Method of manufacturing microneedle structures using soft lithography and photolithography

• US 20020133129A1
• Filed: 03/14/2001
• Published: 09/19/2002
• Est. Priority Date: 03/14/2001
• Status: Active Grant

• Current Assignee: Corium, Inc.
• Original Assignee: The Procter & Gamble Company
• Inventors: Sherman, Faiz Feisal, Owens, Grover David, Arias, Francisco
• Granted Patent: US 6,663,820 B2
• Time in Patent Office: Days
• US Class Current: 604/272
• CPC Class Codes: A61B 5/1411 by percutaneous method, e.g. by lancet
• CPC Class Codes: A61B 5/14514 using means for aiding extraction of interstitial fluid, e.g. microneedles or suction
• CPC Class Codes: A61B 5/150022 for capillary blood or interstitial fluid
• CPC Class Codes: A61B 5/150282 for piercing elements, e.g. blade, lancet, canula, needle
• CPC Class Codes: A61B 5/150419 comprising means for capillary action
• CPC Class Codes: A61B 5/150984 Microneedles or microblades
• CPC Class Codes: A61M 2037/0038 having a channel at the side surface
• CPC Class Codes: A61M 2037/0053 Methods for producing microneedles
• CPC Class Codes: A61M 37/0015 by using microneedles
• CPC Class Codes: B81B 2201/055 Microneedles
• CPC Class Codes: B81C 1/00111 Tips, pillars, i.e. raised structures microneedles A61M37/0015
• CPC Class Codes: B81C 2201/034 Moulding

Abstract

A method for manufacturing microneedle structures is disclosed using soft lithography and photolithography, in which micromold structures made of a photoresist material or PDMS are created. The micromold manufacturing occurs quite quickly, using inexpensive materials and processes. Once the molds are available, using moldable materials such as polymers, microneedle arrays can be molded or embossed in relatively fast procedures. In some cases a sacrificial layer is provided between the forming micromold and its substrate layer, for ease of separation. The microneedles themselves can be solid projections, hollow “microtubes,” or shallow “microcups.” Electrodes can be formed on the microneedle arrays, including individual electrodes per hollow microtube.

Claims

1. A method for fabricating microneedles, said method comprising:

(a) providing a substrate that includes a plurality of microstructures;

(b) coating said substrate with a layer of a first moldable material that takes the negative form of said plurality of microstructures, and hardening said first moldable material;

(c) separating said hardened first moldable material from said substrate, thereby creating a micromold from said hardened first moldable material containing said plurality of microstructures; and

(d) applying a second moldable material onto said micromold, allowing said second moldable material to harden using a soft lithography procedure, then separating said hardened second moldable material from said micromold, thereby creating a microneedle structure from said hardened second moldable material having the three-dimensional negative form of said plurality of microstructures of the patterned micromold.

2. The method as recited in claim 1, wherein said microneedle structure comprises one of:

(a) a plurality of solid protrusions, (b) a plurality of hollow protrusions forming through-holes, (c) a plurality of hollow protrusions forming microcups that do not extend entirely through said hardened second moldable material, or (d) a plurality of solid protrusions, each having at least one surface external channel.

3. The method as recited in claim 1, wherein said first moldable material comprises PDMS, said second moldable material comprises a prepolymer, and said substrate comprises one of silicon or a metallic substance;

and wherein said microneedle structure comprises a polymeric material.

4. The method as recited in claim 1, wherein said substrate is constructed by:

beginning with a wafer material, coating said wafer material with at least one layer of a photoresist material, and patterning said photoresist material with a plurality of microstructures by use of a photolithography procedure, such that said patterned photoresist material comprises said plurality of microstructures; and

wherein said first moldable material is processed and hardened by a second soft lithography procedure.

5. The method as recited in claim 4, wherein said wafer comprises silicon, said photoresist material comprises SU-8, said first moldable material comprises PDMS, and said second moldable material comprises a prepolymer;

and wherein said microneedle structure comprises a polymeric material.

6. The method as recited in claim 1, further comprising:

(e) providing a second substrate that includes a second plurality of microstructures, wherein said second plurality of microstructures is substantially complementary in shape as compared to said first plurality of microstructures;

(f) coating said second substrate with a layer of a third moldable material that takes the negative form of said second plurality of microstructures, and hardening said third moldable material;

(g) separating said hardened third moldable material from said second substrate, thereby creating a second micromold from said hardened third moldable material containing said second plurality of microstructures;

(h) applying a fourth moldable material onto said second micromold, allowing said fourth moldable material to harden using a soft lithography procedure, then separating said hardened fourth moldable material from said second micromold, thereby creating a second microneedle structure from said hardened fourth moldable material having the three-dimensional negative form of said second plurality of microstructures of the patterned second micromold; and

(i) applying a layer of a fifth moldable material upon one of said first or second microneedle structures, placing said first and second microneedle structure into a face-to-face relationship to thereby sandwich said layer of fifth moldable material therebetween, allowing said layer of fifth moldable material to harden using a soft lithography procedure, then separating said hardened fifth moldable material from both said first and second microneedle structures, thereby creating a third microneedle structure from said hardened fifth moldable material having the three-dimensional negative form of both said first and second microneedle structures.

7. The method as recited in claim 6, wherein said first and third moldable materials comprise PDMS, said second and fourth moldable materials comprise a prepolymer, said substrate comprises one of silicon or a metallic substance, and said fifth moldable material comprises a prepolymer;

and wherein said first, second, and third microneedle structures each comprises a polymeric material.

8. The method as recited in claim 1, wherein said first moldable material after hardening exhibits a flexibility characteristic and, therefore, can be deformed to a predetermined extent without breaking;

and further comprising;

after creating said micromold from said hardened, flexible first moldable material, deforming said micromold during the step of applying the second moldable material onto said micromold, thereby creating either a concave or convex micromold.

32. The method as recited in claim 1, further comprising:

hardening a tip of a plurality of microneedles formed of said microstructures.

33. The method as recited in claim 32, wherein said tip is hardened by adding carbon fibers, or by adding a composite material.

34. The method as recited in claim 1, further comprising:

applying said plurality of microneedles to skin, wherein said plurality of flexible microneedles breaks away from a base structure of said microstructures and thereby remaining within a stratum corneum of said skin after said base structure is removed, and wherein said plurality of flexible microneedles are hollow;

applying at least one time a liquid through said plurality of flexible hollow microneedles and thereby through said stratum corneum; and

leaving said flexible hollow microneedles in said stratum corneum over a time duration.

36. The microneedle structure as recited in claim 35, further comprising:

a base member;

wherein said first end comprises a tip of said microneedle structure, and said second end is attached to or integral with said base member.

37. The microneedle structure as recited in claim 36, further comprising:

a longitudinal channel in said base member;

wherein said at least one external channel is in fluidic communication with said longitudinal channel.

38. The microneedle structure as recited in claim 37, further comprising:

a sensor device located proximal to or integral with said base member, wherein said longitudinal channel is in fluidic communication with said sensor device.

9. A method for fabricating microneedles, said method comprising:

(a) providing a substrate material;

(b) coating said substrate material with at least one layer of a photoresist material, and patterning said photoresist material with a plurality of microstructures by use of a photolithography procedure; and

(c) separating said patterned photoresist material from said substrate material, thereby creating a microneedle structure from said patterned photoresist material containing said plurality of microstructures.

10. The method as recited in claim 9, wherein said microneedle structure comprises one of:

(a) a plurality of solid protrusions, (b) a plurality of hollow protrusions forming through-holes, or (c) a plurality of hollow protrusions forming microcups that do not extend entirely through said hardened second moldable material.

11. The method as recited in claim 9, wherein said photoresist material comprises a first layer and a second layer, said first layer being cured before said second layer is applied, and said second layer being patterned by said photolithography procedure.

12. The method as recited in claim 9, further comprising:

applying a layer of acid-dissolvable material between said substrate and said photoresist material at the commencement of said method, and during said step of separating the patterned photoresist material from the substrate, dissolving said acid-dissolvable material as a sacrificial layer.

13. The method as recited in claim 12, wherein said substrate comprises one of a silicon or a metallic substance, said photoresist material comprises SU-8, and said acid-dissolvable material comprises one of PDMS or silicon oxide.

14. The method as recited in claim 12, further comprising:

creating break-away microneedles by briefly etching a portion of said plurality of microstructures proximal to a junction between a base structure and protrusions of the patterned photoresist material containing said plurality of microstructures, said base structure and said microstructure protrusions both being constructed of said photoresist material.

15. The method as recited in claim 12, further comprising:

creating break-away microneedles by using PDMS as the layer of acid-dissolvable material, and by using SU-8 as the at least one layer of photoresist material.

16. The method as recited in claim 9, wherein said photoresist material comprises at least two individual layers, a first of said at least two individual layers being patterned with a first plurality of openings that are of a first size, a second of said at least two individual layers being patterned with a second plurality of openings that are of a second size that is larger than said openings of said first size, said first and second plurality of openings being substantially in alignment with one another;

and after said separation of the substrate from the patterned photoresist material, said plurality of microstructures comprises a plurality of microneedles having sharp tips.

17. The method as recited in claim 9, wherein said microneedle structure comprises a plurality of individual microneedles that have an aspect ratio of at least 3:

1.

19. The method as recited in claim 18, further comprising:

coating said at least one surface of said separate hardened moldable material by use of one of the following procedures;

(a) electroplating, (b) electrodeposition, (c) electroless plating, (d) sputtering, (e) vapor deposition, or (f) plasma deposition;

thereby creating an independent microstructure layer.

20. The method as recited in claim 19, wherein said independent microstructure layer protects and strengthens said plurality of microstructures, and wherein said independent microstructure layer comprises one of:

an electroplated metal or an electroplated polymer.

21. The method as recited in claim 19, further comprising:

separating said independent microstructure layer from said hardened moldable material, thereby creating a microneedle array structure that entirely comprises said microstructure layer made of at least one of;

an electroplated metal, an electroplated polymer, or an electroplated composite material.

22. The method as recited in claim 18, wherein said substrate material comprises silicon, said photoresist material comprises SU-8, and said moldable material comprises PDMS.

24. The method as recited in claim 23, wherein said microneedle structure comprises one of:

(a) a plurality of solid protrusions, (b) a plurality of hollow protrusions forming through-holes, or (c) a plurality of hollow protrusions forming microcups that do not extend entirely through said hardened second moldable material.

25. The method as recited in claim 24, further comprising a polishing or grinding procedure to open one end of said plurality of microcups, thereby creating a plurality of hollow protrusions forming through-holes.

26. The method as recited in claim 24, wherein said substrate comprises one of a silicon or a metallic substance, said photoresist material comprises SU-8, said first moldable material comprises PDMS, and said second moldable material comprises a polymeric material that softens at a temperature less than the softening temperature of said first moldable material.

27. The method as recited in claim 23, wherein during the step of applying said second moldable material onto said microstructures, pressure is applied by use of a second mold half to remove excess uncured material from the furthest extending microstructures, thereby creating through-holes in said microneedle structure upon separation of said microneedle structure from said microstructure.

29. The method as recited in claim 28, wherein said electrically conductive pathways each are sized and positioned so as to cover an area upon said surface that is larger than a spacing between at least two of said plurality of individual protrusions, thereby creating at least one electrode band.

30. The method as recited in claim 28, wherein said electrically conductive pathways each are sized and positioned so as to cover an area upon said surface that is smaller than each of said plurality of individual protrusions, thereby creating a plurality of electrically isolated electrodes, such that at least one such electrode corresponds to a single one of said plurality of individual protrusions.

31. The method as recited in claim 30, wherein said at least one of said plurality of individual protrusions comprises a hollow microneedle, and said at least one of the electrically isolated electrodes comprises a pad surface and a longitudinal segment, said longitudinal segment extending into an inner surface of said hollow microneedle by way of a vapor deposition procedure.

18. A method for fabricating microneedles, said method comprising:

(a) providing a substrate material;

(b) coating said substrate material with at least one layer of a photoresist material, and patterning said photoresist material with a plurality of microstructures by use of a photolithography procedure; and

(c) coating said patterned photoresist material with a layer of moldable material that takes the negative form of said plurality of microstructures, and allowing said moldable material to harden using a soft lithography procedure, then separating said hardened moldable material from both said patterned photoresist material and said substrate material.

23. A method for fabricating microneedles, said method comprising:

(a) providing a substrate material;

(b) coating said substrate material with at least one layer of a photoresist material, and patterning said photoresist material with a plurality of microstructures by use of a photolithography procedure;

(c) applying a first moldable material onto said patterned photoresist material/substrate and allowing said first moldable material to harden using a soft lithography procedure, then separating said hardened first moldable material from said patterned photoresist material/substrate to thereby create a microstructure; and

(d) applying a second moldable material onto said microstructure, and after hardening of said second moldable material, separating said hardened second moldable material from said microstructure, thereby creating a microneedle structure from said hardened second moldable material having the three-dimensional negative form of said microstructure.

28. A method for fabricating microneedles with electrodes, said method comprising:

(a) providing a substrate material;

(b) coating said substrate material with at least one layer of a photoresist material, and patterning said photoresist material with a plurality of microstructures by use of a photolithography procedure, such that said patterned photoresist material comprises said plurality of microstructures;

(c) coating said substrate with a layer of moldable material that takes the negative form of said plurality of microstructures, and hardening said moldable material by a soft lithography procedure;

(d) separating said hardened moldable material from said substrate, thereby creating a mask;

(e) providing a microneedle array structure having a plurality of individual protrusions extending from a base; and

(f) positioning said mask proximal to said microneedle array structure and applying an electrically conductive substance through said mask onto a surface of said microneedle array structure, thereby creating at least one pattern of electrically conductive pathways on said surface.

35. A microneedle structure, comprising:

a longitudinal element having a first end and a second end, said longitudinal element having a side wall extending between said first end and said second end; and

said side wall having at least one external channel running between substantially said first end and said second end.