CN107789096B

CN107789096B - Method for manufacturing biomedical stent

Info

Publication number: CN107789096B
Application number: CN201610806706.6A
Authority: CN
Inventors: 陈敏嘉; 蔡逸峰
Original assignee: Eirbio Technology Co ltd
Current assignee: Caiyifeng; Chen Minjia
Priority date: 2016-09-07
Filing date: 2016-09-07
Publication date: 2021-10-26
Anticipated expiration: 2036-09-07
Also published as: CN107789096A

Abstract

The invention discloses a method for manufacturing a biomedical bracket, which comprises the following steps: and printing the biodegradable high molecular polymer into a porous substrate by using three-dimensional printing equipment. And acquiring a 3D image of the damaged biological tissue by combining medical tomography, and further acquiring a three-dimensional structure of the damaged part. Then, the porous base material is soaked in agar to fill the pores, and then put into liquid nitrogen to be frozen rapidly. Then, the base material in the frozen state is cut by the processing machine to form a bracket structure which has a customized shape and is in accordance with the shape of the damaged part. Once the agar melts, the scaffold returns to a porous structure, which can guide the adhesion and proliferation of cells to promote the regeneration and repair of biological hard tissues.

Description

Method for manufacturing biomedical stent

Technical Field

The present invention relates to a method for manufacturing a biomedical stent, and more particularly, to a method for manufacturing a biomedical stent capable of promoting the regeneration of a damaged biological tissue, using a bio-metabolizable high-molecular polymer.

Background

For regenerative medicine of damaged biological tissues, there is also a great progress with the evolution of tissue engineering technology. In order to regenerate damaged biological hard tissues (such as bones, etc.), the conventional tissue engineering technology has developed a related medical technology that uses a porous scaffold composed of a bio-metabolizable high molecular polymer to fill up the damaged parts and further promote the regeneration of the damaged biological hard tissues along the pores of the scaffold.

Since three-dimensional (3D) printing devices have the advantages of mature technology, low cost, easy customization, etc., most of the current methods for manufacturing porous scaffolds are to melt bio-metabolizable high molecular polymers by three-dimensional printing devices and then perform 3D printing to directly form porous scaffolds with specific three-dimensional structures (i.e., three-dimensional structures corresponding to damaged parts). However, this approach has a significant disadvantage. Because the high molecular polymer is printed by the three-dimensional printing equipment in a molten state, in other words, the high molecular polymer is in a molten state which can slightly flow when being printed; therefore, the pores at the outer surface Boundary (Boundary) of the porous scaffold are easily clogged by the melted and flowing high molecular polymer to lose the pores. Alternatively, the three-dimensional printing device may be used to print the high molecular polymer into a porous substrate in the shape of a flat cylinder or a cube, and then a Computerized Numerical Control (CNC) machine is used to cut the substrate into a porous scaffold with a specific three-dimensional structure corresponding to the damaged portion. However, the substrate is porous, so that the machining machine cannot precisely machine the substrate, and further improvement is needed.

Disclosure of Invention

Therefore, the main objective of the present invention is to provide a biomedical stent and a method for manufacturing the same, wherein a porous stent can be manufactured by using a bio-metabolizable high molecular polymer to promote the regeneration of damaged biological tissues, and the defects of non-porous outer surface boundary of the stent and non-precision machining of a machining machine, which are commonly found in the prior art, can be avoided.

In order to achieve the above object, the present invention provides a method for manufacturing a biomedical stent, comprising the steps of:

step (A): providing a substrate made of a polymer material and having a plurality of pores;

step (B): soaking the base material in a colloid filling liquid to fill the colloid filling liquid in the pores of the base material;

step (C): rapidly cooling the base material soaked with the colloid filling liquid to solidify the base material and the colloid filling liquid; and

step (D): and cutting the cured substrate into a scaffold having a predetermined three-dimensional (3D) structure and having pores.

In one embodiment, the polymer material is a biodegradable polymer, and is selected from one of the following sterile polymers: polycaprolactone (PCL), Polylactic Acid (PLA), Poly-L-lactic Acid (PLLA), Polyvinyl alcohol (PVA); and, the gum filling liquid is Agar (Agar).

In one embodiment, at least one of the following is added to the agar gel: biological tissue culture solution, biological tissue Growth Factor (Growth Factor), Bone Growth Protein (Bone mmorpathogenic Protein, abbreviated as BMP), and Nanocapsules (Nanocapsules).

In one embodiment, the polymer material is printed into the porous substrate by melting the polymer material and printing the melted polymer material into a stack of layers, each layer having a grid-like structure.

In one embodiment, in the step (C), the base material soaked with the colloid filling liquid is placed in a liquid nitrogen environment to achieve the effect of rapid cooling; and, in the step (D), the cured substrate is cut into the scaffold having a predetermined three-dimensional structure and a plurality of pores by a Computerized Numerical Control (CNC) machine.

In one embodiment, before performing step (D), a process for creating a machining path file is executed, which includes the following steps:

step (d 1): scanning a target object by an electronic device and obtaining a computer image of a three-dimensional (3D) model of the target object;

step (d 2): drawing the predetermined three-dimensional structure of the stent by using computer equipment according to a computer image of the three-dimensional model;

step (d 2): and determining and generating a processing path file for the computerized numerical control processing machine to cut the solidified substrate according to the predetermined three-dimensional structure of the support by using the computer equipment.

In one embodiment, the step (D) is followed by one of the following steps (E1), step (E2) or step (E3):

step (E1): continuously maintaining the cut stent with the solidified colloidal filling fluid at a low temperature for storage;

step (E2): raising the temperature of the cut stent to a proper temperature to enable the colloid filling liquid to melt and flow out of the pores of the stent;

step (E2): raising the temperature of the cut stent to a proper temperature to melt the colloid filling liquid and flow out of the pores of the stent, and then electrostatically adsorbing at least one of the following components: biological tissue growth factor, bone growth protein and nanocapsule.

The invention also provides a biomedical stent manufactured according to the manufacturing method, which comprises the following steps: the scaffold is composed of the high polymer material, has the predetermined three-dimensional structure and has a plurality of pores, and the colloid filling liquid is filled in the pores and is in a solidified state.

Drawings

FIG. 1 is a flow chart of an embodiment of a method of fabricating a biomedical stent of the present invention;

FIG. 2 is a schematic view of one embodiment of a three-dimensional printer suitable for use in the method of manufacturing a biomedical support of the present invention;

FIGS. 3A and 3B are schematic views of two embodiments of the porous structure on the substrate or the stent, respectively, according to the present invention;

FIG. 4 is a schematic view of an embodiment of the present invention showing a porous substrate immersed in a colloidal filling solution;

fig. 5 is a schematic diagram illustrating an embodiment of a computer image of a 3D model of the target in the method for manufacturing a biomedical stent according to the present invention.

Description of the symbols:

11-15, 21-22, 31-printing head

32~ pan feeding mouth 33~ roller train

34 to melter 35 to temperature controller

36 to discharge nozzle 37 to bearing platform

38-X-Y axis driver 39-Z axis driver

41 to 42 to base material of polymer material

421 to high molecular material 422 to high molecular material

43-colloid filler liquid 51-3D model

52. 53 to the damaged part

Detailed Description

In order to more clearly describe the biomedical support and the manufacturing method thereof, the present invention will be described in detail with reference to the accompanying drawings.

The invention discloses a plurality of bio-metabolizable high-molecular polymers, which are printed into a three-dimensional porous substrate after being melted by specific parameters of three-dimensional (3D) printing equipment. The shape structure of the substrate is suitable for the structure that a general Computerized Numerical Control (CNC) processing machine can clamp and process cutting. A3D image of a damaged biological tissue is acquired in combination with medical tomography, and image reconstruction modeling and post-processing are performed by a computer, so that a three-dimensional structure of the damaged part of the biological tissue and a processing path file (for example, but not limited to, stl file) of a processing machine are obtained. Then, the filling freezing method is used for soaking the porous base material in the agar and filling the pores with the agar, and then the base material and the agar in the pores are frozen and solidified in liquid nitrogen to temporarily present a non-porous state. At this time, the holder structure is cut by a processing machine to a customized shape that completely conforms to the shape of the damaged portion. Once the agar melts, the scaffold returns to a porous structure and can be used as a scaffold for tissue engineering to guide the attachment and proliferation of cells so as to promote the regeneration and repair of biological hard tissues. As regards the scaffold itself, it can also be metabolized and absorbed by the organism after a period of time, for example between half a year and a year, or even completely replaced by biological hard tissue. The high molecular polymer used in the invention mainly comprises Polycaprolactone (PCL) and Poly-L-lactic Acid (PLLA) singly or in a mixture, and the mixture is fed into 3D printing equipment for 3D printing to form the three-dimensional porous substrate after filament extrusion molding.

Referring to fig. 1, a flowchart of an embodiment of a method for manufacturing a biomedical support according to the present invention includes the following steps:

step 11: a porous substrate made of a polymer material is provided. In this embodiment, in step 11, the polymer material is printed into the porous substrate by a three-dimensional (3D) printer in a 3D printing manner in which the polymer material is melted and printed into a stack of layers, each layer having a grid-like structure. The substrate can later be processed into a porous scaffold with customized 3D structures.

In the invention, the high molecular material is a biodegradable high molecular polymer, and is selected from one of the following sterile materials: polycaprolactone (PCL), Polylactic Acid (PLA), Poly-L-lactic Acid (PLLA), Polyvinyl alcohol (PVA). In particular, in this embodiment, the polymer material may be Polycaprolactone (PCL) or Poly-L-lactic Acid (PLLA), either alone or in combination, and may be used for tissue engineering of damaged portions of biological hard tissues (e.g., bones, etc.) with best effect.

In this embodiment, the 3D printer may be, but is not limited to: a 3D printer using Fused Deposition Modeling (FDM) technology is preferred.

Step 12: soaking the base material in a colloid filling liquid to fill the colloid filling liquid in the pores of the base material. In this embodiment, the gum filling liquid is preferably liquid Agar, and the soaking time is up to or more than one minute, so that the liquid Agar can fill all pores of the substrate. The agar-agar jelly can be prepared by mixing agar powder and water, the weight percentage of the agar powder and the water can fall within the range of 1: 10-1: 1000 according to different agar jelly brands and characteristics, and the low-temperature setting agar jelly is particularly selected according to the temperature resistance of other matching materials. In another embodiment of the present invention, at least one of the following ingredients may be added to the agar gel: biological tissue culture solution, biological tissue Growth Factor (Growth Factor), Bone Growth Protein (BMP for short) and Nanocapsules (Nanocapsules), and the additives can promote cell proliferation and accelerate the repair of damaged parts of biological tissues.

Step 13: and rapidly cooling the base material soaked with the colloid filling liquid to solidify the base material and the colloid filling liquid. In this embodiment, the substrate soaked with the colloid filling liquid is placed in a liquid nitrogen environment for several seconds to achieve the effects of rapid cooling and rapid freezing to solidify the substrate and have a considerable hardness.

Step 14: and cutting the cured substrate into a scaffold having a predetermined three-dimensional (3D) structure and having pores. In this embodiment, the cured substrate with a certain degree of hardness (i.e., hardness that can be precisely cut by a Computer Numerical Control (CNC)) is machined by a CNC (Computer Numerical Control) machine into the scaffold with a predetermined three-dimensional structure corresponding to the damaged portion of the biological tissue and having a plurality of pores.

In the present invention, since the substrate is processed by the processing machine in a cured state (i.e. substantially temporarily equal to a solid object without voids) in which the voids are still cured and the agar gel with a considerable hardness is filled, there is no disadvantage in the prior art that the substrate cannot be accurately processed by the processing machine because it has a plurality of voids. In addition, because the bracket of the invention is manufactured by cutting a substrate with a relatively large size by a processing machine, the defect that the prior art has no pore at the boundary because the bracket structure is directly printed by a 3D printing device is avoided. Therefore, various defects of the prior art can be overcome by the manufacturing method of the biomedical stent.

In an embodiment of the present invention, before performing step 14, a process for creating a processing path file is executed to provide a process for cutting a substrate by a processing machine, which includes the following steps:

step 21: the target object is 3D scanned. In this embodiment, an electronic device scans an object and obtains a computer image of a three-dimensional (3D) model of the object. In this embodiment, a computer image file of a 3D model of a biological tissue (i.e., the target) having a damaged portion, such as but not limited to a computer image file conforming to Digital Imaging and Communications in Medicine (DICOM), can be obtained by scanning the biological tissue having the damaged portion through a Computer Tomography (CT) or Magnetic Resonance Imaging (NMR) technique and apparatus.

Step 22: and establishing a 3D model of the support and a processing path file. In this embodiment, the predetermined three-dimensional structure of the stent is drawn according to the computer image of the three-dimensional model by using a computer device in combination with the existing image editing software or other auxiliary software. In other words, the shape and structure of the damaged part are extracted or mapped from the 3D model of the target object as the predetermined three-dimensional structure of the stent. Then, using the computer device and the existing computer aided machining software, a machining path file for the cnc machine to cut the cured substrate is determined and generated according to the predetermined three-dimensional structure of the support, such as but not limited to: stl file.

In the method for manufacturing a biomedical stent of the present invention, after the step 14, one of the following steps (E1), step (E2) or step (E3) may be further included.

Step (E1): the stent, once cut and still having the solidified colloidal filler fluid, is continuously maintained in a cryogenically frozen state (e.g., without limitation, below 0 degrees celsius). According to the formula of the agar and the characteristics of the additives, the agar is maintained below zero ℃, so that the agar is in a solid state, the characteristics of the additives are not damaged, and the agar is convenient to store and transport. Heating to a temperature suitable for application to a damaged portion of biological tissue while the colloidal filling fluid remains in a non-flowable, gelled state until the stent is to be used in a medical procedure; taking agar as an example, the temperature range may be between: preferably between 10 degrees celsius and 35 degrees celsius.

Step (E2): raising the temperature of the cut stent to a proper temperature to melt the colloid filling liquid and flow out of the pores of the stent, and then obtaining the stent with porous pores. Taking agar as an example, the proper temperature range for allowing agar to melt and flow out can be between: preferably 40-50 deg.C, and can be combined with proper centrifugal device to separate agar without damaging the support.

Step (E2): raising the temperature of the cut stent to a proper temperature, so that the colloid filling liquid is melted and flows out of the pores of the stent, thereby obtaining the stent with multiple pores. Then, the porous support is used for electrostatically adsorbing at least one of the following components: biological tissue growth factor, bone growth protein and nanocapsule. The additives adsorbed on the scaffold can promote the proliferation of cells and accelerate the repair of damaged parts of biological tissues.

According to the above method for manufacturing a biomedical stent of the present invention, a biomedical stent can be manufactured, comprising: the scaffold is composed of the high polymer material, has the predetermined three-dimensional structure and has a plurality of pores, the boundary of the scaffold does not have a state of no pore, and the colloid filling liquid is filled in the pores and is in a solidified state.

Referring to fig. 2, a three-dimensional printer suitable for the method of manufacturing a biomedical stent of the present invention is shown. In this embodiment, the three-dimensional printer is a 3D printer of FDM technology, and includes: a print head 31, a feed port 32, a roller set 33, a melter 34, a temperature controller 35, a discharge nozzle 36, a stage 37, an X-Y axis driver 38, and a Z axis driver 39. In this embodiment, a biodegradable polymer material 41 (such as but not limited to PCL or PLLA alone or in combination) is extruded and molded, and then fed into the print head 31 of the three-dimensional printer from the feeding port 32, and then fed and guided by the roller set 33 to the melting device 34 to be heated to a molten liquid state. Subsequently, the temperature of the temperature controller 35 is controlled to keep the polymer material 41 in a temperature range close to a temperature just slightly higher than the melting point, and the polymer material is continuously extruded from the discharge nozzle 36 and printed on the supporting table 37. At the same time, the print head 31 is driven by the X-Y axis driver 38 to perform a horizontal biaxial movement, so that the polymer material 41 is printed on the supporting platform 37 in a layer structure of interlaced lattice. Then, the X-Y axis driver 38 drives the platform 37 to move downward along the Z axis by a distance approximately equal to the height of one layer of polymer material 41, and then the X-Y axis driver 38 drives the print head 31 to perform horizontal biaxial movement, so that the discharge nozzle 36 continues to superimpose another layer of interlaced latticed polymer material 41 on the immediately interlaced latticed polymer material 41. This is repeated until the polymer material 41 having a mesh-like structure is printed on the platform 37, and the polymer material 41 is printed into the substrate 42 having a predetermined 3D size and a porous structure.

Please refer to fig. 3A and fig. 3B, which are schematic diagrams of two embodiments of the porous structure on the substrate or the support according to the present invention after being magnified by a microscope. In fig. 3A, the porous structure on the substrate or the stent is formed by interweaving and stacking a plurality of longitudinal and transverse linear polymer materials 421; the line width (or line diameter) of the linear polymer materials 421 may be between: preferably in the range of 100 μm to 400 μm, and the length or width dimension of the apertures (spaces) may be in the range of: a range between 200 μm and 1000 μm is preferred. In fig. 3B, the porous structure on the substrate or the stent is formed by interlacing and stacking a plurality of transverse linear polymer materials 422 in an X-shaped cross direction; the line width (or line diameter) of the linear polymer materials 422 may be between: preferably, the range is 100 μm to 400 μm, and the maximum width dimension of the pores may be: a range between 200 μm and 1000 μm is preferred.

Fig. 4 is a schematic view illustrating an embodiment of the present invention in which a porous substrate is immersed in a colloid filling solution. In the present embodiment, the porous substrate 42 is a flat cylinder or a cube suitable for being processed by a CNC machine, and all the pores of the substrate 42 can be filled with the colloid filling liquid 43 by completely soaking the porous substrate 42 in the liquid colloid filling liquid 43 for a predetermined time (for example, but not limited to, more than one minute).

Fig. 5 is a schematic diagram illustrating a computer image of a 3D model of the target in the method for manufacturing a biomedical stent according to the present invention. In this embodiment, a CT or MRI apparatus is used to scan a biological tissue having a damaged portion (i.e., the target object) and obtain a computer image file of the 3D model 51 of the target object. Then, using computer equipment and software, the shape and structure of the damaged

parts

52, 53 are drawn according to the computer image of the 3D model 51 as the predetermined three-dimensional structure of the stent. Then, a machining path file for the CNC machine to cut the cured substrate is determined and generated according to the predetermined three-dimensional structure of the support. Although the present embodiment is an example in which a hard tissue of an animal bone is used as a biological tissue having a damaged portion, the present technology can be applied to tissue engineering of a soft tissue or other tissues of a living body.

The above-described embodiments should not be construed as limiting the applicable scope of the present invention, but should be construed to cover all the technical spirit and the equivalent thereof as defined by the claims. The invention can be further embodied without departing from the spirit and scope of the invention by making equivalent changes and modifications as required by the appended claims.

Claims

1. A method of manufacturing a biomedical stent, comprising:

step (A): providing a substrate which is made of a high polymer material and has a plurality of pores;

step (B): soaking the base material in a colloid filling liquid to fill the colloid filling liquid into the porous gaps of the base material;

step (C): rapidly cooling the base material soaked with the colloid filling liquid to solidify the base material and the colloid filling liquid; wherein, in the step (C), the base material soaked with the colloid filling liquid is placed in a liquid nitrogen environment to achieve the effect of rapid cooling; and

step (D): cutting the cured substrate into a scaffold with a predetermined three-dimensional structure and multiple pores; wherein, in the step (D), the base material in the state of rapid cooling and solidification is cut into the scaffold with a predetermined three-dimensional structure and multiple pores by a computerized numerical control processing machine; that is, the substrate is processed by the processing machine in a cured state in which the voids are still cured and the colloidal filling liquid having a considerable hardness is filled;

wherein, after the step (D), one of the following steps (E1), step (E2) or step (E3) is further included:

step (E1): continuously maintaining the cut stent with the solidified gel filler fluid at a low temperature for storage and transportation until the stent is to be used in a medical procedure, and then warming the stent to a temperature suitable for attachment to a damaged portion of a biological tissue while the gel filler fluid remains in a non-flowable gel state; wherein the temperature of the jelly filling liquid in a jelly state which is not easy to flow can be kept between 10 ℃ and 35 ℃;

step (E2): raising the temperature of the cut stent to a proper temperature to enable the colloid filling liquid to melt and flow out of the porous pores of the stent; the proper temperature range is between 40 ℃ and 50 ℃;

step (E3): raising the temperature of the cut stent to the proper temperature to enable the colloid filling liquid to melt and flow out of the porous pores of the stent; then, the support is used for electrostatically adsorbing at least one of the following components: biological tissue growth factor, bone growth protein and nanocapsule.

2. The method of manufacturing a biomedical stent of claim 1, wherein:

the high molecular material is a biodegradable high molecular polymer, and is selected from one of the following sterile materials: polycaprolactone, polylactic acid, poly-L-lactic acid, polyvinyl alcohol; and the number of the first and second groups,

the colloid filling liquid is agar.

3. The method of claim 2, wherein at least one of the following materials is added to the agar gel: biological tissue culture solution, biological tissue growth factor, bone growth protein and nanocapsule.

4. The method of claim 2, wherein in the step (A), the polymer material is printed into the porous substrate by melting the polymer material and printing the melted polymer material into a stack of layers, each layer having a grid-like structure, by a three-dimensional printer.

5. The method of claim 1, wherein a procedure for creating a processing path file is performed before the step (D), and the method comprises the steps of:

step (d 1): scanning a target object by an electronic device and obtaining a computer image of a three-dimensional model of the target object;

step (d 2): drawing the predetermined three-dimensional structure of the support by using a computer device according to a computer image of the three-dimensional model;

step (d 3): and determining and generating a processing path file for the computerized numerical control processing machine to cut the solidified substrate according to the predetermined three-dimensional structure of the support by using the computer equipment.