Superimposed arc imprint laser writing for fabrication of hollow microneedles

Abstract

Manufacturing a microneedle includes forming a groove in a substrate. This groove follows a closed path and has a depth that varies with position along the closed path. The resulting grooved substrate is then used as a mold for the microneedle.

Description

[0001] SUPERIMPOSED ARC IMPRINT LASER WRITING FOR FABRICATION OF HOLLOW MICRONEEDLES

[0002] CROSS REFERENCE TO RELATED APPLICATIONS

[0003] This application claims priority to US Application No. 63 / 635,762, filed on April 18, 2024, the contents of which are hereby incorporated by reference in their entirety.

[0004] BACKGROUND

[0005] Among the difficulties encountered by those who are addicted to opioids is that of overcoming the withdrawal symptoms that result from attempting to reduce or eliminate one’s intake of the offending opioid. To address this difficulty, it is useful to provide a substitute pharmaceutical compound that satisfies the craving for opioid, thus making it possible to reduce or eliminate one’s intake of the opioid without the temporary but unpleasant side effects of withdrawal.

[0006] Among the known substitutes are methadone, buprenorphine, and naltrexone. These drugs prevent opioids from binding to receptors in the brain, thereby reducing drug-cravings.

[0007] Both methadone and buprenorphine are opioid agonists. They effectively reduce cravings for more potent and addictive drugs such as heroin and fentanyl. Nevertheless, they are not without their own side effects. Some of these are quite dangerous.

[0008] Naltrexone is a viable alternative to methadone. Instead of being an agonist, naltrexone is an opioid antagonist. Common methods of delivering naltrexone include oral capsules and tablets, intramuscular injections, and extended-release implants.

[0009] Although generally effective, these methods come with disadvantages. Oral capsules and tablets offer low bioavailability. Extended-release implants require invasive procedures for both implantation and removal.

[0010] Intramuscular injections avoid the foregoing disadvantages. However, they do involve injections. Since many patients fear needles, this mode tends to have a low patient compliance rate. To some extent, this difficulty can be overcome by reducing the size of the needle. Among the problems that arise in the manufacture of small needles include providing needles with sufficient mechanical strength and fracture resistance, providing a way to achieve convenient loading of a drug and controlled release of that drug, avoiding complexity in the manufacturing process, and avoiding an excessively costly production process.

[0011] Among the known methods for manufacturing a needle are those that rely on plastic deformation. One draws a material, such as a metal, through a die. However, material properties impose a lower limit on how small a needle manufactured this way can be. Other known methods include 3D-printing, micromachining, micro-molding, lithography, and etching.

[0012] SUMMARY

[0013] The invention provides a method for manufacturing extremely fine needles for sustained and personalized drug delivery in a way that both provides meaningful doses and avoids implantation. Such needles are so fine that most patients would not realize that the needles are even present.

[0014] The needles provide a pathway for delivering a drug, such as naltrexone, using a transdermal delivery system. Because it bypasses the digestive system, transdermal delivery offers more consistent and sustained drug release, potentially leading to better control of cravings and reduced risk of relapse. The microneedles are fine enough to offer a pain-free and convenient alternative to injections. This not only improves patient compliance but also reduces the stigma associated with traditional treatment methods.

[0015] A method for manufacturing the needles uses a commercial laser cutter to make molds for the needles by carrying out cross-over arc lithography. This enables scalable fabrication of microneedles with an embedded drug reservoir.

[0016] In one aspect, a method includes manufacturing a microneedle by carrying out a step that includes manufacturing a mold for the microneedle. This step is carried out by forming a groove in a substrate. This groove follows a closed path. The groove’s depth varies with position along the closed path.

[0017] Practices of the method include those in which forming the groove includes ablating the substrate along a first portion of the closed path and ablating the substrate along a second portion of the closed path, the second portion being shorter than the first portion, those in which forming the groove includes ablating the substrate along a first portion of the closed path and ablating a portion of the first portion of the substrate, those in which forming the groove includes ablating the substrate along a first arc of a circle defined by the path and ablating the substrate along a second arc of the circle, the second arc being shorter than the first arc, those in which forming the groove includes ablating the substrate along a first arc of a circle defined by the closed path and ablating a second arc of the circle, the second arc being a portion of the first arc, those in which forming the groove includes ablating the substrate along the closed path, wherein ablating the substrate includes varying an extent of the ablation while ablating the substrate along the closed path, those in which forming the groove includes exposing a first portion of the groove to a first quantity of radiant energy and exposing a portion of the first portion to a second quantity of radiant energy, wherein the second quantity is greater than the first quantity, those in which forming the groove includes exposing a first portion of the groove to radiant energy having a first power density and exposing a second portion of the groove to radiant energy having a second power density, the second power density being greater than the first power density, those in which forming the groove includes exposing a first portion of the groove to radiant energy for a first amount of time and exposing a second portion of the groove to radiant energy for a second amount of time, wherein the second amount of time is greater than the first amount of time, those in which forming the groove includes causing a laser to traverse the closed path, those in which forming the groove includes causing a laser beam to trace out the closed path on the substrate and controlling the laser beam to cause an extent of ablation along the closed path to depend on position along the closed path, those in which forming the groove includes using a laser to ablate the substrate along a first portion of the closed path and using the laser to ablate the substrate along a second portion of the closed path, the second portion being shorter than the first portion, those in which forming the groove includes using a laser to ablate the substrate along a first portion of the closed path and using the laser to ablate a second portion of the substrate, wherein the second portion of the substrate is a portion of the first portion of the substrate, those in which forming the groove includes using a laser to ablate the substrate along a first arc of a circle defined by the closed path and using the laser to ablate a second arc of the circle, the second arc being a portion of the first arc, those in which forming the groove includes using a laser beam to deliver a first quantity of radiant energy to a first portion of the groove and using the laser to deliver a second quantity of radiant energy to a second portion of the groove, wherein the second quantity is greater than the first quantity, and wherein the second portion is a portion of the first portion, those in which forming the groove includes using a laser to illuminate a first portion of the groove with radiant energy having a first power density and using the laser to illuminate a second portion of the groove with radiant energy having a second power density, the second power density being greater than the first power density, those in which forming the groove includes exposing a first portion of the groove to a laser beam for a first amount of time and exposing a second portion of the groove to the laser beam for a second amount of time, wherein the second amount of time is greater than the first amount of time and wherein the second portion of the groove is a portion of the first portion, those in which forming the groove includes causing a laser beam to trace out the closed path on the substrate and controlling incident power along the closed path to cause differences in depth of the groove along the closed path and those in which forming the groove includes causing a laser beam to trace out the closed path on the substrate and controlling a velocity at which the laser beam traverses the closed path, thereby causing different extents of ablation along different sections of the closed path.

[0018] Still other practices include those in which the closed path defines a circle and wherein forming the groove includes using a laser to ablate the substrate along a first arc of a circle defined by the path and using the laser to ablate the substrate along a second arc of the circle, the second arc being shorter than the first arc and those in which the closed path includes a circle.

[0019] In still other practices, the closed path defines a circle and wherein forming the groove includes causing a laser to traverse the circle, thereby defining a first region, causing the laser to traverse a first arc along the circle, the first arc being less than the circle’s circumference, thereby defining a second region of the groove, and causing the laser to traverse a second arc along the close path, shorter than the first arc, thereby defining a third region of the groove. In such practices, the first region forms a base of the micro needle, the second region of the groove forms a shaft of the microneedle, the third region of the groove forms a tip of the microneedle, and the second region is between the first region and the third region.

[0020] Still other practices include those in which manufacturing the mold includes manufacturing a mold for making the microneedle with a diameter of less than half a millimeter. Other practices further include manufacturing a housing for holding a reservoir. In such practices, manufacturing the microneedle includes causing the microneedle to be integral with a base of the housing to enable a fluid to pass between the reservoir and a space outside the reservoir.

[0021] In another practice, the microneedle is a first microneedle, the groove is a first groove, the closed path is a first closed path, and the method further includes manufacturing a second microneedle, manufacturing a reservoir having first and second chambers, filling the first chamber with a first drug, and filling the second chamber with a second drug. In such practices, manufacturing the second microneedle comprises forming a second groove in the substrate, the second groove following a second closed path and having a depth that varies with position in along the second closed path. The first chamber is in fluid communication with the first microneedle and wherein the second chamber is in fluid communication with the second microneedle. As a result, the first microneedle delivers the first drug, and the second microneedle delivers the second drug.

[0022] In another aspect, the invention features an apparatus for manufacturing a microneedle. Such an apparatus includes a laser, a beam steerer for causing a beam of the laser to illuminate different portions of a substrate, and a controller for causing the laser to form a groove in the substrate. This groove follows a closed path and has a depth that varies with position along the closed path.

[0023] A layperson may regard ‘‘microneedle” as a relative term because “micro” is a relative term. However, the term “microneedle” has acquired a distinct meaning in the art that a layperson may not be familiar with. In the context of drug delivery, a microneedle is a very small needle that is used to painlessly and efficiently deliver drugs or vaccines through the skin. The term “microneedle” is sufficiently known in the art so that any person who claims to not know what it is or who regards it as somehow being a relative term is very likely to be a person who is unfamiliar with the relevant art.

[0024] BRIEF DESCRIPTION OF THE DRAWINGS

[0025] FIG. 1 shows a drug-delivery device;

[0026] FIG. 2 shows an apparatus for making the microneedles shown in the device of FIG. 2; FIG. 3 illustrates operation of the apparatus shown in FIG. 2;

[0027] FIG. 4 shows an array of microneedles manufactured using the operation shown in FIG.

[0028] 3; and

[0029] FIG. 5 shows an alternative embodiment of the drug-delivery device for delivery of more than one drug.

[0030] DETAILED DESCRIPTION

[0031] FIG. 1 shows a drug-delivery device 10 having a reservoir 12 that holds a drug 14 that is to be delivered through microneedles 16 via action of a wireless pump 18. The microneedles 16 are hollow needles that are integral with the reservoir 12. Each microneedle 16 has an opening 20 through which the drug 14 passes out of the reservoir 12 and into the patient. This opening 20 has a diameter that is on the order of half a millimeter. A microneedle 16 extends away from the reservoir’s base by about 1.2 millimeters to its distal tip,

[0032] Unlike conventional methods for manufacturing a needle, i.e., by drawing the tube through progressively smaller dies, the method described herein relies on molding. The process for manufacturing the microneedle 16 thus begins with manufacturing a mold.

[0033] Referring to FIG. 2, the manufacturing process begins with a substrate 22. Suitable materials for the substrate 22 include common plastics and metals. Examples of suitable plastics include acrylonitrile butadiene styrene and polymethyl methacrylate. Examples of suitable metals include steel and copper.

[0034] The manufacturing process also requires a laser 24 that produces a beam 26. The laser 24 is one that provides sufficient power to selectively ablate the substrate 22. A suitable laser 24 is one in which the lasing material is carbon dioxide. A suitable substrate 22 is one that comprises acrylic.

[0035] In addition, the manufacturing processes uses a beam steerer 28 for moving the laser’s beam 26 along a circular path 30 on the substrate 22, and control circuitry 32 for modulating various parameters as it traverses arcs 34 of the circular path 30. This results in engraving a path on the substrate. In a preferred embodiment, the control circuitry 32 modulates one or more of: the beam’s velocity, the beam’s power, the number of laser pulses per unit distance, and the number of passes made over the circular path 30. In some embodiments, the control circuitry 32 modulates the beam’s focus. Control over the beam’s focus has been found to be particularly useful for controlling needle’s sharpness.

[0036] The circular path 30 defines an inner circle and an outer circle, the diameters of which define the inner and outer diameter of the microneedle’s inner and outer walls, respectively. The difference between them depends on the sharpness of the beam 22. As the beam 22 traverses this circular path 30, it ablates the substrate 22 at different angular positions.

[0037] Referring now to FIG. 3, ablation by the laser 24 forms a groove 36 that has a depth 38.

[0038] The depth 38 of this groove 36 at a particular angular position depends on the energy delivered to that angular position by the laser 24 over the course of the process. The more energy that the laser 24 delivers, the deeper the groove 36 will be at that position.

[0039] The control circuitry 32 and beam steerer 38 cooperate to modulate the beam’s velocity and its power output to carve out a circular groove 36 whose depth 38 is a function of angular position. In particular, it is possible to carve out a circular groove 36 that represents a piecewise approximation of a beveled distal end 40.

[0040] FIG. 3 shows the process of manufacturing a groove 36 in which the depth 38 of the groove 36 is a step function of angular position.

[0041] The process includes ablating the circular path 30 along overlapping arcs 42, 44, 46 to form a groove 36 of suitable shape for molding a microneedle 16.

[0042] The first ablation step is that of ablating along a first arc 42 to form the base 48 of the microneedle 16. This first arc 42 spans the entire circumference of the circular path 30.

[0043] The process continues with ablating along the second arc 44 to form the shaft 50 of the needle. This second arc 44 spans half of the circumference of the circular path 30.

[0044] The ablation process concludes with ablating along the third arc 56. This third arc 46 is aligned with the second arc 44 to form the tip 52 of the microneedle 16. The third arc 46 is the shortest of the three arcs 42, 44, 46 and spans half the arclength of the second arc 44. This ablation process is carried out many times to form an array of grooves 36, which then results in an array of corresponding microneedles 16 as shown in FIG. 1. At this point, the substrate 22 can now be considered as a mold 22.

[0045] A cleaning process follows the ablation process. Cleaning is carried out by placing the mold 22, with its array of grooves 36, into an ultrasonic bath to remove any debris remaining in the grooves 36. In most cases, three hours of ultrasonic cleaning yields acceptably clean grooves 36.

[0046] With the array of grooves 36 now being ready for use, the next step is to create the mold’s replicate. This is done by casting polydimethylsiloxane with a 5:1 weight ratio of pre-polymer to curing agent on the substrate 22. The resulting casted block is then degassed in a vacuum desiccator using a vacuum pump and subsequently cured in a hot air oven at sixty degrees Celsius for six hours. This results in an array of microneedles 16, as shown in FIG. 4. Suitable materials for use in making microneedles 16 include biocompatible and ultraviolet curable resins.

[0047] The velocity of the laser’s beam 26, its power density, and its focus distance all cooperate to influence the hollow microneedle's length and its sharpness. By varying the laser’s power output and the velocity of its beam 26, it is possible to produce molds for microneedles of varying length, for example four hundred micrometers and eighteen hundred micrometers in length. Overfocusing the laser beam 26, for example by bringing it half a millimeter or so closer, enhances the sharpness of the microneedle’s tip 52. Having the beam 26 repeatedly pass over specific arcs 42, 44, 46 can selectively increases the depth 38 of the groove 36, thereby controlling the overall shape of the mold, and hence the microneedle 16 that it molds.

[0048] The foregoing process of using a laser 24 to ablate along a closed path 30 in a manner that depends on position along the path 30 allows one to create customized molds to manufacture a hollow microneedle 16 in any pattern or shape. There is no particular requirement that the path 30 be circular or that only three arcs 42, 44, 46 be used. This versatility results in a powerful tool for various microneedle applications, both in the drug delivery and sampling space. Hollow microneedles 16 fabricated using the method described herein are usable for broad spectrum drug delivery, including for delivery of small molecules and proteins. They are also useful for sampling and sensing applications, for example for biomarker sampling applications. The microneedles 16 are suitable for delivery of insulin, peptides, and other small molecule compositions. They are also usable for delivery of larger molecules such as DNA and proteins. In addition, such microneedles 16 are usable for sampling of interstitial fluid to enable for detection and quantification of a plethora of biomarkers. Such microneedles 16, when used in conjunction with pumps, reservoirs, and actuators, permit both passive and active sampling and drug delivery. This versatility enables such microneedles 16 to play a central role in personalized medicine, offering painless treatment options and improved patient care.

[0049] In the embodiment shown in FIG. I, the reservoir 12 has a single chamber that is loaded with a single drug 14. An alternative embodiment, shown in FIG. 5, features a multi-chamber reservoir 12 having an annular first chamber 54 and a circular second chamber 56 that are loaded with first and second drugs 58, 60, respectively. In some embodiments, the first and second drugs 58, 60 comprise naltrexone and clonidine.

[0050] As a result, first needles 62, which are in fluid communication with the first chamber 54, deliver the first drug 58 and second needles 64, which are in fluid communication with the second chamber 56, deliver the second drug 60. The parameters associated with drug delivery are controllable by making the first needles 62 and the second needles 64 have different geometries. For instance, if the first drug 58 is to be delivered at a slower rate than the second drug 60, the control circuitry 32 manufactures the first needles 62 with a smaller bore than the second needles 64.

[0051] Having described the invention and a preferred embodiment thereof, what is claimed as new and secured by letters patent is:

Claims

CLAIMS1. A method comprising manufacturing a microneedle, said method comprising manufacturing a mold for said microneedle by forming a groove in a substrate, wherein said groove follows a closed path and has a depth that varies with position along said closed path.

2. The method of claim 1, wherein forming said groove comprises ablating said substrate along a first portion of said closed path and ablating said substrate along a second portion of said closed path, said second portion being shorter than said first portion.

3. The method of claim 1, wherein forming said groove comprises ablating said substrate along a first portion of said closed path and ablating a portion of said first portion of said substrate.

4. The method of claim 1, wherein forming said groove comprises: ablating said substrate along a first arc of a circle defined by said path and ablating said substrate along a second arc of said circle, said second arc being shorter than said first arc.

5. The method of claim 1, wherein forming said groove comprises ablating said substrate along a first arc of a circle defined by said closed path and ablating a second arc of said circle, said second arc being a portion of said first arc.

6. The method of claim 1, wherein forming said groove comprises ablating said substrate along said closed path, wherein ablating said substrate comprises varying an extent of said ablation while ablating said substrate along said closed path.

7. The method of claim 1, wherein forming said groove comprises exposing a first portion of said groove to a first quantity of radiant energy and exposing a portion of said first portion to a second quantity of radiant energy, wherein said second quantity is greater than said first quantity.

8. The method of claim 1, wherein forming said groove comprises exposing a first portion of said groove to radiant energy having a first power density and exposing a secondportion of said groove to radiant energy having a second power density, said second power density being greater than said first power density.

9. The method of claim 1, wherein forming said groove comprises exposing a first portion of said groove to radiant energy for a first amount of time and exposing a second portion of said groove to radiant energy for a second amount of time, wherein said second amount of time is greater than said first amount of time.

10. The method of claim 1, wherein forming said groove comprises causing a laser to traverse said closed path.

11. The method of claim 1, wherein forming said groove comprises: causing a laser beam to trace out said closed path on said substrate and controlling said laser beam to cause an extent of ablation along said closed path to depend on position along said closed path.

12. The method of claim 1, wherein forming said groove comprises using a laser to ablate said substrate along a first portion of said closed path and using said laser to ablate said substrate along a second portion of said closed path, said second portion being shorter than said first portion.

13. The method of claim 1, wherein forming said groove comprises using a laser to ablate said substrate along a first portion of said closed path and using said laser to ablate a second portion of said substrate, wherein said second portion of said substrate is a portion of said first portion of said substrate.

14. The method of claim 1, wherein said closed path defines a circle and wherein forming said groove comprises using a laser to ablate said substrate along a first arc of a circle defined by said path and using said laser to ablate said substrate along a second arc of said circle, said second arc being shorter than said first arc.

15. The method of claim 1, wherein forming said groove comprises using a laser to ablate said substrate along a first arc of a circle defined by said closed path and using said laser to ablate a second arc of said circle, said second arc being a portion of said first arc.

16. The method of claim 1, wherein forming said groove comprises using a laser beam to deliver a first quantity of radiant energy to a first portion of said groove and using said laser to deliver a second quantity of radiant energy to a second portion of said groove, wherein said second quantity is greater than said first quantity, and wherein said second portion is a portion of said first portion.

17. The method of claim 1, wherein forming said groove comprises using a laser to illuminate a first portion of said groove with radiant energy having a first power density and using said laser to illuminate a second portion of said groove with radiant energy having a second power density, said second power density being greater than said first power density.

18. The method of claim 1, wherein forming said groove comprises exposing a first portion of said groove to a laser beam for a first amount of time and exposing a second portion of said groove to said laser beam for a second amount of time, wherein said second amount of time is greater than said first amount of time and wherein said second portion of said groove is a portion of said first portion.

19. The method of claim 1, wherein forming said groove comprises causing a laser beam to trace out said closed path on said substrate and controlling incident power along said closed path to cause differences in depth of said groove along said closed path.

20. The method of claim 1, wherein forming said groove comprises causing a laser beam to trace out said closed path on said substrate and controlling a velocity at which said laser beam traverses said closed path, thereby causing different extents of ablation along different sections of said closed path.

21. The method of claim 1, wherein said closed path comprises a circle.

22. The method of claim 1, wherein said closed path defines a circle and wherein forming said groove comprises causing a laser to traverse said circle, thereby defining a first region, causing said laser to traverse a first arc along said circle, said first arc being less than said circle’s circumference, thereby defining a second region of said groove, causing said laser to traverse a second arc along said close path, shorter than said first arc, therebydefining a third region of said groove, wherein said first region forms a base of said microneedle, wherein said second region of said groove forms a shaft of said microneedle, wherein said third region of said groove forms a tip of said microneedle, and wherein said second region is between said first region and said third region.

23. The method of claim 1, wherein manufacturing said mold for making said microneedle comprises manufacturing said mold for making said microneedle with a diameter of less than half a millimeter.

24. The method of claim 1, further comprising manufacturing a housing for holding a reservoir and wherein manufacturing said microneedle comprises causing said microneedle to be integral with a base of said housing to enable a fluid to pass between said reservoir and a space outside said reservoir.

25. The method of claim 1, wherein said microneedle is a first microneedle, wherein said groove is a first groove, wherein said closed path is a first closed path, wherein said method further comprises manufacturing a second microneedle, manufacturing a reservoir having first and second chambers, filling said first chamber with a first drug, and filling said second chamber with a second drug, wherein manufacturing said second microneedle comprises forming a second groove in said substrate, said second groove following a second closed path and having a depth that varies with position in along said second closed path, wherein said first chamber is in fluid communication with said first microneedle and wherein said second chamber is in fluid communication with said second microneedle, wherein said first microneedle delivers said first drug, and wherein said second microneedle delivers said second drug.

26. An apparatus for manufacturing a microneedle, wherein said apparatus comprises a laser, a beam steerer for causing a beam of said laser to illuminate different portions of a substrate, and a controller for causing said laser to form a groove in said substrate, wherein said groove follows a closed path and has a depth that varies with position along said closed path.CLAIMS1. A method comprising manufacturing a microneedle, said method comprising manufacturing a mold for said microneedle by forming a groove in a substrate, wherein said groove follows a closed path and has a depth that varies with position along said closed path.

2. The method of claim 1, wherein forming said groove comprises ablating said substrate along a first portion of said closed path and ablating said substrate along a second portion of said closed path, said second portion being shorter than said first portion.

3. The method of claim 1, wherein forming said groove comprises ablating said substrate along a first portion of said closed path and ablating a portion of said first portion of said substrate.

4. The method of claim 1, wherein forming said groove comprises: ablating said substrate along a first arc of a circle defined by said path and ablating said substrate along a second arc of said circle, said second arc being shorter than said first arc.

5. The method of claim 1, wherein forming said groove comprises ablating said substrate along a first arc of a circle defined by said closed path and ablating a second arc of said circle, said second arc being a portion of said first arc.

6. The method of claim 1, wherein forming said groove comprises ablating said substrate along said closed path, wherein ablating said substrate comprises varying an extent of said ablation while ablating said substrate along said closed path.

7. The method of claim 1, wherein forming said groove comprises exposing a first portion of said groove to a first quantity of radiant energy and exposing a portion of said first portion to a second quantity of radiant energy, wherein said second quantity is greater than said first quantity.

8. The method of claim 1, wherein forming said groove comprises exposing a first portion of said groove to radiant energy having a first power density and exposing a secondportion of said groove to radiant energy having a second power density, said second power density being greater than said first power density.

9. The method of claim 1, wherein forming said groove comprises exposing a first portion of said groove to radiant energy for a first amount of time and exposing a second portion of said groove to radiant energy for a second amount of time, wherein said second amount of time is greater than said first amount of time.

10. The method of claim 1, wherein forming said groove comprises causing a laser to traverse said closed path.

11. The method of claim 1, wherein forming said groove comprises: causing a laser beam to trace out said closed path on said substrate and controlling said laser beam to cause an extent of ablation along said closed path to depend on position along said closed path.

12. The method of claim 1, wherein forming said groove comprises using a laser to ablate said substrate along a first portion of said closed path and using said laser to ablate said substrate along a second portion of said closed path, said second portion being shorter than said first portion.

13. The method of claim 1, wherein forming said groove comprises using a laser to ablate said substrate along a first portion of said closed path and using said laser to ablate a second portion of said substrate, wherein said second portion of said substrate is a portion of said first portion of said substrate.

14. The method of claim 1, wherein said closed path defines a circle and wherein forming said groove comprises using a laser to ablate said substrate along a first arc of a circle defined by said path and using said laser to ablate said substrate along a second arc of said circle, said second arc being shorter than said first arc.

15. The method of claim 1, wherein forming said groove comprises using a laser to ablate said substrate along a first arc of a circle defined by said closed path and using said laser to ablate a second arc of said circle, said second arc being a portion of said first arc.

16. The method of claim 1, wherein forming said groove comprises using a laser beam to deliver a first quantity of radiant energy to a first portion of said groove and using said laser to deliver a second quantity of radiant energy to a second portion of said groove, wherein said second quantity is greater than said first quantity, and wherein said second portion is a portion of said first portion.

17. The method of claim 1, wherein forming said groove comprises using a laser to illuminate a first portion of said groove with radiant energy having a first power density and using said laser to illuminate a second portion of said groove with radiant energy having a second power density, said second power density being greater than said first power density.

18. The method of claim 1, wherein forming said groove comprises exposing a first portion of said groove to a laser beam for a first amount of time and exposing a second portion of said groove to said laser beam for a second amount of time, wherein said second amount of time is greater than said first amount of time and wherein said second portion of said groove is a portion of said first portion.

19. The method of claim 1, wherein forming said groove comprises causing a laser beam to trace out said closed path on said substrate and controlling incident power along said closed path to cause differences in depth of said groove along said closed path.

20. The method of claim 1, wherein forming said groove comprises causing a laser beam to trace out said closed path on said substrate and controlling a velocity at which said laser beam traverses said closed path, thereby causing different extents of ablation along different sections of said closed path.

21. The method of claim 1, wherein said closed path comprises a circle.

22. The method of claim 1, wherein said closed path defines a circle and wherein forming said groove comprises causing a laser to traverse said circle, thereby defining a first region, causing said laser to traverse a first arc along said circle, said first arc being less than said circle’s circumference, thereby defining a second region of said groove, causing said laser to traverse a second arc along said close path, shorter than said first arc, therebydefining a third region of said groove, wherein said first region forms a base of said microneedle, wherein said second region of said groove forms a shaft of said microneedle, wherein said third region of said groove forms a tip of said microneedle, and wherein said second region is between said first region and said third region.

23. The method of claim 1, wherein manufacturing said mold for making said microneedle comprises manufacturing said mold for making said microneedle with a diameter of less than half a millimeter.

24. The method of claim 1, further comprising manufacturing a housing for holding a reservoir and wherein manufacturing said microneedle comprises causing said microneedle to be integral with a base of said housing to enable a fluid to pass between said reservoir and a space outside said reservoir.

25. The method of claim 1, wherein said microneedle is a first microneedle, wherein said groove is a first groove, wherein said closed path is a first closed path, wherein said method further comprises manufacturing a second microneedle, manufacturing a reservoir having first and second chambers, filling said first chamber with a first drug, and filling said second chamber with a second drug, wherein manufacturing said second microneedle comprises forming a second groove in said substrate, said second groove following a second closed path and having a depth that varies with position in along said second closed path, wherein said first chamber is in fluid communication with said first microneedle and wherein said second chamber is in fluid communication with said second microneedle, wherein said first microneedle delivers said first drug, and wherein said second microneedle delivers said second drug.

26. An apparatus for manufacturing a microneedle, wherein said apparatus comprises a laser, a beam steerer for causing a beam of said laser to illuminate different portions of a substrate, and a controller for causing said laser to form a groove in said substrate, wherein said groove follows a closed path and has a depth that varies with position along said closed path.

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