WO2000016833A1 - Micro-aiguilles micro-usinees sur une surface - Google Patents

Micro-aiguilles micro-usinees sur une surface Download PDF

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Publication number
WO2000016833A1
WO2000016833A1 PCT/US1999/021509 US9921509W WO0016833A1 WO 2000016833 A1 WO2000016833 A1 WO 2000016833A1 US 9921509 W US9921509 W US 9921509W WO 0016833 A1 WO0016833 A1 WO 0016833A1
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WO
WIPO (PCT)
Prior art keywords
microneedle
microneedles
array device
microneedle array
substrate
Prior art date
Application number
PCT/US1999/021509
Other languages
English (en)
Inventor
A. Bruno Frazier
John D. Brazzle
Original Assignee
The University Of Utah Research Foundation
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by The University Of Utah Research Foundation filed Critical The University Of Utah Research Foundation
Priority to AU61515/99A priority Critical patent/AU6151599A/en
Priority to JP2000573793A priority patent/JP2002526273A/ja
Priority to US09/787,498 priority patent/US7048723B1/en
Priority to EP99948307A priority patent/EP1113832A4/fr
Priority to CA002344398A priority patent/CA2344398A1/fr
Publication of WO2000016833A1 publication Critical patent/WO2000016833A1/fr

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Classifications

    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B81—MICROSTRUCTURAL TECHNOLOGY
    • B81C—PROCESSES OR APPARATUS SPECIALLY ADAPTED FOR THE MANUFACTURE OR TREATMENT OF MICROSTRUCTURAL DEVICES OR SYSTEMS
    • B81C99/00—Subject matter not provided for in other groups of this subclass
    • B81C99/0075—Manufacture of substrate-free structures
    • B81C99/008—Manufacture of substrate-free structures separating the processed structure from a mother substrate
    • 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
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12M—APPARATUS FOR ENZYMOLOGY OR MICROBIOLOGY; APPARATUS FOR CULTURING MICROORGANISMS FOR PRODUCING BIOMASS, FOR GROWING CELLS OR FOR OBTAINING FERMENTATION OR METABOLIC PRODUCTS, i.e. BIOREACTORS OR FERMENTERS
    • C12M35/00—Means for application of stress for stimulating the growth of microorganisms or the generation of fermentation or metabolic products; Means for electroporation or cell fusion
    • 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
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B81—MICROSTRUCTURAL TECHNOLOGY
    • B81B—MICROSTRUCTURAL DEVICES OR SYSTEMS, e.g. MICROMECHANICAL DEVICES
    • B81B2201/00—Specific applications of microelectromechanical systems
    • B81B2201/05—Microfluidics
    • B81B2201/055—Microneedles
    • C—CHEMISTRY; METALLURGY
    • C25—ELECTROLYTIC OR ELECTROPHORETIC PROCESSES; APPARATUS THEREFOR
    • C25D—PROCESSES FOR THE ELECTROLYTIC OR ELECTROPHORETIC PRODUCTION OF COATINGS; ELECTROFORMING; APPARATUS THEREFOR
    • C25D1/00—Electroforming
    • C25D1/02—Tubes; Rings; Hollow bodies

Definitions

  • the present invention relates generally to microneedles for the injection and extraction of fluids. More specifically, the present invention relates to an easily fabricated, micromachined array of microneedles or a single microneedle which can be easily attached to a syringe and which are mechanically durable.
  • Micro instrumentation is a rapidly growing area of interest for a broad spectrum of engineering applications.
  • biomedical instrumentation where significant efforts are being made to develop micro biochemical analysis systems, physiological systems, and drug delivery systems.
  • a variety of manufacturing technologies are used to fabricate these micro systems, many of which are categorized under the set of technologies known as micromachining.
  • micromachining The number of biomedical applications for micromachining technologies is rapidly growing. Since micromachining technologies are relatively new, there is an increasing set of manufacturing techniques and critical applications still to be addressed.
  • microneedles have been made out of etched silicon or out of chemical vapor deposited polysilicon, both of which have a tendency to be brittle and break easily. It would therefore be of substantial interest to develop a durable device which is capable of injecting precise quantities of fluids into specific locations with a minimal amount of tissue damage, and which overcomes the difficulties associated with prior microneedle devices.
  • a further object of the invention is to provide an array of microneedles or a single microneedle which can be easily and economically fabricated according to standard micromachining procedures.
  • surface micromachined microneedles are formed as single needles or in two- or three-dimensional microneedle arrays.
  • the microneedles are fabricated on a substrate which can remain attached to the microneedles or can be subsequently removed.
  • the two- or three-dimensional microneedle arrays can have cross-coupling flow channels which allow for pressure equalization, and balance of fluid flow within the microneedle arrays.
  • a plurality of mechanical support members can be integrated into the arrays for stability and to control the penetration depth of the microneedles.
  • a microneedle array device in one embodiment, includes a substrate having a substantially planar surface, and a plurality of hollow non-silicon microneedles on the planar surface of the substrate.
  • Each of the microneedles has a microchannel therethrough that provides communication between at least one input port at a proximal end of each of the microneedles and at least one output port at an opposite distal end that extends beyond an edge of the substrate.
  • a method of fabricating a microneedle device includes providing a substrate with a substantially planar surface, and depositing a metal J material on the planar surface to form one or more bottom walls for one or more microneedles.
  • a top surface of the bottom walls is coated with a photoresist layer to a height corresponding to a selected inner height of a microchannel for each of the microneedles.
  • a metal material is then deposited to form side walls and a top wall upon the bottom walls and around the photoresist layer.
  • the photoresist layer is then removed from each microchannel to form the microneedles.
  • the microneedles can be released from the substrate and used independent of the substrate, if desired.
  • the method of fabricating the microneedle device can include p' etch-stop membrane technology, anisotropic etching of silicon in potassium hydroxide, sacrificial thick photoresist micromolding technology, and micro-electrodeposition technology.
  • Figure 1 is a schematic representation of microneedles in a two-dimensional array according to one embodiment of the present invention
  • Figure 2A is a schematic representation of microneedles in a two-dimensional array according to another embodiment of the present invention.
  • Figure 2B is a schematic representation of microneedles in a two-dimensional array according to another embodiment of the present invention.
  • Figure 3 is a schematic representation of a single microneedle according to a further embodiment of the present invention.
  • Figures 4A-4F depict schematically the fabrication process sequence for forming a microneedle array;
  • Figure 4G depicts an embodiment of a multilumen microneedle formed according to the present invention.
  • Figures 5A and 5B depict alternative methods of assembling two-dimensional needle arrays into three-dimensional needle array devices;
  • Figures 6A-6C are vector magnitude plots showing the effects of fluid flow rate on needle coupling channels and needle channels;
  • Figure 7 is a graph of the flow rate as a function of pressure difference for a microneedle array of the invention.
  • Figure 8 is a graph of the flow rate as a function of pressure for five individual microneedles of the invention.
  • the present invention is directed to micromachined arrays of microneedles and single microneedles which exhibit mechanical durability.
  • the microneedles are capable of injecting precisely controlled amounts of fluid, and can be easily and economically fabricated according to standard micromachining procedures.
  • FIG. 1 A schematic depiction of a micromachined needle array 10 according to one embodiment of the invention is shown in Figure 1.
  • the needle array 10 is formed in a two-dimensional configuration on a substrate 12 having a substantially planar upper surface 14.
  • the substrate 12 is preferably composed of a semiconductor material such as silicon, although other materials can be employed such as glass, metals, ceramics, plastics, and composites or combinations thereof.
  • a plurality of fluidly interconnected hollow microneedles 16 are formed on upper surface 14 of substrate 12.
  • the microneedles 16 each have a bottom wall, two opposing side walls, and a top wall that define a microchannel therein. This provides the microchannel with a transverse cross-sectional profile that is substantially rectangular.
  • Each bottom wall is formed partially on upper surface 14 of substrate 12.
  • the microneedles each have one or more input ports in an input shaft, and a portion of each microneedle 16 including the microchannels extends beyond an edge of upper surface 14 of substrate 12 in a cantilevered section which terminates in a needle tip 18 with a channel opening 20 therein.
  • the microneedles 16 are preferably aligned substantially parallel to each other on substrate 12.
  • the microchannels in the microneedles 16 are preferably dimensioned to have a width between sidewalls of less than about 100 ⁇ m, and more preferably about 0 ⁇ m to about 50 ⁇ m. When the width is zero between the sidewalls, the microneedles 16 effectively become one multilumen microneedle with a plurality of microchannels.
  • the height between the top and bottom walls of the microchannel is also preferably less than about 100 ⁇ m, and more preferably about 2 ⁇ m to about 50 ⁇ m.
  • the length of each microneedle can be from about 0.05 ⁇ m to about 5 mm, and the width of each microneedle can be from about 0.05 ⁇ m to about 1 mm.
  • the center-to-center spacing between individual microneedles can be from about 50 ⁇ m to about 200 ⁇ m.
  • the microneedles can also withstand flow rates of up to about 1.5 cc/sec.
  • the microneedle length extended from the substrate can be varied from less than about 50 ⁇ m (subcutaneous) to several millimeters for fluid delivery/extraction.
  • the distal end of each microneedle can extend beyond the edge of the substrate a distance from about 10 ⁇ m to about 100 mm.
  • the inner cross-sectional dimensions of the microchannels in individual needles can range from about 10 ⁇ m to about 1 mm in width and about 2 ⁇ m to about 50 ⁇ m in height.
  • the microchannel in each of the microneedles can have a cross-sectional area in the range from about 25 ⁇ m 2 to about 5000 ⁇ m 2 .
  • a needle coupling channel member 22 is also formed on upper surface 14 of substrate 12 between microneedles 16.
  • the coupling channel member 22 has a bottom wall, two opposing side walls, and a top wall that define a coupling microchannel therein, which provides for fluid communication between the microchannels of each microneedle 16.
  • the coupling channel member 22 also allows for pressure equalization and balance of fluid flow between microneedles 16.
  • a pair of structural support members 24 are formed on either side of coupling channel member 22 on upper surface 14 of substrate 12.
  • the structural support members 24 mechanically interconnect microneedles 16 to provide rigidity and strength to needle array 10.
  • the support members 24 also precisely control the penetration depth of microneedles 16.
  • the microneedles 16, coupling channel member 22, and support members 24 can be formed from a variety of metal materials such as nickel, copper, gold, palladium, titanium, chromium, alloys or combinations thereof, and the like, as well as other materials such as plastics, ceramics, glass, carbon black, composites or combinations thereof, and the like.
  • the microneedles can be in fluid communication with a single fluid input device or with multiple fluid input devices.
  • a micromachined needle array 30 according to another embodiment of the invention is shown in Figure 2 A.
  • the needle array 30 has a two-dimensional configuration with similar components as needle array 10, except that the substrate has been removed from the array. Accordingly, needle array 30 includes a plurality of microneedles 32 with microchannels therein that are dimensioned as discussed above for needle array 10.
  • the microneedles 32 each terminate at a needle tip 33 with a channel opening 34 therein.
  • a needle coupling channel member 36 with a coupling microchannel therein provides a fluidic interconnection between the microchannels of each microneedle
  • a pair of structural support members 38 are formed on either side of coupling channel member 36 and interconnect with microneedles 32.
  • One or more input ports 37 and output ports 39 can be optionally formed in microneedles 32 to increase fluid input and output flow.
  • the input ports 37 and output ports 39 can be formed in one or more of the bottom wall, side walls, or top wall of microneedles 32 by conventional fabrication processes such as etching.
  • a micromachined needle array 31 according to another embodiment of the invention is shown in Figure 2B.
  • the needle array 31 has a two-dimensional configuration with similar components as needle array 30. except that needle array 31 is formed without a coupling channel member.
  • needle array 30 includes a plurality of microneedles 32 with microchannels therein that are dimensioned as discussed above for needle array 10.
  • the microneedles 32 each terminate at a needle tip 33 with a channel opening 34 therein.
  • a pair of structural support members 38 interconnect with microneedles 32.
  • One or more input ports 37 and output ports 39 can be optionally formed in microneedles 32 to increase fluid input and output flow.
  • FIG. 3 is a schematic representation of a single hollow microneedle 40 according to a further embodiment of the present invention which can be fabricated by standard micromachining techniques.
  • the microneedle 40 has a bottom wall, two opposing side walls, and a top wall that defines a microchannel 42 therein.
  • the microchannel 42 communicates with a flanged inlet end 44 for fluid input.
  • the flanged inlet end 44 can include single or multiple fluid input ports and acts as a structural support for microneedle 40.
  • the flanged inlet end 44 can control penetration depth and can be used to mechanically fix microneedle 40 to a surface that is penetrated.
  • the microneedle 40 terminates at a needle tip 46 at an opposite end from inlet end 44.
  • One or more output ports 48 are formed in microneedle 40 between inlet end 44 and needle tip 46.
  • the output ports 48 can be formed in one or more of the bottom wall, side walls, or top wall of microneedle 40 by conventional fabrication processes such as etching.
  • the microneedle 40 can be formed from a variety of materials such as nickel, copper, gold, palladium, titanium, chromium, alloys thereof, and the like, as well as other materials such as plastics, ceramics, glass, carbon black, composites thereof, etc.
  • the microneedle 40 can be on a substrate as shown for the array of Figure 1 , or can be removed from a substrate as shown for the array of Figure 2A.
  • a substrate 12 having a substantially planar surface 14 is provided, such as a silicon wafer which is polished on both sides.
  • the wafer can have a thickness of about 1 ⁇ m to about 700 ⁇ m, and is preferably about 150 ⁇ m thick.
  • One side of the wafer is heavily doped with boron using high temperature thermal diffusion in order to form a 3-5 ⁇ m thick p+ layer.
  • silicon nitride (Si 3 N 4 ) is deposited on both sides of the wafer using plasma-enhanced chemical vapor deposition (PECVD).
  • PECVD plasma-enhanced chemical vapor deposition
  • the silicon nitride on the undoped side of the wafer is patterned and etched employing photoresist as a mask, and then isotropic etching (a CF 4 plasma for example) is used to etch the exposed silicon nitride to define the area upon which the microneedles are to be fabricated.
  • isotropic etching a CF 4 plasma for example
  • the exposed silicon is anisotropically etched using a potassium hydroxide (KOH) solution.
  • KOH potassium hydroxide
  • the p+ boron layer serves as an etch stop, resulting in a thin sacrificial membrane 52, as shown in Figure 4A.
  • the sacrificial membrane 52 comprises the surface upon which the microneedles are formed and then subsequently released as described below.
  • a metal system of adhesion layers and an electroplating seed layer are deposited (by electron beam evaporation, for example) onto the insulating silicon nitride film.
  • the adhesion and seed layers are typically composed of, but not limited to, titanium, chromium, copper, or combinations thereof.
  • this metal multilayer is patterned.
  • a metal material is then electroplated to form one or more bottom walls 54 (e.g., about 20 ⁇ m thick) for the microneedles, as shown in Figure 4B.
  • Palladium is a preferred metal for the bottom wall since it provides high mechanical strength and durability, is corrosion resistant, provides biocompatibility for use in biomedical applications, and is easily electroplated to within precise dimensions.
  • bottom walls 54 are about 10- 20 ⁇ m in thickness, and about 50 ⁇ m wide.
  • bottom walls 54 have been formed, a commercially available thick photoresist is deposited (e.g. , about 20 ⁇ m thick) and patterned using ultraviolet exposure and alkaline developer, resulting in sacrificial layers 56 as depicted in Figure 4C.
  • a metal seed layer such as gold is sputter deposited (e.g., about 800 A thick) onto the photoresist sacrificial layers 56.
  • the metal seed layer serves as an electrical contact for the subsequent metal electroplating.
  • a metal layer is then electroplated (e.g. , about 20 ⁇ m thick) onto sacrificial layers
  • each microneedle 56 to form the a plurality of side walls 58 and top walls 60 of each microneedle, as shown in Figure 4D.
  • the exposed metal seed layer is then removed using wet etching techniques to expose the underlying photoresist.
  • the wafer is placed in an acetone bath to remove the thick photoresist from inside the microneedle structures, thereby producing a plurality of hollow microneedles 16, as shown in Figure 4E.
  • sacrificial membrane 52 is removed by an isotropic etching technique, such as reactive ion etching in a SF 6 plasma.
  • an isotropic etching technique such as reactive ion etching in a SF 6 plasma.
  • the needle arrays can be released from substrate 12 following surface fabrication on substrate 12. if desired, such as in the embodiment shown in Figure 2A.
  • This method does not require sacrificial membrane formation or KOH etching. Instead, the needle arrays are released using wet etching of the seed metal from underneath the needle structures. If the seed metal is copper, for example, then this can be done by a selective etch of ammonium hydroxide saturated with cupric sulfate.
  • the support members and needle walls formed by micro-electro forming processes provide increased structural integrity.
  • the needle coupling channels minimize the effects of restricted needle passages by providing a redistribution point for fluid flow between the passages.
  • a single microneedle such as shown in Figure 3 can also be fabricated according to the procedure outlined above.
  • fluid outlet ports can be etched into the side walls, top walls, and/or bottom walls of the microneedle(s) if a larger amount of fluid transfer is desired.
  • fabricating method outlined above can be used to form a multilumen microneedle by forming bottom walls 54 with zero spacing therebetween on substrate 12 and carrying out the remaining steps as described above.
  • a resulting multilumen microneedle 26 with a plurality of microchannels 28 is shown in Figure 4G.
  • microneedles and arrays of the present invention can be coated on the inside with biocompatible materials, such as silicon nitride, gold, plastics, etc., by conventional coating processes known to those skilled in the art.
  • biocompatible materials such as silicon nitride, gold, plastics, etc.
  • Figures 5 A and 5B depict alternative methods of assembling two-dimensional needle arrays into three-dimensional needle array devices.
  • a plurality of two-dimensional needle arrays 70 are provided which have been released from a substrate as shown for the array of Figure 2A.
  • the needle arrays 70 are positioned in a stacked configuration with a plurality metallic spacers 72 therebetween to define the distance between any two microneedle arrays in the stack.
  • the stacked needle array configuration is then subjected to flash electroplating to join needle arrays 70 with metallic spacers 72 in a fixed three-dimensional needle array device 74.
  • the needle array device 74 can then be disposed in a machined interface structure 76 such as an acrylic interface, allowing connection to a dispensing means for injecting a liquid such as a syringe.
  • a plurality of two-dimensional needle arrays 80 are provided on substrates 82 such as shown for the array of Figure 1.
  • the needle arrays 80 are positioned in a stacked configuration, with substrates 82 acting as spacers between the arrays 80, to define the distance between any two microneedle arrays in the stack.
  • the stacked needle array configuration is placed in a mold 84 such as an aluminum mold for plastic injection molding.
  • the stacked needle array configuration is then subjected to plastic injection molding. This bonds needle arrays 80 together with a plastic molding material 86, thereby forming a fixed three-dimensional needle array device 88.
  • the needle array device 88 can then be disposed in an interface structure 76 allowing connection to a dispensing device such as a syringe.
  • the two dimensional arrays are manually assembled under a microscope.
  • the two-dimensional arrays are stacked with spacers or with substrates on the arrays and are bonded together with a polymeric adhesive such as a UV-curable adhesive to form a three-dimensional needle array device, which can then be disposed in an interface structure.
  • the fabricated three-dimensional needle array devices are typically dimensioned to have a length of about 5 mm. a width of about 5 mm. and a height of about 2 mm.
  • the interface structures for connection to a syringe can be made from a variety of plastic materials such as acrylics, polystyrene, polyethylene, polypropylene, and the like.
  • the interface structure typically accommodates a three-dimensional needle array device having up to about 25 two dimensional arrays.
  • the interface structures are bonded to the three- dimensional needle array devices with a polymeric adhesive such as a UV-curable adhesive.
  • the interface structures are configured to accept direct syringe connection via a connection means such as a conventional Luer-lock connector.
  • interface structures can be formed for a single two-dimensional array or a single microneedle so as to accept direct syringe connection via a connector such as a Luer-lock connector.
  • the micromachined microneedles of the invention have many benefits and advantages. These include reduced trauma at penetration sites due to their small size, greater freedom of patient movement because of the minimal penetration depth of the needles, a practically pain-free drug delivery due to the smaller cross section of the needle tip and distribution of fluid force, and precise control of penetration depth from needle extension length.
  • the microneedles have the ability to deliver drugs to localized areas, and are advantageous in their ability to be stacked and packaged into a three-dimensional device for fluid transfer.
  • micromachined microneedles can be used in a wide variety of biomedical applications.
  • the microneedles can withstand typical handling and can subcutaneously deliver medication without the usual discomfort associated with conventional needles.
  • the microneedles are minimally invasive, in that the microneedles only penetrate just beyond the viable epidermis, reaching the capillaries and minimizing the chance of encountering and damaging the nerves present in the area of penetration.
  • Example 1 A two dimensional microneedle array was fabricated according to the procedure outlined above to have to have 25 microneedles.
  • the inner dimensions of the hollow microneedles were made to be of inner cross-sectional area of 40 x 20 ⁇ m 2 (width by height) and outer cross-sectional area of 80 x 60 ⁇ m 2 .
  • the needle coupling channels were 100 ⁇ m wide, and provided fluid communication between each needle channel.
  • Two sets of 60 x 100 ⁇ m 2 structural supports were located 250 ⁇ m from each needle end. Each needle channel was 2 mm long, while the width of the 25 needle array was 5.2 mm.
  • the center-to-center spacing between individual needles was 200 ⁇ m.
  • the needle wall thickness was approximately 20 ⁇ m of electroformed metal.
  • Needle arrays were fabricated from electroformed low stress nickel sulphamate, gold cyanide, and palladium electroforming solutions.
  • the bath chemistry and electroplating conditions were selected and precisely controlled to allow formation of low stress depositions on top of a 3-5 ⁇ m sacrificial membrane.
  • the surface roughness of the electroplated metals was found by Atomic Force Microscope (AFM) to be approximately 15 nm, resulting in a relative roughness of 0.00056.
  • AFM Atomic Force Microscope
  • the inner dimensions were approximately 30 x 20 ⁇ m 2
  • outer dimensions were approximately 80 x 60 ⁇ m 2
  • the needle tips were formed with 45° angles for ease of penetration.
  • Example 2 Analytical and computer modelling were performed in order to assess how the cross- flow design feature unique to this invention can be used to equalize the pressure distribution across the needle channels, to generally determine the relationships between input pressure and fluid delivery rates for the array, and to investigate the interrelationships amongst the physical dimensions of the needle array.
  • the purpose of the model is (a) to determine the relationship between the input pressure and the fluid delivery rates for the microneedle array and (b) to investigate the relationships between the physical dimensions of the microneedle array (cross-sectional areas of the primary and coupling channels) and the effect on restricted flow within the microneedle array. Pressure equalization may become necessary in the event that some of the individual needle channels become obstructed.
  • the model described herein can be used to characterize the fluid flow rates throughout the micromachined needle array and to determine the most effective design dimensions.
  • Cartesian coordinates can be expressed as:
  • V is the fluid velocity vector
  • f represents the external forces (such as gravity, for example)
  • ⁇ is the fluid viscosity
  • Vp is the pressure gradient required to move the fluid.
  • the equation is known as the Navier- Stokes equation. For the case of a Newtonian fluid with uniform physical properties (water. for example) and negligible effects from external forces moving through a rectangular channel, the flow is two-dimensional and can be simplified to:
  • the numerical model is solved for an array of 10 microneedles.
  • Each needle channel is 40 ⁇ m in width and 2 mm long, while the needle coupling channels which interconnect each needle channel are 100 ⁇ m in width.
  • the vectors that run along the center of each needle channel depict the highest fluid flow rate (1.459 cc/sec), while the small vectors in the middle of each needle coupling channel depict a zero fluid flow rate.
  • the pressure drop across the length of each individual needle was 16.2 kPa.
  • the model was fairly successful at illustrating the effect that the needle coupling channels have on the rest of the system. The model indicates that an equilibrium in the fluid interaction within the needle coupling channels is obtained and that the fluid flow within the needle coupling channels appears not to interfere with the fluid flow in the needle channels.
  • FIG. 6A The effect that the needle coupling channels have on the rest of the system is shown in the vector magnitude plot of Figure 6A.
  • This plot shows the magnitude of the fluid rate components, with the vectors in the middle of each needle channel 92 representing the greatest magnitude (1.471 cc/sec), while the small vectors in the center of each needle coupling channel 94 represent a vector magnitude of zero.
  • the fluid flow rates remain static within the needle coupling channels when there is no opposition (i.e., clog) to the flow within the needle channels.
  • the input needle channels (indicated on the left in Figure 6A) have the same fluid flow rate as the output needle channels (indicated on the right of Figure 6A).
  • Figure 6B is a vector plot of the flow in needle channels 92 when one input is obstructed.
  • the model indicates that the flow in the channel adjacent to the clogged needle is augmented by the incoming fluid flow from other needle channels by means of the needle coupling channels.
  • Flow within the needle coupling channel 94 is as high as 0.912 cc/sec.
  • the overall flow rate through the array remains constant due to conservation of mass. However, the flow rate within the individual output needle channels is decreased to compensate for the clogged passage.
  • the flow rate in the input needle channels is 1.459 cc/sec, while the flow rate in the output channels is 1.276 cc/sec. This indicates a 14.3 percent decrease in the flow rate in individual needle channels.
  • a developing flow region is present at the entrance of the output needle channel, extending approximately 100 ⁇ m from the needle coupling channel. While this figure shows the interaction between only three needle channels, the needle coupling channels redistribute fluid throughout the entire array. It was found that all of the fluid flow rates were identical in all of the output needle channels with an accuracy of 0.0001 cc/sec.
  • Figure 6C shows a vector plot illustrating the effect that the needle coupling channel 94 has on the needle channels 92 when an output is obstructed.
  • the flow in the needle channels adjacent to the clog act to augment the outgoing fluid flow to the other needle channels by means of the needle coupling channels.
  • Flow within the needle coupling channels is as high as 0.831 cc/sec.
  • the overall flow rate through the needle array again remains constant due to conservation of mass. However, the flow rate within the individual output needles is increased to compensate for the clogged passage.
  • the flow rate in the input needle channels is 1.246 cc/sec, while the flow rate in the output needle channels is 1.453 cc/sec. This indicates a 16.6 % increase in the flow rate in individual needle channels.
  • a developing flow region is present at the entrance of the output needle channel, extending approximately 100 ⁇ m from the needle coupling channel. The flow rates in the output needle channels are the same to within an accuracy of 0.0001 cc/sec.
  • the ANSYS model successfully characterized the flow in the microchannels using the specified dimensions.
  • the flow within the needle coupling channels remains static, while in Figures 6B and 6C, the flow within the needle coupling channels dynamically tends towards the needle channels of less resistance.
  • Fluid flow rates within the needle coupling channels adjacent to the obstruction showed an increase of 90%, while the fluid flow rates at the far end of the array showed an increase of less than 10%.
  • the fluid flow rates in individual needle channels show an increase or decrease depending on the location of the obstruction.
  • the needle coupling channels therefore, act to redistribute the fluid flow as necessary when needle inputs or outputs are clogged.
  • Example 3 Flows in channels of similar dimensions were compared experimentally.
  • Figure 7 represents data for flow of water in 3000 x 600 x 30 ⁇ m 3 (length x width x height).
  • the microchannels in this example were fabricated according to the procedures described previously.
  • the plot of the data in Figure 7 serves to show the agreement between the data and the predictions of the Navier-Stokes (N-S) theory and the model based on the micropolar fluid theory.
  • N-S Navier-Stokes
  • Example 4 Five packaged microneedles were fabricated according to the procedures described hereinabove. Fluid flow rate tests were conducted to determine the rate of flow through each packaged microneedle as a function of pressure. Each microneedle was attached to a standard 5 cc syringe filled with water and affixed vertically in a test stand. The test stand was positioned in proximity to an Instron (model 4400) load frame so that the calibrated load cell would come in contact with the syringe plunger. The load frame has the capability of maintaining a constant force on the syringe plunger over specified periods of time. Prior to each test, a sealed flask was placed on a scale and zeroed.
  • the flask was filled and kept at a constant level to keep the surface area of the water nearly constant. This method helps to maintain a constant rate of evaporation, which was also monitored during the tests.
  • the load frame was set to apply a constant force over a period of thirty minutes, while the sealed flask was used to capture the water dispensed by the syringe. After the thirty minute period, the load was removed and the flask was placed on a scale to measure the resultant amount of water that had accumulated.
  • the scale (Sartorius model 1602 MP8-1 ) was enclosed in a glass case and has a resolution of 100 ⁇ g.
  • the evaporation rate was checked prior to each test by placing the sealed flask on the scale and noting the weight loss over a period of thirty minutes. The value obtained was then added to the resultant data from the needle tests.
  • each needle shaft were 200 ⁇ m wide and 60 ⁇ m thick, and the tip dimensions were less than 15 x 15 ⁇ m 2 .
  • the length of the tapered portion was 1 mm and the distance from the tip to the first output port was approximately 300 ⁇ m.
  • the total length of the microneedles was 6 mm, with inner channel dimensions of 140 ⁇ m wide and 20 ⁇ m high.
  • the wall thickness of each needle was approximately 20 ⁇ m and the microneedle output ports were on the top and bottom with dimensions of 30 ⁇ m 2 . The output ports were separated by 30 ⁇ m and there were nine ports on the top and 12 ports on the bottom.
  • the fluid flow experiments were performed on the five packaged microneedles at pressures ranging from 1 to 70 psi.
  • the fabricated needles were packaged into an interface using UV-curable epoxy. Pressures were applied to each microneedle at 30 minute intervals while the weight of the water that had accumulated during each test was recorded. The weight data was converted into fluid flow rates for the needles based on the density of water at 25°C and the results are shown in the graph of Figure 8.
  • the microneedles demonstrated flow rates in the range of 0.00384 to 2.67 ⁇ L/min with applied pressures of 1 to 70 psi.
  • the packaged microneedles also exhibited the ability to withstand pressures exceeding 100 psi.

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Abstract

La présente invention concerne des micro-aiguilles (32) micro-usinées sur une surface, réalisées sous forme d'aiguilles prises une à une (32) ou montées en matrices bidimensionnelles ou tridimensionnelles (30). Ces micro-aiguilles (32) sont fabriquées sur un substrat (12) qui peut rester solidaire des micro-aiguilles (32) ou peut en être séparé ultérieurement. Ces matrices bidimensionnelles ou tridimensionnelles de micro-aiguilles (30) peuvent comporter des canaux d'écoulement à couplage croisé (36) qui assurent un équilibrage des pressions et de l'écoulement du fluide dans les matrices de micro-aiguilles (30). Chaque micro-aiguille (32) est traversée d'un micro-canal (36) qui met en communication au moins un orifice d'entrée (37) à l'extrémité proximale des micro-aiguilles (32), et au moins un orifice de sortie (39), de l'autre côté, à l'extrémité distale.
PCT/US1999/021509 1998-09-18 1999-09-17 Micro-aiguilles micro-usinees sur une surface WO2000016833A1 (fr)

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Application Number Priority Date Filing Date Title
AU61515/99A AU6151599A (en) 1998-09-18 1999-09-17 Surface micromachined microneedles
JP2000573793A JP2002526273A (ja) 1998-09-18 1999-09-17 表面マイクロマシニングしたマイクロニードル
US09/787,498 US7048723B1 (en) 1998-09-18 1999-09-17 Surface micromachined microneedles
EP99948307A EP1113832A4 (fr) 1998-09-18 1999-09-17 Micro-aiguilles micro-usinees sur une surface
CA002344398A CA2344398A1 (fr) 1998-09-18 1999-09-17 Micro-aiguilles micro-usinees sur une surface

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US60/101,064 1998-09-18

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* Cited by examiner, † Cited by third party
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WO2003070623A1 (fr) * 2002-02-25 2003-08-28 Hitachi Chemical Co., Ltd. Unite de support de systeme microfluidique et son procede de fabrication
US6629949B1 (en) 2000-05-08 2003-10-07 Sterling Medivations, Inc. Micro infusion drug delivery device
US6659982B2 (en) 2000-05-08 2003-12-09 Sterling Medivations, Inc. Micro infusion drug delivery device
WO2005087305A1 (fr) * 2004-03-12 2005-09-22 Agency For Science, Technology And Research Procedes et moules s'utilisant dans la fabrication de micro-aiguilles a orifice lateral
US6982058B2 (en) 1999-12-08 2006-01-03 Baxter International, Inc. Method for fabricating three dimensional structures
US7066922B2 (en) 2001-10-26 2006-06-27 Massachusetts Institute Of Technology Transdermal transport device with suction
WO2007003398A2 (fr) * 2005-07-01 2007-01-11 MAX-PLANCK-Gesellschaft zur Förderung der Wissenschaften e.V. Systeme d'electrodes, son utilisation et procede pour le produire
WO2007003399A2 (fr) * 2005-07-01 2007-01-11 MAX-PLANCK-Gesellschaft zur Förderung der Wissenschaften e.V. Dispositif d'electrodes, utilisation et procedes de realisation associes
WO2008027011A1 (fr) * 2006-08-28 2008-03-06 Agency For Science, Technology And Research Micro-aiguilles et procédés pour fabriquer des micro-aiguilles
US7442303B2 (en) 1999-12-08 2008-10-28 Baxter International Inc. Microporous filter membrane, method of making microporous filter membrane and separator employing microporous filter membranes
US7473244B2 (en) 2000-06-02 2009-01-06 The University Of Utah Research Foundation Active needle devices with integrated functionality
WO2010122222A2 (fr) 2009-04-20 2010-10-28 Valtion Teknillinen Tutkimuskeskus Microaiguille
JP2010279704A (ja) * 2002-02-08 2010-12-16 Intuity Medical Inc 自律携帯式検体監視装置又は薬剤送給装置
US8465468B1 (en) 2000-06-29 2013-06-18 Becton, Dickinson And Company Intradermal delivery of substances
US8480971B2 (en) 2004-11-30 2013-07-09 Hitachi Chemical Co., Ltd. Analytical pretreatment device
US8920696B2 (en) 2009-08-27 2014-12-30 Korea University Research And Business Foundation Nano pattern writer
CN104874098A (zh) * 2015-04-08 2015-09-02 上海交通大学 一种空心金属微针及其批量制备方法
CN109336049A (zh) * 2018-10-11 2019-02-15 宁波大学 一种微结构操作方法及操作装置

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JP2007229825A (ja) * 2006-02-27 2007-09-13 Hirosaki Univ 微小電気機械構造、その製造方法および微小電気機械素子
JP5629503B2 (ja) * 2010-06-23 2014-11-19 見城　晃 注射針の製造方法および注射針

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US5591139A (en) * 1994-06-06 1997-01-07 The Regents Of The University Of California IC-processed microneedles

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Cited By (34)

* Cited by examiner, † Cited by third party
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US7442303B2 (en) 1999-12-08 2008-10-28 Baxter International Inc. Microporous filter membrane, method of making microporous filter membrane and separator employing microporous filter membranes
US7784619B2 (en) 1999-12-08 2010-08-31 Baxter International Inc. Method of making microporous filter membrane
US6982058B2 (en) 1999-12-08 2006-01-03 Baxter International, Inc. Method for fabricating three dimensional structures
US6629949B1 (en) 2000-05-08 2003-10-07 Sterling Medivations, Inc. Micro infusion drug delivery device
US6659982B2 (en) 2000-05-08 2003-12-09 Sterling Medivations, Inc. Micro infusion drug delivery device
US7473244B2 (en) 2000-06-02 2009-01-06 The University Of Utah Research Foundation Active needle devices with integrated functionality
US8986280B2 (en) 2000-06-29 2015-03-24 Becton, Dickinson And Company Intradermal delivery of substances
US9242052B2 (en) 2000-06-29 2016-01-26 Becton, Dickinson And Company Method for altering drug pharmacokinetics based on medical delivery platform
US8708994B2 (en) 2000-06-29 2014-04-29 Becton, Dickinson And Company Method for altering drug pharmacokinetics based on medical delivery platform
US9005182B2 (en) 2000-06-29 2015-04-14 Becton, Dickinson And Company Intradermal delivery of substances
US8998877B2 (en) 2000-06-29 2015-04-07 Becton, Dickinson And Company Intradermal delivery of substances
US9339613B2 (en) 2000-06-29 2016-05-17 Becton, Dickinson And Company Intradermal delivery of substances
US8465468B1 (en) 2000-06-29 2013-06-18 Becton, Dickinson And Company Intradermal delivery of substances
US7066922B2 (en) 2001-10-26 2006-06-27 Massachusetts Institute Of Technology Transdermal transport device with suction
JP2010279704A (ja) * 2002-02-08 2010-12-16 Intuity Medical Inc 自律携帯式検体監視装置又は薬剤送給装置
US8889084B2 (en) * 2002-02-25 2014-11-18 Hitachi Chemical Company, Ltd. Micro fluid system support and manufacturing method thereof
US20090274581A1 (en) * 2002-02-25 2009-11-05 Hitachi Chemical Co., Ltd. Micro fluid system support and manufacturing method thereof
WO2003070623A1 (fr) * 2002-02-25 2003-08-28 Hitachi Chemical Co., Ltd. Unite de support de systeme microfluidique et son procede de fabrication
US8865090B2 (en) 2002-02-25 2014-10-21 Hitachi Chemical Co., Ltd. Micro fluid system support and manufacturing method thereof
WO2005087305A1 (fr) * 2004-03-12 2005-09-22 Agency For Science, Technology And Research Procedes et moules s'utilisant dans la fabrication de micro-aiguilles a orifice lateral
US8671544B2 (en) 2004-03-12 2014-03-18 Agency For Science, Technology And Research Methods and moulds for use in fabricating side-ported microneedles
US8480971B2 (en) 2004-11-30 2013-07-09 Hitachi Chemical Co., Ltd. Analytical pretreatment device
US8480970B2 (en) 2004-11-30 2013-07-09 Hitachi Chemical Co., Ltd. Analytical pretreatment device
WO2007003398A3 (fr) * 2005-07-01 2007-03-15 Max Planck Gesellschaft Systeme d'electrodes, son utilisation et procede pour le produire
WO2007003399A3 (fr) * 2005-07-01 2007-04-12 Max Planck Gesellschaft Dispositif d'electrodes, utilisation et procedes de realisation associes
WO2007003399A2 (fr) * 2005-07-01 2007-01-11 MAX-PLANCK-Gesellschaft zur Förderung der Wissenschaften e.V. Dispositif d'electrodes, utilisation et procedes de realisation associes
WO2007003398A2 (fr) * 2005-07-01 2007-01-11 MAX-PLANCK-Gesellschaft zur Förderung der Wissenschaften e.V. Systeme d'electrodes, son utilisation et procede pour le produire
WO2008027011A1 (fr) * 2006-08-28 2008-03-06 Agency For Science, Technology And Research Micro-aiguilles et procédés pour fabriquer des micro-aiguilles
WO2010122222A2 (fr) 2009-04-20 2010-10-28 Valtion Teknillinen Tutkimuskeskus Microaiguille
US9462969B2 (en) 2009-04-20 2016-10-11 Teknologian Tutkimuskeskus Vtt Oy Microneedle
US8920696B2 (en) 2009-08-27 2014-12-30 Korea University Research And Business Foundation Nano pattern writer
CN104874098A (zh) * 2015-04-08 2015-09-02 上海交通大学 一种空心金属微针及其批量制备方法
CN109336049A (zh) * 2018-10-11 2019-02-15 宁波大学 一种微结构操作方法及操作装置
CN109336049B (zh) * 2018-10-11 2023-10-24 宁波大学 一种微结构操作方法及操作装置

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JP2002526273A (ja) 2002-08-20
AU6151599A (en) 2000-04-10

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