CN110153651B - Large aspect ratio flat metal microneedle array, preparation method and auxiliary device for clamping and piercing thereof - Google Patents
Large aspect ratio flat metal microneedle array, preparation method and auxiliary device for clamping and piercing thereof Download PDFInfo
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- CN110153651B CN110153651B CN201910391947.2A CN201910391947A CN110153651B CN 110153651 B CN110153651 B CN 110153651B CN 201910391947 A CN201910391947 A CN 201910391947A CN 110153651 B CN110153651 B CN 110153651B
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
- A61M37/00—Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin
- A61M37/0015—Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin by using microneedles
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- B—PERFORMING OPERATIONS; TRANSPORTING
- B23—MACHINE TOOLS; METAL-WORKING NOT OTHERWISE PROVIDED FOR
- B23P—METAL-WORKING NOT OTHERWISE PROVIDED FOR; COMBINED OPERATIONS; UNIVERSAL MACHINE TOOLS
- B23P15/00—Making specific metal objects by operations not covered by a single other subclass or a group in this subclass
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
- A61M37/00—Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin
- A61M37/0015—Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin by using microneedles
- A61M2037/0023—Drug applicators using microneedles
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
- A61M37/00—Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin
- A61M37/0015—Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin by using microneedles
- A61M2037/0053—Methods for producing microneedles
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- Dermatology (AREA)
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- General Health & Medical Sciences (AREA)
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- Mechanical Engineering (AREA)
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Abstract
一种大长径比平面金属微针阵列、制备方法及其夹持、刺入辅助装置，属于医疗器械技术领域。将大尺寸金属薄片裁剪为小型金属薄片；加工由上下两块金属盖板组成的夹持工装，工装上下盖板内侧设有凹槽，凹槽内放置金属薄片，通过螺栓紧固；设计微针阵列的几何形状和尺寸，对工装和金属薄片作为整体进行线切割，得到具有多个微针针体的平面金属微针阵列。另外，本发明还提供了该大长径比平面金属微针阵列的组装夹持装置和刺入辅助装置，将组装好的刺入辅助装置放置于皮肤上，微针阵列通过辅助装置刺入皮肤。本发明通过简单组装可大批量制成微针阵列，成本低效率高，能够保证微针尖端加工精度；且能够全面提高大长径比微针的使用可靠性。
A large aspect ratio flat metal microneedle array, a preparation method and an auxiliary device for clamping and piercing thereof belong to the technical field of medical devices. Cut large-sized metal sheets into small metal sheets; process a clamping tool consisting of upper and lower metal cover plates, the inner side of the upper and lower cover plates of the tool is provided with grooves, and metal sheets are placed in the grooves and fastened by bolts; design micro-needles The geometry and size of the array, the tool and the metal sheet as a whole are wire-cut to obtain a planar metal microneedle array with multiple microneedle needle bodies. In addition, the present invention also provides an assembly and clamping device and a piercing auxiliary device for the large aspect ratio flat metal microneedle array, the assembled piercing auxiliary device is placed on the skin, and the microneedle array penetrates the skin through the auxiliary device . The invention can manufacture microneedle arrays in large quantities through simple assembly, has low cost and high efficiency, can ensure the machining accuracy of the microneedle tips, and can comprehensively improve the use reliability of the large aspect ratio microneedles.
Description
Technical Field
The invention belongs to the technical field of medical instruments, and relates to a large-length-to-diameter-ratio planar metal microneedle array, a preparation method and a clamping and puncturing auxiliary device thereof.
Background
Microneedles (MN) generally refer to micro needles that have a length of tens of microns to several millimeters and a tip diameter of less than tens of microns. The microneedle is used for puncturing the skin cuticle, so that the biological barrier effect of the skin cuticle is broken through, a micron-sized drug delivery channel is formed on the skin surface layer, and experiments show that the transdermal drug delivery efficiency can be improved by orders of magnitude, and the types and the range of transdermal drug delivery are greatly expanded. In addition, because the micro-needle has a tiny size, the wound and the pain generated when the micro-needle pierces the skin are tiny, so that the micro-needle does not cause obvious discomfort of a drug delivery patient, is beneficial to preventing infection and is more beneficial to wound recovery. Due to the advantages mentioned above, microneedle technology has been gaining attention in the field of transdermal drug delivery in recent decades.
In addition to being used for transdermal drug delivery, microneedles have received increasing attention in recent years in the fields of biomedical measurements and microsampling analysis. However, unlike transdermal drug delivery techniques in which the microneedles only need to pierce the superficial tissues of the skin, the microneedles for biological micro-sampling analysis need to pierce the tissues to a certain depth, so the length of the sampling microneedles is often in the order of millimeters. In order to enable the sampling microneedle to have the advantages of small wound and light pain, the transverse size of the sampling microneedle still needs to be as small as possible, so that the length-diameter ratio of the sampling microneedle is very large, and difficulty is brought to the preparation and the use of the sampling microneedle. Firstly, the higher the microneedle height is, the higher the processing difficulty and cost are, and the conventional microneedle processing technologies such as photoetching, deep reactive ion etching, x-ray etching and the like are difficult to be used for processing the microneedle with the large length-diameter ratio; second, the large length to diameter ratio of the microneedles during penetration into the skin tends to induce buckling or breaking of the microneedles, resulting in penetration failure.
In view of the manufacturing problem of the sampling microneedle with large length-to-diameter ratio, korea scholars have successfully prepared a sampling microneedle with a length of 2 mm by using polymer drawing and forming combined with a metal plating process, which is called as "Ultra-high aspect micro needle", and related results are published in the authoritative journal < Advanced Materials >. In brief, the process utilizes a drawing head with a plurality of micron-sized micro-columns to draw the SU-8 glue in a molten state, and the SU-8 glue is drawn into a column shape with controllable height. And after cooling and shaping, carrying out metal coating on the surface of the columnar SU-8 adhesive, finally dissolving the SU-8 adhesive and reserving the metal coating, and finally obtaining the millimeter-sized metal sampling microneedle array with the large length-diameter ratio. Obviously, the manufacturing process is ingenious in design, and the metal microneedle with the large length-diameter ratio can be successfully prepared, but the manufacturing process is relatively complex, the cost is high, and the mass production is difficult. In addition, how to ensure that the microneedle array consisting of the columnar microneedles with large length-to-diameter ratio does not bend or break when penetrating into the skin is not effectively solved.
Disclosure of Invention
The invention provides a planar metal microneedle array with a large length-diameter ratio, a preparation method and a processing and puncturing auxiliary device thereof, aiming at the problems existing in the manufacturing and using processes of a sampling microneedle with a large length-diameter ratio.
In order to achieve the purpose, the invention provides the following technical scheme:
a preparation method of a planar metal microneedle array with a large length-diameter ratio comprises the following steps:
the first step is as follows: the microneedle material is made of medical stainless steel or titanium alloy sheet metal with good biocompatibility and good strength and toughness, and the thickness of the sheet metal is 20-200 microns.
The second step is that: the metal sheet is cut into small metal sheets 5 with proper sizes, and the recommended sizes are 30-50 mm in length and 10-30 mm in width.
The third step: special sheet clamping tool for processing
The tool consists of an upper metal cover plate and a lower metal cover plate 1 which are completely the same, and the total thickness of each cover plate is 5-10 mm; processing grooves 2 matched with the small metal sheets 5 in size on the inner walls of the upper cover plate and the lower cover plate of the tool, wherein the length and the width of each groove are consistent with those of the metal sheets 5 and are used for placing the metal sheets 5, and the depth of each groove of the upper cover plate and the depth of each groove of the lower cover plate are 1-5 mm; the edges of the periphery of the upper cover plate body and the lower cover plate body 1 are provided with through holes 3 for passing through fastening bolts 4. The clamping tool material is a metal material such as stainless steel, 45# steel and the like with good conductivity and high strength.
And fourthly, placing the small metal sheets 5 in the grooves 2 of any metal cover plate 1, wherein the number of the metal sheets 5 placed at one time is adjusted according to the thickness of the metal sheets and the depth of the grooves, and the recommended number of the metal sheets placed at one time is 20-200. Another metal cover plate 1 is placed on the cover plate on which the metal sheet 5 is placed, and the grooves face the metal sheet 5 and are aligned up and down; then the upper and lower metal cover plates 1 are sealed and fastened through the fastening bolts 4, and the metal sheets 5 are compacted and integrated with the upper and lower cover plates 1.
Fifthly, designing the geometric shape and the dimension specification of the sheet-shaped plane metal microneedle
The sheet-shaped planar metal microneedle array comprises a substrate 6 for a subsequent clamping part and a microneedle body 7 with a large length-diameter ratio, wherein the height of the microneedle body 7 with the large length-diameter ratio is 1-5 mm, the root width of the microneedle body is 50-500 microns, and the thickness of the microneedle body is the thickness of the metal sheet 5. The microneedle bodies 7 with the large length-diameter ratio are arranged above the substrate 6, the number of microneedles on each substrate is 3-50, and the distance between the microneedles is 0.25-10 mm; two sides above the substrate 6 are respectively provided with a positioning shoulder 8 for positioning and guiding the puncture auxiliary device; the middle part below the substrate 6 is provided with a positioning guide groove 9 for assembling the subsequent substrate 6.
The large length-diameter ratio microneedle body 7 adopts an equal strength design along the length direction, namely the width change of the large length-diameter ratio microneedle body 7 needs to ensure that the maximum bending stress of each cross section is equal everywhere when the tip of the microneedle body 7 is under the action of transverse concentrated load, the root of the microneedle body 7 is assumed to be an x-axis starting point, the x-axis is located on a longitudinal symmetric axis of the microneedle body 7, and the width direction is assumed to be a y-axis, so that the equal strength design requirements x and y meet the following relations:
in the formula L0The length of the microneedle body 7 is shown, and C is a constant which comprehensively reflects the yield strength of the material, the thickness of the microneedle and the load size.
And a sixth step: and (3) clamping the packaged metal sheet and the tool in the fourth step onto a linear cutting device, determining a wire moving path by the linear cutting device according to the geometric shape and the dimension of the sheet planar metal microneedle designed in the fifth step, performing linear cutting on the tool and the metal sheet 5 as a whole, and processing a substrate 6 and a microneedle body 7 by the metal sheet 5. In the process of linear cutting, 8-shaped path cutting is adopted for processing the needle point of the microneedle needle body 7, and the sharpness degree of the needle point of the microneedle is ensured. In addition, in the processing process, two sides of the substrate 6 are not completely cut, a part 10 which is 2-5 mm away from the cutting process and is used for keeping the integrity of the clamping tool is reserved, the clamping tool and the metal sheet 5 are still integrated after processing, the metal microneedle array is prevented from being washed away by cooling liquid in the processing process, the used tool is guaranteed to have high enough structural rigidity, and the tool can be reused.
The seventh step: and (4) detaching the fastening bolt 4 on the tool, taking out the processed metal sheet 5, and cleaning to obtain the uncut microneedle substrate.
And eighthly, cutting the microneedle substrate obtained in the seventh step, removing materials in reserved areas on two sides of the substrate 6, and peeling the sheet-shaped planar metal microneedles from the metal sheet 5 to obtain the sheet-shaped planar metal microneedle array with a plurality of microneedle bodies.
A planar metal microneedle array with a large length-diameter ratio is characterized in that a sheet-shaped planar metal microneedle array is composed of a substrate 6 for a subsequent clamping part and a microneedle body 7 with a large length-diameter ratio, the height of the microneedle body 7 with the large length-diameter ratio is 1-5 mm, the root width of the microneedle body is 50-500 microns, and the thickness of the microneedle array is the thickness of a metal sheet 5. The microneedle bodies 7 with the large length-diameter ratio are arranged above the substrate 6, the number of microneedles on each substrate is 3-50, and the distance between the microneedles is 0.25-10 mm; two sides above the substrate 6 are respectively provided with a positioning shoulder 8 for positioning and guiding the puncture auxiliary device; the middle part below the substrate 6 is provided with a positioning guide groove 9 for assembling the subsequent substrate 6. The large length-diameter ratio microneedle body 7 adopts an equal strength design along the length direction, namely the width change of the large length-diameter ratio microneedle body 7 needs to ensure that the maximum bending stress of each cross section is equal everywhere when the tip of the microneedle body 7 is under the action of transverse concentrated load, the root of the microneedle body 7 is assumed to be an x-axis starting point, the x-axis is located on a longitudinal symmetric axis of the microneedle body 7, and the width direction is assumed to be a y-axis, so that the equal strength design requirements x and y meet the following relations:
in the formula L0The length of the microneedle body 7 is shown, and C is a constant which comprehensively reflects the yield strength of the material, the thickness of the microneedle and the load size.
The assembling and clamping device for the planar metal microneedle array with the large length-diameter ratio comprises a main body 11 and a partition plate 15, wherein the main body 11 and the partition plate 15 are made of light metal or high polymer materials, and are made of aluminum alloy or polytetrafluoroethylene and the like, but are not limited to the two materials.
The main body 11 is a box-shaped cuboid structure with an opening at one side, and the bottom of the inner cavity is provided with a slide rail 12 matched with the microneedle substrate bottom guide groove 9; the bottom of the main body 11 is provided with a threaded hole 13 for subsequently mounting a handle; the side of the main body 11 is provided with a threaded through hole 14 for tightening the partition 15 by a bolt 16. The large length-diameter ratio plane metal microneedle array is vertically placed in the assembling and clamping device, and the microneedle body 7 faces upwards. The width of the cavity of the main body 11 is consistent with that of the microneedle substrate 6; the depth of the cavity is consistent with the height of the outer edge of the substrate 6 (not including the height of the needle bodies 7 and the positioning shoulders), namely, the plane of the positioning shoulders of the substrate 6 and the upper surface of the main body 11 are positioned on the same plane; the length of the cavity is determined according to the number of the microneedle substrates to be clamped and the distance between the substrates, and the suggested length range is 10-40 mm. The partition plate 15 is of a thin cuboid structure and is used for positioning each microneedle substrate when the microneedle array is assembled; the width of the partition 15 is consistent with the depth of the cavity of the main body 11, the length of the partition is consistent with the width of the cavity of the main body 11, the thickness of the partition is 1-5 mm, and the bottom of the partition 15 is provided with a groove matched with the guide groove 9 at the bottom of the substrate 6.
Vertically placing the planar metal microneedle array with a large length-diameter ratio in a cavity of a clamping device main body 11, and separating each substrate by a partition plate 15; the bolt 16 penetrates through the threaded through hole 14 on the side surface of the clamping device and presses the partition plate 15, so that each microneedle substrate is kept stable. During clamping, one side of the microneedle substrate close to the microneedle body is higher than the partition plate 15 and the upper surface of the clamping device main body, the specific height is determined by the size of the positioning shoulders 8 at two sides of the microneedle substrate 6, and after clamping is completed, a hand-held handle 17 is installed at a threaded hole 13 at the bottom of the clamping device main body 11, so that the assembly and clamping of the planar metal microneedle array with the large length-diameter ratio are completed.
A puncture auxiliary device of a planar metal microneedle array with a large length-diameter ratio comprises a rectangular frame main body 18, a positioning partition plate 20 and a small positioning partition plate 21, wherein the rectangular frame main body 18 and the positioning partition plate 20 are made of light metal or high polymer materials, and are made of aluminum alloy or polytetrafluoroethylene and other materials, but are not limited to the two materials; the small positioning spacer 21 and the microneedle substrate 6 are made of the same material.
The rectangular frame body 18 is a rectangular parallelepiped with an upper opening and a lower opening, and is placed above the assembly clamping device. The length and the width of the inner frame of the rectangular frame main body 18 are consistent with the length and the width of the cavity of the clamping device main body 11, the height of the rectangular frame main body 18 is consistent with the height of the positioning shoulders 8 at two sides of the microneedle substrate, and threaded through holes 19 for passing through the cap-free bolts 22 are formed in two sides of the rectangular frame main body 18 and used for subsequent jacking. The height of the positioning partition plate 20 is consistent with that of the rectangular frame main body 18, the length of the positioning partition plate 20 is consistent with that of the partition plate 15 of the clamping device, the thickness of the positioning partition plate 20 is consistent with that of the partition plate 15 of the clamping device, and the corresponding position of the positioning partition plate 20 and the microneedle body is slightly polished by fine sand paper. The two positioning clapboards 20 are separated by small positioning clapboards 21, and a gap 23 between the two positioning clapboards 20 is used for passing through the microneedle body 7. The height of the small positioning partition 21 is consistent with that of the partition positioning partition 20, the width of the small positioning partition is 0.1-1 mm smaller than that of the positioning shoulders 8 at two sides of the microneedle substrate (6), and the thickness of the small positioning partition is consistent with that of the microneedle substrate, so that the gap 23 between the positioning partitions 20 is consistent with that of the microneedle substrate.
The locating clapboard 20 is assembled into the rectangular frame main body 18, the locating small spacer 21 is placed at the two ends of each locating clapboard 20, the distance between the locating clapboards 20 is consistent with the thickness of the microneedle, the contact part of the locating clapboard 20 and the microneedle body is polished, and the gap between the microneedle body and the locating clapboard 20 can be ensured so as to avoid serious scraping. The cap-free bolt 22 passes through a threaded hole on one side of the end face of the rectangular frame main body 18 and is used for pressing the positioning partition plate 20 and the small positioning spacer 21 and keeping a one-to-one corresponding relation with the clamping device. The skin area to be punctured is sterilized, the assembled puncturing aid is placed on the skin, and the assembled microneedle array is punctured into the skin through the gaps 23 of the positioning spacers 20 in the aid.
Further, in consideration of reliability in use, glue 502 is used at both ends of the positioning spacer 20 to reinforce the connection between the positioning spacer 20, the positioning small spacer 21 and the rectangular frame body 18.
Compared with the prior art, the invention has the beneficial effects that:
(1) the design of the sheet-shaped planar microneedle is beneficial to simplifying the processing procedure, the use is flexible, and three-dimensional microneedle arrays with different specifications can be manufactured by simple assembly; the method can process the metal microneedle array in batch at one time, greatly improves the efficiency compared with other microneedle processing methods, and has relatively low cost due to the linear cutting processing technology, so the method for processing the microneedle array provided by the invention has low cost.
(2) After the clamping tool is used, except that the material on the path through which the cutting wire passes is cut off, other parts still keep complete, so that on one hand, the clamping tool can be ensured to have high enough rigidity for subsequent repeated clamping, and on the other hand, the material of the clamping tool on the processing path is cut off, and only the metal sheet is required to be cut when the clamping tool is subsequently reused, so that the number of metal microneedles which can be processed at one time is further increased, the efficiency is improved, and the cost is reduced. If carry out the monolithic cutting to the foil, because thickness is very thin, very little lateral force will make the micropin warp, when needing to process the micropin height when higher, this deformation is bigger, and the precision is more difficult to guarantee, and the centre gripping frock is a whole with the compaction of multi-disc foil, can improve work piece rigidity, prevents to lead to the machining dimension deviation because of the lateral force during the cutting, improves precision and workable micropin length by a wide margin, satisfies the processing needs of big slenderness ratio micropin.
(3) In the machining process, an 8-shaped machining path is adopted when the tip end of the micro needle is cut, so that the tip passivation caused by the fact that the direction is directly changed at the tip can be effectively avoided, and the machining precision of the tip end of the micro needle is guaranteed; the microneedle adopts the design of uniform strength along the width direction, can effectively improve the buckling resistance of the microneedle along the width direction, and can prevent the buckling failure of the microneedle along the width direction when the microneedle is penetrated into the skin.
Drawings
FIG. 1 is a front view of a three-dimensional view of a machining fixture;
FIG. 2 is a top plan view of the three-dimensional view of the machining fixture;
FIG. 3 is a side view of the clamping device for machining in three views;
FIG. 4 is a schematic view of a metal substrate after clamping mounting;
FIG. 5 is a schematic view of a planar microneedle array in sheet form having isostrength needles;
FIG. 6 is a schematic view of a wire cutting processing path;
FIG. 7 is a schematic view of the holding tool and the microneedle array substrate after cutting and before detachment;
FIG. 8 is an overall view of the cut microneedle array sheet and a substrate;
fig. 9 is a front view of a microneedle array assembly holder in three views;
fig. 10 is a top view of a microneedle array assembly holder in three views;
fig. 11 is a side view of a microneedle array assembly holder in three views;
fig. 12 is a spacer for microneedle substrate positioning in a microneedle array assembly holder;
fig. 13 is a front view in schematic form after microneedle array assembly clamping is completed;
fig. 14 is a top view of the microneedle array assembly after clamping is complete;
fig. 15 is a side view in schematic form after microneedle array assembly clamping is complete;
fig. 16 is a front view of a three-dimensional view of a microneedle array penetration assistance apparatus;
fig. 17 is a front view of a three-dimensional view of a microneedle array penetration assistance apparatus;
fig. 18 is a front view of a three-dimensional view of a microneedle array penetration assistance apparatus;
fig. 19 is a septum for microneedle spacer positioning within a microneedle penetration assistance device;
fig. 20 is a schematic view of a microneedle array penetration assistance device after assembly.
In the figure: 1, an upper cover plate body and a lower cover plate body; 2, grooves; 3, bolt through holes; 4, fastening a bolt; 5 is a metal sheet; 6 a substrate; 7 a microneedle body; 8, positioning shoulders; 9 a guide groove; 10 parts that are not cut in order to maintain the integrity of the clamping fixture; 11 assembling a clamping device main body; 12, a slide rail; 13 a threaded hole; 14 a threaded through hole; 15 a partition plate; 16 bolts; 17 a hand-held handle; 18 a rectangular frame body; 19 a threaded through hole; 20 positioning the partition board; 21 positioning a small spacer; 22 a capless bolt; 23 gap.
Detailed Description
The technical scheme of the invention is described in detail in the following with reference to the accompanying drawings. The metal microneedle array is processed in batches at one time, the total cutting thickness of the metal microneedle array is calculated by 2 cm, for example, the upper and lower integral wall thickness of a tool is 5 mm, the groove depth is 2 mm, the thickness of each metal sheet is 100 microns, the quantity of the microneedles which can be cut at one time is 140, compared with other microneedle processing methods, the efficiency is greatly improved, and the cost of the linear cutting processing technology is relatively low, so that the microneedle array processing method provided by the invention is low in cost. After the clamping tool is used, except that the material on the path where the cutting wire passes is cut off, other parts still keep complete, the efficiency can be improved, and the cost can be reduced. The clamping tool compacts a plurality of metal sheets into a whole, improves the rigidity of a workpiece, prevents the machining size deviation caused by lateral force during cutting, greatly improves the precision and the length of the machinable microneedle, and meets the machining requirement of the microneedle with a large length-diameter ratio. The 8-shaped processing path is adopted during the cutting of the tip of the micro-needle, so that the processing precision of the tip of the micro-needle is ensured. The microneedle adopts the design of uniform strength along the width direction, improves the buckling resistance of the microneedle along the width direction, prevents the microneedle from buckling and losing efficacy along the width direction when penetrating into the skin, and simultaneously adopts a special penetrating auxiliary device to provide additional constraint in the thickness direction for the microneedle, thereby comprehensively improving the use reliability of the microneedle with the large length-diameter ratio. The specific embodiment is as follows:
a preparation method of a planar metal microneedle array with a large length-diameter ratio comprises the following steps:
the first step is as follows: the microneedle material is made of a metal sheet material with good biocompatibility and good strength and toughness, and in this embodiment, a medical 304 stainless steel sheet is adopted, and the stainless steel sheet has a length of 1000 mm, a width of 100 mm and a thickness of 80 μm.
The second step is that: the foil described in the first step is cut into small foils 5 of suitable size, in this example 50 mm long by 25 mm wide by 80 μm thick.
The third step: processing a special sheet clamping tool, wherein the appearance structure of the tool is shown in figures 1, 2 and 3;
the clamping tool comprises an upper metal cover plate 1 and a lower metal cover plate 1 which are identical, the length of the upper cover plate and the lower cover plate of the clamping tool in the embodiment is 80 mm, the width of the upper cover plate is 55 mm, the thickness of the plate is 6 mm, the inner wall of each cover plate is provided with a groove 2 matched with the size of the small sheet S2, the depth of each groove in the embodiment is 1.5 mm, the length of each groove is 50 mm, and the width of each. In the embodiment, the stainless steel with good conductivity and high strength is adopted as the tool material. 6M 6 bolt through holes 3 used for subsequent bolt connection and fixation are processed on two sides of the clamping tool, and the number of the holes can be adjusted according to actual needs.
Fourthly, the 100 small metal sheets 5 are placed in the grooves 2 of any metal cover plate 1 and stacked. Another metal cover plate 1 is placed on the cover plate on which the metal sheet 5 is placed, and the grooves face the metal sheet 5 and are aligned up and down; and then, the upper and lower metal cover plates 1 are packaged and fastened through the fastening bolts 4, the metal sheets 5 are compacted and integrated with the upper and lower cover plates 1, and the packaged metal sheets and the whole machining and clamping tool shown in the figure 4 are obtained.
Fifthly, designing the geometric shape and the dimension specification of the sheet-shaped plane metal microneedle
The sheet-like planar metal microneedle array is composed of a substrate 6 for a subsequent holding section and a microneedle body 7 with a large length-to-diameter ratio. In this embodiment, the shape of the needle body in the sheet-shaped microneedle array is shown in fig. 5, the thickness of the microneedle body 7 is the thickness of the metal sheet itself, the needle body is designed to have equal strength along the width direction, that is, the change of the width of the microneedle ensures that the maximum bending stress at each cross section of the microneedle is equal when the tip of the microneedle is subjected to the action of a transverse concentrated load, the root of the microneedle is assumed to be the starting point of the x axis, the x axis is the longitudinal symmetric axis of the microneedle, and the width direction is assumed to be the y axis, so that the equal strength design requirements x and y satisfy the following:
in the formula L0C is a constant, the height of the microneedle body in this example is 1.5 mm, the width of the base is 150 μm, and C can be calculated as 0.00194 from the width and length of the microneedle base. Fig. 5 is a schematic view of a monolithic microneedle array. Fig. 5 shows at 8 a positioning shoulder for positioning the subsequent penetration assisting device, and fig. 5 shows at 9 a positioning groove for subsequent substrate assembly.
In this embodiment, for example, the number of microneedles on a single substrate is selected to be 7, the distance is 3.5 mm, the height of the portion of the substrate excluding the needle body is 13 mm, the bottom of the substrate is provided with a groove 9 as shown in fig. 5, the height of the groove is 5 mm and the width of the groove is 5 mm in this embodiment, positioning shoulders 8 as shown in fig. 5 are left on two sides of the microneedle substrate close to the needle body for positioning during subsequent microneedle array puncturing, and the size of the portion is 3 mm in height and 3 mm in width in this embodiment.
And a sixth step: and (3) clamping the packaged metal sheet and the tool in the fourth step onto a linear cutting device, determining a wire moving path by the linear cutting device according to the geometric shape and the dimension specification of the sheet planar metal microneedle designed in the fifth step, performing linear cutting on the tool and the metal sheet 5 as a whole according to the wire moving path shown in fig. 6, and processing a substrate 6 and a microneedle body 7 by the metal sheet 5. In the process of linear cutting, 8-shaped path cutting is adopted for processing the needle point of the microneedle needle body 7, and the sharpness degree of the needle point of the microneedle is ensured. In addition, during the processing, a little material is left on two sides of the single microneedle substrate as shown by reference numeral 10 in fig. 6 or 7 and is not cut, and the height of the uncut part is 2 mm and the width is 2 mm in the embodiment. A schematic view of the cut foil and the tool without disassembly is shown in fig. 7 (top view).
The seventh step: the fastening bolts 4 on the jig were removed, and the processed metal foil 5 was taken out and washed to obtain a microneedle substrate as shown in fig. 8 when it was not cut.
And eighthly, cutting the microneedle substrate obtained in the seventh step, removing materials in reserved areas on two sides of the substrate 6, and peeling the sheet-shaped planar metal microneedles from the metal sheet 5 to obtain the sheet-shaped planar microneedle array shown in fig. 5.
The utility model provides an equipment clamping device of big length-diameter ratio plane metal micropin array, special micropin thin slice equipment clamping device includes main part 11, baffle 15, and main part 11, baffle 15 adopt aluminium alloy material. The whole clamping device is a box-shaped cuboid with an opening at one side, a slide rail 12 matched with the S9 microneedle substrate bottom groove is arranged at the bottom of the inner cavity, as shown by the reference numeral 12 in figures 9, 10 and 11, the inner cavity has the size of 25 mm in length, 20 mm in width, 10 mm in height and 5 mm in wall thickness. A threaded hole 13 for mounting a handheld handle is processed at the bottom of the assembly body, and threaded holes 14 are processed on the end faces of two sides of the assembly body and used for tightly jacking a partition plate 15 through bolts 16; the overall three-dimensional view of the clamping device is shown in figures 9, 10 and 11. The partition 15 for positioning is made of an aluminum alloy material in the embodiment, the height of the partition 15 is 10 mm, and the length of the partition needs to be consistent with the width of the cavity of the main body 11, namely 20 mm; the width of the partition 15 is set as required, in this embodiment, 3.5 mm is taken, and the number of the partition blocks is 7; the bottom of the clapboard 15 is provided with a groove with the same size as the groove at the bottom of the microneedle substrate.
The sheet-shaped planar microneedle array shown in fig. 5 and the partition 15 are sequentially arranged and placed in the holding device body 11, the microneedle substrate and the partition are compacted and fixed by the threaded through hole 14 shown in fig. 9, 10 and 11 on the end face of any side of the bolt holding device, the hand-held handle 17 is installed in the threaded hole 13 in the bottom of the holding device, and finally the microneedle array shown in fig. 13, 14 and 15 after tissue completion is obtained.
A puncture assisting device for a planar metal microneedle array with a large length-diameter ratio comprises a rectangular frame body 18, a positioning partition plate 20 and a positioning small spacer 21, and is shown in figures 16, 17 and 18. The rectangular frame main body 18 and the positioning clapboard 20 are made of aluminum alloy materials; the small positioning spacer 21 and the microneedle substrate 6 are made of the same material.
The rectangular frame body 18 is a rectangular parallelepiped with an upper and lower opening, and is disposed above the assembly holding device. The length and the width of the inner frame are consistent with those of the cavity of the clamping device main body 11. The height of the rectangular frame body 18 needs to match the size of the positioning shoulder 8 shown in fig. 5, in this embodiment, the size of the part is 3 mm high and 3 mm wide, and the height needs to be consistent with the size of the microneedle substrate higher than the partition plate; threaded through holes 19 for passing through the cap-free bolts 22 are formed in two sides of the rectangular frame body 18 and used for subsequent jacking.
As shown in fig. 19, the height of the positioning partition 20 is 3 mm, which is the same as the height of the rectangular frame body 18; the length of the positioning partition plate 20 is consistent with that of the partition plate 15 of the clamping device and is 20 mm; the thickness of the positioning clapboard 20 is consistent with that of the clapboard 15 of the clamping device, and the corresponding position of the positioning clapboard 20 and the microneedle body is slightly polished by fine sand paper. The two positioning clapboards 20 are separated by small positioning clapboards 21, and a gap 23 between the two positioning clapboards 20 is used for passing through the microneedle body 7. The height of the small positioning spacer 21 is consistent with that of the positioning partition plate 20 and is 3 mm; the spacer width should be slightly less than the width of the positioning shoulder 8 as shown in fig. 5 described in S9, which in this embodiment is 2.8 mm; the thickness is consistent with that of the microneedle substrate. The positioning frame, the spacer, and the spacer described in S24 are assembled to finally obtain the microneedle array penetration assisting apparatus as shown in fig. 20.
The positioning partition plate 20 is assembled into the rectangular frame main body 18, the small positioning spacers 21 are placed at two ends of each positioning partition plate 20, the distance between the positioning partition plates 20 is consistent with the thickness of the microneedles, the cap-free bolts are adopted to compress and package the microneedles from one side of the rectangular frame main body 18, the positioning partition plates 20 and the small positioning spacers 21 are compressed, and the microneedle array puncture auxiliary device shown in fig. 20 is obtained. The connection between the positioning spacer 20, the positioning small spacers 21 and the rectangular frame body 18 is reinforced with 502 glue at both ends of the positioning spacer 20, and the finally assembled penetration assisting device is shown in fig. 20. The area of skin to which the drug is to be applied is sterilized, the assembled penetration assisting device shown in fig. 20 is placed on the skin, and the assembled microneedle array shown in fig. 13, 14 and 15 is penetrated into the skin through the gaps 23 of the respective positioning spacers 20 in the assisting device.
Although the present invention has been described in detail with reference to the preferred embodiments, it will be understood by those skilled in the art that various changes may be made and equivalents may be substituted without departing from the spirit and scope of the invention as defined in the appended claims.
Claims (8)
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| WO2020017436A1 (en) | 2018-07-19 | 2020-01-23 | 久光製薬株式会社 | Microneedle sheet production method and microneedle sheet |
| CN112191964B (en) * | 2020-09-07 | 2021-11-19 | 大连理工大学 | Method for preparing three-dimensional metal microneedle array by directly utilizing razor blade |
| CN113199207B (en) * | 2021-03-22 | 2022-08-23 | 东莞溪河精密技术有限公司 | Metal sheet processing technology and communication equipment |
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| US7226461B2 (en) * | 2002-04-19 | 2007-06-05 | Pelikan Technologies, Inc. | Method and apparatus for a multi-use body fluid sampling device with sterility barrier release |
| CN101830428B (en) * | 2010-01-18 | 2013-05-08 | 大连理工大学 | Method for manufacturing super hydrophobic surface by microneedle array |
| CN101905856B (en) * | 2010-06-11 | 2012-10-10 | 北京大学 | Method for preparing plane hollow microneedle for transdermal administration |
| SG11201400529SA (en) * | 2011-11-02 | 2014-05-29 | Chee Yen Lim | The plastic microneedle strip |
| CN106512199B (en) * | 2014-06-16 | 2019-07-16 | 游学秋 | Different plane microneedle array and preparation method thereof |
| CN107335131A (en) * | 2016-05-03 | 2017-11-10 | 山东元旭光电股份有限公司 | A kind of metal micro-needle and preparation method thereof |
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