WO2020227900A1 - 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 - Google Patents

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 Download PDF

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Publication number
WO2020227900A1
WO2020227900A1 PCT/CN2019/086697 CN2019086697W WO2020227900A1 WO 2020227900 A1 WO2020227900 A1 WO 2020227900A1 CN 2019086697 W CN2019086697 W CN 2019086697W WO 2020227900 A1 WO2020227900 A1 WO 2020227900A1
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WO
WIPO (PCT)
Prior art keywords
microneedle
positioning
metal
substrate
partition
Prior art date
Application number
PCT/CN2019/086697
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English (en)
French (fr)
Inventor
马国军
吴承伟
安小龙
韩啸
张伟
吕永涛
马建立
Original Assignee
大连理工大学
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Application filed by 大连理工大学 filed Critical 大连理工大学
Priority to PCT/CN2019/086697 priority Critical patent/WO2020227900A1/zh
Priority to US16/960,177 priority patent/US11951271B2/en
Publication of WO2020227900A1 publication Critical patent/WO2020227900A1/zh

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Classifications

    • 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
    • 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
    • B23P17/00—Metal-working operations, not covered by a single other subclass or another group in this subclass
    • B23P17/04—Metal-working operations, not covered by a single other subclass or another group in this subclass characterised by the nature of the material involved or the kind of product independently of its shape
    • 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
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y10—TECHNICAL SUBJECTS COVERED BY FORMER USPC
    • Y10T—TECHNICAL SUBJECTS COVERED BY FORMER US CLASSIFICATION
    • Y10T29/00—Metal working
    • Y10T29/49—Method of mechanical manufacture
    • Y10T29/49995—Shaping one-piece blank by removing material

Definitions

  • the invention belongs to the technical field of medical devices, and relates to a large aspect ratio flat metal microneedle array, a preparation method and a clamping and piercing auxiliary device.
  • Microneedle generally refers to a microneedle with a length of tens of microns to a few millimeters and a tip diameter of less than tens of microns.
  • MN Microneedle
  • the transdermal drug delivery efficiency can be improved by orders of magnitude, and the transdermal delivery can be greatly expanded. Type and scope of medicine.
  • microneedle technology has been widely concerned in the field of transdermal drug delivery in the past ten years.
  • microneedles In addition to being used for transdermal drug delivery, microneedles have also received more and more attention in the fields of biomedical measurement and micro-sampling analysis in recent years. However, unlike the percutaneous drug delivery technology, the microneedle only needs to pierce the surface tissue of the skin. The microneedle used for biological micro-sampling analysis needs to penetrate the tissue to a certain depth, so the length of the sampling microneedle is often on the order of millimeters. In order to make the sampling microneedle still have the advantages of less trauma and less pain, the lateral size of the sampling microneedle still needs to be as small as possible, so that the aspect ratio of the sampling microneedle is large, which brings about the preparation and use of the sampling microneedle difficult.
  • the higher the height of the microneedle the higher the processing difficulty and cost.
  • the existing conventional microneedle processing techniques such as photolithography, deep reactive ion etching, and X-ray etching are difficult to use for microneedle processing with large aspect ratios;
  • the slender size of the microneedle with a large aspect ratio can easily induce buckling or breakage of the microneedle, leading to failure of penetration.
  • metal coating is performed on the surface of the cylindrical SU-8 glue, and finally the SU-8 glue is dissolved but the metal coating is retained, and finally a metal sampling microneedle array with a high aspect ratio of millimeters is obtained.
  • the manufacturing process is ingeniously designed and can successfully prepare metal microneedles with a large aspect ratio.
  • the manufacturing process is relatively complicated, the cost is high, and mass production is difficult.
  • how to ensure that such a microneedle array composed of cylindrical microneedles with a large aspect ratio does not buckle or break when penetrating the skin has not been effectively resolved.
  • the present invention provides a large aspect ratio planar metal microneedle array, a preparation method, and processing and penetration auxiliary devices.
  • the invention has high efficiency and cost. Low, good performance and other advantages, suitable for mass production and actual use.
  • a method for preparing a large aspect ratio flat metal microneedle array includes the following steps:
  • the microneedle material is made of medical stainless steel or titanium alloy foil material with good biocompatibility, strength and toughness, and the thickness of the foil is 20 to 200 microns.
  • Step 2 Cut the metal foil into small metal foils 5 of appropriate size.
  • the recommended size is 30-50 mm long and 10-30 mm wide.
  • the third step processing special sheet clamping tooling
  • the tooling is composed of two identical upper and lower metal cover plates 1, each with a total thickness of 5-10 mm; on the inner wall of the upper and lower cover plates of the tooling, a groove 2 matching the size of the small metal sheet 5 is processed, that is, concave
  • the length and width of the groove are the same as the length and width of the aforementioned metal sheet 5, which is used to place the metal sheet 5.
  • the depth of the grooves of the upper and lower cover plates are both 1 to 5 mm; Through hole 3.
  • the clamping tooling materials are metal materials such as stainless steel and 45# steel with good conductivity and high strength.
  • the small metal foil 5 is placed in the groove 2 of any metal cover plate 1.
  • the number of metal foils 5 placed at a time is adjusted according to the thickness of the foil and the depth of the groove. It is recommended that the number of pieces to be placed at a time is 20 ⁇ 200 sheet.
  • the sheet 5 is integrated with the upper and lower cover 1.
  • the fifth step is to design the geometry and size specifications of the sheet metal microneedle
  • the sheet-like planar metal microneedle array is composed of a substrate 6 for the subsequent clamping part and a microneedle body 7 with a large aspect ratio.
  • the height of the microneedle body 7 with a large aspect ratio is 1 to 5 mm, and the root of the needle body
  • the width is 50-500 microns, and the thickness is the thickness of the metal foil 5 itself.
  • the large length-to-diameter ratio microneedle body 7 is arranged on the top of the substrate 6.
  • the number of microneedles on each substrate is 3-50, and the spacing is 0.25-10 mm; both sides of the substrate 6 are provided with A positioning shoulder 8 is used to pierce the auxiliary device for positioning and guiding; a positioning and guiding groove 9 is provided in the middle of the lower part of the substrate 6 for subsequent assembly of the substrate 6.
  • the large aspect ratio microneedle body 7 adopts an equal strength design along the length direction, that is, the width of the large aspect ratio microneedle body 7 needs to ensure that the microneedle needle body 7 is horizontally loaded when the tip is subjected to a lateral concentrated load.
  • Step 6 Clamp the metal sheet and tooling packaged in Step 4 to the wire cutting equipment.
  • the wire cutting equipment determines the wire path according to the geometric shape and size specifications of the sheet metal microneedle designed in Step 5.
  • the tooling and the metal foil 5 are used as a whole for wire cutting, and the metal foil 5 is processed to form a substrate 6 and a microneedle body 7.
  • the tip of the microneedle body 7 is cut using an "8"-shaped path to ensure the sharpness of the tip of the microneedle.
  • the two sides of the substrate 6 are not completely cut, leaving 2 ⁇ 5 mm in order to maintain the integrity of the clamping tooling, which is not cut 10, to ensure that the clamping tooling and the metal sheet 5 are still integrated after processing , which not only prevents the metal microneedle array from being washed away by the cooling liquid during processing, but also ensures that the tooling after use still has sufficiently high structural rigidity, making the tooling reusable.
  • Step 7 Remove the fastening bolt 4 on the tooling, take out the processed metal sheet 5 and clean it to obtain the microneedle substrate without cutting.
  • the microneedle substrate obtained in the seventh step is cut, and the material in the reserved areas on both sides of the substrate 6 is removed, and the sheet-like flat metal microneedle is peeled from the metal foil 5 to obtain a needle body with multiple microneedles Sheet-like planar metal microneedle array.
  • a flat metal microneedle array with a large aspect ratio is composed of a substrate 6 for the subsequent clamping part and a microneedle body 7 with a large aspect ratio.
  • the height of 7 is 1 to 5 mm
  • the width of the root of the needle body is 50 to 500 microns
  • the thickness is the thickness of the metal sheet 5 itself.
  • the large length-to-diameter ratio microneedle body 7 is arranged on the top of the substrate 6.
  • the number of microneedles on each substrate is 3-50, and the spacing is 0.25-10 mm; both sides of the substrate 6 are provided with A positioning shoulder 8 is used to pierce the auxiliary device for positioning and guiding; a positioning and guiding groove 9 is provided in the middle of the lower part of the substrate 6 for subsequent assembly of the substrate 6.
  • the large aspect ratio microneedle body 7 adopts an equal strength design along the length direction, that is, the width of the large aspect ratio microneedle body 7 needs to ensure that the microneedle needle body 7 is horizontally loaded when the tip is subjected to a lateral concentrated load.
  • the dedicated microneedle sheet assembly and clamping device includes a main body 11 and a partition board 15.
  • the main body 11 and the partition board 15 are made of light metal or polymer materials. Materials such as aluminum alloy or polytetrafluoroethylene, but not limited to these two materials.
  • the main body 11 is a box-shaped rectangular parallelepiped structure with an opening on one side.
  • the bottom of the cavity is provided with a slide rail 12 matching the guide groove 9 at the bottom of the microneedle substrate; the bottom of the main body 11 is provided with a threaded hole 13 for subsequent installation of the handle. ;
  • the side of the main body 11 is provided with a threaded through hole 14 for tightening the partition plate 15 through the bolt 16.
  • the planar metal microneedle array with large aspect ratio is vertically placed in the assembly holding device with the microneedle needle body 7 facing upward.
  • the width of the cavity of the main body 11 is the same as the width of the microneedle substrate 6; the depth of the cavity is the same as the height of the outer edge of the substrate 6 (not including the height of the needle body 7 and the positioning shoulder), that is, the plane of the substrate 6 positioning shoulder It is located on the same plane as the upper surface of the main body 11; the length of the cavity is determined according to the number of microneedle substrates to be clamped and the distance between the substrates, and the recommended length ranges from 10 to 40 mm.
  • the partition 15 has a thin rectangular parallelepiped structure and is used to position each microneedle substrate when the microneedle array is assembled; the partition 15 has the same width as the cavity depth of the main body 11, and the length is the same as the cavity width of the main body 11, and the thickness is 1 -5 mm, the bottom of the partition 15 is provided with a groove matching the guide groove 9 at the bottom of the substrate 6.
  • the large aspect ratio flat metal microneedle array is vertically placed in the cavity of the main body 11 of the holding device, and each substrate is separated by a partition 15; the bolt 16 passes through the threaded through hole 14 on the side of the holding device and squeezes
  • the partition 15 keeps each microneedle substrate stable.
  • the side of the microneedle substrate close to the microneedle body is higher than the partition 15 and the upper surface of the clamping device body.
  • the specific height is determined by the size of the positioning shoulders 8 on both sides of the microneedle substrate 6.
  • a hand-held handle 17 is installed at the bottom threaded hole 13 of the main body 11 of the clamping device to complete the assembly and clamping of the planar metal microneedle array with large aspect ratio.
  • a piercing auxiliary device for a flat metal microneedle array with a large aspect ratio includes a rectangular frame body 18, a positioning partition 20, and a positioning small partition 21.
  • the plate 20 is made of light metal or polymer materials, and materials such as aluminum alloy or polytetrafluoroethylene are selected, but not limited to these two materials; the positioning spacer 21 is made of the same material as the microneedle substrate 6.
  • the rectangular frame body 18 is a frame-shaped cuboid with upper and lower openings, and is used to be placed above the assembly and clamping device.
  • the length and width of the inner frame of the rectangular frame body 18 are consistent with the cavity length and width of the clamping device body 11, and the height of the rectangular frame body 18 is the same as the height of the positioning shoulders 8 on both sides of the microneedle substrate.
  • a threaded through hole 19 for passing through the capless bolt 22 is provided for subsequent tightening.
  • the positioning partition 20 is specifically shown in FIG.
  • the height of the positioning partition 20 is the same as the height of the rectangular frame body 18
  • the length of the positioning partition 20 is the same as the length of the partition 15 of the clamping device
  • the thickness of the positioning partition 20 Consistent with the thickness of the spacer 15 of the clamping device, the positioning spacer 20 and the corresponding position of the microneedle body are lightly polished with fine sandpaper.
  • the positioning partitions 20 are spaced between each other by positioning small partitions 21, and the gap 23 between the two positioning partitions 20 is used to pass the microneedle body 7.
  • the height of the positioning spacer 21 is the same as the height of the spacer positioning spacer 20, the width is 0.1 ⁇ 1 mm smaller than the width of the positioning shoulders 8 on both sides of the microneedle substrate (6), and the thickness is the same as that of the microneedle substrate. It is used to ensure that the gap 23 between the positioning spacers 20 is consistent with the thickness of the microneedle substrate.
  • the positioning partition 20 is assembled into the rectangular frame body 18, and positioning small partitions 21 are placed at both ends of each positioning partition 20, so that the spacing of the positioning partitions 20 is consistent with the thickness of the microneedles.
  • the contact area of the needle body is polished to ensure that there is a gap between the microneedle needle body and the positioning partition 20 to avoid serious scratches.
  • the capless bolts 22 pass through the threaded holes on one side of the end surface of the rectangular frame body 18 to compress the positioning partition 20 and the positioning small partition 21, and maintain a one-to-one correspondence with the clamping device.
  • the skin area to be pierced is disinfected, the assembled piercing auxiliary device is placed on the skin, and the assembled microneedle array is pierced into the skin through the gap 23 of each positioning partition 20 in the auxiliary device.
  • 502 glue is used at both ends of the positioning partition 20 to reinforce the connection between the positioning partition 20, the positioning small partition 21 and the rectangular frame main body 18.
  • the sheet-like flat microneedle design is conducive to simplifying the processing procedure and is flexible in use. It can be made into three-dimensional microneedle arrays of different specifications through simple assembly; metal microneedle arrays can be processed in batches at one time, and other microneedles Compared with the processing method, the efficiency is greatly improved, coupled with the relatively low cost of the wire cutting processing technology, so the microneedle array processing method provided by the present invention is low in cost.
  • the clamping tooling compacts multiple metal sheets into a whole, which can improve the rigidity of the workpiece, prevent the deviation of the processing size due to lateral force during cutting, greatly improve the accuracy and the length of the microneedle that can be processed, and meet the processing of microneedles with large aspect ratios need.
  • the "8"-shaped processing path is adopted when cutting the tip of the microneedle, which can effectively avoid the tip passivation caused by changing the direction directly at the tip, thereby ensuring the precision of the microneedle tip processing; the microneedle is along the width direction
  • the use of equal strength design can effectively improve the anti-buckling ability of the microneedle in the width direction, and prevent the buckling failure in the width direction when the microneedle penetrates the skin.
  • a special penetration assist device is used to provide additional constraints in the thickness direction of the microneedle. It can effectively improve the anti-buckling ability of the microneedle along the thickness direction, and prevent the buckling failure in the thickness direction when the microneedle penetrates the skin, thereby comprehensively improving the reliability of the microneedle with a large aspect ratio.
  • Figure 1 is a front view of the clamping device for processing in three views
  • Figure 2 is a top view of the clamping device for processing in three views
  • Figure 3 is a side view in three views of the clamping device for processing
  • Figure 4 is a schematic diagram of the metal substrate after clamping and mounting
  • Fig. 5 is a schematic diagram of a sheet-like planar microneedle array with a needle body of equal strength
  • Figure 6 is a schematic diagram of a wire cutting processing path
  • FIG. 7 is a schematic diagram of the clamping tool and the microneedle array substrate when the cutting is completed and not disassembled;
  • FIG. 8 is an overall schematic diagram of the sheet-shaped microneedle array and the substrate after the cutting is completed
  • Figure 9 is a front view of the microneedle array assembly and clamping device in three views.
  • Figure 10 is a top view of the microneedle array assembly and clamping device in three views
  • Figure 11 is a side view of the microneedle array assembly and clamping device in three views
  • Figure 12 is a spacer used for positioning the microneedle substrate in the microneedle array assembly and clamping device
  • Figure 13 is a front view in a schematic diagram after the microneedle array is assembled and clamped
  • FIG. 14 is a top view in a schematic diagram after the assembly and clamping of the microneedle array is completed;
  • Figure 15 is a side view in a schematic diagram after the microneedle array is assembled and clamped
  • Figure 16 is a front view of the microneedle array piercing auxiliary device in three views
  • Figure 17 is a front view of the microneedle array piercing auxiliary device in three views
  • Figure 18 is a front view of the microneedle array piercing auxiliary device in three views
  • Figure 19 shows the spacer used for positioning the microneedle septum in the microneedle piercing auxiliary device
  • Figure 20 is a schematic diagram of the microneedle array penetration assist device after the assembly is completed.
  • 1 upper and lower cover main body 2 grooves; 3 bolt through holes; 4 fastening bolts; 5 sheet metal; 6 substrate; 7 microneedle body; 8 positioning shoulders; 9 guide grooves; 10 for retaining clips
  • the part that maintains the integrity of the tooling without cutting 11 assembly and clamping device body; 12 slide rail; 13 threaded hole; 14 threaded through hole; 15 partition; 16 bolt; 17 handheld handle; 18 rectangular frame body; 19 threaded through hole ; 20 positioning partitions; 21 positioning small partitions; 22 without cap bolts; 23 clearance.
  • the present invention processes metal microneedle arrays in batches at one time, and calculates the ideal total cutting thickness of 2 cm for wire cutting.
  • the overall wall thickness of the upper and lower parts of the tooling is 5 mm
  • the groove depth is 2 mm
  • the thickness of each sheet of metal is 100 microns.
  • the number of microneedles that can be cut at one time is 140, which is greatly improved in efficiency compared with other microneedle processing methods. Coupled with the relatively low cost of wire cutting technology, the microneedle array processing method provided by the present invention has low cost.
  • the clamping tooling compacts multiple metal sheets into a whole, improves the rigidity of the workpiece, prevents the deviation of the processing size due to the lateral force during cutting, greatly improves the accuracy and the length of the microneedle that can be processed, and meets the processing needs of the microneedle with large aspect ratio .
  • the "8" shape processing path is adopted to ensure the precision of the tip of the microneedle.
  • the microneedle adopts an equal strength design along the width direction to improve the anti-buckling ability of the microneedle along the width direction, and prevent the buckling failure in the width direction when the microneedle penetrates the skin.
  • a special penetration assist device is used to provide the microneedle with thickness direction Additional constraints, comprehensively improve the reliability of the use of microneedles with large aspect ratio.
  • the specific implementation example is as follows:
  • a method for preparing a large aspect ratio flat metal microneedle array includes the following steps:
  • the microneedle material is a thin metal sheet with good biocompatibility, strength and toughness.
  • a medical 304 stainless steel sheet is used.
  • the size of the stainless steel sheet is 1000 mm in length, 100 mm in width, and 80 ⁇ m in thickness.
  • the second step cut the metal flakes described in the first step into small metal flakes 5 of appropriate size.
  • the length is 50 mm
  • the width is 25 mm
  • the thickness is 80 microns.
  • the third step processing special sheet clamping tooling, the appearance structure of the tooling is shown in Figure 1, 2 and 3;
  • the clamping tool is composed of two identical upper and lower metal cover plates 1.
  • the upper and lower covers of the clamping tool are 80 mm in length, 55 mm in width, and 6 mm in thickness.
  • the inner wall of the cover is set to the same size as the small sheet described in S2.
  • the matching groove 2 has a depth of 1.5 mm in this embodiment, a groove length of 50 mm and a width of 25 mm.
  • the tooling material uses stainless steel with good conductivity and high strength.
  • Six M6 bolt through holes 3 for subsequent bolt connection and fixing are machined on both sides of the clamping tool. The number of holes can be adjusted according to actual needs.
  • the 100 small metal sheets 5 are placed in the groove 2 of any metal cover plate 1 for stacking. Place the other metal cover plate 1 on the cover plate where the metal foil 5 has been placed, with the groove facing the metal foil 5, and align it up and down; then tighten the upper and lower metal cover plates 1 through the fastening bolts 4 to compact the metal
  • the sheet 5 is integrated with the upper and lower cover plates 1 to obtain the packaged metal sheet and the processing and clamping tool as shown in FIG. 4.
  • the fifth step is to design the geometry and size specifications of the sheet metal microneedle
  • the sheet-like planar metal microneedle array is composed of a substrate 6 for the subsequent clamping part and a microneedle body 7 with a large aspect ratio.
  • the shape of the needle body in the sheet-shaped microneedle array is shown in Figure 5.
  • the thickness of the microneedle body 7 is the thickness of the metal foil itself.
  • the needle body is designed with equal strength along the width direction, that is, the microneedle width changes to ensure When the tip of the needle is subjected to a lateral concentrated load, the maximum bending stress at each cross section is equal.
  • FIG. 5 is a schematic diagram of a single microneedle array. 8 in FIG. 5 is a positioning shoulder reserved for the positioning of the subsequent piercing auxiliary device, and 9 in FIG. 5 is a positioning groove for subsequent substrate assembly.
  • the substrate does not count the height of the needle body part of 13 mm, and the bottom is provided with a groove 9 as shown in Fig. 5.
  • the groove has a height of 5 mm and a width of 5 mm.
  • the positioning shoulders 8 shown in Figure 5 are left on both sides of the microneedle substrate near the needle body for subsequent positioning during microneedle array penetration.
  • the size of this part in this embodiment is It is 3 mm high and 3 mm wide.
  • Step 6 Clamp the metal foil and tooling packaged in Step 4 to the wire cutting equipment.
  • the wire cutting equipment determines the wire path according to the geometry and size specifications of the sheet metal microneedle designed in Step 5.
  • the wire walking path shown in FIG. 6 performs linear cutting on the tooling and the metal foil 5 as a whole, and the metal foil 5 processes the substrate 6 and the microneedle body 7.
  • the tip of the microneedle body 7 is cut using an "8"-shaped path to ensure the sharpness of the tip of the microneedle.
  • a small amount of material is left on both sides of the single microneedle substrate as shown by the reference numeral "10" in FIG. 6 or FIG. 7 without cutting.
  • the uncut part has a height of 2 mm and a width of 2 mm.
  • the schematic diagram of the cut sheet metal and tooling without disassembly is shown in Figure 7 (top view).
  • Step 7 Remove the fastening bolts 4 on the tooling, take out the processed metal sheet 5 and clean it to obtain the microneedle substrate as shown in FIG. 8 when it is not cut.
  • the microneedle substrate obtained in the seventh step is cut, and the material in the reserved areas on both sides of the substrate 6 is removed, and the sheet-like flat metal microneedles are peeled from the metal foil 5 to obtain the sheet as shown in FIG. 5. Shaped plane microneedle array.
  • the dedicated microneedle sheet assembling and clamping device includes a main body 11 and a partition board 15, which are made of aluminum alloy.
  • the clamping device as a whole is a box-shaped cuboid with one side open, and the bottom of the cavity is provided with a sliding rail 12 matching the bottom groove of the microneedle substrate of S9, as shown in Fig. 9, 10, and 11 with reference numeral "12 "As shown, the size of the inner cavity is 25 mm long, 20 mm wide, 10 mm high, and the wall thickness is 5 mm.
  • Threaded holes 13 are machined at the bottom of the assembly for the installation of hand grips, and threaded holes 14 are machined on both sides of the assembly for tightening the partition 15 with bolts 16; the overall three views of the clamping device are shown in Figures 9 and 10 , 11 shown.
  • the partition 15 used for positioning is made of aluminum alloy in this embodiment.
  • the height of the partition 15 is 10 mm.
  • the length of the partition must be the same as the width of the cavity of the main body 11, that is, 20 mm.
  • the width of the partition 15 is set as required. In this embodiment, 3.5 mm is taken, and the number of partitions is 7; the bottom of partition 15 is provided with grooves of the same size as the bottom of the microneedle substrate.
  • a piercing auxiliary device for a flat metal microneedle array with a large aspect ratio includes a rectangular frame main body 18, a positioning partition 20, and a positioning small spacer 21, as shown in Figures 16, 17, and 18. .
  • the rectangular frame body 18 and the positioning spacer 20 are made of aluminum alloy material; the small positioning spacer 21 is made of the same material as the microneedle substrate 6.
  • the rectangular frame body 18 is a frame-shaped rectangular parallelepiped with upper and lower openings, and is arranged above the assembly and clamping device.
  • the length and width of the inner frame are consistent with the length and width of the cavity of the main body 11 of the clamping device.
  • 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 this part is 3 mm high and 3 mm wide, and the height needs to be higher than that of the microneedle substrate.
  • the dimensions of the rectangular frame body 18 are the same; both sides of the rectangular frame body 18 are provided with threaded through holes 19 for passing capless bolts 22 for subsequent tightening.
  • the positioning partition 20 is specifically shown in FIG. 19, the height of the positioning partition 20 is the same as the height of the rectangular frame body 18, which is 3 mm; the length of the positioning partition 20 is the same as the length of the partition 15 of the clamping device, which is 20 mm; the thickness of the positioning partition 20 is the same as the thickness of the clamping device partition 15, and the corresponding position of the positioning partition 20 and the microneedle body is lightly polished with fine sandpaper.
  • the positioning partitions 20 are spaced between each other by positioning small partitions 21, and the gap 23 between the two positioning partitions 20 is used to pass the microneedle body 7.
  • the height of the positioning spacer 21 is the same as the height of the positioning partition 20, which is 3 mm; the width of the spacer should be slightly smaller than the width of the positioning shoulder 8 as shown in FIG. 5 in S9, and the width in this embodiment is 2.8 Mm; the thickness is the same as the microneedle substrate. Assemble the positioning frame, the partition and the spacer described in S24, and finally obtain the microneedle array penetration auxiliary device as shown in FIG. 20.
  • the positioning partition 20 is assembled into the rectangular frame body 18, and positioning small partitions 21 are placed at both ends of each positioning partition 20 to make the spacing of the positioning partitions 20 consistent with the thickness of the microneedles.
  • the side of the main body 18 is compressed and packaged, and the positioning partition 20 and the positioning small partition 21 are compressed to obtain the microneedle array penetration auxiliary device as shown in FIG. 20.
  • 502 glue is used to reinforce the connection between the positioning partition 20, the positioning small partition 21 and the rectangular frame body 18.
  • the piercing auxiliary device after the final assembly is as shown in FIG. 20.

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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。

Description

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 技术领域
本发明属于医疗器械技术领域，涉及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。
 背景技术
微针(Microneedle, MN)一般是指长度在几十微米到几毫米，尖端直径在几十微米以下的微型针头。利用微针刺破皮肤角质层，从而突破皮肤角质层生物屏障作用，在皮肤表层形成微米级的药物输送通道，实验表明可以呈数量级地提高药物经皮输送效率，同时还大幅扩充了经皮输药的种类和范围。此外，由于微针尺寸微小，所以刺破皮肤时产生的创伤和疼痛感都非常微小，不仅不会引起输药患者的明显不适，而且还有利于防止感染，更有利于创口恢复。正是因为有上述诸多优点，近十几年来，微针技术在经皮给药领域已被广泛关注。
除用于经皮输药以外，微针近年来在生物医学测量及微量采样分析领域也受到越来越多的关注。但与经皮输药技术中微针只需刺破皮肤表层组织不同，用于生物微量采样分析的微针需要刺入组织内一定深度，所以采样微针的长度往往在毫米量级。为了使采样微针仍具有创伤小、疼痛轻的优点，采样微针的横向尺寸仍然需要尽可能的微小，使得采样微针的长径比很大，从而给采样微针的制备及使用带来困难。首先，微针高度越高，加工难度和成本也越高，现有光刻、深反应离子刻蚀、x射线刻蚀等常规微针加工工艺很难用于大长径比微针加工；其次，在刺入皮肤过程中大长径比微针的细长尺寸容易诱发微针的屈曲或断裂，导致刺入失败。
针对大长径比采样微针的制造问题，韩国学者曾采用聚合物拉拔成型结合金属电镀工艺成功制备了一种长度可以达到2毫米的采样微针，被称为“Ultra-high aspect microneedle”，相关成果也发表在权威杂志<Advanced Materials>上。简单而言，该工艺利用带有若干微米级微柱的拉拔头对处于熔融状态的SU-8胶进行拉拔， SU-8胶被拉拔成柱状，高度可控。冷却定型后再对柱状SU-8胶表面进行金属镀膜，最后将SU-8胶进行溶解但保留金属镀层，最终得到高度为毫米级的大长径比金属采样微针阵列。显然，该制造工艺设计巧妙，可成功制备出大长径比金属微针，但相对而言制造工艺较复杂，成本较高，难以批量生产。此外，如何确保这种由大长径比柱状微针构成的微针阵列在刺入皮肤时不发生屈曲或断裂仍未有效解决。
 技术问题
针对大长径比采样微针制造及使用过程中存在的问题，本发明提供一种大长径比平面金属微针阵列、制备方法及其加工与刺入辅助装置，该发明具有效率高、成本低、性能好等优点，适合批量生产和实际使用。
 技术解决方案
一种大长径比平面金属微针阵列的制备方法，包括以下步骤：
第一步：微针材料采用生物相容性好、强度和韧性俱佳的医用不锈钢或钛合金金属薄片材料，金属薄片厚度20~200微米。
第二步：将所述金属薄片剪裁为大小合适的小型金属薄片5，推荐尺寸为长30~50毫米，宽10~30毫米。
第三步：加工专用的薄片夹持工装
工装由上下两块完全相同的金属盖板1组成，每块盖板总体厚度为5~10毫米；在工装上下盖板内壁加工与所述小型金属薄片5尺寸相匹配的凹槽2，即凹槽长宽与前述金属薄片5长宽一致，用于放置金属薄片5，上下盖板凹槽的深度均为1~5毫米；上下盖板主体1四周边缘处加工用于通过紧固螺栓4的通孔3。所述夹持工装材料为导电性能良好、强度高的不锈钢、45#钢等金属材料。
第四步，将所述小型金属薄片5放置在任一金属盖板1的凹槽2内，一次放置的金属薄片5片数根据薄片厚度和凹槽深度进行调整，推荐一次放置片数20~200片。将另一金属盖板1放置到已放置好金属薄片5的盖板之上，凹槽朝向金属薄片5，上下对齐；然后通过紧固螺栓4将上下金属盖板1封装紧固，压实金属薄片5，与上下盖板1成为一整体。
第五步，设计片状平面金属微针的几何形状和尺寸规格
片状平面金属微针阵列由用于后续夹持部分的基片6和大长径比微针针体7组成，大长径比微针针体7的高度为1~5毫米，针体根部宽度为50~500微米，厚度为金属薄片5自身厚度。所述的大长径比微针针体7均与设于基片6上方，每片基片上微针个数为3~50根，间距0.25~10毫米；基片6上方两侧均设有一个定位肩8，用于刺入辅助装置进行定位导向；基片6下方中部设有一个定位导向槽9，用于后续基片6进行组装。
所述的大长径比微针针体7沿长度方向采用等强度设计，即大长径比微针针体7的宽度变化需要确保微针针体7在尖端受横向集中载荷作用时各横截面处的最大弯曲应力处处相等，假定微针针体7根部为x轴起点，且x轴位于微针针体7的纵对称轴，宽度方向假定为y轴，则等强度设计要求x、y满足以下关系：
Figure 211285dest_path_image001
，式中L 0为微针针体7长度， C为综合反映材料屈服强度、微针厚度、载荷大小的常数。
第六步：将第四步封装好的金属薄片和工装装夹到线切割设备上，线切割设备根据第五步设计的片状平面金属微针的几何形状和尺寸规格确定走丝路径，对工装和金属薄片5作为整体进行线切割，金属薄片5加工出基片6和微针针体7。线切割过程中，对微针针体7的针尖加工采用 “8”字形路径切割，确保微针针尖尖锐程度。另外，加工过程中，基片6两侧不完全切割，预留2~5毫米为了保持夹持工装完整性而不切割的部分10，确保夹持工装和金属薄片5在加工后仍为一整体，既防止所加工时金属微针阵列被冷却液冲走，又能保证使用后的工装仍具有足够高结构刚度，使得工装可重复使用。
第七步：卸下工装上的紧固螺栓4，取出已加工的金属薄片5并进行清洗，得到未裁剪时的微针基片。
第八步，对第七步得到的微针基片进行裁剪，去除基片6两侧预留区域的材料，使片状平面金属微针从金属薄片5剥离，得到具有多个微针针体的片状平面金属微针阵列。
一种大长径比平面金属微针阵列，片状平面金属微针阵列由用于后续夹持部分的基片6和大长径比微针针体7组成，大长径比微针针体7的高度为1~5毫米，针体根部宽度为50~500微米，厚度为金属薄片5自身厚度。所述的大长径比微针针体7均与设于基片6上方，每片基片上微针个数为3~50根，间距0.25~10毫米；基片6上方两侧均设有一个定位肩8，用于刺入辅助装置进行定位导向；基片6下方中部设有一个定位导向槽9，用于后续基片6进行组装。所述的大长径比微针针体7沿长度方向采用等强度设计，即大长径比微针针体7的宽度变化需要确保微针针体7在尖端受横向集中载荷作用时各横截面处的最大弯曲应力处处相等，假定微针针体7根部为x轴起点，且x轴位于微针针体7的纵对称轴，宽度方向假定为y轴，则等强度设计要求x、y满足以下关系：
Figure 880164dest_path_image002
，式中L 0为微针针体7长度，C为综合反映材料屈服强度、微针厚度、载荷大小的常数。
一种大长径比平面金属微针阵列的组装夹持装置，专用微针薄片组装夹持装置包括主体11、隔板15，主体11、隔板15采用轻质金属或高分子材料制备，选用铝合金或聚四氟乙烯等材料，但不限于这两种材料。
所述的主体11为一侧开口的盒状长方体结构，内腔底部设有与微针基片底部导向槽9相匹配的滑轨12；主体11底部设有用于后续安装手柄用的螺纹孔13；主体11侧面设有一个螺纹通孔14，用于通过螺栓16对隔板15进行顶紧。大长径比平面金属微针阵列垂直放置于组装夹持装置内，微针针体7朝上。所述的主体11腔体宽度与微针基片6的宽度一致；腔体深度与基片6外侧边缘高度一致（不包括针体7和定位肩的高度），即基片6定位肩所在平面与主体11上表面位于同一平面；腔体长度根据拟夹持的微针基片片数和各基片之间的间距确定，建议长度范围10~40毫米。所述的隔板15为薄长方体结构，微针阵列装配时用于定位各微针基片；隔板15宽度与主体11腔体深度一致，长度与主体11的腔体宽度一致，厚度为1-5毫米，隔板15底部设有与基片6底部导向槽9匹配的凹槽。
将大长径比平面金属微针阵列垂直放置于夹持装置主体11 的腔体内，每片基片之间通过隔板15隔开；螺栓16穿过夹持装置侧面螺纹通孔14，挤压隔板15，使各微针基片保持稳定。夹持时微针基片靠近微针针体一侧高于隔板15和夹持装置主体上表面，具体高出尺寸由微针基片6两侧定位肩8的尺寸决定，夹持好之后在夹持装置主体11的底部螺纹孔13处安装手持手柄17，完成大长径比平面金属微针阵列的组装夹持。
一种大长径比平面金属微针阵列的刺入辅助装置，所述的刺入辅助装置包括矩形框主体18、定位隔板20、定位小隔片21，所述矩形框主体18、定位隔板20采用轻质金属或高分子材料制备，选用铝合金或聚四氟乙烯等材料，但不限于这两种材料；所述定位小隔片21与微针基片6同材料。
所述的矩形框主体18为上下开口的框状长方体，用于放置在组装夹持装置上方。矩形框主体18的内框长度、宽度与夹持装置主体11的腔体长度、宽度一致，矩形框主体18的高度与微针基片两侧定位肩8的高度一致，矩形框主体18两侧设置用于通过无帽螺栓22的螺纹通孔19，用于后续顶紧。所述的定位隔板20具体如图21所示，定位隔板20的高度与矩形框主体18的高度一致，定位隔板20长度与夹持装置的隔板15长度一致，定位隔板20厚度与夹持装置隔板15的厚度一致，定位隔板20与微针针体对应位置处采用细砂纸轻微打磨。定位隔板20两两之间通过定位小隔片21间隔，两个定位隔板20之间的间隙23用于通过微针针体7。所述的定位小隔片21的高度与隔板定位隔板20高度一致，宽度比微针基片(6)两侧定位肩8的宽度小0.1~1毫米，厚度与微针基片一致，用于确保定位隔板20之间间隙23与微针基片厚度一致。
所述的定位隔板20装配至矩形框主体18内，在每片定位隔板20两端放置定位小隔片21，使定位隔板20间距与微针厚度一致，定位隔板20与微针针体接触处打磨，能确保微针针体与定位隔板20之间存有空隙，以免发生严重刮碰。无帽螺栓22通过矩形框主体18端面一侧螺纹孔，用于压紧定位隔板20与定位小隔片21，且与夹持装置保持一一对应关系。对需要刺入的皮肤区域进行消毒处理，将组装好的刺入辅助装置放置于皮肤上，再将组装好的微针阵列通过辅助装置中各定位隔板20的间隙23刺入皮肤。
进一步的，考虑到使用的可靠性，在定位隔板20两端采用502胶水加固定位隔板20、定位小隔片21和矩形框主体18之间的连接。
 有益效果
（1）片状的平面微针设计有利于简化加工程序，而且使用灵活，通过简单组装便可制成不同规格的三维微针阵列；可一次性成批量加工金属微针阵列，与其它微针加工方法相比效率大幅提高，再加上线切割加工技术相对较低的成本，所以本发明所提供的微针阵列加工方法成本低廉。
（2）夹持工装使用过后除了切割丝所经路径处的材料被切割掉外，其它部分仍保持完整，这一方面能保整工装有足够高的刚度供后续重复夹持使用，另一方面由于加工路径处工装材料已被切除，后续再使用时只需切割金属薄片本身，从而进一步增加一次可加工的金属微针的片数，提高效率并降低成本。如果对金属薄片进行单片切割，由于厚度很薄，很小的侧向力就会使微针变形，当所需加工微针高度越高时，这种变形更大，精度更难以保证，而夹持工装将多片金属薄片压实为一整体，可以提高工件刚度，防止切割时因侧向力导致加工尺寸偏差，大幅提高精度和可加工微针长度，满足大长径比微针的加工需要。
（3）加工过程中，微针尖端切割时采用“8”字型加工路径，可以有效避免直接在尖端进行变向而导致的尖端钝化，从而保证微针尖端加工精度；微针沿宽度方向采用等强度设计，可以有效提高微针沿宽度方向的抗屈曲能力，防止微针刺入皮肤时沿宽度方向发生屈曲失效，同时而采用专门的刺入辅助装置给微针提供厚度方向的附加约束，可以有效提高微针沿厚度方向的抗屈曲能力，防止微针刺入皮肤时沿厚度方向发生屈曲失效，从而全面提高大长径比微针的使用可靠性。
 附图说明
图1为加工用夹持装置三视图中的主视图；
图2为加工用夹持装置三视图中的俯视图；
图3为加工用夹持装置三视图中的侧视图；
图4为金属基片夹持安装后的示意图；
图5为具有等强度针体的片状平面微针阵列示意图；
图6为线切割加工路径示意图；
图7为切割完成后未拆卸时的夹持工装与微针阵列基片示意图；
图8为切割完成后的片状微针阵列与基片的整体示意图；
图9为微针阵列组装夹持装置三视图中的主视图；
图10为微针阵列组装夹持装置三视图中的俯视图；
图11为微针阵列组装夹持装置三视图中的侧视图；
图12为微针阵列组装夹持装置内用于微针基片定位的隔板；
图13为微针阵列组装夹持完成后的示意图中的主视图；
图14为微针阵列组装夹持完成后的示意图中的俯视图；
图15为微针阵列组装夹持完成后的示意图中的侧视图；
图16为微针阵列刺入辅助装置三视图中的主视图；
图17为微针阵列刺入辅助装置三视图中的主视图；
图18为微针阵列刺入辅助装置三视图中的主视图；
图19为微针刺入辅助装置内用于微针隔片定位的隔板；
    图20为微针阵列刺入辅助装置装配完成后的示意图。
图中：1上下盖板主体；2凹槽；3螺栓通孔；4紧固螺栓；5为金属薄片；6基片；7微针针体；8定位肩；9导向槽；10为了保持夹持工装完整性而不切割的部分；11组装夹持装置主体；12滑轨；13螺纹孔；14螺纹通孔；15隔板；16螺栓；17手持手柄；18矩形框主体；19螺纹通孔；20定位隔板；21定位小隔片；22无帽螺栓；23间隙。
 本发明的实施方式
以下结合附图详细描述本发明的技术方案。本发明一次性成批量加工金属微针阵列，以线切割较理想的总切割厚度2厘米计算，例如工装上下整体壁厚5毫米，凹槽深度2毫米，每片金属薄片的厚度为100微米，则一次可切割的微针数量为140片，与其它微针加工方法相比效率大幅提高，再加上线切割加工技术相对较低的成本，所以本发明所提供的微针阵列加工方法成本低廉。夹持工装使用过后除了切割丝所经路径处的材料被切割掉外，其它部分仍保持完整，能够提高效率并降低成本。夹持工装将多片金属薄片压实为一整体，提高工件刚度，防止切割时因侧向力导致加工尺寸偏差，大幅提高精度和可加工微针长度，满足大长径比微针的加工需要。微针尖端切割时采用“8”字型加工路径，保证微针尖端加工精度。微针沿宽度方向采用等强度设计，提高微针沿宽度方向的抗屈曲能力，防止微针刺入皮肤时沿宽度方向发生屈曲失效，同时采用专门的刺入辅助装置给微针提供厚度方向的附加约束，全面提高大长径比微针的使用可靠性。具体实施例如下：
一种大长径比平面金属微针阵列的制备方法，包括以下步骤：
第一步：微针材料采用生物相容性好、强度和韧性俱佳的金属薄片材料，本实施例中采用医用304不锈钢薄片，不锈钢薄片尺寸长为1000毫米，宽100毫米，厚度80微米。
第二步：将第一步所述金属薄片剪裁为大小合适的小型金属薄片5，本实施例中长50毫米，宽25毫米，厚度80微米。
第三步：加工专用的薄片夹持工装，工装外观结构如图1、2、3所示；
夹持工装由完全相同的上下两块金属盖板1组成，本实施例中夹持工装上下盖长80毫米，宽55毫米，板厚6毫米，盖板内壁设置与S2所述小型薄片尺寸相匹配的凹槽2，本实施例中凹槽深度1.5毫米，凹槽长50毫米，宽25毫米。本实施例中工装材料采用导电性能良好、强度高的不锈钢。在夹持工装两侧加工用于后续螺栓连接固定的6个M6螺栓通孔3，孔的数量可根据实际需要调整。
第四步，将所述100片小型金属薄片5放置在任一金属盖板1的凹槽2内，进行堆叠。将另一金属盖板1放置到已放置好金属薄片5的盖板之上，凹槽朝向金属薄片5，上下对齐；然后通过紧固螺栓4将上下金属盖板1封装紧固，压实金属薄片5，与上下盖板1成为一整体，得到如图4所示的封装好的金属薄片和加工夹持工装整体。
第五步，设计片状平面金属微针的几何形状和尺寸规格
片状平面金属微针阵列由用于后续夹持部分的基片6和大长径比微针针体7组成。本实施例中片状微针阵列中针体形状为图5所示，微针针体7厚度即为金属薄片自身厚度，针体沿宽度方向为等强度设计，即微针宽度变化要确保微针在尖端受横向集中载荷作用时各横截面处的最大弯曲应力处处相等，假定微针根部为x轴起点，且x轴即为微针的纵对称轴，宽度方向假定为y轴，则这种等强度设计要求x、y满足以下关系：
Figure 342369dest_path_image001
，式中L 0为微针长度，C为常数，此实施例中微针针体高度1.5毫米，底部宽度150微米，C根据微针底部宽度和长度可计算得到为0.0612。图5为单片微针阵列示意图。图5中的8为留于后续刺入辅助装置定位的定位肩，图5中9为用于后续基片组装用的定位槽。
本实施例中如单片基片上的微针个数选为7根，间距3.5毫米，基片不计针体部分高度13毫米，底部设置如图5中所示凹槽9，本实施例中凹槽高度5毫米，宽度5毫米，微针基片靠近针体处两侧留置如图5中所示的定位肩8，用于后续微针阵列刺入时定位，本实施例中该部分尺寸为高3毫米，宽3毫米。
第六步：将第四步封装好的金属薄片和工装装夹到线切割设备上，线切割设备根据第五步设计的片状平面金属微针的几何形状和尺寸规格确定走丝路径，按照图6所示的走丝路径对工装和金属薄片5作为整体进行线切割，金属薄片5加工出基片6和微针针体7。线切割过程中，对微针针体7的针尖加工采用 “8”字形路径切割，确保微针针尖尖锐程度。另外，加工过程中，单片微针基片两侧留如图6或图7中附图标记“10”所示少许材料不切割，本实施例中不切割部分高度2毫米，宽度2毫米。切割完成后的金属薄片和工装未拆卸时的示意图如图7所示（俯视图）。
第七步：卸下工装上的紧固螺栓4，取出已加工的金属薄片5并进行清洗，得到如图8所示的未裁剪时的微针基片。
第八步，对第七步得到的微针基片进行裁剪，去除基片6两侧预留区域的材料，使片状平面金属微针从金属薄片5剥离，得到如图5所示的片状平面微针阵列。
一种大长径比平面金属微针阵列的组装夹持装置，专用微针薄片组装夹持装置包括主体11、隔板15，主体11、隔板15采用铝合金材料。所述夹持装置整体为一侧开口的盒状长方体，内腔底部设有与S9所述微针基片底部凹槽匹配的滑轨12，如图9、10、11中附图标记“12”所示，内腔尺寸为长25毫米、宽20毫米、高10毫米，壁厚5毫米。在装配体底部加工用于安装手持手柄的螺纹孔13，装配体两侧端面加工有螺纹孔14，用于通过螺栓16对隔板15进行顶紧；夹持装置整体三视图如图9、10、11所示。用于定位的隔板15在本实施例中隔板采用铝合金材料，隔板15高度10毫米，隔板长度需与主体11的腔体宽度一致，即20毫米；隔板15宽度根据需要设定，本实施例中取3.5毫米，隔板块数为7块；隔板15底部设有与微针基片底部凹槽尺寸一致的凹槽。
将如图5所示的片状平面微针阵列和隔板15依次排布，放置于夹持装置主体11中，采用螺栓夹持装置任意一侧端面的如图9、10、11中所示的螺纹通孔14对微针基片与隔板进行压实固定，将手持手柄17安装于夹持装置底部螺纹孔13中，最终得到如图13、14、15所示的组织完成后的微针阵列。
一种大长径比平面金属微针阵列的刺入辅助装置，所述的刺入辅助装置包括矩形框主体18、定位隔板20、定位小隔片21，如图16、17、18所示。所述矩形框主体18、定位隔板20采用铝合金材料；所述定位小隔片21与微针基片6同材料。
所述的矩形框主体18为上下开口的框状长方体，设于组装夹持装置上方。内框长度、宽度与夹持装置主体11的腔体长度、宽度一致。矩形框主体18高度需与图5中所示的定位肩8尺寸匹配，本实施例中该部分尺寸为高3毫米，宽3毫米，所述高度需与所述微针基片高出隔板的尺寸一致；矩形框主体18两侧设置用于通过无帽螺栓22的螺纹通孔19，用于后续顶紧。
所述的定位隔板20具体如图19所示，定位隔板20的高度与矩形框主体18的高度一致，为3毫米；定位隔板20长度与夹持装置的隔板15长度一致，为20毫米；定位隔板20厚度与夹持装置隔板15的厚度一致，定位隔板20与微针针体对应位置处采用细砂纸轻微打磨。定位隔板20两两之间通过定位小隔片21间隔，两个定位隔板20之间的间隙23用于通过微针针体7。所述的定位小隔片21的高度与定位隔板20高度一致，为3毫米；隔片宽度应略小于S9中所述如图5中所示的定位肩8宽度，本实施例中宽度2.8毫米；厚度与微针基片一致。将定位框、隔板以及S24所述隔片进行组装，最终得到如图20所示的微针阵列刺入辅助装置。
所述的定位隔板20装配至矩形框主体18内，在每片定位隔板20两端放置定位小隔片21，使定位隔板20间距与微针厚度一致，采用无帽螺栓从矩形框主体18一侧进行压紧封装，压紧定位隔板20与定位小隔片21，得到如图20所示的微针阵列刺入辅助装置。在定位隔板20两端采用502胶水加固定位隔板20、定位小隔片21和矩形框主体18之间的连接，最终组装完成后的刺入辅助装置如图20所示。对需要施加药物的皮肤区域进行消毒处理，将组装好的如图20所示的刺入辅助装置放置于皮肤上，再将如图13、14、15所示组装好的微针阵列通过辅助装置中各定位隔板20的间隙23刺入皮肤。
本发明实施例仅用于说明并解释本发明的技术方案而非限制，尽管参照较佳实施例对本发明进行了详细说明，本领域的普通技术人员应当理解，可以对发明的技术方案进行修改或者等同替换而不脱离本发明技术方案的精神和范围，其均应涵盖在本发明的权利要求范围中。

Claims (8)

  1. 一种大长径比平面金属微针阵列的制备方法，其特征在于，包括以下步骤：
    第一步：微针材料采用医用不锈钢或钛合金金属薄片材料，金属薄片厚度20~200微米；
    第二步：将所述金属薄片剪裁为大小合适的小型金属薄片(5)，长30~50毫米，宽10~30毫米；
    第三步：加工专用的薄片夹持工装
    工装由上下两块完全相同的金属盖板(1)组成，每块盖板总体厚度为5~10毫米；在工装上下盖板内壁加工与所述小型金属薄片(5)尺寸相匹配的凹槽(2)，即凹槽长宽与前述金属薄片(5)长宽一致，用于放置金属薄片(5)，上下盖板凹槽的深度均为1~5毫米；上下盖板主体1四周边缘处加工用于通过紧固螺栓(4)的通孔(3)；
    第四步，将所述小型金属薄片(5)放置在任一金属盖板(1)的凹槽(2)内，一次放置的金属薄片(5)片数根据薄片厚度和凹槽深度进行调整，推荐一次放置片数20~200片；将另一金属盖板(1)放置到已放置好金属薄片(5)的盖板之上，凹槽朝向金属薄片(5)，上下对齐；然后通过紧固螺栓(4)将上下金属盖板(1)封装紧固，压实金属薄片(5)，与上下金属盖板(1)成为一整体；
    第五步，设计片状平面金属微针的几何形状和尺寸规格
    片状平面金属微针阵列由用于后续夹持部分的基片(6)和大长径比微针针体(7)组成；所述的大长径比微针针体(7)均设于基片(6)上方；基片(6)上方两侧均设有一个定位肩(8)，用于刺入辅助装置进行定位导向；基片(6)下方中部设有一个定位导向槽(9)定位导向槽(9)，用于后续基片(6)进行组装；
    第六步：将第四步封装好的金属薄片和工装装夹到线切割设备上，线切割设备根据第五步设计的片状平面金属微针的几何形状和尺寸规格确定走丝路径，对工装和金属薄片(5)作为整体进行线切割，金属薄片(5)加工出基片(6)和微针针体(7)；线切割过程中，对微针针体(7)的针尖加工采用 “8”字形路径切割，确保微针针尖尖锐程度；另外，加工过程中，基片(6)两侧预留2~5毫米不进行切割，确保夹持工装和金属薄片(5)在加工后仍为一整体；
    第七步：卸下工装上的紧固螺栓(4)，取出已加工的金属薄片(5)并进行清洗，得到未裁剪时的微针基片；
    第八步，对第七步得到的微针基片进行裁剪，去除基片(6)两侧预留区域的材料，使片状平面金属微针从金属薄片(5)剥离，得到具有多个微针针体的片状平面金属微针阵列。
  2. 根据权利要求1所述的一种大长径比平面金属微针阵列的制备方法，其特征在于，所述的夹持工装材料为导电性能良好、强度高的不锈钢、45#钢金属材料。
  3. 权利要求1-2任一所述的方法制备得到的大长径比平面金属微针阵列，其特征在于，所述的片状平面金属微针阵列由用于后续夹持部分的基片(6)和大长径比微针针体(7)组成，大长径比微针针体(7)的高度为1~5毫米，针体根部宽度为50~500微米，厚度为金属薄片(5)自身厚度；所述的大长径比微针针体(7)均与设于基片(6)上方，每片基片上微针个数为3~50根，间距0.25~10毫米；基片(6)上方两侧均设有一个定位肩(8)，用于刺入辅助装置进行定位导向；基片(6)下方中部设有一个定位导向槽(9)定位导向槽(9)，用于后续基片(6)进行组装；
    所述的大长径比微针针体(7)沿高度方向采用等强度设计，即大长径比微针针体(7)的宽度变化需要确保微针针体(7)在尖端受横向集中载荷作用时各横截面处的最大弯曲应力处处相等，假定微针针体(7)根部为x轴起点，且x轴位于微针微针针体(7)的纵对称轴，宽度方向假定为y轴，则等强度设计要求x、y满足以下关系：
    Figure 910221dest_path_image001
    ，式中L 0为微针针体(7)长度，C为综合反映材料屈服强度、微针厚度、载荷大小的常数。
  4. 一种权利要求3所述的大长径比平面金属微针阵列的组装夹持装置，其特征在于，所述的组装夹持装置包括主体(11)、隔板(15)；主体(11)、隔板(15)材料为轻质金属或高分子材料；
    所述的主体(11)为一侧开口的盒状长方体结构，内腔底部设有与微针基片底部定位导向槽(9)相匹配的滑轨(12)；主体(11)底部设有用于后续安装手柄用的螺纹孔(13)；主体(11)侧面设有一个螺纹通孔(14)，用于通过螺栓(16)对隔板(15)进行顶紧；大长径比平面金属微针阵列垂直放置于组装夹持装置内，微针针体(7)朝上；所述的主体(11)腔体宽度与微针基片(6)的宽度一致；腔体深度与基片(6)外侧边缘高度一致，即基片(6)定位肩所在平面与主体(11)上表面位于同一平面；腔体长度根据拟夹持的微针基片片数和各基片之间的间距确定，建议长度范围10~40毫米；所述的隔板(15)为薄长方体结构，微针阵列装配时用于定位各微针基片；隔板(15)宽度与主体(11)腔体深度一致，长度与主体(11)的腔体宽度一致，厚度为1-5毫米，隔板(15)底部设有与基片(6)底部定位导向槽(9)匹配的凹槽；
    将大长径比平面金属微针阵列垂直放置于夹持装置主体(11) 的腔体内，每片基片之间通过隔板(15)隔开；螺栓(16)穿过夹持装置侧面螺纹通孔(14)，挤压隔板(15)，使各微针基片保持稳定；夹持时微针基片靠近微针针体一侧高于隔板(15)和夹持装置主体上表面，具体高出尺寸由微针基片(6)两侧定位肩(8)的尺寸决定，夹持好之后在夹持装置主体(11)的底部螺纹孔(13)处安装手持手柄17，完成大长径比平面金属微针阵列的组装夹持。
  5. 根据权利要求4所述的大长径比平面金属微针阵列的组装夹持装置，其特征在于，所述的主体(11)、隔板(15)选用铝合金或聚四氟乙烯。
  6. 一种权利要求3所述的大长径比平面金属微针阵列的刺入辅助装置，其特征在于，所述的刺入辅助装置包括矩形框主体(18)、定位隔板(20)、定位小隔片(21)，所述矩形框主体(18)、定位隔板(20)材料为轻质金属或高分子材料；所述定位小隔片(21)与微针基片(6)同材料；
    所述的矩形框主体(18)为上下开口的框状长方体，用于放置在组装夹持装置上方；矩形框主体(18)的内框长度、宽度与夹持装置主体(11)的腔体长度、宽度一致，矩形框主体(18)的高度与微针基片两侧定位肩(8)的高度一致，矩形框主体(18)两侧设置用于通过无帽螺栓(22)的螺纹通孔(19)，用于后续顶紧；所述的定位隔板(20)，定位隔板(20)的高度与矩形框主体(18)的高度一致，定位隔板(20)长度与夹持装置的隔板(15)长度一致，定位隔板(20)厚度与夹持装置隔板(15)的厚度一致，定位隔板(20)与微针针体对应位置处采用细砂纸轻微打磨；定位隔板(20)两两之间通过定位小隔片(21)间隔，两个定位隔板(20)之间的间隙(23)用于通过微针针体(7)；所述的定位小隔片(21)的高度与隔板定位隔板(20)高度一致，宽度比微针基片(6)两侧定位肩(8)的宽度小0.1~1毫米，厚度与微针基片一致，用于确保定位隔板(20)之间间隙(23)与微针基片厚度一致；
    所述的定位隔板(20)装配至矩形框主体(18)内，在每片定位隔板(20)两端放置定位小隔片(21)，使定位隔板(20)间距与微针厚度一致，定位隔板(20)与微针针体接触处打磨，能确保微针针体与定位隔板(20)之间存有空隙，以免发生严重刮碰；无帽螺栓(22)通过矩形框主体(18)端面一侧螺纹孔，用于压紧定位隔板(20)与定位小隔片(21)，且与夹持装置保持一一对应关系；对需要刺入的皮肤区域进行消毒处理，将组装好的刺入辅助装置放置于皮肤上，再将组装好的微针阵列通过辅助装置中各定位隔板(20)的间隙(23)刺入皮肤。
  7. 根据权利要求6所述的大长径比平面金属微针阵列的刺入辅助装置，其特征在于，所述矩形框主体(18)、定位隔板(20)选用铝合金或聚四氟乙烯。
  8. 根据权利要求6或7所述的大长径比平面金属微针阵列的刺入辅助装置，其特征在于，在定位隔板(20)两端采用502胶水加固定位隔板(20)、定位小隔片(21)和矩形框主体(18)之间的连接。
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