Abstract:
A microneedle array device and its fabrication method are provided. The microneedle array device comprises a supporting pad and a plurality of microneedles. Each microneedle has a top portion with a via thereon, thereby the microfluid may flow in or out. The intersection between the top portion and the inner tube of a microneedle forms a convex needle structure, and is almost perpendicular to the upper surface. For each microneedle, a hollow closed tube is formed between the top portion and the supporting pad. The fabrication method uses substrates with high transmittance and a plurality of convex area thereon as upper and lower caps, and applies a photolithography process to fabricate a microneedle array mold. It then sputters or electroplates metal material on the mold. The microneedle array is formed after having taken off the mold.

Description:
CROSS-REFERENCES TO RELATED APPLICATIONS 
   This is a division of U.S. patent application Ser. No. 10/994,105, filed Nov. 19, 2004 now abandoned. 

   FIELD OF THE INVENTION 
   The present invention generally relates to a microneedle array structure, and more specifically to a microneedle array device, and a method of forming the same. 
   BACKGROUND OF THE INVENTION 
   The current microneedle array may be made of silicon (Si substrate), metal or polymer. The manufacturing methods of Si substrate microneedle array can further be categorized as using wet etching or dry etching. The manufacturing process of metal microneedle array can further be categorized as using electroplating or deposition. The manufacturing process of polymer microneedle array can be further categorized as using molding or photolithography. 
   Among the methods of microneedle array, the most widely adopted is using Si substrate to fabricate the hollow needles or mold. However, the fabrication process of using Si substrate is more complicated, as disclosed in WO0217985, and requires many steps of wet/dry etching and thin film deposition. As it takes a longer time to fabricate, the yield rate is low and the cost is high. U.S. Pat. No. 6,334,856 disclosed a method of fabricating a microneedle array having flat needle tips and tapered tubes, as shown in  FIG. 1 . This type of design limits the width of the flow channel and the flexibility of the needle. To fabricate the needle higher than 100 um, the needle density must be restricted in compromise for an appropriate size of aperture and strength of needle structure. The restriction of low needle density further causes the problem of insufficient sampling. In addition, the Si substrate microneedles are brittle and break easily. 
   The tip of the hollow microneedle in most prior arts is designed as flat, except the design disclosed in WO0217985 (see  FIG. 2 ), which is a slant. This is because a slant tip is easier to penetrate the human skin for micro-sampling than the flat tip, as the human skin is flexible. 
   Kim et al. disclosed a method for fabricating metal microneedle array in Journal of Micromechanics and Micro engineering in 2004. They spread two layers of SU-8 on a glass substrate and used a back exposure to seperately bake the two layers of SU-8. They also used reactive ion etching to obtain an SU-8 pillar array structure, and then used sputtering, electroplating, planarization and polishing to fabricate a tapered metal hollow microneedle array, as shown in  FIG. 3 . However, the method requires multiple layers of SU-8 to achieve the layered effect and the high aspect ratio of the pillar is prone to slant or twist. The fabrication process is difficult to maintain the quality. 
   U.S. Pat. No. 6,663,820 disclosed another method of using lithography and photolithography to fabricate polymer microneedle array, as shown in  FIG. 4 . This method has the advantages of rapid fabrication of micromold and microneedle, and low fabrication cost of the material and process. However, the flat-tip microneedles are still limited in the application. In addition, the polymer microneedles of this method do not have microchannels or reservoirs, and require additional fabrication process to attach the microchannels and reservoirs, if necessary. It is, therefore, difficult to have this method applied for mass production. 
   Numerous methods of fabricating microneedle array have been proposed. Regardless of the material used, the object of the microneedle array includes the capability to penetrate the human skin for micro-injection or micro-sampling painlessly, easy to fabricate, low in fabrication cost and safe to use. 
   SUMMARY OF THE INVENTION 
   The present invention has been made to overcome the aforementioned drawback of conventional bonding methods of fabricating microneedle array. The primary object of the present invention is to provide a microneedle array device, including a supporting pad and a plurality of microneedles. The supporting pad has an upper surface. Each microneedle has a slant or concave top portion with a via thereon, thereby the microfluid may flow in or out. The intersection between the top portion and the inner tube of a microneedle forms a convex needle structure. Each microneedle stands on the upper surface of the supporting pad and is almost perpendicular to the upper surface. A hollow closed tube is formed between the top portion and the supporting pad. 
   The supporting pad further includes a bottom portion and at least a layer of reservoir. The reservoir is located above the bottom portion and below the microneedle. The reservoir can be further divided, if necessary, into a plurality of reservoir units, with reservoir units separated from one another to prevent the microfluid flowing from one unit to another. The monolithic metal structure of the present invention includes convex needle structure formed by the intersection of the slant or concave top portion of each microneedle and the inner tube of a microneedle. The main feature of the present invention includes the safety of use and the reduction of pain when the microneedles are used. Furthermore, the rigidity and the slant uniformity of the microneedle with slant top portion are both improved so that it is suitable for molding and mass production. 
   Another object of the present invention is to provide a method of fabricating a microneedle array device, including the steps of: (1) providing a substrate, and forming a plurality of concave areas on a surface of the substrate; (2) spreading a layer of photo-sensitive material on the substrate and covering a layer of light transmission material on top of the photo-sensitive material; (3) using a patterned mask for exposing and lithographic processing of the photo-sensitive material on the light transmission material to obtain a polymer hollow microneedle array mold based on the light transmission material; and (4) using the polymer hollow microneedle array mold to form a microneedle array device. 
   According to the present invention, there are several techniques to be used in step (1) of forming a plurality of concave areas, including etching, X-ray photo-etching, ultra-violet etching, ion beam etching and excimer laser micromachining. Step (4) of the method further includes the following sub-steps: ( 4   a ) coating a layer of metal on the outer surface of the polymer hollow microneedle array mold and the light transmission material to form a microneedle array; and ( 4   b ) removing the polymer hollow microneedle array mold from the microneedle array. In step (4), the techniques for coating metal to the surface of the polymer hollow microneedle array mold include electroplating, electroless plating, evaporation, and sputtering. The metal used can be Cu, Cr, Ni, Fe, Au, Pt, Pd, stainless steel and their alloys. The present invention uses the coating of photo-sensitive polymer on the concave areas of the substrate and covering with a light transmission material, which is exposed to define an outline of the microneedle and using lithography to obtain a polymer hollow microneedle array mold using the high light transmission material as the base for further fabrication of a metal microneedle array. The advantages of the fabrication method of the present invention are simple process and low in cost. 
   The foregoing and other objects, features, aspects and advantages of the present invention will become better understood from a careful reading of a detailed description provided herein below with appropriate reference to the accompanying drawings. 

   
     BRIEF DESCRIPTION OF THE DRAWINGS 
       FIG. 1  shows a conventional flat-top microneedle array made of Si substrate. 
       FIG. 2  shows a conventional slant top microneedle array made of Si substrate. 
       FIG. 3  shows a conventional flat-top microneedle array made of metal. 
       FIG. 4  shows a conventional flat-top microneedle array made of polymer. 
       FIG. 5A  shows a cross-sectional view of the first embodiment of a microneedle array device of the present invention. 
       FIG. 5B  shows a schematic view of the concave top of a microneedle of the present invention. 
       FIG. 5C  shows a schematic view of the first embodiment of a microneedle array device of the present invention. 
       FIGS. 6A and 6B  show respective top views of the microneedles having different inner tube shapes. 
       FIGS. 7A-7J  show the fabrication method of the first embodiment of a microneedle array device of the present invention. 
       FIGS. 8A and 8B  show respective top cross-sectional views of the different shapes of concave areas of Si substrate of the present invention. 
       FIG. 9A  shows a cross-sectional view of the second embodiment of a microneedle array device of the present invention. 
       FIG. 9B  shows a schematic view of the second embodiment of a microneedle array device of the present invention. 
       FIG. 9C  shows a top view of  FIG. 9B . 
       FIG. 10A  shows a cross-sectional view of the third embodiment of a microneedle array device of the present invention. 
       FIG. 10B  shows a schematic view of the third embodiment of a microneedle array device of the present invention. 
       FIG. 11C  shows a top view of  FIG. 10B . 
       FIGS. 11A-11K  show the fabrication method of the second embodiment of the present invention. 
       FIGS. 12A-12L  show the fabrication method of the third embodiment of the present invention. 
   

   DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS 
     FIG. 5A  shows a cross-sectional view of a microneedle array device  50  of the present invention. As shown in  FIG. 5A , microneedle array device  50  includes a supporting pad  51  and a plurality of microneedles  52 . Supporting pad  51  includes an upper surface  511 . For the purpose of safety and effective skin penetration, the top portion of each microneedle  52  includes a convex needle structure  521 . The top portion of microneedle  52  can be a slant  523  or a concave surface  523   a,  as shown in  FIG. 5B . The top portion of microneedle  52  intersects with tube wall  524  to form convex needle structure  521 . In addition, top portion  523  or  523   a  includes a via  522 , which allows the follow of a microfluid, for example, a medicine to flow out or a blood to flow in. According to the present invention, the microneedle array is a monolithic metal structure with each microneedle  52  standing on and perpendicular to the upper surface  511  of supporting pad  51 , and a hollow closed tube being formed between top portion  523  ( 523   a ) and supporting pad  51 . 
     FIG. 5C  shows a schematic view of the structure of microneedle array device  50  of the present invention. The top portion  523  of each microneedle  52  is a slant, and the cross-section of tube wall  524  forms a closed oval, circular, or triangular shape, as shown in  FIG. 6A  and  FIG. 6B , respectively. The metal for fabricating microneedle array can be Cu, Cr, Ni, Fe, Au, Pt, Pd, stainless steel, or their alloys. The range of the aperture of each microneedle is 10-70 um, the outer circumference is 80-250 um, and the height is 100-600 um. 
     FIGS. 7A-7J  show the fabrication method of the first embodiment of the present invention. First, a substrate is provided, including a plurality of concave areas on the surface. According to the present invention, there are several techniques for forming a plurality of concave areas, including etching, X-ray photo-etching, ultra-violet etching, ion beam etching and excimer laser micromaching. The present embodiment uses an anisotropic wet etching for explanation. 
   As shown in  FIG. 7A , a single crystal silicon with a grainorientation [1,0,0] is used as a substrate  700 , and a protective layer  702  is deposited on the surface. Protective layer  702  can be made of Si 3 N 4 . The wet etching areas  705  are defined, as shown in  FIG. 7B , followed by wet etching. The solution commonly used in silicon anisotropic wet etching includes potassium hydroxide (KOH) and Tetra-methyl-ammonium hydroxide (TMAH). After etching the silicon, a plurality of concave areas  710  are formed. Each concave area  710  has two slants  711 , as shown in  FIG. 7C . Slant  711  defines a slant top  523  of each microneedle. The shape of the plurality of concave areas can vary in accordance with the fabrication process, for example, a V-shape  710   a  or U-shape  710   b,  as shown in  FIG. 8A  and  FIG. 8B , respectively. In other words, a U-shaped concave area  710  defines a concave curvy top portion  523   a  of a microneedle. 
   Before the coating of photo-sensitive material  720 , a sacrificial layer or mold release layer  715  is coated on top of substrate  700  for the subsequent mold release, as shown in  FIG. 7D . The commonly used material for the sacrificial or mold release layer includes SU-8, Al, Au, silicon rubber and Teflon. 
   The next step is to spread a photo-sensitive material  720  on top of sacrificial layer  715 , and a light transmission material  730  on top of photo-sensitive material layer  720 , as shown in  FIG. 7E . Photo-sensitive material  720  used in the present invention is SU-8, a negative photo-resist developed by Microlithography Chemical Corporation (USA), or JSR 430N, a positive or negative photo-resist developed by Japanese Synthetic Rubber (Japan). Light transmission material can be either glass or PMMA. 
   The next step is exposure and lithography to obtain a polymer hollow microneedle array mold  760  using light transmission material  730  as a base. As shown in  FIG. 7F , a patterned mask  750  defining the shape of tube wall  524  and via  522  of microneedle  52  is used before the exposure. The shapes can be either oval, circular  524   a,  or triangular  524   b,  as shown in  FIG. 5C ,  FIG. 6A , and  FIG. 6B , respectively. If SU-8 negative photo-resist is used as photo-sensitive material  720 , the bond forms at a later stage of the exposure to light and stays during the development. The un-exposed part is dissolved. After the mold release, a polymer hollow microneedle array mold  760  having a plurality of polymer microneedles is obtained for subsequent metal plating, as shown in  FIG. 7G . Because the present invention directly applies photo-sensitive material  720  on the slant of concave areas  710  on substrate or the concave curvy top, the top portion  761  of polymer microneedle  765  is also slant or concave curvy surface. Microneedle  765  has a via  762  reaching light transmission material  730 . 
   Finally, polymer hollow microneedle array mold  760  is used to form a microneedle array device  50 , as shown in  FIG. 7J . The forming of a microneedle array device step further includes the following two sub-steps: (a) coating a metal layer  780  on the outer surfaces of polymer hollow microneedle array mold  760  and light transmission material layer  730  to form a microneedle array device  50 , and (b) removing polymer hollow microneedle mold  760  from microneedle array device  50 . 
   Similarly, before the coating of metal layer  780  in sub-step (a), a sacrifical layer or mold release layer  770  is deposited on the outer surfaces of polymer hollow microneedle array mold  760  and light transmission material layer  730 , and a starting layer  771  ( FIG. 7H ) is electroplated to electro-cast. The material for sacrificial layer  770  includes either Cu, Al, or Au. The material for starting layer  771  is any metal. 
   In sub-step (a), the electroplating, electroless plating, evaporation and sputtering is used to plate metal layer  780  on the upper surface ( FIG. 7I ) of strating layer  771 . The metal for plating metal layer  780  may include Cu, Cr, Ni, Fe, Au, Pt, Pd, stainless steel, and their alloys. 
   In sub-step (b), the technique for removing polymer hollow microneedle array mold  760  from microneedle array device  50  is to remove sacrificial layer  770  deposited on the outer surfaces of polymer hollow microneedle array mold  760  and light transmission material layer  730 . The technique includes oxygen plasma removal, thermal removal, solvent removal, aqueous removal or photo-degradation removal. 
     FIG. 9A  and  FIG. 10A  show the second and the third embodiments of a microneedle array device of the present invention, respectively. 
     FIG. 9A  is similar to the structure shown in  FIG. 5A . The difference lies in microneedle array device  90  in  FIG. 9A  that has a reservoir layer  91  below a plurality of microneedles  52  and above bottom portion  92 . Reservoir layer  91  is for storing or mixing the medicine or collecting blood sample. As shown in  FIG. 9B  and  FIG. 9C , reservoir  91  may be further divided into a plurality of reservoir unit  93 . Reservoir units  93  are separate from one another to block the flow of microfluid. They may be used for blood analysis. 
   Similarly, microneedle array device  100  in  FIG. 10A  has two reservoir layers  101  below a plurality of microneedles  52  and above bottom portion  102 . Reservoir layer  101  is for storing or mixing the medicine or collecting blood sample. As shown in  FIG. 10B  and  FIG. 10C , reservoir layers  101  may be further divided into a plurality of reservoir unit  103 . Reservoir units  103  are separate from one another to block the flow of microfluid. 
     FIGS. 11A-11K  show the fabrication method of the second embodiment of the present invention. 
   The fabrication method of the second embodiment is similar to that of first embodiment. The only difference is in the exposure and development step. Because the second embodiment has a reservoir layer  91  in the structure, the second embodiment requires an additional exposure than the first embodiment. During the second exposure, a corresponding patterned mask  750   a  is used to define reservoir layer  91  and the shape of reservoir units  93  within. By adjusting the exposure dosage to control the depth “a” of the reservoir layer, the result of this step is to obtain a polymer hollow microneedle array mold  160 . The remaining steps of the fabrication are identical to those in  FIG. 7A-7J . 
     FIGS. 12A-12L  show the fabrication method of the third embodiment of the present invention. 
   The fabrication method of the third embodiment is also similar to that of first embodiment. The only difference is still in the exposure and development step. Similarly, because the third embodiment has two more reservoir layers  101  in the structure, the third embodiment requires two additional exposures than the first embodiment. During the second and third exposures, a corresponding patterned mask  750   a,    750   b  is used to define, respectively, each reservoir layer  101  and the shape of reservoir units  103  within. By adjusting the exposure dosage to control the depths “a” and “b” of the reservoir layers, the result of this step is to obtain a polymer hollow microneedle array mold  260 . Therefore, according to the present invention, the first exposure is to form the shape and the structure of the microneedles, and the second and subsequent exposures are for forming the shape and the structure of the reservoir layer. The remaining steps of the fabrication are identical to those in  FIG. 7A-7J . 
   In summary, compared to the other molding techniques, the present invention directly applies photo-sensitive polymer on the concave areas of the substrate to form a polymer hollow microneedle array mold having slants and concave curvy surface. Then, the polymer hollow microneedle array mold is used with the evaporation and electroplating techniques to fabricate metal microneedle array device. This method greatly reduces the complexity of the fabrication and the cost of the material. The metal microneedle array electroplated on the polymer hollow microneedle array mold has a good rigidity and slant uniformity, and is suitable for mass production. The present invention may be widely used in blood sampling, micro-sampling and medication injection systems. 
   Although the present invention has been described with reference to the preferred embodiments, it will be understood that the invention is not limited to the details described thereof. Various substitutions and modifications have been suggested in the foregoing description, and others will occur to those of ordinary skill in the art. Therefore, all such substitutions and modifications are intended to be embraced within the scope of the invention as defined in the appended claims.