KR102655715B1 - Manufacturing method of medical nanosheets using polycaprolactone, medical nanosheets manufactured by this method - Google Patents

Abstract

The present invention relates to a method for manufacturing medical nanosheets using polycaprolactone and medical nanosheets manufactured therefrom, and more specifically, to medical nanosheets using polycaprolactone to enable mass production through multi-nozzles while being biocompatible. It relates to a nanosheet manufacturing method and medical nanosheets manufactured therefrom.
In the present invention, polycaprolactone is dissolved in two or more organic solvents to prepare a polycaprolactone solution with a concentration of 6 to 14 wt%, and the polycaprolactone solution thus prepared is electrospun using a multi-nozzle to produce medical nanosheets. By manufacturing it, the technical point is that not only is it biocompatible, minimizing side effects on the skin, but it is also easy to mass-produce, so it can be used in various products such as hemostasis.

Description

Method for manufacturing medical nanosheets using polycaprolactone, medical nanosheets manufactured therefrom

The present invention relates to a method for manufacturing medical nanosheets using polycaprolactone, and medical nanosheets manufactured therefrom. More specifically, the present invention relates to medical nanosheets using polycaprolactone to enable mass production through multi-nozzles while being biocompatible. It relates to a nanosheet manufacturing method and medical nanosheets manufactured therefrom.

In general, medical nanosheets are sheet-shaped products made of healthcare fibers related to life, maintaining and improving health, or fibers for surgery and treatment, and are used in products such as surgical functional materials, gowns, gloves, and bed covers used in hospitals. , tissue adhesion prevention pads, surgical biodegradable sutures, and products such as hemostatic wrap are used in a variety of ways.

Among them, hemostasis is used for the purpose of stopping bleeding symptoms, and can be said to be an important surgical medical product that can be applied to everything from mild bleeding caused by abrasions to major bleeding caused by various reasons such as surgery and accidents.

In other words, the hemostasis process that occurs within the human body is physiologically very complex, so there is a limit to completely preventing bleeding. For example, in the case of severe tissue damage due to an unexpected accident or excessive bleeding that may occur during surgical procedures during surgery, hemostasis must be used because the physical and chemical hemostatic effects that naturally function within the human body alone cannot completely prevent bleeding. It will happen.

These hemostasis not only must be capable of complete hemostasis and wound healing, but must also be free of toxicity and side effects such as fever or inflammation when applied to the human body. They must also function naturally in the human body by quickly absorbing flowing blood and forming a protective layer at the bleeding site. In order to induce hemostasis by recruiting blood coagulation factors related to hemostasis, a certain level of water absorption capacity is required.

In relation to this, 'Improved absorbable hemostatic agent and its manufacturing method (registration number: 10-1624625)' refers to an oxidized regenerated cellulose-based product made by oxidizing regenerated cellulose (ORC), which is an absorbent fabric or knitted fabric, among products developed as hemostatic fabrics. is starting. The principle of hemostasis according to this is that it does not participate in the blood coagulation process in the living body, but when it comes into contact with the blood in the bleeding area, it swells and covers the bleeding area, thereby contracting the tissue around the blood vessel and hemostasis. However, oxidized regenerated cellulose is acidic during hemostasis, and there is a risk of denaturing the activity of blood coagulation factors such as thrombin and fibrinogen, which are involved in the blood coagulation process.

Accordingly, hemostatic fabrics containing blood coagulation factors such as thrombin and fibrinogen and manufactured in the form of absorbable non-woven fabrics, fabrics, or knits have been proposed, but they have the disadvantage of not having sufficient hemostatic effects and wound healing effects.

In addition, an alginate sponge manufactured by freeze-drying a hydrogel formed by dissolving alginic acid or alkaline metal salt of alginic acid at a certain concentration has also been proposed, but this also has unsatisfactory hemostatic and wound healing effects.

In addition, some products developed as hemostats have the problem of causing side effects such as causing heat similar to burns in tissues around the application area or causing cytotoxicity when applied to the human body, and some of the hemostats are not biocompatible. This is so small that it is unsuitable for surgical operations. In particular, medical nanosheets such as hemostasis as described above are difficult to continuously mass produce, which is undesirable in terms of production efficiency.

Therefore, there is a need to develop technology for medical nanosheets that have excellent biocompatibility and can be mass-produced while minimizing side effects on the human body.

Domestic Patent Publication No. 10-1624625, registered on May 20, 2016.

The present invention was invented to solve the above problems, and provides a method for manufacturing medical nanosheets using polycaprolactone to enable mass production through multi-nozzles while being biocompatible, and medical nanosheets manufactured therefrom. This is considered a technical solution.

In order to solve the above technical problem, the present invention includes the first step of dissolving polycaprolactone in two or more organic solvents to prepare a polycaprolactone solution with a concentration of 6 to 14 wt%; And a second step of manufacturing a nanosheet by electrospinning the polycaprolactone solution and discharging it in the form of a filament. In the second step, the polycaprolactone solution is electrospun upward from a multi-nozzle, Manufacturing of medical nanosheets using polycaprolactone, characterized by continuous electrospinning by adjusting the TCD (tip to collector distance) to 250 to 350 mm and applying a voltage of 10 to 50 kV at a flow rate of 200 to 800 μl/min. Provides a method.

In order to solve the above other technical problems, the present invention provides a medical nanosheet manufactured by the above method.

According to the method of manufacturing a medical nanosheet using polycaprolactone of the present invention as a means of solving the above problem, polycaprolactone, a biocompatible or biocompatible polymer, is electrospun to increase the healing rate of the wound area and It has the effect of producing nanosheets that not only minimize the possibility of bleeding but also reduce side effects on the human body.

In addition, since electrospinning can be performed by installing up to 4 multi-nozzles with about 14 nozzle tips, continuous electrospinning is possible compared to the case of installing a single nozzle, which has the effect of mass producing nanosheets. there is.

1 is a flowchart showing a method of manufacturing a medical nanosheet according to the present invention.
Figure 2 is a photograph showing electrospinning of a polycaprolactone solution according to the present invention.
Figure 3 is a photograph showing a medical nanosheet according to the present invention.
Figure 4 is an SEM photograph showing the medical nanosheet according to Example 1.

Hereinafter, the present invention will be described in detail.

Figure 1 shows a flow chart of the manufacturing method of medical nanosheets according to the present invention. Referring to Figure 1, the medical nanosheet of the present invention includes a first step (S20) of preparing a polycaprolactone solution with a concentration of 6 to 14 wt% by dissolving polycaprolactone in two or more organic solvents, and a polycaprolactone solution. It can be manufactured through the second step (S20) of producing a nanosheet by electrospinning and discharging it in the form of a filament.

In order to manufacture the medical nanosheet as described above, the first step is to prepare a polycaprolactone solution with a concentration of 6 to 14 wt% by dissolving polycaprolactone in two or more organic solvents (S20).

Before explaining, polycaprolactone is a biocompatible polymer that has non-toxicity, non-carcinogenicity, biodegradability, biocompatibility, and excellent mechanical properties. It has mechanical properties and high water content.

Polycaprolactone having these characteristics can be dissolved in two or more organic solvents at room temperature to prepare a polycaprolactone solution with a concentration of 6 to 14 wt%. In the case of two or more organic solvents, various applications are possible. For example, a solution of dimethylformamide (DMF) and chloroform mixed in a volume ratio of 10 to 40:60 to 90 can be used as the organic solvent.

The concentration of the polycaprolactone solution prepared through this process may be in the range of 6 to 14 wt% to achieve optimal electrospinning performance. Problems caused by the concentration of the polycaprolactone solution being less than 6 wt% or exceeding 14 wt% are As follows.

As the concentration of the polycaprolactone solution approaches 6wt%, the concentration of the polycaprolactone solution decreases and the viscosity also decreases. By accelerating the consumption rate of the polycaprolactone solution during electrospinning, the hardening phenomenon of the Taylor cone can be improved. . At this time, the viscosity of the polycaprolactone solution depends on the attractive and repulsive forces between polycaprolactone and exhibits the characteristics of intermolecular interactions, so it can be said to be an important factor affecting the formation and average diameter of fibers.

Accordingly, when the concentration of the polycaprolactone solution is less than 6wt%, there is a problem that the concentration is too low and the biocompatibility of the nanosheet becomes minimal. During electrospinning, it is sprayed as a solution rather than fiberized, so it is spun in the form of beads rather than fibers. Accordingly, there is a problem in that it cannot be made into nanosheet form.

If the concentration of the polycaprolactone solution exceeds 14wt%, it takes more than 40 minutes just to fill the polycaprolactone solution for electrospinning, and because the viscosity increases, even if the flow rate during electrospinning exceeds 800㎕/min, the syringe is damaged. A shedding phenomenon occurs.

As a result, not only does the injection itself not occur, but the taylor cone is not maintained. In other words, due to the nature of the organic solvent, the volatilization rate is fast, and during electrospinning, the taylor cone may become opaque and solidify over time. Therefore, for rapid use of the polycaprolactone solution, the concentration should exceed 14 wt%. It is important to prevent this from happening.

Due to this increase in viscosity, condensation occurs in the polycaprolactone solution, or the filament-shaped fibers ejected during the electrospinning process show agglomeration, rendering the product unusable. Therefore, when the concentration of the polycaprolactone solution exceeds 14wt%, the thickness of the electrospun filament becomes very thick, making it difficult for it to be ejected or fiberize. Therefore, it is recommended to manufacture the polycaprolactone solution so that the concentration does not exceed a maximum of 14wt%. desirable.

Next, the second step is to manufacture a nanosheet by electrospinning the polycaprolactone solution and discharging it in the form of a filament (S20).

In the present invention, electrospinning is performed by applying an electric field greater than the surface tension of the polycaprolactone solution, causing splitting of the taylor cone formed at the end of the nozzle tip 121 to form a fiber, which is the polycaprolactone solution according to the present invention. This can be confirmed through Figure 2, which shows the electrospinning of the lactone solution.

Figure 2 is an enlarged photograph of the electrospinning machine 100 that allows the polycaprolactone solution to be electrospun, with a holder 110 at the bottom and a predetermined interval along the lateral or longitudinal direction on the holder 110. A plurality of multi-nozzles 120 are arranged, nozzle tips 121 are installed at regular intervals along the longitudinal direction on the upper surface of the multi-nozzles 120, and are placed at regular intervals on the upper part of the holder 110. It may be configured to include a collector 130. Referring to part A of FIG. 2, fibers in the form of droplets can be seen being electrospun from the nozzle tip 121 to the collector 130 disposed at a certain distance from the upper part of the multi-nozzle 120.

Using the electrospinning machine 100 shown in FIG. 2, the polycaprolactone solution is electrospun upward from the multi-nozzle 120, and the TCD (tip to collector distance) is adjusted to 250 to 350 mm to 200 to 800 ㎕/ By continuously electrospinning by applying a voltage of 10 to 50 kV at a flow rate of min, it is possible to manufacture nanosheets in the form of non-woven fabric. While the polycaprolactone solution is being electrospun through the electrospinning machine 100, if it is necessary to remove the polycaprolactone solution deposited on the nozzle tip 121, a wooden stick is wrapped with a rubber material having an insulating effect. It is desirable to use a tool of the form.

Here, the collector 130 provides a space in which the nanofilaments electrospun from the nozzle tip 121 can be stacked. The narrower the distance between the collector 130 and the nozzle tip 121, the more the nanofilaments from the nozzle tip 121. The force with which the polycaprolactone solution radiates upward increases, and as the distance between the collector 130 and the nozzle tip 121 increases, the force decreases, so it is important to set the optimal distance.

If the distance between the collector 130 and the nozzle tip 121 during electrospinning, that is, the TCD is controlled to less than 250 mm, the distance between the collector 130 and the nozzle tip 121 is too narrow, and the collector (130) is in a solution state rather than fiberized. 130) Polycaprolactone, which is discharged from the nozzle tip 121 in the form of droplets because it can stick to the surface, has the disadvantage of making it difficult to create a flat surface of the nanosheet.

If the TCD is adjusted to exceed 350 mm, the electrospinning performance may deteriorate because the distance between the collector 130 and the nozzle tip 121 is too far, and because the distance between the nozzle tip 121 and the collector 130 is long, the discharged There is a disadvantage in that the thickness of the fiber is inevitably inconsistent, making it unproductable.

For this reason, the distance between the collector 130 and the nozzle tip 121 is preferably adjusted within the range of 250 to 350 mm, and for electrospinning into a stable fiber form, it is most preferable that the TCD is 280 mm.

In the case of electrospinning flow rate below 200㎕/min, the polycaprolactone solution forms on the nozzle tip 121, making it difficult to electrospinning stably. In particular, the polycaprolactone solution may not be supplied consistently to all nozzle tips 121. This has the disadvantage of forming unstable radioactivity and uneven filament thickness. When electrospinning a polycaprolactone solution at a flow rate exceeding 800㎕/min, the polycaprolactone solution also forms on the nozzle tip 121 or overflows, preventing the discharged filament from forming a uniform fibrous shape. There is a downside to this.

When electrospinning, the voltage is preferably adjusted within the range of 10 to 50 kV. If the voltage is less than 10kV, electrospinning cannot start, so radioactivity is greatly reduced and a voltage of at least 10kV must be supplied. In other words, if a voltage of less than 10kV is supplied, electrospinning must wait indefinitely until electrospinning occurs, so electrospinning performance is not efficient. This is not possible. In addition, it is undesirable because fiber aggregation occurs in low voltage sections where the voltage is less than 10kV. On the other hand, when exceeding 50kV, radioactivity increases, but the radiation is easily interrupted and splits to form an unstable jet, and the physical properties of the polycaprolactone solution in which the electrospinning is being performed may be altered. Therefore, the voltage must exceed 50kV. It is desirable to set it not to do so. For efficient operation of electrospinning performance, it is most desirable to use a voltage of 30kV.

In the electrospinning process, it is preferable that the distance that the collector 130 moves left and right is 80 mm. Since the collector 130 can be moved left and right in a wide range of 80 mm, the distance between 0.19 and 0.28 ㎛ while being wound using a roller is It is possible to manufacture nanosheets distributed with thin and uniform fibers.

Figure 3 is a photograph showing the medical nanosheet according to the present invention. Referring to Figure 3, the TCD is adjusted to 250 to 350 mm, and a voltage of 10 to 50 kV is applied at a flow rate of 200 to 800 ㎕/min to continuously electrospinning, thereby confirming the nanosheets in the form of non-woven fabrics that are continuously produced. do.

Through electrospinning using the multi-nozzle 120 as described above, nanosheets that are electrospun stably and uniformly distributed with a thin thickness are manufactured with less polycaprolactone solution forming phenomenon. In particular, electrospinning using a single nozzle Since continuous electrospinning is possible, there is an advantage in mass producing nanosheets.

Hereinafter, embodiments of the present invention will be described in more detail as follows. However, the following examples are merely illustrative to aid understanding of the present invention and are not intended to limit the scope of the present invention.

<Example 1>

A solution of polycaprolactone (Mw: 80,000 g/mol, Sigma aldrich) mixed with dimethylformamide and chloroform in a ratio of 15:85 was used as an organic solvent and stirred at room temperature until completely dissolved to obtain polycapro with a concentration of 6 wt%. A lactone solution was prepared.

After adjusting the distance between the nozzle tip of the electrospinning machine and the collector to 280 mm, a polycaprolactone solution with a concentration of 6 wt% was electrospun while applying a 30 kV voltage at a flow rate of 500 μl/min to prepare a nonwoven nanosheet.

Figure 4 shows an SEM photograph of the medical nanosheet according to Example 1. Figures 4(a), Figure 4(b), Figure 4(c), and Figure 4(d) show enlarged SEM photographs of the nanosheets at different magnifications. In particular, looking at Figure 4(d), the nanosheets are It was confirmed that the constituting filaments showed an overall uniform fibrous shape and that the thickness of each filament was distributed in the range of 0.19 to 0.28㎛. Through this, it can be seen that if the filament thickness is less than 0.19㎛, the durability of the nanosheet is not good, and if it exceeds 0.28㎛, it is undesirable in terms of improving physical properties.

In summary, the present invention relates to a method for manufacturing medical nanosheets using polycaprolactone, wherein polycaprolactone is dissolved in two or more organic solvents to prepare a polycaprolactone solution with a concentration of 6 to 14 wt%, and the prepared By electrospinning the polycaprolactone solution upward from the multi-nozzle 120, nanosheets can be continuously mass-produced.

Therefore, according to the present invention, polycaprolactone, a biocompatible or biocompatible polymer, is used, the distance between the nozzle tip 121 and the collector 130 is adjusted to 250 to 350 mm, and the flow rate of 200 to 800 ㎕/min is 10. By continuously electrospinning while applying a voltage of 50 to 50 kV, not only can the healing rate of the wound area be increased and the possibility of rebleeding be minimized, but unlike conventional electrospinning through a single nozzle to produce nanosheets, multi-nozzle ( 120), continuous electrospinning is possible, which is significant in that the production efficiency of nanosheets can be maximized.

The above description is merely an illustrative explanation of the technical idea of the present invention, and those skilled in the art will be able to make various modifications and variations without departing from the essential characteristics of the present invention. Accordingly, the embodiments disclosed in the present invention are not intended to limit the technical idea of the present invention, but are for explanation, and the scope of the technical idea of the present invention is not limited by these examples. The scope of protection of the present invention should be interpreted in accordance with the scope of the patent claims, and all technical ideas within the equivalent scope should be interpreted as being included in the scope of rights of the present invention.

100: Electroradiator
110: stand
120: Multi-nozzle
121: Nozzle tip
130: Collector

Claims (2)

A first step of preparing a polycaprolactone solution with a concentration of 6 to 14 wt% by dissolving polycaprolactone with a molecular weight of 80,000 g/mol in an organic solvent mixed with dimethylformamide and chloroform in a volume ratio of 15:85; and
A second step of manufacturing a nanosheet by electrospinning the polycaprolactone solution and discharging it in the form of a filament;
The second step is,
The polycaprolactone solution is electrospun upward from a multi-nozzle, and the TCD (tip to collector distance) is adjusted to 250 to 350 mm, and a voltage of 10 to 50 kV is applied at a flow rate of 200 to 800 ㎕/min to continuously electrolyze. Radiating,
The multi-nozzle has up to 14 nozzle tips arranged in a straight line at equal intervals,
The multi-nozzles are arranged one or two to four at equal intervals,
Characterized in that the filament thickness of the nanosheet is 0.19 ~ 0.28㎛,
Method for manufacturing hemostatic medical nanosheets using polycaprolactone. delete