaining the entire manufacturing process of the 3D soft tube (tube). 3D customization started with acquiring 3D model data as shown in A and B of FIG. 2. 3D data can be selected by reconstructing and integrating 2D DICOM images obtained by multiple medical imaging technologies such as CT and MRI. The PVA template was successfully printed as shown in Fig. 2C.

Next, dip coating was performed on the PVA template. Four polymer solutions were used: 1) PCL (polycaprolactone) solution, 2) TPU (Thermoplastic Polyurethane) solution, 3) PCL solution in which salt particles are dispersed, and 4) TPU solution in which salt particles are dispersed. Each of these polymer solutions was dip-coated and the solvent was dried, and the core template was dissolved in water and removed to obtain the same tubular structure as the template (FIG. 2D).

3 is a photograph of a tubular structure manufactured by FDM-based 3D printing and a cross-section (FIG. 3A), a photograph of a tubular structure manufactured by a dip coating method and its cross-section (FIG. 3B), and This is a picture of their mechanical compliance. As shown in Fig. 3A, even in the case of printing with a single path, the wall thickness of the tube was 0.4 mm or more. However, the tube made by dip coating has a very thin wall as shown in FIG. 3B. Due to the difference in thickness, the printed tube and the dip coated tube exhibited mechanical compliance differences (FIG. 3C and D). As described above, it was confirmed that the manufacturing method of the tube by the dip coating method can produce a mechanically flexible tube that cannot be realized by 3D printing.

Mechanical properties of thin-walled tubes

Before quantitative evaluation of mechanical properties, the PVA template was immersed in water to smooth the surface. This makes it possible to rule out damage to the mechanical properties.

Fig. 4 shows the mechanical properties of each coating PCL and TPU compared. As expected, the dip-coated specimen showed a ductile behavior than the 3D printed specimen (Fig. 4A). 3D printed specimens were broken at 75%, while dip coated samples were broken at 289% for PCL coating and 449% for TPU coating. In terms of strength and elastic modulus, the dip coated sample showed better softness than the 3D printed sample. The tensile strength of the PCL 3D printed specimen, the tensile strength of the PCL coated specimen, and the tensile strength of the TPU coated specimen were 11.86 MPA, 1.98 MPa, and 5.65 MPa, respectively. In the same order, the elastic modulus (2% secant) was 174.38 MPA, 15.89 MPa, 6.66 MPa. As such, the method according to the polymer solution coating is superior to 3D printing in achieving mechanical flexibility.

In addition, selecting an appropriate soft material such as TPU can reduce the mechanical stiffness to 10 MPa or less, which is close to the level of flexible tissue.

Fabrication and characteristics of flexible porous tube

Despite the mechanical flexibility of the thin tubular parts, their properties are far from living tissues with a low elastic modulus of several MPa or kPa. To make the tubular structure more smooth, a salt-dissolution (leaching) step was introduced in the dip coating process.

5 is a schematic diagram of a process of performing dip coating using a polymer solution in which salt powder is dispersed, and a SEM photograph showing the result thereof. After dip coating the template in the polymer solution in which the salt particles were dispersed, the solvent was evaporated, and the salt particles contained in the solidified polymer film were immersed in sonicate water to dissolve.

M-SIEVE를 통해 필터링한) 기공 크기가 조절되고 기공은 필름의 표면과 내부에 전체적으로 잘 분산되어 위치하였다(도 5의 C) The film formed by coating the polymer solution without containing salt particles has a relatively smooth surface (Fig. 5B), but the film formed by eluting the salt particles after coating the polymer solution in which the salt particles are dispersed has a high porosity. You have a morphology. Depending on the size of the salt particles (45-

The pore size (filtered through M-SIEVE) was adjusted, and the pores were well distributed throughout the surface and inside of the film (Fig. 5C).

When the dip coating was treated in a single step, it was possible to obtain thin tubes with a wall thickness of less than 100 μm. In order to further control the thickness of the tube, a tube having a thickness of about 1 mm could be manufactured by performing a plurality of dip coating processes.

6 schematically illustrates a case in which a plurality of dip coatings is performed, and a salt particle elution process is performed after a plurality of dip coatings are performed, and a salt particle dissolution process is performed at each step after each dip coating step is finished. It is a schematic diagram and a SEM photograph showing the result and a graph on the mechanical properties. If the elution process of salt particles after performing a plurality of dip coatings is carried out after the coating process is completed, the coating thickness becomes thicker than the size of the salt particles due to the plurality of coating layers of the salt slurry, and salt particles that are not exposed to water are not eluted. It may remain inside the film (Fig. 6A). In the cross-sectional view of the multilayer coating film (left image in Fig. 6B), the middle region (dash box) appears to have low porosity due to incomplete leaching of salt particles. In the image on the right side of FIG. 6B, residual salts that are not leached on the inner surface of the film can be observed.

On the other hand, when the process of eluting the salt particles was repeated after each dip coating step (C in FIG. 6), it was observed that the pore network was well distributed without residual salt particles on both the inside and the surface of the film. 6E is a stress-strain curve of a PCL sample obtained after repeated leaching and post-leaching treatment. The repeated leached sample showed a 267% increase in draw ductility than the post-leached sample. Regarding flexibility, the elastic modulus of the repeated leached samples is about 30% lower than that of the post-leached samples (Fig. 6F). In addition, the post-leaching-treated sample shows a relatively large change in modulus. The deterioration properties of the post-penetration treated sample are due to residual salt particles distributed in the sample. Therefore, all leaching processes were carried out with the following repeated leaching process.

The material diversity of dip coatings influences the combination of particle-leaching processes. 7 is a graph showing mechanical properties of porous and non-porous samples according to the type of polymer material. For the PCL material, TPU can be used as a base material to be mixed with salt particles, and the salt-leached porous sample simply exhibits lower stiffness than the dip coated sample (Fig. 7A and B). To confirm the elastic properties, we conducted resilience tests on porous PCL and TPU samples. As shown in C of FIG. 7, the PCL sample showed non-recoverable plastic deformation upon 30% stretching. It showed elastic behavior within 20% stretching. The TPU sample showed good resilience after 50% stretching.

With a range of possible elastic resilience, the modulus of the samples was compared at different strain values (Fig. 7D).

Figure 8 shows the values of the mechanical properties of representative natural living tissues.

As a result of the experiment, the artificial porous structure (20% secant) was 4.67 MPa for PCL and 2.33 MPa for TPU, which is comparable to that of natural living tissue. The TPU sample was shown to have sufficient deformability in the high strain range with a 50% secant modulus of 1.47 MPa.

Artificial tube Fabrication of multilayer structures

9 is a perspective cross-sectional view schematically showing a multilayered artificial tube structure, and a SEM photograph of a sample implementing the same and a graph showing mechanical properties. 9A, the artificial tube multilayer structure is a multilayer structure formed by a multi-step dip coating process, and can be applied as a tube through which a physiological liquid such as blood passes. 9B is a cross-sectional SEM photograph of a multi-layer porous tube (PCL-TPU-TPU-PCL) manufactured by a process of repeatedly eluting salts each time each layer is dip-coated.

9C shows the tensile behavior of the hybrid tube and two different homogeneous PCL and TPU tubes. As expected, the hybrid multilayer porous tube (PCL-TPU-TPU-PCL) according to the present invention exhibited mechanical properties of the intermediate degree between a multilayer porous tube made of only PCL and a multilayer porous tube made of only TPU.

10 is a photograph showing the results of needle punching and suture tension test of the artificial tube structure.

FIG. 10A shows the results after needle-passing porous and non-porous tubes made of PCL and TPU, respectively, through an operating room. Porous PCL and porous TPU tubes show good resilience, while others (especially PCL non-porous tubes) show irreparable defects. In addition, the crack toughness of the sample against the tension of the permeated suture thread was tested and shown in FIG. 10B. When the suture thread was penetrated and pulled for stitching, all samples except TPU showed tailed crack traces in the pulling direction.

After the artificial tube structure is implanted in the human body, it is subjected to severe mechanical conditions. Therefore, resilience is one of the most important requirements. Although the PCL sample of the four-layer structure consisting of only PCL has a porous morphology, there is a limitation in recovery after wrinkle (FIG. 10C). In contrast, a PCL sample of a four-layer structure made of only TPU shows good resilience (Fig. 10D). The hybrid multilayer porous tube (PCL-TPU-TPU-PCL) showed an intermediate value but acceptable resilience (FIG. 10E).

1: hollow porous inner wall layer 2: hollow portion
3: middle layer 5: outer wall layer
10: medical artificial tube multilayer structure

Claims (19)

A hollow porous inner wall layer made of a first biocompatible water-insoluble polymer and constituting the inner wall of the medical artificial tube structure;
An intermediate layer coated on the outer surface of the hollow porous inner wall layer and made of a water-insoluble polymer having high flexibility and resilience; And
It is coated on the outer surface of the intermediate layer, the outer wall layer made of a second biocompatible water-insoluble polymer; having, a medical artificial tube multilayer structure. The method of claim 1,
The first biocompatible non-aqueous polymer and the second biocompatible non-aqueous polymer are independently of each other, respectively, polycaprolactone, polyethylene, polypropylene, polyamide, polymethyl methacrylate, polyvinyl chloride, polyglycolic acid, and polylactic acid. And at least one or more selected from the group consisting of polylactic-glycolic acid copolymers. The method of claim 1,
The medical artificial tube multilayer structure, characterized in that the water-insoluble polymer having high flexibility and resilience is at least one selected from the group consisting of polyurethane, natural rubber, synthetic rubber and silicone elastomer. The method of claim 1,
The first biocompatible water-insoluble polymer and the second biocompatible water-insoluble polymer are polycaprolactone, respectively, and the water-insoluble polymer having high flexibility and resilience is a thermoplastic polyurethane. The method of claim 1,
The intermediate layer is a medical artificial tube multilayer structure, characterized in that the multilayer structure of two or more layers. The method of claim 1,
The hollow porous inner wall layer and the outer wall layer is a medical artificial tube multilayer structure, characterized in that the multilayer structure of two or more, respectively. The method of claim 1,
The total thickness of the hollow porous inner wall layer is 10 to 1000 μm, the total thickness of the intermediate layer is 10 to 1000 μm, and the total thickness of the outer wall layer is 10 to 1000 μm. The method of claim 1,
The hollow porous inner wall layer is a medical artificial tube multilayer structure, characterized in that it further comprises an antithrombotic agent. (S1) preparing a hollow medical artificial tube template formed of a water-soluble polymer;
(S2) A coating solution in which water-soluble powders are dispersed and a first biocompatible non-aqueous polymer is dissolved in a solvent is coated on the outer surface of the medical artificial tube template, the solvent is removed, and the water-soluble powders are dissolved in water, and the medical artificial tube template Forming a porous inner wall layer on the outer surface of the;
(S3) forming an intermediate layer on the outer surface of the porous inner wall layer by coating an outer surface of the porous inner wall layer with a coating solution in which a water-insoluble polymer having high flexibility and resilience is dissolved in a solvent and removing the solvent;
(S4) coating an outer surface of the intermediate layer with a coating solution in which a second biocompatible non-aqueous polymer is dissolved in a solvent, and removing the solvent to form an outer wall layer; And
(S5) dissolving and removing the medical artificial tube template with water; including, a method of manufacturing a medical artificial tube multilayer structure. The method of claim 9,
The water-soluble polymer is at least one or more selected from the group consisting of polyvinyl alcohol, maltitol, and gelatin. The method of claim 9,
The method of manufacturing a medical artificial tube multilayer structure, characterized in that the water-soluble powder is a salt. The method of claim 9,
The first biocompatible non-aqueous polymer and the second biocompatible non-aqueous polymer are independently of each other, respectively, polycaprolactone, polyethylene, polypropylene, polyamide, polymethyl methacrylate, polyvinyl chloride, polyglycolic acid, and polylactic acid. And at least one selected from the group consisting of polylactic-glycolic acid copolymers. The method of claim 9,
The method of manufacturing a medical artificial tube multilayer structure, characterized in that the water-insoluble polymer having high flexibility and resilience is at least one selected from the group consisting of polyurethane, natural rubber, synthetic rubber, and silicone elastomer. The method of claim 9,
The first biocompatible water-insoluble polymer and the second biocompatible water-insoluble polymer are polycaprolactone, respectively, and the water-insoluble polymer having high flexibility and resilience is a thermoplastic polyurethane. Manufacturing method. The method of claim 9,
The method of manufacturing a medical artificial tube multilayer structure, characterized in that repeating the step of (S3) two or more times. The method of claim 9,
The method of manufacturing a medical artificial tube multilayer structure, characterized in that the steps of (S2) and (S4) are repeated two or more times independently of each other. The method of claim 9 or 15,
The method of manufacturing a medical artificial tube multilayer structure, characterized in that the average particle diameter of the water-soluble powder is 10 to 50 μm. The method of claim 9,
The method of manufacturing a medical artificial tube multilayer structure, characterized in that the thickness of the porous outer wall layer formed in the step (S2) is 1 to 2 times the average particle diameter of the water-soluble powder. The method of claim 1,
A method of manufacturing a medical artificial tube multilayer structure, characterized in that an antithrombotic agent is further added to the coating solution of (S2).

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