WO2024181854A1 - Shape memory polymer with improved degradability and method for preparing same - Google Patents

Abstract

The present invention relates to a shape memory polymer with improved degradability and a method for preparing same and, more specifically, to: a shape memory polymer which is synthesized by inducing chemical bonding between a copolymer, which comprises a lactone monomer and glycidyl methacrylate, and silane-treated inorganic particles, so as to maintain shape memory properties and, at the same time, exhibit significantly improved short-term degradability; and a method for preparing same. The shape memory polymer according to the present invention maintains shape memory properties within the body temperature range due to having a low melting temperature, and due to the chemical bonding between inorganic particles that are surface-treated with silane and a copolymer comprising a lactone monomer and glycidyl methacrylate, exhibits higher dispersibility as compared to physical bonding, and thus has the advantages of enhanced mechanical properties and improved degradability, compared to the parent copolymer. In addition, the shape memory polymer has the advantage of having controllable degradability since the crystallinity of the polymer chain can be controlled, when inserted into the body. In particular, the shape memory polymer according to the present invention can be degraded in vivo within a short period of time, and thus has the advantage of being usable as a medical material for manufacturing various medical devices for in vivo tissue regeneration.

Description

Shape memory polymer with improved degradability and method for producing the same

The present invention relates to a shape memory polymer with improved degradability and a method for producing the same, and more specifically, to a shape memory polymer synthesized by inducing a chemical bond between a copolymer of a lactone monomer and glycidyl methacrylate and a silane-treated inorganic particle so as to maintain shape memory characteristics while significantly improving short-term degradability, and a method for producing the same.

Synthetic polymers have advantages over natural polymers, such as superior mechanical properties, easy functionalization, high elastic strain, and low price, and are thus attracting attention as useful materials that can replace natural polymers.

Among them, polycaprolactone (poly(ε-caprolactone), PCL) is a biocompatible, shape-memory polymer (SMP) type biodegradable polymer that has been approved by the US FDA for biomedical applications and is a stable material. Although polycaprolactone is a biocompatible material, it is not minimally invasive when inserted into the body, so there is a problem in relieving patient discomfort.

Herein, the inventors of the present invention have developed various types of polycaprolactone-polymethacrylate copolymers [PCL-co-PGMA) by polymerizing ε-caprolactone monomer and glycidyl methacrylate (GMA) (Korean Patent No. 10-1906472, Korean Patent No. 10-2355542, Korean Patent Publication No. 10-2021-0158356), and the copolymers prepared in this way have various melting points depending on the adjustment of the introduction amounts of ε-caprolactone and glycidyl methacrylate, and have shape memory properties with a high deformation recovery rate in the body temperature range, so that they have the advantage of being usefully utilized in physiological and medical application devices.

Meanwhile, tissue engineering is a technology that aims to replace or restore our bodies damaged by accidents or diseases by creating and transplanting biosubstitutes. Biomaterials used in tissue engineering must have excellent biocompatibility, be non-toxic, and have mechanical, physical properties, and molding processability that can be adjusted to suit the purpose and use, and biodegradability must also be considered.

Among implantable medical devices, non-degradable ones can cause problems such as corrosion and strictures with long-term use, so biodegradability is particularly important for implantable medical devices. In addition, if degradability can be controlled, there is an advantage in that various medical devices can be manufactured to suit the area to which the medical device is applied. In particular, scaffolds for tissue engineering, which serve as a support for cells to support and grow, must have a large surface area and porosity, and must be able to control biodegradability.

Accordingly, the inventors of the present invention have made efforts to develop a polymer that can be decomposed in a living body in a short period of time while maintaining shape memory properties suitable as a physiological medical application device with a high deformation recovery rate in a body temperature range, and as a result, were able to develop a polymer complex in which inorganic particles surface-treated with silane and a copolymer containing a lactone monomer and glycidyl methacrylate are cross-linked, and completed the present invention by confirming that the polymer complex can be effectively decomposed in a living body in a short period of time while being provided with minimally invasive properties due to shape memory properties.

The present invention aims to provide a shape memory polymer synthesized to improve short-term resolution, a method for producing the same, and a use thereof.

To achieve the above purpose, the present invention provides a shape memory polymer in which an inorganic particle surface-treated with silane and a copolymer including a lactone monomer and glycidyl methacrylate are crosslinked.

In the present invention, the inorganic particles surface-treated with silane may be inorganic particles of gelatin, collagen, chitosan, alginate, cellulose or hydroxyapatite surface-treated with silane.

In the present invention, the silane may be mercaptopropyl trimethoxy silane (3-Mercaptopropyl trimethoxy silane) or trimethoxysilylpropyl acrylate (3-Trimethoxysilylpropyl acrylate).

In the present invention, the copolymer is

A compound represented by the following chemical formula (1):

Chemical formula (1)

In the above chemical formula (1),

R ₁ , R ₂ and R ₃ are independently hydrogen (H) or an alkyl group having 1 to 6 carbon atoms,

m and n are integers from 1 to 20, independently of each other,

A, B ₁ and B ₂ are independently oxygen (O) or sulfur (S),

x and y represent the mole % of repeating units,

x+y is 100, and x is between 80 and 95;

A compound represented by the following chemical formula (2):

Chemical formula (2)

In the above chemical formula (2),

x is an integer between 1 and 20,

m and n represent the mole % of repeating units,

m+n is 100, and m is between 80 and 96; or

A compound represented by the following chemical formula (3):

Chemical formula (3)

In the above chemical formula (3),

x and y are integers from 1 to 20, independently of each other,

m and n represent the mole % of repeating units,

m+n is 100 and m is 70 to 99; may be a copolymer.

In the present invention, the shape memory polymer may have a shape restoring ability of 50% or more at 30 to 60°C.

In the present invention, the shape memory polymer may have a resolution improved by at least twice compared to the copolymer.

The present invention also provides a method for producing the shape memory polymer, comprising the following steps:

(a) a step of mixing a copolymer comprising inorganic particles surface-treated with silane, a lactone monomer and glycidyl methacrylate, and a crosslinking agent; and

(b) a step of cross-linking the mixture.

In the present invention, the particles surface-treated with silane may be inorganic particles of chitosan, alginate, cellulose or hydroxyapatite surface-treated with silane.

In the present invention, the inorganic particles surface-treated with the silane can be mixed in an amount of 1 to 20 wt% relative to the copolymer.

In the present invention, the crosslinking agent may be at least one selected from the group consisting of potassium persulfate, ammonium persulfate, benzoyl peroxide, diauryl peroxide, dicumyl peroxide, hydrogen peroxide, azobisisobutuyronitrile, Irgacure, Darocure, lithium phenyl-2,4,6-trimethylbenzoylphosphinate (LAP), diphenyl(2,4,6-Trimethylbenzoyl)phosphine (TPO), and ethyl(2,4,6-trimethylbenzoyl)phenylphosphinate (TPO-L).

In the present invention, the crosslinking agent can be mixed in an amount of 0.1 to 5.0 wt% relative to the copolymer.

In the present invention, the crosslinking may be thermal crosslinking or photocrosslinking.

In the present invention, the crosslinking is thermal crosslinking, and may be crosslinked by applying a pressure of 1 to 20 MPa at 100 to 160°C for 10 to 30 minutes.

In the present invention, the crosslinking is photocrosslinking, and may be crosslinked by irradiating UV at an intensity of 100 to 500 mW/ ^cm2 for 100 to 1000 seconds.

The present invention also relates to a medical material comprising the shape memory polymer.

In the present invention, the medical material may be a material for vascular or non-vascular transplantation.

In the present invention, the medical material may be a material for tissue depression reconstruction selected from the group consisting of the nose, sinuses, chin, face, craniofacial area, cheekbone, forehead, and skin.

In the present invention, the medical material may be a material for transplantation into a bone cavity or a cartilage damaged area.

The present invention also provides a scaffold for tissue engineering comprising the shape memory polymer.

The shape memory polymer according to the present invention has a low melting temperature, so that it maintains shape memory properties in a body temperature range, while exhibiting higher dispersibility than physical bonding through chemical bonding between inorganic particles surface-treated with silane and a copolymer including a lactone monomer and glycidyl methacrylate, thereby having advantages of enhanced mechanical properties and improved degradability compared to the parent copolymer. In addition, it has an advantage of being able to control degradability because the crystallinity of the polymer chain can be controlled when inserted into the body. In particular, the shape memory polymer according to the present invention can be degraded in a short period of time in the body, so that it has the advantage of being usable as a medical material for manufacturing various medical devices for in vivo tissue regeneration.

Figure 1 shows the results of measuring the Raman spectrum to confirm the structure of silane-treated Hydroxyapatite.

Figure 2 shows the results of analyzing the reproducibility of shape memory characteristics of one embodiment of the present invention and a comparative example using a dynamic mechanical analyzer (DMA).

Figure 3 shows a cross-sectional image of a porous scaffold manufactured using one embodiment of the present invention.

Figure 4 shows the results of confirming the shape restoring ability of a porous scaffold manufactured using one embodiment of the present invention.

Figure 5 shows the results of comparing (a) the elastic modulus and (b) the compressive strength of one embodiment of the present invention and a comparative example, measured using a universal testing machine (UTM).

Figure 6 is a result showing the in vitro decomposition behavior over time of one embodiment of the present invention and a comparative example.

Figure 7 shows the results of confirming the in vivo decomposition behavior over time using H&E staining after transplanting an embodiment of the present invention and a comparative example into a rat.

Figure 8 is a result of comparing the new tissue formation areas of one embodiment of the present invention and a comparative example based on the H&E staining results of Figure 7.

Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. In general, the nomenclature used herein and the experimental methods described below are well known and commonly used in the art.

The term "about" as used herein can be interpreted to mean approximately, roughly, roughly, or to a certain extent. When the term "about" is used with a numerical range, it is interpreted to modify that range by extending the boundaries above and below the specified numerical value. Generally, the term "about" is used herein to modify a numerical value above and below a specified value by a variance of 10%.

shape memory polymer

The present invention relates to a shape memory polymer crosslinked with an inorganic particle surface-treated with silane and a copolymer containing a lactone monomer and glycidyl methacrylate.

In the present invention, a "shape memory polymer (SMP)" means a polymer that has the property of returning to its original shape when an object is made to have a certain shape under specific conditions and the shape is subsequently changed by an external impact, when the object is made to have the same initial conditions (temperature, light, pH, humidity, etc.).

The shape memory polymer according to the present invention maintains the shape memory characteristics of a copolymer containing a lactone monomer and glycidyl methacrylate, while significantly improving short-term decomposition performance due to the effect (crystallization change) of inorganic particles surface-treated with silane.

That is, the feature that the shape memory polymer according to the present invention maintains shape memory characteristics while significantly improving short-term decomposition performance is because the inorganic particles surface-treated with silane and the copolymer containing a lactone monomer and glycidyl methacrylate form a cross-linking bond, i.e., a chemical bond, rather than a simple complexation (mixing or physical dispersion).

The shape memory polymer according to the present invention is a copolymer comprising an inorganic particle surface-treated with silane and a lactone monomer and glycidyl methacrylate, which is crosslinked and has an effect of decomposing by nearly 50% within 7 days.

In addition, the shape memory polymer according to the present invention has the characteristics of increasing the elastic modulus and compressive strength compared to the copolymer containing the lactone monomer and glycidyl methacrylate by crosslinking the inorganic particles surface-treated with silane and the copolymer containing the lactone monomer and glycidyl methacrylate, while the inorganic particles are uniformly distributed within the polymer matrix and the external force is evenly distributed.

The inorganic particles surface-treated with silane used in the present invention may be, but are not limited to, inorganic particles of gelatin, collagen, chitosan, alginate, cellulose or hydroxyapatite surface-treated with silane.

In the present invention, the silane may be mercaptopropyl trimethoxy silane or trimethoxysilylpropyl acrylate, but is not limited thereto.

In the present invention, when the inorganic particles are surface-treated with silane, the mixing ability with various organic substances is improved due to the functional groups at the terminals. In addition, when a chemical bond is induced between the surface-treated inorganic particles and a biocompatible polymer, the role of the inorganic particles as a nucleating agent increases compared to physical complexation, so that the crystal structure of the polymer can be controlled, and through this, the degradability characteristics can be controlled.

In manufacturing the shape memory polymer according to the present invention, for effective crosslinking with a copolymer including a lactone monomer and glycidyl methacrylate, the inorganic particles surface-treated with silane may be micro-sized inorganic particles or nano-sized inorganic particles, and preferably have a particle size of 1 nm to 300 μm. Among these, it is more preferable to use nano inorganic particles to enhance the mixing property with the copolymer and to achieve nano-dispersion.

In one embodiment, the shape memory polymer in the present invention is a copolymer [(PCL-co-PGMA)] in which an ε-caprolactone monomer and a glycidyl methacrylate monomer are polymerized, and is crosslinked with an inorganic particle surface-treated with the silane.

In the above copolymer, the arrangement order of the ε-caprolactone monomer and the glycidyl methacrylate monomer is not particularly limited, and may be arranged alternately, randomly, or in blocks.

In addition, a hydroxyl group or the like may be bonded to the terminal of the copolymer. A copolymer having a hydroxyl group bonded to the terminal like this can be produced by polymerization using an initiator having a hydroxyl group bonded to the terminal.

1. 2 arm copolymer

In one embodiment, the copolymer comprising a lactone monomer and glycidyl methacrylate used in the present invention may be a 2-arm copolymer, and the 2-arm copolymer may be represented by the following chemical formula (1):

Chemical formula (1)

In the above chemical formula (1),

R ₁ , R ₂ and R ₃ are independently hydrogen (H) or an alkyl group having 1 to 6 carbon atoms,

m and n are integers from 1 to 20, independently of each other,

A, B ₁ and B ₂ are independently oxygen (O) or sulfur (S),

x and y represent the mole % of repeating units,

x+y is 100, and x is between 80 and 95.

Specifically, the 2-arm copolymer has the chemical formula (1).

R ₁ , R ₂ and R ₃ are independently hydrogen (H) or a methyl group (CH3-),

m and n are independently integers from 3 to 12,

A, B ₁ and B ₂ are all oxygen (O),

x and y represent the mole % of repeating units,

x+y=100, where x can be between 88 and 94.

More specifically,

R ₁ , R ₂ and R ₃ are independently hydrogen (H),

m and n are independently integers from 5 to 6,

A, B ₁ and B ₂ are independently oxygen (O),

x and y represent the mole % of repeating units,

x+y=100, where x is between 88 and 94.

The above chemical formula (1) can be represented by the following chemical formula (1'):

Chemical formula (1')

In the above chemical formula (1')

m and n are integers from 1 to 20, independently of each other,

x and y represent the mole % of repeating units,

x+y is 100, and x is between 80 and 95.

In the chemical formula (1) or (1'), x and y represent mole % of repeating units, x+y is 100, and x can be 80 to 95, or 88 to 94.

As a specific example, the 2-arm copolymer according to the present invention may be a 2-arm PCL-PGMA copolymer of ε-caprolactone monomer and glycidyl methacrylate.

In the present invention, the 2-arm copolymer is described in detail in Korean Patent No. 10-1906472 and Korean Patent No. 10-2355542, which are incorporated herein by reference in their entireties.

2. 4 arm copolymer

In another embodiment, the copolymer comprising a lactone monomer and glycidyl methacrylate used in the present invention may be a 4-arm copolymer, and the 4-arm copolymer may be represented by the following chemical formula (2):

In the above chemical formula (2),

x is an integer between 1 and 20,

m and n represent the mole % of repeating units,

m+n is 100, and m is between 80 and 96.

In the chemical formula (2) of the present invention, x may be an integer from 2 to 10. In other specific examples, x may be an integer from 2 to 9, an integer from 2 to 8, an integer from 2 to 7, an integer from 2 to 6, an integer from 2 to 5, an integer from 3 to 10, an integer from 3 to 9, an integer from 3 to 8, an integer from 3 to 7, an integer from 3 to 6, an integer from 3 to 5, an integer from 4 to 10, an integer from 4 to 9, an integer from 4 to 8, an integer from 4 to 7, an integer from 4 to 6, an integer from 4 to 5, an integer from 5 to 10, an integer from 5 to 9, an integer from 5 to 8, an integer from 5 to 7, or an integer from 5 to 6. Most specifically, a compound in which x in the chemical formula (2) is 5 may be used, but is not limited thereto.

More specifically, in the chemical formula (2), m and n represent mole % of repeating units, m+n is 100, and m can be 70 to 99, 85 to 96, 88 to 96, 90 to 96, 92 to 96, or 94 to 96.

Here, mole % means the ratio of repeating units of m and n, and specifically, it can mean mole fraction. For example, it can mean the mole fraction of repeating units of PCL and PGMA in PCL-co-PGMA.

As a specific example, the 4-arm copolymer according to the present invention may be a 4-arm PCL-PGMA copolymer of an ε-caprolactone monomer and glycidyl methacrylate. The 4-arm PCL-PGMA may include a central carbon having four carbon-carbon bonding arms.

In the present invention, the 4-arm copolymer is described in detail in Korean Patent Publication No. 10-2021-0158356, which is incorporated herein by reference in its entirety.

3. 6 arm copolymer

In another embodiment, the copolymer comprising a lactone monomer and glycidyl methacrylate used in the present invention may be a 6-arm copolymer, and the 6-arm copolymer may be represented by the following chemical formula (3):

Chemical formula (3)

In the above chemical formula (3),

x and y are integers from 1 to 20, independently of each other,

m and n represent the mole % of repeating units,

m+n is 100, and m is between 70 and 99.

More specifically, in the chemical formula (3), m and n represent the molar % of repeating units, m+n is 100, and m can be 70 to 99, 85 to 96, 88 to 96, 90 to 96, 92 to 96, or 94 to 96.

Here, mole % means the ratio of repeating units of m and n, and specifically, it can mean mole fraction. For example, it can mean the mole fraction of repeating units of PCL and PGMA in PCL-co-PGMA.

The compound of the above chemical formula (3) can control the shape restoration temperature, etc. depending on the amount of ε-caprolactone monomer and glycidyl methacrylate monomer constituting it.

More specifically, in the chemical formula (3), x and y are each independently an integer from 1 to 20, which can be controlled by the carbon number of the lactone series monomer and the initiator in the step of synthesizing the compound of the chemical formula (3).

For example, when epsilon caprolactone (ε-CL) is used, x can be 3, and when dipentaerythritol is used, y can be 1. In addition, the number of x can be controlled by using monomers such as α-acetolactone, β-propiolactone, γ-butyrolactone, and δ-valerolactone instead of epsilon caprolactone (ε-CL), and the number of y can be controlled by using an initiator such as 6 arm PEG instead of dipentaerythritol. In the present invention, x and y can be easily controlled by a person skilled in the art.

The compound of the chemical formula (3) of the present invention can be prepared by reacting an α-acetolactone, β-propiolactone, γ-butyrolactone, δ-valerolactone or ε-caprolactone monomer with an acrylic monomer containing a glycidyl group and an initiator.

For example, the compound of the chemical formula (3) of the present invention can be prepared by a ring-opening polymerization reaction of dipentaerythritol, caprolactone, and glycidyl methacrylate.

In this case, the reactivity can be improved by adding a catalyst or by adding a polymerization inhibitor together with or simultaneously with the initiator during the initial reaction when the polymerization conversion is almost zero, thereby inhibiting the reaction between the temperature-sensitive glycidyl methacrylate groups.

The compound of the chemical formula (3) of the present invention can be prepared by including a step of reacting dipentaerythritol, caprolactone, and glycidyl methacrylate. The reaction can be characterized by being a ring-opening polymerization reaction. The reaction can be characterized by reacting in the presence of a catalyst selected from the group consisting of 1,5,7-triazabicyclo(4.4.0)dec-5-ene, tin(II) (2-ethylhexanoate), trimethylopropane tris(3-mercaptopropionate), and zinc succinate, but is not limited thereto.

In particular, it is preferable to use 1,5,7-Triazabicyclo(4.4.0)dec-5-ene as a catalyst, which can shorten the synthesis time of the compound, as a substance for inducing simultaneous ring-opening polymerization of two monomers (CL, GMA).

In the present invention, an initiator and/or polymerization inhibitor can be added during the initial reaction, i.e., before adding glycidyl methacrylate, to inhibit the reaction between methacrylate groups.

In addition, the polymerization inhibitor plays a role in suppressing the exothermic reaction that occurs locally in the latter half of the polymerization and eliminating unreacted residual radicals to terminate the reaction.

When the initiator and polymerization inhibitor are reacted with the monomers caprolactone and glycidyl methacrylate at about 110°C for about 6 hours, the ring structure in the monomers opens and a polycaprolactone-polyglycidyl methacrylate (6 arm PCL-PGMA) copolymer with six arms is synthesized.

The above initiator may be characterized as being dipentaerythritol, and specifically, the present invention may be characterized in that a six-arm polycaprolactone-polyglycidyl methacrylate (6-arm PCL-PGMA) copolymer is synthesized by the initial addition of the above initiator.

The polymerization inhibitor may be at least one selected from the group consisting of hydroquinone, hydroquinone monomethyl ether, p-benzoquinone, and phenothiazine, but is not limited thereto. Preferably, the polymerization inhibitor may be hydroquinone.

The method for producing a compound of chemical formula (3) may be characterized by reacting dipentaerythritol, caprolactone, and glycidyl methacrylate at 80 to 140°C, preferably 100 to 130°C, for example, at about 110°C.

In this case, if the synthesis of the compound of the chemical formula (3) of the present invention proceeds at a temperature below 100°C, the catalytic reaction may not proceed, and if the synthesis of the compound of the present invention proceeds at a temperature exceeding 130°C, the problem of a decrease in the catalytic reaction rate may occur.

As a preferred embodiment, the polymerization mechanism of the compound of chemical formula (3) can be expressed as follows.

[Reaction Formula 1]

The above cross-linking reaction may be characterized as a photocross-linking reaction or a thermal cross-linking reaction, but is not limited thereto.

The compound of chemical formula (3) may have a structure of a copolymer in which an ε-caprolactone monomer and an acrylic monomer containing a glycidyl group are polymerized. For example, the compound of chemical formula (3) may have a structure of a copolymer [PCL-co-PGMA)] in which an ε-caprolactone monomer (CL; caplolactone) and a glycidyl methacrylate (GMA) monomer are polymerized.

In the compound of chemical formula (3), the arrangement order of the ε-caprolactone monomer and the glycidyl methacrylate monomer is not particularly limited and may be arranged alternately, randomly, or in blocks.

In addition, a hydroxyl group or the like may be bonded to the terminal of the copolymer. A copolymer having a hydroxyl group bonded to the terminal like this can be produced by polymerization using an initiator having a hydroxyl group bonded to the terminal.

Meanwhile, the glycidyl group included in the glycidyl methacrylate monomer may be a crosslinkable functional group, and may be a photocrosslinkable functional group or a thermally crosslinkable functional group. In addition, the copolymer may have shape memory properties by crosslinking.

The shape memory polymer according to the present invention may be characterized in that the inorganic particles surface-treated with silane are contained in an amount of about 1 to about 20 wt% relative to the copolymer. In one embodiment, the inorganic particles surface-treated with silane are contained in an amount of about 3 to about 18 wt% relative to the copolymer. In another embodiment, the inorganic particles surface-treated with silane are contained in an amount of about 1 to about 15 wt% relative to the copolymer. In yet another embodiment, the inorganic particles surface-treated with silane are contained in an amount of about 5 to about 15 wt% relative to the copolymer. In yet another embodiment, the inorganic particles surface-treated with silane are contained in an amount of about 10 to about 20 wt% relative to the copolymer. In yet another embodiment, the inorganic particles surface-treated with silane are contained in an amount of about 10 to about 15 wt% relative to the copolymer. For example, the inorganic particles surface-treated with silane may be contained in an amount of about 15 wt% relative to the copolymer.

When the weight ratio of the inorganic particles surface-treated with the above silane and the copolymer is outside the above-mentioned range, crosslinking of the copolymer and the inorganic particles surface-treated with the silane does not occur smoothly.

In the present invention, the shape memory polymer has a shape restoring force (or shape restoring ability) of 50% or more, preferably, at a temperature of 30 to 60°C, or at any range of temperatures within the temperature of 30 to 60°C, for example, at a temperature of 35 to 55°C, or at any temperature within the temperature of 30 to 60°C, for example, at about 35°C, about 36°C, about 37°C, about 38°C, about 39°C, about 40°C, about 41°C, about 42°C, about 43°C, about 44°C, about 45°C, about 46°C, about 47°C, about 48°C, about 49°C, about 50°C, about 51°C, about 52°C, about 53°C, about 54°C, about 55°C, about 56°C, about 57°C, about 58°C, about 59°C, or about 60°C. For example, it may be about 55% or more, about 60% or more, about 65% or more, about 70% or more, about 75% or more, about 80% or more, about 85% or more, about 90% or more, about 95% or more, or about 100%, but is not limited thereto.

In the present invention, the shape memory polymer may have a resolution improved by about 2 times or more, for example, about 2.1 times or more, about 2.2 times or more, about 2.3 times or more, about 2.4 times or more, about 2.5 times or more, about 2.6 times or more, about 2.7 times or more, about 2.8 times or more, about 2.9 times or more, about 3.0 times or more, about 3.1 times or more, about 3.2 times or more, about 3.3 times or more, about 3.4 times or more, or about 3.5 times or more, compared to a polycaprolactone-polyglycidyl methacrylate copolymer.

In the present invention, the shape memory polymer can exhibit a resolution of about 40% or more, about 45% or more, about 50% or more, about 55% or more, or about 60% or more within 7 days under biomimetic conditions.

As a specific example, the 6-arm copolymer according to the present invention may be a 6-arm PCL-PGMA copolymer of an ε-caprolactone monomer and glycidyl methacrylate.

In the present invention, the 6-arm copolymer is described in detail in Korean Patent No. 10-2516991, which is incorporated herein by reference in its entirety.

Manufacturing method

In another aspect, the present invention relates to a method for producing a shape memory polymer, comprising the following steps:

(a) a step of mixing a copolymer comprising inorganic particles surface-treated with silane, a lactone monomer and glycidyl methacrylate, and a crosslinking agent; and

(b) a step of cross-linking the mixture.

In the present invention, the inorganic particles surface-treated with the silane may be mixed in an amount of about 1 to about 20 wt% relative to the copolymer, and in one embodiment, the inorganic particles surface-treated with the silane may be mixed in an amount of about 3 to about 18 wt% relative to the copolymer, in another embodiment, the inorganic particles surface-treated with the silane may be mixed in an amount of about 1 to about 15 wt% relative to the copolymer, in yet another embodiment, the inorganic particles surface-treated with the silane may be mixed in an amount of about 5 to about 15 wt% relative to the copolymer, in yet another embodiment, the inorganic particles surface-treated with the silane may be mixed in an amount of about 10 to about 20 wt% relative to the copolymer, in yet another embodiment, the inorganic particles surface-treated with the silane may be mixed in an amount of about 10 to about 15 wt% relative to the copolymer, for example, the inorganic particles surface-treated with the silane may be mixed in an amount of about 15 wt% relative to the copolymer.

In the present invention, the crosslinking agent may be at least one selected from the group consisting of potassium persulfate, ammonium persulfate, benzoyl peroxide, diauryl peroxide, dicumyl peroxide, hydrogen peroxide, azobisisobutuyronitrile, Irgacure, Darocure, lithium phenyl-2,4,6-trimethylbenzoylphosphinate (LAP), diphenyl(2,4,6-Trimethylbenzoyl)phosphine (TPO), and ethyl(2,4,6-trimethylbenzoyl)phenylphosphinate (TPO-L).

In the present invention, the crosslinking agent may be mixed in an amount of about 0.1 to about 5.0 wt% relative to the copolymer. For example, the crosslinking agent may be added in an amount of about 0.2 to about 2.0 wt%, preferably about 0.5 wt% relative to the copolymer.

In the present invention, the crosslinking may be thermal crosslinking or photocrosslinking.

In the present invention, the crosslinking is thermal crosslinking, and may be crosslinked by applying a pressure of about 1 to about 20 MPa at about 100 to about 160°C for about 10 to about 30 minutes.

In one embodiment, the crosslinking may be crosslinking by applying a pressure of about 1 to about 20 MPa for about 10 to about 30 minutes at a temperature of about 100 to about 160°C, and preferably crosslinking by applying a pressure of about 5 to about 15 MPa for about 10 to about 30 minutes at about 120 to about 150°C, but is not limited thereto.

In the present invention, the crosslinking is photocrosslinking, and may be crosslinked by irradiating UV at an intensity of about 100 to about 500 mW/ ^cm2 for about 100 to about 1000 seconds.

In one embodiment, the crosslinking may be performed by irradiating UV of about 360 to about 370 nm at an intensity of about 100 to about 500 mW/ ^cm2 for about 100 to about 1000 seconds, and preferably, by irradiating UV of about 365 nm at an intensity of about 200 to about 300 mW/ ^cm2 for about 200 to about 500 seconds, but is not limited thereto.

use

The shape memory polymer according to the present invention can be applied to all products requiring a synthetic polymer with shape memory properties and improved degradability.

Therefore, from another aspect, the present invention relates to a medical material comprising the shape memory polymer.

In one embodiment, the medical material may be a material for vascular or non-vascular transplantation, i.e., a material for manufacturing a device or insert for transplantation into a blood vessel or non-vascular vessel.

In another aspect, the medical material may be a material for reconstructing a tissue depression selected from the group consisting of the nose, the paranasal sinuses, the chin, the facial region, the craniofacial region, the cheekbone, the forehead, and skin, that is, a material for manufacturing an apparatus or an insert for transplanting one or more tissues selected from the group consisting of the nose, the paranasal sinuses, the chin, the facial region, the craniofacial region, the cheekbone, the forehead, and skin to a depressed portion.

In another aspect, the medical material may be a material for implantation into a bone cavity or a cartilage damage site, that is, a material for manufacturing a device or insert for implantation into a bone cavity or a cartilage damage site.

In another aspect, the present invention relates to a scaffold for tissue engineering comprising the shape memory polymer.

A tissue engineering scaffold including the above shape memory polymer can have the characteristic of acting as a prototype of a tissue due to its shape memory properties and supporting cell attachment, proliferation, division, and creation of new tissue, and can have the characteristic of controlling the decomposition rate by controlling the crosslinking ratio of the copolymer and the inorganic particles.

A scaffold for tissue engineering comprising a shape memory polymer according to the present invention has excellent biocompatibility and cytocompatibility as well as improved biodegradability, and can be utilized as a porous artificial graft material for, for example, autologous bone replacement.

From another perspective, the present invention relates to the use of the shape memory polymer as a medical material.

In another aspect, the present invention relates to the use of the shape memory polymer in the manufacture of medical materials, medical devices or medical implants.

In another aspect, the present invention relates to a surgical or surgical method including a step of applying a medical device or implant made of a medical material including the shape memory polymer to a subject (e.g., a human or a mammal) in need thereof.

Example

Hereinafter, the present invention will be described in more detail through examples. It will be apparent to those skilled in the art that these examples are intended only to illustrate the present invention, and the scope of the present invention is not to be construed as being limited by these examples.

Example 1. Shape memory polymer containing 5 phr of hydroxyapatite (HAp)

1-1. Preparation of silane-treated Hydroxyapatite nanoparticles

A magnetic bar was placed in a 3-neck round bottom flask, 6 g of hydroxyapatite (Skyspring nanomaterials) was added, 100 ml of ethanol was added, and stirred. After 6 ml of 3-Mercaptopropyltrimethoxy silane (TCI) was added, the flask inlet was blocked, and stirred at 70°C for 48 hours. Afterwards, centrifugation was performed at 5000 rpm for 3 minutes using a centrifuge (Eppendorf), and then washing. The final reactant was then dried in a vacuum to obtain silane-treated nanoparticles.

To confirm the structure of silane-treated Hydroxyapatite, Raman spectrum (Horriba, LabRam Aramis) was measured according to the manufacturer's instructions. The Raman spectra of pure Hydroxyapatite without silane treatment and silane-treated Hydroxyapatite were compared, and a peak corresponding to thiol group around 2600 cm ^-1 was observed in the silane-treated Hydroxyapatite (Fig. 1). This confirmed that silane treatment was performed on the surface of Hydroxyapatite nanoparticles.

1-2. 2 arm 94PCL-06PGMA manufacturing

A 3-neck round bottom flask was placed with a magnetic bar, and 1,6-hexanediol (initiator, 0.5 mmol, Sigma Aldrich) and hydroquinone (inhibitor, HQ, 1 mmol, Sigma Aldrich) were added. The flask inlet was blocked, vacuumed for 10 minutes, and then nitrogen was purged at a rate of 50 cc/min. Purified ε-caprolactone (ε-CL, 94 mmol, Sigma Aldrich) was injected into the flask using a 20G syringe needle. Mixing was performed at 110°C and 180 rpm for 10 minutes. Glycidyl methacrylate (monomer, GMA, 6 mmol, Sigma Aldrich) was injected using a 20G syringe needle. After 10 min of injection of glycidyl methacrylate, 1,5,7-Triazabicyclo(4.4.0)dec-5-ene (TBD, catalyst, 1 mmol, Sigma Aldrich) dissolved in 1 mL of acetonitrile (ACN, Sigma Aldrich) was injected using a 20G syringe needle (1 mmolTBD/1 mL ACN). Then, the flask was reacted at 110°C for 6 h. The final reactant was dissolved in 15 mL of chloroform (Daejung chemicals & metals Co., LTD., Korea) and precipitated in 400 mL of cold ethyl ether (Daejung chemicals & metals CO., LTD., Korea) at 4°C. The obtained sediment was filtered and then vacuum dried.

HD(1,6-hexanediol) was used as an initiator, TBD(1,5,7-Triazabicyclo(4.4.0)dec-5-ene) was used as a catalyst, HQ(hydroquinone) was used as an inhibitor, and CL(ε-caprolactone) and GMA(glycidyl methacrylate) were used as monomers.

1-3. Preparation of shape memory polymer containing hydroxyapatite nanoparticles

To prepare shape memory polymers containing hydroxyapatite nanoparticles, a 2-arm PCL-PGMA copolymer was dissolved in NMP (Sigma aldrich) at a 1:1 (w:v) ratio, and then silane-treated hydroxyapatite nanoparticles and a crosslinker, Irgacure2959, were additionally dissolved. The silane-treated hydroxyapatite nanoparticles and the crosslinker, Irgacure2959, were dissolved in an amount of 5 wt% and 0.5 wt%, respectively, based on the amount of the 2-arm PCL-PGMA copolymer. After sufficient mixing, the mixed solution was applied to a constant mold of the desired shape, and then irradiated with UV (365 nm) at an intensity of 265 mW/cm ² for 300 s to obtain a crosslinked sample.

Example 2. Shape memory polymer containing 15 phr of hydroxyapatite (HAp)

Silane-treated Hydroxyapatite was prepared as described in Example 1-1, and 2 arm 94PCL-06PGMA was prepared as described in Example 1-2.

Cross-linked samples were prepared in the same manner as in Example 1-3, only varying the amount of added hydroxyapatite (see Table 4).

Comparative example. Polycaprolactone-polyglycidyl methacrylate shape memory polymer

In a comparative example, the crosslinking agent Irgacure2959 was additionally dissolved in the solution in which the 2-arm 94PCL-06PGMA copolymer manufactured in Example 1-2 was dissolved. At this time, the crosslinking agent Irgacure2959 was dissolved in an amount of 0.5 wt% based on each 2-arm PCL-PGMA copolymer. After sufficiently mixing, the mixed solution was applied to a constant mold of a desired shape, and then irradiated with UV (365 nm) at 265 mW/cm ² intensity for 300 seconds to obtain a crosslinked sample.

Experimental Example 1. Melting Temperature Analysis

To confirm the thermal properties of Example 1, Example 2, and Comparative Example, melting points were measured within a temperature range of -70°C to 150°C using differential scanning calorimetry (DSC, Netzsch) according to the manufacturer's instructions.

The results are as shown in Table 5, and all examples showed peaks at temperatures around 35 to 37°C, similar to the comparative examples. From these results, it was expected that the addition of nanoparticles of hydroxyapatite would not significantly affect the thermal properties of the polymer and that the shape memory properties could be maintained in the body temperature range.

Experimental Example 2. Analysis of Shape Memory Behavior

2-1. Shape Restoration Ability

In order to compare the shape recovery ability of Example 1, Example 2, and Comparative Example, each sample was stretched by 50 to 60%. After exposing the stretched sample to a temperature of 40 to 45°C, the shape recovery ability (%) was confirmed according to Equation (1).

As a result, as shown in Table 6, Example 1, Example 2, and Comparative Example all exhibited a shape restoring ability of 80% or more. As expected from the thermal properties, the Example also confirmed shape memory properties in the body temperature range like the Comparative Example, and through this, it was found that the shape memory polymer can be utilized in the body temperature range even when hydroxyapatite is added.

2-2. Repeatability

Meanwhile, the shape memory behavior of Example 2 and Comparative Example 1 was measured using a dynamic mechanical analyzer (DMA, TA instrument). To this end, the sample was heated to 50°C, stretched by 4 to 6%, cooled to -10°C, and fixed. After that, when the temperature was raised to 50°C again, it was checked four times whether it returned to its original shape.

As a result, as shown in Fig. 2, it was confirmed that both Example 2 and Comparative Example 1 maintained shape memory characteristics reproducibly in four repeated tests.

2-3. Shape memory properties after manufacturing porous scaffolds

Example 2 was manufactured in the form of a porous scaffold so that it could be inserted into the body.

To manufacture a porous scaffold, 2 g of alginate beads (Samchun) and 5 mg of Irgacure2959 (Sigma aldrich), a crosslinking agent, were evenly dispersed in 1 ml of NMP, and then Example 2 was added and mixed. Example 2 was evenly mixed with the alginate beads, placed into a certain mold, and irradiated with UV (365 nm) at 265 mW/cm ² intensity for 300 seconds to obtain a sample. Thereafter, the alginate beads were removed using a 0.1 M ethylene-diamine-tetra-acetic acid solution (EDTA, Sigma aldrich), to manufacture a scaffold with a porous structure.

As a result, a porous scaffold having a porous structure with a size of several micrometers to 100 micrometers could be manufactured from Example 2 (Fig. 3).

Meanwhile, to confirm the shape memory behavior of the manufactured scaffold, the sample was compressed by 30% and exposed to 40 to 45°C, and then the shape recovery ability (%) was confirmed according to Equation (1).

As a result, it was confirmed that the shape of the porous scaffold was restored by more than 80% (Fig. 4).

Experimental Example 3. Mechanical Strength Analysis

To compare the mechanical properties of Example 2 and Comparative Example 1, the elastic modulus and compressive strength of each sample were measured using a universal testing machine (UTM, Instron) according to the manufacturer's instructions.

As a result, it was confirmed that both the elastic modulus and the compressive strength increased when hydroxyapatite nanoparticles were included (Fig. 5). In the case of Example 2 containing hydroxyapatite nanoparticles, the elastic modulus increased by 34% and the compressive strength increased by 69% compared to the comparative example. This is interpreted as being because the nanoparticles are uniformly dispersed within the polymer matrix, thereby evenly distributing the external force.

Experimental Example 4. Analysis of Decomposition Behavior

4-1. In vitro degradation behavior

When inflammation occurs due to disease or injury, lactate, etc. is produced, lowering the acidity of the body. In vitro experiments were conducted to simulate this body environment by preparing a 1N hydrochloric acid buffer solution (1N hydrochloric acid solution, Samchun) with a pH of 6. Example 2 and a comparative example were included, and the decomposition pattern over time was observed at 37°C.

As a result, the example according to the present invention showed a higher decomposition behavior than the comparative example in all time periods, and in particular, it was confirmed that more than about 45% was decomposed within 8 days (Fig. 6).

4-2. In vivo degradation behavior

A porous scaffold was implanted subcutaneously into the flank of 6-week-old BALB/C mice (Orient Bio) and its in vivo degradation behavior was confirmed for 60 days. The experiment was conducted with 5 mice per group.

Specifically, mice were anesthetized by intraperitoneal injection of Zoletil ^® 50 (injection amount: 20 mg/kg). The mouse skin of the area to be transplanted was shaved and disinfected with 70% alcohol. The skin was incised to a size of 1 cm, and the porous scaffold prepared by dissecting the skin and muscle was transplanted subcutaneously into the mouse. After transplantation, the resected skin area was sutured with 6-0 silk suture and disinfected with povidone-iodine (Korea Pharma Co., Ltd.). The scaffold transplantation process was performed in a sterile environment.

60 days after scaffold implantation, the nuclei and extracellular matrix of cells that had migrated into the porous scaffold were stained using H&E staining, and the correlation between the degree of scaffold degradation and the degree of tissue regeneration was confirmed.

For H&E staining, the transplanted scaffold and surrounding tissues were collected and fixed in 10% formalin (Tech&Innovation) for 48 hours. The fixed tissue samples were then dehydrated in distilled water for 30 minutes, treated with ethanol, and made into paraffin blocks. The paraffin blocks were sectioned into 7 μm thick sections, and the nuclei and extracellular matrix were stained with hematoxylin solution (Sigma aldrich) and eosin solution (Sigma aldrich), respectively. The samples were mounted and observed under an optical microscope.

As a result, when Example 2 was transplanted, the extracellular matrix area was stained more darkly compared to when the comparative example was transplanted, which means that tissues can grow more quickly in the area where Example 2 was transplanted as the decomposition of Example 2 progresses more quickly (Fig. 7).

When the area of the darkly dyed part was compared with that immediately after transplantation, in the case of the comparative example, the area of the darkly dyed part increased by an average of 8.7% after 60 days compared to that immediately after transplantation, and in the case of the example 2, the area of the darkly dyed part increased by an average of 33.7% after 60 days compared to that immediately after transplantation (Fig. 8). As a result of comparing the decomposition ability over the same period under in vivo conditions, it was found that in the case of the comparative example, decomposition occurred about 3.8 times faster.

While the specific parts of the present invention have been described in detail above, it will be apparent to those skilled in the art that such specific descriptions are merely preferred embodiments and that the scope of the present invention is not limited thereby. Accordingly, the actual scope of the present invention will be defined by the appended claims and their equivalents.

[National Research and Development Project that Supported This Invention]

[Task ID] 1711174400

[Task Number] RS-2020-KD0000152

[Ministry Name] Multi-Ministry (Ministry of Science and ICT, Ministry of Trade, Industry and Energy, Ministry of Health and Welfare, Ministry of Food and Drug Safety)

[Project Management (Specialized) Agency Name] (Foundation) Inter-Ministry Full Cycle Medical Device Research and Development Project Group

[Research Project Name] Inter-Ministry Full-cycle Medical Device Research and Development Project (R&D) (Ministry of Science and ICT, Ministry of Health and Welfare, Ministry of Trade, Industry and Energy)

[Research Project Name] Development of a body temperature-sensitive medical device to assist vascular anastomoses to improve the success rate of surgical transplantation

[Contribution rate] 1/1

[Name of the organization performing the project] TMD Lab Co., Ltd.

[Research Period] 2020.09.01 ~ 2023.12.31

Claims (19)

1. A shape memory polymer cross-linked with a copolymer comprising an inorganic particle surface-treated with silane and a lactone monomer and glycidyl methacrylate.
2. In the first paragraph, the inorganic particles surface-treated with silane are shape memory polymers that are inorganic particles of gelatin, collagen, chitosan, alginate, cellulose or hydroxyapatite surface-treated with silane.
3. A shape memory polymer in claim 1, wherein the silane is mercaptopropyl trimethoxy silane (3-Mercaptopropyl trimethoxy silane) or trimethoxysilylpropyl acrylate (3-Trimethoxysilylpropyl acrylate).
4. In the first paragraph, the copolymer

   A compound represented by the following chemical formula (1):

   Chemical formula (1)

   

   In the above chemical formula (1),

   R1, R2 and R3 are independently hydrogen (H) or an alkyl group having 1 to 6 carbon atoms,

   m and n are integers from 1 to 20, independently of each other,

   A, B1 and B2 are independently oxygen (O) or sulfur (S),

   x and y represent the mole % of repeating units,

   x+y is 100, and x is between 80 and 95;

   A compound represented by the following chemical formula (2):

   Chemical formula (2)

   

   In the above chemical formula (2),

   x is an integer between 1 and 20,

   m and n represent the mole % of repeating units,

   m+n is 100, and m is between 80 and 96; or

   A compound represented by the following chemical formula (3):

   Chemical formula (3)

   

   In the above chemical formula (3),

   x and y are integers from 1 to 20, independently of each other,

   m and n represent the mole % of repeating units,

   A shape memory polymer, comprising a copolymer, wherein m+n is 100 and m is 70 to 99.
5. In the first paragraph, the shape memory polymer is a shape memory polymer having a shape restoring ability of 50% or more at 30 to 60°C.
6. In the first paragraph, the shape memory polymer is a shape memory polymer having a resolution improved by at least twice compared to the copolymer.
7. A method for manufacturing a shape memory polymer according to claim 1, comprising the following steps:

   (a) a step of mixing a copolymer comprising inorganic particles surface-treated with silane, a lactone monomer and glycidyl methacrylate, and a crosslinking agent; and

   (b) a step of cross-linking the mixture.
8. A method for producing a shape memory polymer in claim 7, wherein the particles surface-treated with silane are chitosan, alginate, cellulose or hydroxyapatite particles surface-treated with silane.
9. A method for producing a shape memory polymer, wherein in claim 7, the inorganic particles surface-treated with silane are mixed in an amount of 1 to 20 wt% relative to the copolymer.
10. A method for producing a shape memory polymer in claim 7, wherein the crosslinking agent is at least one selected from the group consisting of potassium persulfate, ammonium persulfate, benzoyl peroxide, diauryl peroxide, dicumyl peroxide, hydrogen peroxide, azobisisobutuyronitrile, Irgacure, Darocure, lithium phenyl-2,4,6-trimethylbenzoylphosphinate (LAP), diphenyl(2,4,6-Trimethylbenzoyl)phosphine (TPO), and ethyl(2,4,6-trimethylbenzoyl)phenylphosphinate (TPO-L).
11. A method for producing a shape memory polymer, wherein in claim 7, the crosslinking agent is mixed in an amount of 0.1 to 5.0 wt% relative to the copolymer.
12. A method for producing a shape memory polymer, wherein in claim 7, the crosslinking is thermal crosslinking or photocrosslinking.
13. A method for producing a shape memory polymer, wherein the crosslinking in claim 12 is thermal crosslinking, and crosslinking is performed by applying a pressure of 1 to 20 MPa at 100 to 160°C for 10 to 30 minutes.
14. A method for producing a shape memory polymer, wherein in claim 12, the crosslinking is photocrosslinking, and crosslinking is performed by irradiating UV at an intensity of 100 to 500 mW/cm ² for 100 to 1000 seconds.
15. A medical material comprising a shape memory polymer according to any one of claims 1 to 6.
16. In claim 15, the medical material is a material for vascular or non-vascular transplantation.
17. In claim 15, the medical material is a material for reconstructing a tissue depression selected from the group consisting of the nose, sinuses, chin, face, craniofacial area, cheekbone, forehead, and skin.
18. In claim 15, the medical material is a material for transplantation into a bone cavity or a cartilage damaged area.
19. A scaffold for tissue engineering comprising a shape memory polymer according to any one of claims 1 to 6.

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