CN115139514A

CN115139514A - Preparation method of degradable easily-separable microneedle array for 3D printing

Info

Publication number: CN115139514A
Application number: CN202210785834.2A
Authority: CN
Inventors: 韩晓筱; 袁磊; 陈锋; 陆益栋; 赵阳光
Original assignee: Shanghai Heiyan Medical Technology Co ltd; Hunan University
Current assignee: Shanghai Heiyan Medical Technology Co ltd; Hunan University
Priority date: 2022-07-04
Filing date: 2022-07-04
Publication date: 2022-10-04
Anticipated expiration: 2042-07-04
Also published as: CN115139514B

Abstract

The invention discloses a preparation method of a degradable easily-separated microneedle array for 3D printing, which comprises the following steps: s1, directly generating a G-code by utilizing the macro function of Excel, importing the G-code into Reetier-Host software to verify the shape of a graph, and determining the printing sequence and number of needle bodies, the height of a microneedle, the sizes of the top and the bottom and the distance between the needle bodies; s2, leading out the G-code from the Repeter-Host software and guiding the G-code into a Raise3D Pro2 printer, controlling the printing of a bottom plate by a left nozzle, realizing the printing of a microneedle body by a right nozzle, wherein the bottom plate is made of a flexible environment-friendly material, and the microneedle body is made of a degradable material; and S3, regulating and controlling parameters based on the setting of the G-code, realizing the rapid stretching of the filaments in the nozzle by utilizing the rapid movement of the nozzle, and finishing the manufacture of the micro-needle by utilizing the combination of a 3D printing process and a stretching method. The preparation method of the degradable easily-separable microneedle array for 3D printing ensures the precision of microneedles and simplifies the process of manufacturing separable microneedles by using a mold.

Description

Preparation method of degradable easily-separable microneedle array for 3D printing

Technical Field

The invention relates to the technical field of medicine and biological manufacturing, in particular to a preparation method of a degradable easily-separated microneedle array for 3D printing.

Background

The degradable microneedle is a polymer microneedle which can be automatically degraded in vivo after the microneedle is released, and has good biocompatibility and mechanical property. Because the micro-needle can be degraded in vivo, the micro-needle is not afraid of breakage, and the tip is not polluted, so that the compliance of a patient is improved to a certain extent.

Since the degradable microneedles are mainly made of degradable polymers, there are many polymer choices and many choices in the manner of preparation. Currently, the most common preparation methods include: (1) processing a mould: in this method, microneedles are manufactured using a high-precision template, but the manufacturing process of the mold is complicated, the manufacturing cost of the mold is high with high precision, and the microneedle array manufactured using the mold cannot be manufactured individually in terms of shape and the number of microneedles. (2) 3D printing and manufacturing: with the progress of technology, the 3D printing field is increasingly large, and products manufactured by 3D printing are also increasing.

In addition, fused Deposition Modeling (FDM) is also currently the most widely used, most commonly used printing device. At present, by utilizing the characteristics of more types of available materials and simultaneous working of multiple available nozzles, the publication No. CN 110693855A is named as 'a preparation method of a 3D printing microneedle patch and application thereof', the technology utilizes a double-nozzle fused deposition forming FDM 3D printer, one nozzle prints a substrate of the microneedle patch, the other nozzle prints a columnar array of the microneedle patch, and the columnar array contains insulin drugs capable of intelligently responding and adjusting blood sugar, thereby realizing intelligent control of drug release, and solving the problem that the number and other characteristic parameters of the existing microneedle array cannot be modified arbitrarily. However, the method of modeling, slicing and remanufacturing cannot directly manufacture a microneedle array with a qualified size, and requires post-treatment (chemical treatment or physical treatment) to manufacture the microneedle array, and the microneedle array after the chemical treatment contains alkaline chemical substances, which may affect drug properties or human bodies.

In addition, most degradable microneedles are manufactured in a mode of facilitating separation of the microneedle body and the substrate, so that the microneedle can be used for keeping the needlepoint in the body after the microneedles are applied, and other parts are removed, so that the compliance of a patient is improved, and the safety of a wound is guaranteed.

At present, such a separate microneedle is mainly manufactured by a template method, but the whole operation process is complicated, and individualization in manufacturing cannot be realized. For example, publication No. CN 110947085A entitled "a method for accelerating the formation and rapid dissolution of a polyvinyl alcohol soluble microneedle and a microneedle prepared thereby", which uses a template method to manufacture microneedles, although the method is simple and rapid, and is convenient for mass production, the disadvantage that the template method cannot be personalized manufacturing cannot be escaped.

According to the manufacturing of the separated micro-needle, the material selection of the substrate and the needle body gradually moves from the same material to different materials, so that the degradability of the tip part can be ensured, the waste of the materials can be reduced, the flexible substrate also gradually becomes one of the selection of the micro-needle substrate, and the bonding of the needle body and the skin is improved.

Disclosure of Invention

The invention aims to provide a preparation method of a degradable easily-separated microneedle array for 3D printing, which can ensure the precision of microneedles only by utilizing a post-treatment process and can synchronously realize the preparation of separated microneedles by utilizing a 3D printing process.

In order to achieve the purpose, the invention provides a preparation method of a degradable easily-separated microneedle array for 3D printing, which comprises the following steps:

s1, directly generating a G-code by utilizing the macro function of Excel, importing the G-code into a Repetier-Host software to verify the shape of a graph, and determining the printing sequence and number of pins, the height of the micropins, the sizes of the top and the bottom and the space between the pins;

s2, leading out the G-code from the Repeter-Host software and guiding the G-code into a Raise3D Pro2 printer, controlling the printing of a bottom plate by a left nozzle, realizing the printing of a microneedle body by a right nozzle, wherein the bottom plate is made of a flexible environment-friendly material, and the microneedle body is made of a degradable material;

and S3, regulating and controlling parameters of printing speed, idle stroke speed and printing temperature based on the G-code, realizing rapid stretching of filaments in the nozzle by utilizing rapid movement of the spray head, and finishing microneedle manufacturing by utilizing the combination of a 3D printing process and a stretching method.

Preferably, the specific operation in step S3 is as follows:

(1) The parameter regulation and control of the printing speed, the idle stroke speed and the printing temperature need to realize the matching among the parameters, thereby completing the regulation and control of the machine;

(2) The shape of the micro-needle is designed in relation to the moving speed of the nozzle, namely the idle stroke speed, which is also called as the stretching speed, so that the quality of the micro-needle is controlled, and the shape of the micro-needle can also be controlled.

Preferably, in the step S2, the flexible environment-friendly material is TPU, and is fed at a left nozzle when in use; the degradable material is PLA, which is fed at the right jet when in use.

Preferably, in step S2, the flexible material includes, but is not limited to, TPU, and the degradable material includes, but is not limited to, PLA.

Preferably, in step S3, the printing speed is 800mm/min, the idle stroke speed range is 2000-10000mm/min, and the printing temperature is 210 ℃.

A microneedle patch prepared by the preparation method of the degradable easily-separable microneedle array based on 3D printing.

Preferably, the number of the microneedle arrays is 4 multiplied by 4, the height of the microneedles is 1500 to 2000 μm, the tip size is 70 to 100 μm, the bottom size is 500 to 1000 μm, and the distance between the needles is 5mm.

Therefore, the preparation method of the degradable easily-separable microneedle array by 3D printing is adopted, the stretching method is combined with the 3D printing technology, and the process of directly manufacturing the microneedles by using FDM equipment is realized by controlling parameters, so that the influence on medicines and patients caused by the post-treatment process is omitted. In addition, the shape of the microneedle can be controlled through the regulation and control of the 3D printing parameters, so that the 3D manufacturing of the easily separated microneedle is realized, and the process of manufacturing the separable microneedle by using the mold is simplified.

The technical solution of the present invention is further described in detail by the accompanying drawings and embodiments.

Drawings

Fig. 1 is a microscopic structure view of a 3D printed microneedle patch;

fig. 2 is a front view of a 3D printed microneedle patch;

fig. 3 is a top view of a 3D printed microneedle patch;

fig. 4 is an enlarged schematic view of a 3D printed microneedle patch;

FIG. 5 is a schematic illustration of microneedle shapes formed at different idle stroke speeds;

fig. 6 is a pictorial view of a microneedle patch;

fig. 7 is a schematic view of differently shaped microneedles.

Detailed Description

The technical scheme of the invention is further explained by the attached drawings and the embodiment.

Unless defined otherwise, technical or scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.

It will be evident to those skilled in the art that the invention is not limited to the details of the foregoing illustrative embodiments, and that the present invention may be embodied in other specific forms without departing from the spirit or essential attributes thereof. The present embodiments are therefore to be considered in all respects as illustrative and not restrictive, the scope of the invention being indicated by the appended claims rather than by the foregoing description, and all changes which come within the meaning and range of equivalency of the claims are therefore intended to be embraced therein, and any reference signs in the claims are not to be construed as limiting the claims.

Furthermore, it should be understood that although the present description refers to embodiments, not every embodiment may contain only a single embodiment, and such description is for clarity only, and those skilled in the art should integrate the description, and the embodiments may be combined as appropriate to form other embodiments understood by those skilled in the art. These other embodiments are also covered by the scope of the present invention.

It should also be understood that the above-mentioned embodiments are only for explaining the present invention, and the protection scope of the present invention is not limited thereto, and any person skilled in the art should be covered by the protection scope of the present invention by the technical solutions and the inventive concepts of the present invention equivalent substitutions or changes within the technical scope of the present invention disclosed by the present invention.

The use of the word "comprising" or "comprises" and the like in the present invention means that the element preceding the word covers the element listed after the word and does not exclude the possibility of also covering other elements. The terms "inner", "outer", "upper", "lower", and the like indicate orientations or positional relationships based on those shown in the drawings, and are only for convenience in describing the present invention and simplifying the description, but do not indicate or imply that the referred devices or elements must have a specific orientation, be constructed and operated in a specific orientation, and thus are not to be construed as limiting the present invention, and when the absolute position of the described object is changed, the relative positional relationships may be changed accordingly. In the present invention, unless otherwise expressly stated or limited, the terms "attached" and the like are to be construed broadly, e.g., as meaning a fixed connection, a removable connection, or an integral part; either directly or indirectly through intervening media, either internally or in any other relationship. The specific meanings of the above terms in the present invention can be understood by those skilled in the art according to specific situations. The term "about" as used herein has a meaning well known to those skilled in the art, and preferably means that the term modifies a value within the range of ± 50%, ± 40%, ± 30%, ± 20%, ± 10%, ± 5% or ± 1% thereof.

All terms (including technical or scientific terms) used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs unless specifically defined otherwise. It will be further understood that terms, such as those defined in commonly used dictionaries, should be interpreted as having a meaning that is consistent with their meaning in the context of the relevant art and will not be interpreted in an idealized or overly formal sense unless expressly so defined herein.

Techniques, methods, and apparatus known to those of ordinary skill in the relevant art may not be discussed in detail but are intended to be part of the specification where appropriate.

The disclosures of the prior art documents cited in the present description are incorporated by reference in their entirety and are therefore part of the present disclosure.

The invention discloses a preparation method of a degradable easily-separated microneedle array for 3D printing, which comprises the following steps:

the G-code file is written before printing, so that the whole printing path is printed according to the requirement of the user in the printing process, and the direct writing can also reduce the slicing process, so that the influence of slicing software on the final printing result is reduced.

By applying Excel macro editing, structural design is directly carried out on a required structure on an Excel interface, printing parameters can be adjusted, the structure can be guided into a Raise3D Pro2 printer after a G-code is generated and is detected by Repeter-Host software to be correct, printing of a micro-needle structure is realized, if a printing result is unqualified, the structure can be directly modified on the Excel interface, so that a slicing link is reduced, and the manufacturing efficiency is improved.

The control of the printer of the present invention is as follows: the left nozzle adopts TPU wire rods to control the printing of the bottom plate; and the right nozzle adopts PLA to realize the printing of the microneedle body. And the parameters of the microneedles are as follows: the number of the micro-needle arrays is 4 multiplied by 4, the height of the micro-needle is 1500 mu m to 2000 mu m, the size of the tip is 70 mu m to 100 mu m, the size of the bottom is 500 mu m to 1000 mu m, and the distance between the needle bodies is 5mm.

The most critical of the whole printing process is the regulation and control of parameters, the optimal parameters are obtained mainly through experimental process tests, and the selection of the parameters is also carried out under the principle of following control variables.

For the regulation of printing parameters: (1) test for printing temperature: firstly, according to the glass transition temperature of the material and the suggested temperature of the wire rod which is 180-230 ℃, one temperature is taken every 10 ℃ to test the printing result, and the fact that when the temperature is 230 ℃, the liquid flows out too much and the curing time is long due to overhigh temperature is found; when the temperature is 180 ℃ and 190 ℃, the connection between the needle body and the bottom plate is not good during printing; when the temperature is 200 ℃, the phenomenon that the needle body is not well connected with the bottom plate still occurs in the printing process, and the printing effect is the best at 210-220 ℃. In order to ensure that the size of the tip of the microneedle is good, the microneedle printing temperature is set to be 210 ℃ according to the principle that the lower the temperature is, the faster the curing is.

(2) Determination of recovery value and recovery speed: in order to ensure the printing quality of the first layer and the stable combination of the layers, the recovery value and the recovery speed need to be determined, and the quality is optimal under the condition of matching the recovery value of 7mm with the recovery speed of 8000 mm/min.

(3) Selection of printing speed: the printing speed is a key parameter for determining the total printing quantity of the material and the quality of a printing result, and for the printing quality, the slower printing speed is better in the final printing result, so in order to ensure the printing quality, the reasonable printing speed range of the material is combined, the printing speed range of the constant microneedle volume is obtained by utilizing volume conservation, the printing speed is determined to be 800-10000mm/min, then 800mm/min and 1000mm/min are respectively taken, then a speed value is taken every 1000mm/min for detection, the printing quality with the speed of 800mm/min is the best under the matching of relevant parameters such as a recovery value (recovery speed) and printing temperature, and 800mm/min is selected as the printing speed.

(4) Selecting an idle stroke speed: the idle stroke speed refers to the speed of nozzle movement during unprinted events, and is the speed required for the stretching process of the microneedles after printing, and the speed directly determines the sharpness of the microneedles and the shape of the microneedles. By testing the speed range of 1000mm/min to 10000mm/min, one speed value is taken per 1000mm/min, after selecting the parameters according to the previous: the printing temperature is 210 ℃, the recovery value is 7 mm/recovery speed is 8000mm/min, the printing speed is 800mm/min, and a plurality of groups of experiments are carried out to determine the printing quality and the shape of the microneedle.

The final classification can be based on different microneedle shapes: when the speed is 8000mm/min to 10000mm/min, the printed microneedle is a spindle-shaped microneedle, and the microneedle is convenient to separate a needle body from a base part, namely a separable microneedle; when the speed is 2000mm/min, the shape of the printed micro-needle is far larger than the tip part at the bottom, so that the micro-needle has enough strength, is suitable for manufacturing solid micro-needles or coating micro-needles and the like, and can prevent the micro-needle from breaking; at 1000mm/min, the micro-needle with the sharpness of 70-100 μm cannot be stretched due to the low speed, so the requirement is not met; and when the speed is between 2000mm/min and 8000min/min, the shape is also between that of the spindle-shaped microneedle and the large-bottom microneedle.

Example one

As shown in fig. 1, 2, 3 and 6, the whole microneedle patch structure of the 3D printed microneedle patch mainly comprises three parts, namely a microneedle needle body (1), an adhesive patch (2) and a microneedle substrate (3). The micro-needle body is made of PLA which is a degradable material, the adhesive patch (such as a non-toxic acrylic coating, medical non-toxic water emulsion, medical non-toxic solvent adhesive and the like) is used for better adhering the skin and the micro-needle to prevent the micro-needle from falling off, and the micro-needle substrate is made of a flexible TPU material, so that the micro-needle can be more attached to the skin.

As shown in fig. 4, the microneedle has a monolithic structure, and it can be seen that the microneedle is enlarged to have a trapezoidal truncated cone structure, the top dimension is 70-100 μm, the bottom dimension is 500-1000 μm, and the entire height is 1500 μm. The microneedle array is a 4 x 4 array structure, and the distance between the needles is 5mm.

Example two

The structure of the needle body of the micro-needle is similar to a spindle structure, and the structure is mainly realized by adjusting the idle stroke speed. The dimensions of the respective portions of the microneedles formed at different stretching speeds (idle stroke speeds) and the dimensions of the central portions of the microneedles formed at different stretching speeds (idle stroke speeds) and the actual dimensions are shown in table 1, table 2 and fig. 5.

Table 1 table of dimensions of portions of microneedles formed at different stretching speeds (idle stroke speeds)

Table 2 table of ratio of central dimension to actual dimension of theoretical microneedle formed at different stretching speeds (idle stroke speed)

Drawing speed (mm/min)	RO (ratio of theory to reality)
		2000	2.09
3000	1.86
		4000	1.63
5000	1.81
		6000	1.67
7000	1.16
		8000	0.91
9000	0.95
		10000	0.93

In order to control the microneedle structure, different structures are realized by adjusting the stretching speed (idle stroke speed), and for this reason, it is convenient to show the microneedle structure that the actual top is directly set to RT, the actual bottom size is set to RB, and the actual middle size is set to RM. According to the trapezoidal median theory: the middle size = (upper bottom size + lower bottom size)/2, theoretical microneedle middle size RM1 can be obtained, then the ratio of the theoretical microneedle middle size RM1 to the actually measured microneedle middle size can be obtained, R0 is set, and according to the ratio and the microneedle shape measured under a microscope, such as a microneedle monomer map a, B, and C in fig. 7, it can be clearly seen that when R0 > 2, the microneedle structure is in a large bottom shape, such as in fig. 7 (a); when R0 is more than 1 and less than or equal to 2, the structure is a common needle-shaped microneedle, as shown in figure 7 (b); when 1. Ltoreq.R 0, the structure is a spindle-shaped structure, as shown in FIG. 7 (c).

When the shape is matched with the stretching speed (idle stroke speed), when the idle stroke speed is 2000mm/min, the shape is a large bottom microneedle structure, as shown in fig. 7 (a); when the idle stroke speed is between 2000mm/min and 8000mm/min, the structure is a common conical microneedle, as shown in figure 7 (b); when the idle stroke speed is more than 8000mm/min, the structure is a spindle-shaped structure, as shown in fig. 7 (c).

According to the method, the high-quality microneedle array is directly manufactured by using FDM, and the microneedles are manufactured by combining 3D printing and a traditional stretching method, so that the problems that a post-processing process is needed after the 3D printing and the damage is caused by the post-processing process are overcome, and the defect that parameters such as the stretching speed cannot be controlled by the traditional stretching method is overcome. Secondly, by applying the novel method, the microneedles with easily separated shapes can be manufactured by regulating and controlling the printing parameters, so that the separable microneedle array can be manufactured by the 3D printing technology.

Therefore, the preparation method of the degradable easily-separable microneedle array by 3D printing ensures the precision of the microneedles and simplifies the process of manufacturing the separable microneedles by using the mold.

Finally, it should be noted that: the above embodiments are only for illustrating the technical solutions of the present invention and not for limiting the same, and although the present invention is described in detail with reference to the preferred embodiments, those of ordinary skill in the art should understand that: modifications and equivalents may be made to the invention without departing from the spirit and scope of the invention.

Claims

1. A preparation method of a degradable easily-separable microneedle array for 3D printing is characterized by comprising the following steps:

s1, directly generating a G-code by utilizing the macro function of Excel, importing the G-code into Reetier-Host software to verify the shape of a graph, and determining the printing sequence and number of needle bodies, the height of a microneedle, the sizes of the top and the bottom and the distance between the needle bodies;

and S3, regulating and controlling parameters of printing speed, idle stroke speed and printing temperature based on the G-code setting, realizing the rapid stretching of the filaments in the nozzle by utilizing the rapid movement of the spray head, and finishing the microneedle manufacturing by utilizing the combination of a 3D printing process and a stretching method.

2. The preparation method of the degradable easily separable microneedle array according to claim 1, wherein the step S3 comprises the following steps:

3. The preparation method of the degradable easily separable microneedle array for 3D printing according to claim 1, wherein: in the step S2, the flexible environment-friendly material is TPU, and is fed into a left spray head when in use; the degradable material is PLA, which is fed at the right hand jet when in use.

4. The preparation method of the degradable easily separable microneedle array according to claim 1, wherein the preparation method comprises the following steps: in step S2, the flexible material includes but is not limited to TPU, and the degradable material includes but is not limited to PLA.

5. The preparation method of the degradable easily separable microneedle array for 3D printing according to claim 1, wherein: in step S3, the printing speed is 800mm/min, the idle stroke speed range is 2000-10000mm/min, and the printing temperature is 210 ℃.

6. A microneedle patch prepared based on the preparation method of the degradable easily separable microneedle array for 3D printing according to any one of claims 1 to 5.