WO2009072830A2

WO2009072830A2 - Hollow microneedle array

Info

Publication number: WO2009072830A2
Application number: PCT/KR2008/007195
Authority: WO
Inventors: Woo Sung Nam; Sin Kil Cho
Original assignee: Incyto Co., Ltd.
Priority date: 2007-12-07
Filing date: 2008-12-05
Publication date: 2009-06-11
Also published as: WO2009072830A3; KR20090059971A

Abstract

A hollow microneedle array includes a needle part having a plurality of hollow microneedle and a substrate part supporting the needle part. The needle includes an upper portion inserted into ski and a base portion communicated with the upper portion and supporting the upper portion. An upper end of the upper portion has such an outer diameter that reduces pain upon penetration into the skin. A diameter of the upper portion smoothly increases as it goes to the other end thereof so as to reduce pain upon penetration into the skin. An aspect ratio of the diameter of the upper end of the upper portion to a length of the needle is high to enable deep penetration into the skin. A diameter of the base portion generally exponentially increases as it goes to a lower end of the base portion so as to increase total strength of the needle in both longitudinal and lateral directions. Further, the needle is made of biocompatible metal having good mechanical properties.

Description

Description HOLLOW MICRONEEDLE ARRAY

Technical Field

[1] The present invention relates to a hollow microneedle array.

Background Art

[2] In general, biopsy is removal and examination of a sample from the living body of a patient to diagnose the disease of the patient. The biopsy is very important procedure for diagnosis and treatment of the disease of the patient.

[3] However, large quantity of chemicals is required to analysis the tissue sample, which is obtained from the patient by large conventional biopsy tool. Furthermore, patients are faced with discomfort and risk associated with the tissue biopsy.

[4] To solve above mentioned problems, microbiopsy/precision cutting devices are proposed using micromachining and precision capabilities, which is disclosed in US Pat. No. 5,928,161 to Krulevitch et al. with title "Microbiopsy/Precision cutting devices".

[5] However, in case of the microbiopsy/precision cutting devices, the biopsy procedure is very complicated and requires skill and experience of an operator. Further, the microbiopsy/precision cutting devices are only used to take tissue samples and can not be used to treat lesion area of the tissue by injecting medication into the tissue.

[6] Generally, needles are used in clinic to sample analytical materials such as blood for diagnosis of various diseases, or to inject drug into the body. Conventional needles are mostly macroneedle having millimeter size diameters, which is quite large compared to a blood cell. A shaft of microneedle having such diameter may cause serious injury to the body tissue during its penetration and also cause pain to the patient. With the development of various diagnosing techniques and diagnosing chips, the demand for extracting analytical materials from the body has increased. However, a needle which may cause pain during its use and leave an external mark on the skin has hindered the use of such various diagnosing techniques and devices.

[7] Such hindrance may be overcome by employing microneedle having micrometer scale diameter, which can find various uses. For example, the microneedle may be used as a precise injection/extraction needle in cell biology, a drug delivery system, and an injection/extraction head in micro chemical process. Further, since small size needle helps reduce inconvenience and pain from the patient, it is more beneficial to use small size needle. This is proved by a study on silicon electric microprobe. According to the study, it is proved that the silicon microprobe having several tens micrometer scale diameter can penetrate the body tissues without serious injury to the body.

[8] Conventionally, a glass microneedle having several μm inner diameter has been used.

In general, such microneedle is formed by heating an end portion of glass pipette and drawing the heated portion until the diameter of the end portion becomes to several μm. Since most animal cell, such as human cell, have 10 to 20 μm sizes, such microneedle can be employed to inject and extract blood or gas to and from the single cell. However, it is very difficult to control the size of a needle shaft during manufacturing the needle with the above mentioned general method. Furthermore, the manufactured needle is not strong but fragile so that fragments thereof may be left in the body. Since the glass pipette needle is not a conductor, it is difficult for the needle to be integrated with electronic devices.

[9] The microneedle is characterized by a painless skin penetration and no external injury unlike conventional needles. It is required that a diameter of an upper portion of the needle is minimized to achieve the painless skin penetration. The microneedle is required to have sufficient physical strength to penetrate a stratum corneum of 10-20 μm, which is the most strong obstacle of the skin. Moreover, right amount of length of the needle long enough to reach a capillary tube should be considered to increase efficiencies of the detection of materials to be analyzed and drug delivery.

[10] To solve drawbacks of the above mentioned glass pipette microneedle, various microneedles are proposed.

[11] For example, by using double etching technique, a hollow silicon microneedle with an inclination angle was developed by Nanopass Ltd. (WO0217985; WO2005049107; "Silicon Micromachined Hollow Microneedles for Transdermal Liquid Transport", Journal of microelectrochemical systems, VoI 12, No. 6, December 2003). Hollow silicon microneedles of side-open type and cross type were suggested by Griss and Sterne in Stanford University ("Side-Opened Out-of- Plane Microneedles for Mi- crofluidic Transdermal Liquid Transfer", Journal of microelectro-chemical systems, Vol. 12, No. 3, June 2003; US patent application No.US2004267205). Such microneedles caused pain upon penetration of the skin owing to their large diameter, and were not efficient in extracting materials to be analyzed from the body and drug delivery owing to their length, below 500/M.

[12] A method for preparing hollow microneedles was disclosed by Prausnitz, at the

University of Georgia, which includes fabricating a mold by using a laser, deposition, and electroplating ("Hollow Metal Microneedles for Insulin Delivery to Diabetic Rats", IEEE Transactions on biomedical engineering, Vol. 52, No. 5, May 2005). However, the hollow metal microneedles prepared by the above method, also had the problem of other conventional methods with respect to diameter and length.

[13] Another method for preparing a novel hollow glass microneedle which has a length of about 900/M and an inclination angle by extending a glass micropipette, was further suggested by Prausntiz, at the University of Georgia ("Microinfusion Using Hollow Microneedles", Pharmaceutical Research, Vol. 23, No. 1, January 2006, and "Mechanism of fluid infusion during microneedle insertion and retraction", Journal of Controlled Release, 2006, 357361). However, this method also failed to prepare hollow microneedles having a diameter (outer diameter) of 50/M or less. Further, such hollow microneedle made of glass, i.e. a non-conducting substance, had a limitation in its commercialization due to problems in combining it with a variety of electronic devices.

[14] Although other various types of hollow microneedles have been suggested by 3M, P

&G, BD technologies, Alza Corporation and the like, none of these could provide a means to effectively solve the problems connected with diameter, length and hardness.

[15] Accordingly, there still has been a great demand for a hollow microneedle which has a diameter fine enough to achieve painless penetration of the skin, a length which is long enough to penetrate the deeper area of the skin, and suitable strength.

[16] Meanwhile, as one of methods for manufacturing micro structure, Micro-

Electro-Mechanical System (MEMS) based on deposition and UV mask technology has been used. The MEMS is used to manufacture elements, which is almost same method employed in manufacturing semiconductor devices such as microprocessor and memory device. Accordingly, MEMS manufacturing technology is used to manufacture one or more mechanical or electronic devices by removing one or more of deposition layers or newly depositing a layer, and is a process including photo etching and/or micro etching.

[17] Since, however, deposition thickness functions as to determine the length of the microneedle to be finally realized, such process has limitation to realize a needle having long length to a diameter of upper portion of the needle. Further, the needle upon penetration has dull edge rather than sharp streamline, resulting in low skin penetration capability and increasing probability of breaking the needle. In the field of those microneedles, highly adjusting aspect ratio of the diameter of the upper portion of the needle to the length and the skin penetration capability are very important factors. Disclosure of Invention Technical Problem

[18] It is, therefore, the object of the present invention to provide a hollow microneedle array employing a hollow microneedle having a diameter small enough to reduce or mitigate pain and external injury upon penetration; a length sufficient enough to penetrate the skin deeply, and a strength strong enough to prevent skin damage owing to needle debris generated by broken needle in the skin. Technical Solution

[19] In accordance with one aspect of the present invention, there is provided a hollow microneedle array, includingg: a needle part having a plurality of hollow microneedle; and a substrate part supporting the needle part; wherein the needle includes an upper portion inserted into skin; and a base portion communicated with the upper portion and supporting the upper portion; an upper end of the upper portion has such an outer diameter that reduces pain upon penetration into the skin; a diameter of the upper portion smoothly increases as it goes to the other end thereof so as to reduce pain upon penetration into the skin; an aspect ratio of the diameter of the upper end of the upper portion to a length of the needle is high to enable deep penetration into the skin; a diameter of the base portion generally exponentially increases as it goes to a lower end of the base portion so as to increase total strength of the needle in both longitudinal and lateral directions; and the needle is made of biocompatible metal having good mechanical properties.

[20] In accordance with another aspect of the present invention, there is provided a method of injecting drug using the above hollow microneedle array.

[21] In accordance with still another aspect of the present invention, there is provided a method of extracting blood cell from a human body by using the above hollow microneedle array.

[22] In accordance with still another aspect of the present invention, there is provided an apparatus for detecting material or transferring drug including the above hollow microneedle array.

Advantageous Effects

[23] The microneedle in accordance with the present invention has small diameter, a length long enough to penetrate the stratum corneum of the skin, and a sharp streamline so as to penetrate the skin more easily than the microneedle having the shape of dull edge. Further, since diameters of base portion of the needle are generally exponentially increased as it goes to a basal end of the base portion, longitudinal strength and lateral strength of the whole needle are increased so that, as compared to conventional needles having same diameter and length, the needle has high penetration capability and does not easily bend and break because it can resist force of the skin acting on the needle in a lateral direction. Accordingly, possibility of remaining the residue of the broken needle in the skin is minimized. As a result, the hollow microneedle in accordance with the present invent may be used in a various way, in particular, injection of drugs in the body and sampling of the material to be analyzed such as blood. Brief Description of Drawings

[24] The objects and features of the present invention will become apparent from the following description of embodiments given in conjunction with the accompanying drawings, in which:

[25] Fig. 1 is a perspective view showing a frame having 2x2 pattern formed thereon in accordance with an embodiment of the present invention;

[26] Figs. 2(a) to 2(f) are schematic views showing manufacturing process of solid microneedle in accordance with the embodiment of the present invention;

[27] Figs. 3(a) to 3(c) are views showing structure of the solid microneedle in accordance with the embodiment of the present invention;

[28] Figs. 4(a) to 4(f) are schematic views showing metal deposition and protection of an upper portion of the solid microneedle in accordance with the embodiment of the present invention;

[29] Figs. 5(a) to 5(b) are schematic views showing hollow microneedle manufacturing method by metal plating of metal deposited solid microneedle and removing the solid microneedle in accordance with the embodiment of the present invention;

[30] Figs. 6(a) to 6(c) are views showing structure of the hollow microneedle in accordance with the embodiment of the present invention;

[31] Figs. 7(a) to 7(b) are views showing an exemplary microfluidic system employing the hollow microneedle in accordance with the embodiment of the present invention;

[32] Figs. 8(a) to 8(b) are views showing an exemplary microactuator employing the hollow microneedle in accordance with the embodiment of the present invention; and

[33] Fig. 9 is a schematic view showing a state of taking blood using the hollow microneedle in accordance with the embodiment of the present invention.

[34] Mode for the Invention

[35] As used herein, the term "upper end" of a microneedle means one end of the microneedle, at which a diameter is the minimum.

[36] As used herein, the term "effective length" means a vertical length of the needle inserted in the skin.

[37] As used herein, the term "base portion" means a portion which is not inserted in the skin.

[38] As used herein, the term "solid type microneedle" means a microneedle without hollow holes or microspike.

[39] An outer diameter of the upper end of the hollow microneedle in accordance with an embodiment of the present invention is set to reduce pain upon penetration to the skin. In general, the amount of the pain depends on area of the skin and the depth of the needle penetrated the skin. However, a diameter below 50/M is a diameter which can reduce pain even in sensitive areas. A microneedle having outer diameter of generally Oμm to 100/M can reduce pain. Accordingly, the outer diameter of the microneedle in accordance with the present invention is determined to have above mentioned range and the diameter smoothly increases within the effective length. Further, the microneedle has the effective length long enough to deeply penetrate into the skin. Moreover, a diameter of base portion of the needle exponentially increases as it goes to its lower end, thereby increasing strength of the needle.

[40] It is preferable that an aspect ratio of the upper end diameter to the length is set to about 1:5 to 1:70. Within this range, vertical strength of the hollow microneedle in accordance with the present invention can be increased to a level above the conventional requirement compared to a needle having rectilinear edge and the microneedle requires minimized force to penetrate the skin, thereby enabling easy skin penetration without pain and injury.

[41] In accordance one embodiment of the present invention, the microneedle having the above aspect ratio of the upper end diameter to the length is formed to have an upper end outer diameter (OD) of 10/M to 45/zπ) preferably 30/M to 40μπ) an inner diameter (ID) of 5/M to 25/zπ) and un upper portion effective length 500/M to 2000/M. In this case, a lower end of the base portion may have an outer diameter of 180/M to 200/M and an inner diameter of 130/M to 160/M.

[42] The microneedle in accordance with the present invention may be formed by smoothly connecting the outer periphery of the base portion 1, 2, and 3 peripheries of circles at respective heights. [43] The microneedle in accordance with an embodiment of the present invention may be formed by smoothly connecting a base end outer circle (ODO) of about 500/M; a first circle (ODl) of about 300/M at 500/M height (hi) from the base end; a second circle (OD2) of about 100/M at 1000/M height (h2) from the first circle; and a third circle (OD3) of about 30/M at 1500/M height (h3), i.e., effective length, from the second circle, thereby having total length of 3000/M (h=hl+h2+h3).

[44] The microneedle in accordance with another embodiment of the present invention may be formed by smoothly connecting a base end outer circle (ODO) of about 350/M; a first circle (ODl) of about 210/M at 300/M height (hi) from the base end; a second circle (OD2) of about 70/M at 700/M height (h2) from the first circle; and a third circle (OD3) of about 30/M at 1000/M height (h3), i.e., effective length, from the second circle, thereby having total length of 2000/M (h=hl+h2+h3).

[45] The microneedle in accordance with still another embodiment of the present invention may be formed by smoothly connecting a base end outer circle (ODO) of about 200/M; a first circle (ODl) of about 120/M at 100/M height (hi) from the base end; a second circle (OD2) of about 50/M at 300/M height (h2) from the first circle; and a third circle (OD3) of about 30/M at 600/M height (h3), i.e., effective length, from the second circle, thereby having total length of 1000/M (h=hl+h2+h3).

[46] The hollow microneedle in accordance with the present invention is made of biocompatible polymer or metal having characteristics of high biocompatibility without toxic, carcinogen, and immune response; high mechanical properties such as tensile strength, modulus of elasticity, and wear resistance; and strong anti-corrosion in corrosive environment of the human body. Though, such materials are not limited thereto, the materials preferably includes stainless steel, Ni, Cr, Al, Au, Ag. Cu, Ti, Co, or alloy made therefrom. In accordance with an embodiment of the present invention, the hollow microneedle includes a Ti-Cu-Ti inner layer of 0.1/M to 1/M and a Ni outer layer of 5/M to 80/ffl) but not limited thereto.

[47] Hereinafter, preferable manufacturing method to realize the above hollow microneedle will be described.

[48] In accordance with an embodiment of the present invention, a manufacturing method of the hollow microneedles includes the steps of: (a) coating the surface of a substrate with a viscous material; (b) solidifying the coated viscous material while drawing the viscous material after contacting with a frame having a pattern formed thereon; (c) cutting a certain part of the drawn viscous material coating to form a solid type microneedle; (d) depositing biocompatible metal on the surface of the solid type mi- croneedle; (e) protecting an upper end portion of the solid type microneedle obtained from the step (d), and then metal-plating the surface of the resulting microneedle with biocompatible metal; and (f) removing the solid type microneedle.

[49] In accordance with another embodiment of the present invention, the manufacturing method of the hollow microneedles includes the steps of: (a) coating the surface of a substrate with a viscous material; (b) solidifying the coated viscous material while drawing the viscous material after contacting with a frame having a pattern formed thereon; (c) cutting a certain part of the drawn viscous material coating to form a solid type microneedle; (d) depositing biocompatible metal on the surface of the solid type microneedle; (e) metal-plating the surface of the microneedle obtained from the step (d) with biocompatible metal; (f) cutting an upper portion of the solid type microneedle obtained from the step (e); and (g) removing the solid type microneedle.

[50] The object of the present invention further includes a hollow microneedle array, in which a needle part having needles with high aspect ratio of an upper end diameter to a length combined with base. In this case, the base is a bottom of plate shape functioning as stably supporting one or more of the needle part.

[51] In accordance with an embodiment of the present invention, the needle part is arranged in an array such as 2x2, 3x3, 4x4, 5x5, or combination thereof, or another array such as triangle lattice, rectangle lattice, pentagon lattice, hexagon lattice, or combination thereof.

[52] Moreover, the hollow microneedle of the array thereof in accordance with the present invention may be used in various purposes. For example, the hollow microneedle or the array may be used in a way of combining them with a device for sampling blood cell from the skin and delivering drugs such as anticancer drug and antibiotics; and a microfluidic system having various sensors for detecting a material to be analyzed from the body such as blood and analyzing the detected material.

[53] Though the present invention is described with hollow microneedle having a hole at a central portion thereof, the object of the present invention further includes a solid type microneedle having structure of microspike without the hole at the central portion thereof, i.e., closed.

[54] Hereinafter, the present invention will be described in detail with reference to drawings.

[55] Fig. 1 is a view showing a frame 10 manufactured with a 2x2 pattern array in accordance with an embodiment of the present invention, the frame 10 being used for drawing a viscous material. The diameter of the manufactured microneedle depends on a diameter of the pattern formed on the frame 10, but the diameter of the solid type microneedle may be formed smaller than that of the frame 10. Further, increasing a number of the pattern formed on the frame 10 enables mass production of the microneedle. It is preferable that the substance of the microneedle is metal or reinforced plastic having strong temperature and humidity resistance, but not limited thereto. Each frame may be used again after manufacturing the microneedle and cleaning.

[56] Figs. 2(a) to 2(b) are views showing manufacturing method of the solid microneedle.

First, a paraffin wax film, foil, or band is attached onto the substrate 20 having high conductivity such as glass and metal for easy separation with the substrate 20, then a film 21 is formed by coating with a material to be used to make a shape of the microneedle or to be used to make the microneedle. The material coated, a drawing speed, and applied temperature are main factors to determine a structure of the microneedle to be formed, and those factors may be properly adjusted according to length and diameter to be manufactured.

[57] Firstly, the solid microneedle is manufactured by a drawing lithography suitable to realize high aspect ration of the upper end diameter to the diameter. An entire area of a surface of the substrate 20 is coated with SU-8™(available from Microchem Corp.), acryl-based polymer, silicon-based-polymer, polycarbonate-based polymer, or copolymer therefrom. Alternatively, an area where the microneedle is manufactured, i.e., an area contacting with the frame 10 manufactured in a desired form, is selectively pattern-coated, then maintain certain temperature so as not to solidify the coated material. Thereafter, when the coated material is drawn with the frame 10 after contacting the frame 10 manufactured in the desired form with a surface of the coated viscous material, the coated material is drawn in a upper or a lower direction forming a thin and long structure. In this case, the drawing may be done either by moving the frame 10 in the upper or lower direction after fixing the substrate 10, or by moving the substrate 20 in the upper or lower direction after fixing the frame 10. Then, the manufacturing of the solid microneedle is accomplished by applying force beyond the tensile strength to the coated material, which is done by accelerating the upward speed of the frame, or by cutting the coated material at a certain point. Though, a substance 21 coated on the substrate to form the solid microneedle can be made of any kind of material, the substance 22 should be removed by a solvent, e.g., acetone, and so forth, after metal-plating. A temperature applied when the microneedle is formed and the drawing speed of the frame 10 may be properly adjusted according to a property of the coated material, e.g., viscosity and the structure of the desired solid microneedle. In accordance with an embodiment of the present invention, the cutting at a certain point is done by accelerating the drawing speed to apply a force beyond the tensile strength to the material or by using a laser, but not limited thereto.

[58] Referring to Fig. 3, (a) is a cross sectional view showing a 2x2 array of the solid microneedle 30 manufactured according to the present invention, (b) is a plan view of the 2x2 array of the solid microneedle 30, and (c) is a perspective view of the 2x2 array.

[59] Fig. 4 is a schematic view showing a metal deposition and an upper protection of the solid microneedle(30). The solid microneedle 30 of the Fig. 2 (a) to (c) is deposited with biocompatible material, then an upper portion thereof is protected. In this case, the deposition process is performed by conventional deposition process in an inert gas environment including argon and nitride gas environment, and the protection of the upper portion is performed by contacting a substrate 30 coated with protection material to the upper portion of the metal deposited needle as shown in Fig. 4 (a) to (f). Such protection material is, e.g., enamel, SU-8, and so forth, but not limited thereto.

[60] As for the biocompatible metal, stainless steel, Al, Cr, and so forth, which are materials for a needle of a disposable syringe approved by the KFDA (Korea Food & Drug Administration), can be used. The metals should not be toxic or carcinogenic for the human body, but have excellent biocompatibility without the immune response, good mechanical properties such as tensile strength, modulus of elasticity, wear resistance or the like, and strong corrosion resistance which can endure the corrosive environment in the human body. The biocompatible material includes Ni, Au, Ag, Cu, Ti, Co, or an alloy made therefrom, but not limited thereto.

[61] Fig. 5 is a schematic view showing a manufacturing process of a hollow microneedle

50 by metal-depositing and metal-plating an upper portion protected solid microneedle 30 with the biocompatible metal (a) and removing the solid microneedle 30 (b). The plating process is performed by conventional electroplating, but not limited thereto. The removing of the solid microneedle 30 is performed by using proper solvent, combustion, or physical method.

[62] Meanwhile, the metal microneedle can be coated with a lubricant such as glycerin for the convenience of penetrating the skin, or with an anticoagulant solution such as citrate or EDTA to prevent blood coagulation during blood collection.

[63] In the mean time, Figs. 6 (a) to (c) are views showing a structure of a hollow microneedle array manufactured according to the present invention, Fig. 6(a) is a cross sectional view showing the hollow microneedle array manufactured according to the present invention, Fig. (b) is a plan view showing a 2x2 array of the hollow mi- croneedle, and Fig. (c) is a perspective view showing the 2x2 array of the hollow microneedle. Since a size of a hole of the microneedle is small causing clogging of the hole by fine particle, the function of the single microneedle can be jeopardized. Therefore, when the needle is manufactured with an array, total function of the array can be maintained even several clogging of the needles in the array while increasing delivery amount.

[64] Fig. 7 (a) and Fig. 7(b) are views showing a combination of a hollow microneedle 50 array with a microfluidic system 60 and 60'. The microfluidic channel system in accordance with an embodiment of the present invention includes a sensor; a drug injection part fluidically communicated with the sensor and the microfluidic channel; and the hollow microneedle 50 array. Referring to Fig. 7, there is combination of a base portion of the hollow microneedle 50 and the microfluidic system to sample a material such as blood from the body for analysis and deliver the drug. The drug injecting part may be formed with respect to a number of sets of the hollow microneedles, or may be formed in a different way. A selection of the sensor of the microfluidic system is not limited to a specific sensor, and may be suitably done according to the material to be analysed and its detection purpose. A capillary hole opened to the outside may be formed at a predetermined location of the hollow microneedle in order to smoothly inject drug specimen into the capillary tube of the body. As such, the hollow microneedle according to the present invention may used by combining with various types of the microfluidic system depending on the purpose.

[65] Fig. 8 is a view showing an example where a hollow microneedle 50 of the present invention is applied to a microactuator 70 and 70'. The microactuator is a device required by portable equipment for extracting materials to be analyzed from the body and for drug delivery. The hollow microneedle of the present invention can be used to extract the materials to be analyzed and to deliver the drugs, by being combined with the microactuator. Similarly, a hollow microneedle of the present invention can be variously used in a piezoelectric pump, Mesotherapy, and so forth. Further, the hollow microneedle can be applied to a syringe.

[66] Fig. 9 is a schematic view showing a process of extracting blood by using 2x2 pattern hollow microneedle array in accordance with an embodiment of the present invention.

[67]

[68] Hereinafter, the present invention will be described in further detail with reference to embodiments. It is to be understood, however, that these embodiments are illustrative only, and the scope of the present invention is not limited thereto.

[69]

[70] Manufacturing of solid type microneedle

[71] SU-8 2050 photoresist (commercially purchased from Microchem) having a viscosity of 14,000 cSt was used to fabricate solid microneedles 30. The SU-8 2050 was coated on a metal substrate to a certain thickness, and it was maintained at 120 OC for 5 minutes to maintain its flowing state. Then, the coated material was brought into contact with a frame 10 having 2x2 patterns formed thereon having a diameter of 200/M (See Fig. 1). The temperature of the substrate 20 was slowly lowered to 950C to 90 OC over about 5 minutes to solidify the coated SU-8 2050 and to increase the adhesion between the frame 10 and the SU-8 2050. Then, while the temperature was slowly lowered from 95-90 OQ the coated SU-8 2050 was drawn at the speed of 0.7/M/S for 50 minutes using the frame 10 which adhered to the coated SU-8 2050. After 50 minutes of drawing, solid microneedles 30, each having a length of about 2,100/iiϊ) were formed. Subsequently, the solid microneedles 30 of 3,000/M or more were obtained by increasing drawing speed to 24μm/s(refer to Fig. 2). The formed microneedles 30 could be separated from the frame 10 by increasing the drawing speed or cutting. As a result, solid microneedles 30, each having an upper end diameter of 5 /in) an effective length of 1,500/irq and a total length of 3,000/ffl) were fabricated.

[72]

[73] Manufacturing of hollow microneedle

[74] Three layers of Ti-Cu-Ti ( 100nm-300nm- 100nm) were deposited on the SU-8 solid type microneedle 30 prepared from above method by using sputtering (Fig. 4b). Next, the upper end portion of the solid type microneedle was protected with enamel or a substrate 40 coated with SU-8 2050 (See, Figs. 4(c) to 4(f)). The enamel or SU-8 2050 treatment to the upper end portion is to prevent the upper end portion from being metal-plated in the subsequent step (Fig. 5(a)). Then, a surface of the solid type microneedle 30, the upper end part of which was protected, was electroplated with nickel (Fig. 5(a)). The Ni electroplating was carried out with 1 A/dm2 current density and 0.206/M plating speed for 75 minutes, resulting in a plated metal thickness of 10/M. The plated structure was placed into boiling water at a temperature in the range of 900C to IOOOC for 30 minutes to firstly remove the solid type microneedle made of SU-8 2050 and sealed enamel, or SU-2050, and resulting structure was again placed into an SU-8 remover (commercially available from Microchem Corp.) or acetone for about 1 hour to secondly remove them (Fig. 5(b)). [75] Fig. 6(a) is a cross sectional view of the completed hollow metal microneedle. It was found that the manufactured hollow metal microneedle 50 had an outer diameter (OD) of 30/M; an inner diameter (ID) of 5/M; an effective length of 1, 500/M; and a total length of 3,000/M. Fig. 6(b) is a plan view of a hollow metal microneedle 50, and Fig. 6(c) is a perspective view thereof.

[76] While the invention has been shown and described with respect to the embodiments, it will be understood by those skilled in the art that various changes and modifications may be made without departing from the scope of the invention as defined in the following claims.

[77]

Claims

[1] A hollow microneedle array, comprising: a needle part having a plurality of hollow microneedle; and a substrate part supporting the needle part; wherein the needle includes an upper portion inserted into skin; and a base portion communicated with the upper portion and supporting the upper portion; an upper end of the upper portion has such an outer diameter that reduces pain upon penetration into the skin; a diameter of the upper portion smoothly increases as it goes to the other end thereof so as to reduce pain upon penetration into the skin; an aspect ratio of the diameter of the upper end of the upper portion to a length of the needle is high to enable deep penetration into the skin; a diameter of the base portion generally exponentially increases as it goes to a lower end of the base portion so as to increase total strength of the needle in both longitudinal and lateral directions; and the needle is made of biocompatible metal having good mechanical properties.

[2] The hollow microneedle array of claim 1, wherein the aspect ratio of the diameter of the upper end of the upper portion to the length of the needle is 1:5 to 1:70.

[3] The hollow microneedle array of claim 1, wherein an outer diameter of the upper end of the upper portion is greater than Oμm and less than 100/M.

[4] The hollow microneedle array of claim 1, wherein an outer diameter of the upper end of the upper portion is 30/M to 40μπ) an inner diameter thereof is 5 /M to

25μia, and a length thereof is 500/M to 2000/M.

[5] The hollow microneedle array of claim 4, wherein an outer diameter of an upper end of the upper portion is 180/M to 200/M and an inner diameter thereof is

130/M to 160/M.

[6] The hollow microneedle array of claim 5, wherein the biocompatible metal having good mechanical properties includes stainless steel, Ni, Cr, Al, Au, Ag.

Cu, Ti, Co, or alloy made therefrom.

[7] The hollow microneedle array of claim 6, wherein the needles includes an inner layer of Ti-Cu-Ti and an outer layer of Ni.

[8] The hollow microneedle array of claim 1, wherein the needle part is formed in 2x2, 3x3, 4x4, 5x5 arrays, or combination thereof.

[9] The hollow microneedle array of claim 1, wherein the needle part is formed in triangle, rectangle, pentagon, hexagon array, or combination thereof.

[10] A method of injecting drug using the hollow microneedle array according to claim 1.

[11] A method of extracting blood cell from a human body by using the hollow microneedle array according to claim 1. [12] An apparatus for detecting material or transferring drug comprising the hollow microneedle array according to claim 1. [13] The apparatus for detecting material or transferring drug of claim 12 further comprising: a sensor; and a microfluidic system having a drug injection part fluidically connected with the sensor through a microfluidic channel; wherein the drug injection part is fluidically connected with a lower end portion of the hollow microneedle array.