U.S. patent application number 13/554781 was filed with the patent office on 2013-07-18 for 3d fabrication of needle tip geometry and knife blade.
This patent application is currently assigned to University of Utah Research Foundation. The applicant listed for this patent is Sung K. Lee, Charles L. Thomas. Invention is credited to Sung K. Lee, Charles L. Thomas.
Application Number | 20130184609 13/554781 |
Document ID | / |
Family ID | 40534927 |
Filed Date | 2013-07-18 |
United States Patent
Application |
20130184609 |
Kind Code |
A1 |
Lee; Sung K. ; et
al. |
July 18, 2013 |
3D FABRICATION OF NEEDLE TIP GEOMETRY AND KNIFE BLADE
Abstract
The present invention provides a method for creating a beveled
needle or a blade. The method employs a side wall surface of an
angled post as a base to control beveled tip geometry. The
invention provides needles, microneedle arrays, blades and
microblade arrays with sufficient sharpness and toughness.
Inventors: |
Lee; Sung K.; (Euless,
TX) ; Thomas; Charles L.; (Salt Lake City,
UT) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Lee; Sung K.
Thomas; Charles L. |
Euless
Salt Lake City |
TX
UT |
US
US |
|
|
Assignee: |
University of Utah Research
Foundation
Salt Lake City
UT
|
Family ID: |
40534927 |
Appl. No.: |
13/554781 |
Filed: |
July 20, 2012 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
11818622 |
Jun 14, 2007 |
8250729 |
|
|
13554781 |
|
|
|
|
60830307 |
Jul 12, 2006 |
|
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Current U.S.
Class: |
600/573 ;
249/127; 264/219; 604/173; 604/272; 606/167 |
Current CPC
Class: |
A61M 37/0015 20130101;
A61M 2037/0046 20130101; Y10T 29/49982 20150115; A61M 2037/0053
20130101; A61B 17/205 20130101; A61M 2037/003 20130101; A61B
2017/00526 20130101; B29C 33/42 20130101; A61B 17/3211
20130101 |
Class at
Publication: |
600/573 ;
604/272; 606/167; 604/173; 264/219; 249/127 |
International
Class: |
B29C 33/42 20060101
B29C033/42 |
Claims
1. An implement, the implement prepared by: creating at least one
inclined structure which defines an angle of an angled tip of the
implement, the angle defining the implement's sharpness; and
building at least one needle mold structure or at least one blade
mold structure on the inclined structure.
2. The implement of claim 1, wherein the at least one inclined
structure is created by one or more of mechanical machining, laser
ablation, lithography, abrasion, electric discharged machining
(EDM), electric chemical machining (ECM), etching, or
deposition.
3. The implement of claim 1, wherein building the least one needle
mold structure or at least one blade mold structure on the inclined
structure comprises building a microneedle array mold structure
including a plurality of needle mold structures on the inclined
structure, and wherein the implement is combined with one or more
other implements to from a microneedle array with a controllable
beveled angle needle tip, the angle of the controllable beveled
angle needle tip being controlled by the inclined structure.
4. A method for making a mold structure for an implement, the
method comprising: applying an elastomer over an implement, the
implement prepared by: creating at least one inclined structure
which defines an angle of an angled tip of the implement, the angle
defining the implement's sharpness; and building at least one
needle mold structure or at least one blade mold structure on the
inclined structure; and removing the implement to obtain the
elastomer mold structure.
5. The method according to claim 4, wherein the elastomer is
PDMS.
6. The method according to claim 4, further comprising: applying an
elastomer over the mold structure to obtain an elastomer structure;
disassociating the elastomer structure from the mold structure;
applying a solvent soluble material over the elastomer structure;
and removing the elastomer structure to obtain a soluble mold
structure.
7. The method according to claim 6, wherein the solvent soluble
material is PVA.
8. A mold structure, the mold structure prepared by: applying an
elastomer over an implement, the implement prepared by: creating at
least one inclined structure which defines an angle of an angled
tip of the implement, the angle defining the implement's sharpness;
and building at least one needle mold structure or at least one
blade mold structure on the inclined structure; and removing the
implement to obtain the elastomer mold structure.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application is a continuation of U.S. patent
application Ser. No. 11/818,622, filed on Jun. 14, 2007 and
entitled "3D FABRICATION OF NEEDLE TIP GEOMETRY AND KNIFE BLADE,"
now allowed, which application claims the benefit of and priority
to U.S. Provisional Application Ser. No. 60/830,307, filed on Jul.
12, 2006, entitled "3D FABRICATION OF NEEDLE TIP GEOMETRY AND KNIFE
BLADE," the entirety of each of which are incorporated herein by
reference.
TECHNICAL FIELD
[0002] The invention relates to the field of device fabrication,
such as, fabrication and manufacture of microneedles or
microblades.
BACKGROUND
[0003] Various forms of drug delivery systems, such as patches,
capsules, and needles, are known in the art to administer drugs to
a subject. Various methods of extracting blood samples, for
example, making a small cut with a blade, are also available. Among
the current drug delivery systems and methods of extracting blood
samples, a hypodermic needle is commonly used, and is known as one
of the most effective devices.
[0004] However, using a conventional hypodermic needle has several
disadvantages. For example, penetration of skin using a
conventional hypodermic needle may cause pain to a subject. Also,
mishandling of a conventional hypodermic needle may result in
infections caused by human immunodeficiency virus (HIV), hepatitis
B and C viruses, etc..sup.[1-6] Hence, many researchers have been
developing hypodermic needles in small scale referred to as
"microneedles," to administer drugs or extract blood.
[0005] Employing diffusion effects, a microneedle can deliver a
drug through the skin without deep penetration. Skin thickness
varies depending on its location. Normally, human skin comprises
three layers: stratum corneum, viable epidermis, and dermis. A
microneedle can penetrate the first two layers of the human skin,
which is about 150 .mu.m, to deliver a drug effectively. For
collecting blood samples from a human, the length of a microneedle
should be in the range of about 500 .mu.m.
[0006] Usually, three different materials are used for creating a
hollow microneedle: silicon-based material including glass, metal,
and photosensitive polymers. McAllister et al. developed a hollow
microneedle based on silicon dioxide (SiO.sub.2), in out of plane
and lateral fashion, using a heavy chemical etching
process..sup.[7-8] Stoeber et al. also applied a similar
fabrication process to create a hollow microneedle..sup.[9] Both
McAllister et al. and Stoeber et al. used bulk micromachining
technology to create the outer microneedle geometry, and used deep
reactive ion etching (DRIE) or reactive ion etching (RIE) to create
the hollow geometry. First, the process begins with the hollow
holes created by the RIE technique followed by growing silicon
dioxide thermally which will later become a needle structure.
Machined Pyrex.RTM. is then anodically bonded to a silicon wafer to
create a space for reservoir. At last, the silicon wafer is etched
back with tetramethylammonium hydroxide to define the height of the
needle. For lateral microneedles, it is fabricated by using a
surface micromachining technique. A patterned silicon dioxide layer
defines microchannels, and a nitride layer is deposited to create
the top and side walls. Multiple ethylendiamminepyrocatechol (EDP)
etches are carried out to complete the process.
[0007] Brazzle et al. created a metallic microneedle in a lateral
fashion using surface micromachining technique..sup.[10-11] The
sequence of photolithography is carried out for patterning silicon
nitride (Si.sub.3N4) on a heavily doped silicon substrate and
etched in potassium hydroxide (KOH) to build a platform for the
microneedle. Palladium is then electroplated on the patterned area
to define the bottom wall followed by spinning a layer of
photoresist. A 20 .mu.m thick photoresist is patterned and
developed to form the shape of the inside of the needle. Further
electroplating is performed to build the side walls and top wall
for encapsulating the photoresist. Finally, the photoresist is
etched to leave a hollow metallic microneedle. McAllister et al.
also manufactured a metallic microneedle array, which has square
cross-section channel, using similar procedures. The base layer is
electroplated followed by depositing and patterning a sacrificial
thick photoresist. A seed layer is then sputtered onto the
photoresist. Next, the side and top walls are electroplated.
Finally, the photoresist is removed and the needle structure is
lifted from the substrate.
[0008] A more realistic, out of plane, microneedle array has been
developed by Kim et al. using a tapered negative photoresist
(SU-8)..sup.[12] The tapered SU-8 post, which has angles between
3.1 to 5 degrees, is created using backside exposure on top of the
SU-8 block which functions as a base. The seed layers are
deposited, and electroplating is carried out to obtain 200 .mu.m
and 400 .mu.m in length and thickness of 10 .mu.m and 20 .mu.m,
respectively.
[0009] Moon et al. presented a different approach of microneedle
fabrication using a deep X-ray to create an inclined polymeric
microneedle..sup.[13-14] The fabrication process begins with
exposing polymethylemetacrylate (PMMA), a positive photoresist,
under X-ray vertically followed by successive exposure in a
pre-defined angle without moving the substrate. These two steps
define a sharp needle tip at the region of interception of the
exposures. A sharp tip angle below 40 degree is achieved with the
needle length of between 600 .mu.m to 1000 .mu.m.
[0010] Kuo et al. reported fabrication of polymeric microneedles
using SU-8..sup.[15] A trapezoidal trench is created by potassium
hydroxide (KOH) etch on 100 silicon wafer. The angle of the trench
(about 35.3 degrees: measured from the vertical to the etched
surface) is used to determine the angle of the beveled tip of a
microneedle. After KOH etching is used to obtain the trapezoidal
grooves, SU-8 is then applied and patterned using lithographic
technique to create an array of hollow needle structures. Partial
SU-8 development is carried out to expose the ends of the
microneedle structure. These partially exposed needle structures
are covered with another layer of SU-8 to form the base. The second
SU-8 layer is further patterned and developed. The length of the
microneedle is about 600 .mu.m. A negative mold is also replicated
with polydimethylesiloxane (PDMS). The report shows that these
needles can successfully penetrate skin.
[0011] However, silicon-based microneedle structures tend to be
brittle. Stiffness and toughness of metallic microneedles are still
in question due to their thin walls. Flat needle tips of these
metallic microneedles are not suitable for skin penetration. For
microneedles made of photosensitive polymer, the stiffness of the
needle structures and the strength between the needle structures
and the bases are uncertain, even though the needles are capable of
skin penetration.
[0012] Sparks et al. developed a microneedle array with sharp
beveled tips using combinations of LIGA and soft lithography
technique..sup.[24] Two dimensional sawtooth profile was patterned
on polymethylmethacrylate (PMMA) to create the beveled tip
microneedle using Deep x-ray lithography (DXRL). The angle of the
sawtooth design becomes the beveled angle of the final microneedle
tip. The four different angles were tested from 25 to 40 degrees.
The sawtooth structure is then cut in pieces, stacked on top of
each other piece, turned, and the side wall was glued on a
conductive substrate to form a 8.times.10 mm area for microneedle
array. The second radiation performed on a glass slab to create a
mask patterned of equilateral triangles with a hole pattern for
defining the microneedle and the hollow features directly on the
sawtooth structure. After exposure and partial development of the
PMMA substrate, electroplating was carried out to form the metal
layer around the needle structures. The thickness of the metal
layer provides space for creating a base of the microneedle array.
A successive development of the microneedle opens the bottom of the
hollow features. Next, polyvinyl alcohol (PVA) is cast onto the
microneedle array and used as a sacrificial template to replicate
the microneedle array consisted of PMMA (material for actual
microneedle structure) and a metal (for a base). Finally, PMMA is
cast on the replicated PVA mold. Dissolving the PVA mold in water
reveals the final product of plastic microneedle array. Advantage
of the technique described above is that use of molding process
opens the possibility of mass production for the beveled plastic
microneedle array. The difficulty in assembly of sawtooth structure
from the 21/2 D in order to create 3D inclined structure, and in
alignment of second radiation to create hollow features on the
needle structure as well as use of expensive DXRL technique become
disadvantages.
[0013] Perennes et al. created microneedle arrays and blades in
plane by means of etching the patterned single crystal
silicon..sup.[25] First, the patterned single crystal silicon is
etched to form the microchannels which will become the hollow
structure in the needle. Second, fusion bonding of silicon to
silicon is performed to seal the etched microchannels. Next, the
plasma etching is carried out around the embedded microchannels
according to the 2D beveled needle layout. At last, anisotropic
etching creates the microneedle with the vertical side wall as well
as it opens the microchannel on the side of the beveled surface
along the vertical wall. In addition, the fabrication of microblade
uses same manufacturing steps excluding creating microchannels and
fusion bonding process. This technique can produce controllable
21/2 D in plane microneedle arrays and microblades. However, the
material used in the experiment is brittle and the cutter length of
the blade is too short.
[0014] Although many microneedle fabrication processes have been
developed, and there is a steady growth of using microneedles, the
majority of the biomedical industry is still reluctant to adopt
various microneedle fabrication techniques for needle production. A
good needle structure should meet at least the following criteria:
(1) adequate stiffness to prevent premature buckling failure, (2)
adequate sharpness to penetrate a rubber-like skin, (3) adequate
toughness to avoid particle breakage which may clog the vein, (4)
sufficiency in length for use as a drug delivery or a body fluid
extracting device, and (5) adequate biocompatibility.
SUMMARY OF THE INVENTION
[0015] Provided is, among other things, a method for preparing a
needle with or without a hollow section, a needle array, a blade,
or a blade array, the method comprising: creating at least one
inclined or skewed structure that defines the angle of the needle
or blade tip. The inclined structure can be created by various
techniques including but are not limited to mechanical machining,
laser ablation, lithography, abrasion, electric discharged
machining (EDM), electric chemical machining (ECM) and etching.
Multiple exposures can be used for creating the inclined structure.
A needle or blade mold structure or an actual needle or blade
structure can be built upon the inclined structure.
[0016] In certain embodiments, provided is a mold structure for a
needle, a needle array, a blade or a blade array. The mold
structure is built upon at least one inclined structure, which
controls the angle and thus the sharpness of the needle or blade.
Various materials, such as metal, plastic, polymer, and/or
biocompatible materials, can be deposited onto a mold structure to
create a needle, a needle array, a blade or a blade array for a
specific application.
[0017] In certain embodiments, also provided are devices including
needles, blades, microneedle arrays, and microblade arrays, wherein
the sharpness of the needle or blade is controlled by at least one
inclined structure. The device provided by the invention can be of
any size, in either length or diameter, and/or of various
shapes.
DESCRIPTION OF THE FIGURES
[0018] FIG. 1: A schematic of light angles traveling through a
limestone glass substrate. .THETA..sub.1 and .THETA..sub.2 are
incident angles for the glass substrate and SU-8. .THETA..sub.3 is
the refractive angle in SU-8.
[0019] FIG. 2: An array of skewed posts.
[0020] FIG. 3: A schematic of a microneedle manufacturing process:
a) a glass substrate, b) metal layer deposition, c) a positive
photoresist deposition, d) patterning the photoresist for etching
the metal layer, e) spin-coating SU-8 photoresist, f) back-side
exposure to create tilted posts, g) spin-coating SU-8 and
patterning for needle mold structures, h) developing but not
post-exposure bake, i) spin-coating another SU-8 layer for
extending post and creating a base, j) developing and performing
post-exposure bake, k) depositing a seed layer, l) nickel
electroplating, and m) CMP to open the end of the needle base and
remove SU-8.
[0021] FIG. 4: An example of inside structures of wells.
[0022] FIG. 5: An array of wells before electroplating.
[0023] FIG. 6: A picture showing posts used for creating hollow
structures during electroplating for a microneedle array.
[0024] FIG. 7: The front view of a beveled metallic
microneedle.
[0025] FIG. 8: An angled view of a beveled metallic
microneedle.
[0026] FIG. 9: A round microneedle post with a flat tip.
[0027] FIG. 10: An angled view of round microneedle post array.
[0028] FIG. 11: A backside view at 45 degree angle of round
microneedle post.
[0029] FIG. 12: Various cross sections of a blade or a mold and a
side view of a needle structure or mold.
[0030] FIG. 13: One design for creating microneedle and microneedle
mold structures.
[0031] FIG. 14: One design for tapered microneedle and microneedle
mold structures.
[0032] FIG. 15: Designs for blade and blade mold structures.
[0033] FIG. 16: One design for a die cutter.
DETAILED DESCRIPTION OF THE INVENTION
[0034] A beveled metallic needle is developed using a
three-dimensional ("3D") SU-8 mold structure. Microneedle array
with controllable beveled angle of the needle tip in metal, plastic
and other materials can also be made. The 3D mold is fabricated
using an angled exposure onto the SU-8 to create a skewed surface
which will become a beveled surface followed by a series of
vertical exposures to create wells which will then become needle
posts. Development of various depths with a single exposure is a
crucial factor for creating a mold structure with a beveled
surface. Similar fabrication procedures can be adopted to create a
blade or micro-blade. The invention provides complex design for
controllable 3D tip geometry.
[0035] Existing microneedle fabrication techniques cannot control
the needle tip geometry in 3D. Some existing techniques can produce
an angled needle. However, the present invention offers far more
flexibilities. For example, the present invention can provide a
tubular hollow needle with an angled tip. The present invention can
also provide controlled sharp needle tip or other 3D geometries for
various purposes such as easy penetration for drug delivery, blood
and/or cell extraction, cell manipulation or transfer, etc. A 3D
knife blade with controlled blade can also be created for
microsurgical applications. The fabrication can be carried out in
either a vertical or a horizontal layout.
[0036] In one aspect, the invention provides a method for preparing
a needle with or without a hollow section, a needle array, a blade
or a blade array, the method comprising: creating at least one
inclined or skewed structure that defines the angle of the needle
or blade tip. The inclined structure can be created by various
techniques including but are not limited to mechanical machining,
laser ablation, lithography, abrasion, electric discharged
machining (EDM), electric chemical machining (ECM), and etching.
Multiple exposures can be used for creating the inclined structure.
The inclined structure can be made of various materials. A mold
structure or an actual needle (array) or blade (array) structure
can be built upon the inclined structure.
[0037] In one embodiment, the mold structure comprises a well with
a post inside the well, which well defines a part of the needle
wall, and which post defines a part of the hollow section of the
needle. A layer of material deposited upon the mold structure
becomes a part of the needle wall. A specific example of the
present invention is illustrated in FIG. 3 (a) through (m). The
present embodiment should be deemed more general than illustrated
in FIG. 3. In another embodiment, the mold structure comprises a
well without a post inside, applying a layer of material upon the
mold structure results in a needle without a hollow section, or a
blade.
[0038] It is to be noted, the masks for patterning a needle or
blade (mold) structure, as exemplified in FIG. 3(g), can be of
various shapes, such as oval, square or diamond. Using different
shaped masks thus produces needles or blades of various cross
sections, as exemplified in FIG. 12. In order to function as a
blade effectively, the cross section of the mold is more likely
stretched in one direction than the other. In a particular
embodiment, a gray scale mask, as exemplified in FIG. 14(d), is
used to create a tapered needle or blade structure. A gray scale
can also be used for controlling or varying exposure dosage of
light sources.
[0039] The inclined structure or inclined post that defines the
angle of a needle or blade tip can be built upon a substrate. The
inclined post may have various angles relative to the substrate,
thus providing a needle or blade tip with various angles, and thus
providing a needle or blade tip with varying sharpness. A more
skewed post will provide a flatter needle tip. A skewed post is
exemplified in FIG. 3 (f). The post can be made of a photoresist
material. For example, a negative photoresist such as SU-8 is
deposited onto a substrate. The backside of the substrate is
exposed under UV light at a desired angle, and then the SU-8 layer
is developed in an appropriate bath. The angle of the post relative
to the substrate is defined by the direction of the UV irradiation.
Such deposition, irradiation and development techniques of
photoresist are commonly known in the art of lithography or
photolithography. More specifically, a post-exposure bake can be
performed. After development of the photoresist layer, a rinse
step, e.g., rinsing with isopropyl alcohol, can be applied to check
the degree of development and remove uncrosslinked photoresist.
Treatment procedures of photoresist such as baking or rinsing are
also known in the art. It is also known in the art that photoresist
can be patterned by other light sources such as laser and X-ray. A
point light source, e.g., laser, can be used to irradiate, at a
defined angle, a defined area, as exemplified in FIG. 16.
[0040] The substrate, which the inclined post is built upon, can be
transparent to a light source. For example, the substrate can be
glass or plastic. In one embodiment, a UV-transparent substrate is
coated with a non-UV transparent material, such as a metal layer,
e.g., chromium. The coated substrate is patterned to create areas
that are UV transparent. Patterning of the coated substrate can be
facilitated by a layer of photoresist. Patterning techniques of a
substrate or a photoresist layer are known in the art, and are
exemplified as follows. A positive photoresist, such as AZ 1518, is
deposited onto a metal-coated substrate. The substrate is baked and
exposed to UV light under a patterned mask. The patterned
photoresist is developed, and then the surface of the metal-coated
substrate is etched to define a mask to be used for creating an
inclined post that defines the tip angle of a needle. An example of
patterning a metal-coated substrate is illustrated in FIG. 3 (a)
through (d). In another embodiment, when a UV-transparent substrate
is used, a patterned mask can be placed under the substrate to
facilitate UV exposure from the backside, and thus coating of the
substrate with a non-UV transparent material is not necessary.
[0041] However, the substrate needs not to be transparent to a
light source. For example, one can expose a photoresist layer
deposited on a substrate from the top with a light source set at an
appropriate angle to produce an inclined post, as exemplified in
FIG. 14 (a).
[0042] It should be appreciated, in various embodiments of the
invention, when a certain structure is obtained, regardless of the
shape and/or material the structure is built of, a layer of
material, such as an elastomer, can be applied upon this original
structure to produce a negative or a mold of the original
structure, which layer of material fills the cavity of the original
structure. In addition, a sacrificial mold structure can be
obtained by applying a solvent soluble material over a replicated
elastomer structure. An example for such a solvent soluble material
is PVA.
[0043] The inclined post can be in a vertical position, as
exemplified in FIG. 3, or in horizontal position, as exemplified in
FIG. 15 (A). It should be appreciated that, in certain cases, one
inclined structure is required to create a sharp edge or tip, as
exemplified in FIG. 15 (B)(b). In some other cases, at least two
inclined structures are needed to form a cutting edge of a blade,
as exemplified in FIG. 15 (B)(a).
[0044] A blade or needle mold structure can be built by depositing
a layer of photoresist, such as SU-8, on the inclined post. The
thickness of this layer defines the length (height) of the needle
or blade. Therefore, the thickness of this layer of photoresist may
be adjusted to obtain a needle or blade of desired height. This
layer of photoresist can be patterned with UV exposures, resulting
in a well with a post inside the well. FIG. 3 (g) shows an example
of patterning of a photoresist material with UV exposure. The well
and the post provided by this layer of photoresist are exemplified
in FIG. 3 (h). The post provided by this layer will become a part
of the hollow section of a needle. The well provided by this layer
defines the needle wall. It is to be noted that patterning of this
layer of photoresist material can create a well of various shapes
or sizes, thus providing a needle with a wall of various shapes or
thickness. Also, patterning of this layer can create a needle with
variously shaped post, thus creating variously shaped hollow
section, although a needle with a cylindrical hollow section is
preferred and practical. Such patterning techniques to create a
well and a post of various sizes or shapes are well known in the
art of lithography. Prior to UV irradiation, this layer of
photoresist may be soft-baked.
[0045] Consequently, a layer of photoresist material, such as SU-8,
is deposited upon the well with a post inside, which post defines
the hollow section of the needle and which well defines the needle
wall. This layer of photoresist can be patterned resulting in an
extended post in the well, and creating a base for the needle. An
example of creating the extended post and the needle base is
illustrated in FIGS. 3 (i) and (j). This layer of photoresist may
be soft-baked prior to UV irradiation and/or baked after UV
irradiation. Then a development step is performed to obtain a mold
structure, namely, a well with a (extended) post inside the
well.
[0046] Appropriate materials can be deposited upon a mold structure
to form a needle or a blade. Such materials may be metal, such as
nickel, palladium, stainless steel, and/or other materials such as
polymers and ceramics. The mold structure can be removed to obtain
the needle. Deposition of a metal upon a mold structure can be
carried out by electroplating. Prior to electroplating, a seed
layer may be deposited onto a mold structure. After electroplating,
chemical polishing may be used to remove access electroplated
material. An example of depositing a seed layer, electroplating and
opening the needle base is illustrated in FIG. 3 (k) through
(m).
[0047] It is to be noted that a person skilled in the art can make
modifications to the methods as described. For example, a person
skilled in the art can make modifications to the disclosed mold
structure thus fabricate a mold structure comprising a well without
a post inside. Applying a material upon the mold structure results
in a needle without a hollow section, or a blade. For another
example, a blade of an arbitrary shape, such as a die cutter, can
be created following similar principle and/or procedures. As well,
the sequences of the procedures in various embodiments of the
invention can be changed. It is also to be noted that the method
described can provide an array of inclined structures, thus
providing a needle or blade array mold structure, and thus
providing a needle array, a microneedle array, a blade array or a
microblade array.
[0048] It will be appreciated that a process for producing a needle
or blade structure may comprise a process of creating a mold
structure. For example, in FIG. 3, the process for creating a
needle mold comprises steps (a) through (k). Consequently steps (l)
and (m) produces a needle structure built upon the mold. However,
once a needle structure is obtained, a negative mold can be easily
built by applying a layer of material, such as elastomer, over the
needle or blade structure. An example of such elastomer is PDMS.
Obtaining a mold structure by applying an elastomer over an actual
needle structure is exemplified in FIG. 13.
[0049] In another aspect, the invention provides a mold structure
that facilitates fabrication of a needle, a needle array, a blade
or a blade array. Such a mold structure can be built by various
embodiments of the method disclosed. In one embodiment, a mold
structure is built upon at least one inclined structure, which
controls the angle of the needle or blade tip. A needle mold may
comprise a well with a post inside the well, which well defines a
part of the needle wall, and which post defines a part of the
hollow section of the needle. A specific example of a needle mold
is illustrated in FIG. 3 (h) through (j). The need or blade mold
provided by the present invention should be deemed more general
than illustrated in FIG. 3 (h) through (j). A blade or needle mold
structure may comprise a well without a post inside, which well
defines part of the blade or needle body.
[0050] In certain embodiments, provided are devices including
needles, blades, needle arrays, microneedle arrays, blade arrays
and microblade arrays, wherein the angle or sharpness of the blade
or needle are controlled by at least one inclined structure. A
device provided herein can be of any size, in either length or
diameter. By varying the patterning of exposures, devices of
various shapes can be obtained. Various materials, such as metal,
plastic, polymer, and/or biocompatible materials, can be deposited
onto a mold structure to create a needle or a blade for a specific
application. The devices can be used in drug delivery, sample
collection, surgical settings and other areas. Microneedles (or
micropipettes) can be used as a component in biomedical diagnostic
devices for drug delivery, blood extraction, or transport.
Microblades can be used in surgical devices that require
micro-scale blade. Arrays of microneedles or microblades can be
used for high throughput screening or diagnostic assays, and other
far reaching yet not foreseeable applications.
[0051] The present invention is further described in the following
non-limiting examples, which are offered by way of illustration and
are not intended to limit the invention in any manner.
EXAMPLES
Example 1
Creation of Sharp Metallic Microneedles and Microneedle Arrays
[0052] A new manufacturing method to create a beveled metallic
microneedle is introduced. The method uses a side wall surface of
an angled post as a base for the needle tip to create the beveled
tip geometry for easy skin penetration. With proper dimensional
corrections, the microneedle manufactured using the present method
allows to keep the strength of the needle structure while
increasing skin penetration ability since the cross-section area of
the needle post structure is not required to sacrifice. Therefore,
the microneedle provided by the present method can be used in
clinical practice providing a safe and painless administration, but
without potential concerns.
[0053] Construction of angled structures using inclined exposure
fabrication technique is available for many applications, e.g.,
microfilter, microchannel, microstructures, etc..sup.[16-23] The
first fabrication step for a microneedle was performed with
backside exposure on a layer of SU-8. On a patterned metal layer
coated on a glass substrate, SU-8 was applied and exposed from the
back to create inclined post. The angle of the post is then used to
determine the angle of the microneedle structure. Since the UV
light travels through air, glass, and SU-8 in sequence, the range
of the angle governed by Snell's law as below.
sin .theta. 1 n 2 = sin .theta. 2 n 1 ##EQU00001##
Where, .THETA..sub.1 and .THETA..sub.2 are the incident and
refractive angles, respectively, n.sub.1 and n.sub.2 are the
refractive index of the medium where the light is entering and
leaving, respectively. According to Snell's law, the incident angle
of the UV light that travels through the SU-8 layer is determined
by the refraction index of the glass substrate. To determine the
incident angle of the light at the interface between SU-8 and the
glass substrate, the refraction index used for the glass and SU-8
were approximately 1.52 and 1.67 at 365 nm wave lengths,
respectively. From this, the range of the refracted light that can
be used to define the beveled angle on the tip of the microneedle
should be about between 0 to 36.78 degrees. FIG. 1 shows the paths
of the light traveled through the all three mediums and Table 1
shows the range of angles for the beveled microneedle tip that can
be obtained from SU-8 in every 10 degrees of incident angles of
air. The calculated angles for the glass are used for incident
light angles of the SU-8. FIG. 2 shows the actual skewed post
fabricated during the microneedle manufacturing.
TABLE-US-00001 TABLE 1 Approximate beveled angle range of the
microneedle air* glass* SU8* 0 0 0 10 6.55991952 5.9684576 20
13.0036574 11.817937 30 19.2048975 17.421641 40 25.0169643
22.637704 50 30.2634408 27.303849 60 34.7330422 31.236921 70
38.1861803 34.242047 80 40.3834451 36.136094 90 41.1395104
36.784174 *Angles in degrees
Refractive index for air, glass, and SU-8 is 1, 1.52, and 1.67,
respectively.
[0054] Therefore, patterning of any tube geometries on top of the
side wall surface of the inclined post which faces upward allows
creating a beveled surface on the bottom of the microneedle mold
structure. This bottom surface later becomes the beveled surface of
the microneedle structure.
[0055] The fabrication procedures to create an out of plane
metallic beveled microneedle are illustrated in FIG. 3. There are
four major microneedle manufacturing stages. FIG. 3 (a) to (f)
shows the first manufacturing stage described as following. The
manufacture begins as performing a metal layer deposition, Chromium
(Cr), of about 0.1 .mu.m on a limestone glass substrate using a
Denton discovery 18 sputtering system. A positive photoresist (AZ
1518) is then spun onto the metal layer for patterning square
arrays after baking and exposing it under the Ultra Violet (UV)
light. Developing patterned photoresist followed by etching the
metal layer defines a mask to be used for creating the array of
skewed posts. SU-8 (2075), a negative photoresist, is then
spin-coated on the patterned metal layer at 500 rpm with
acceleration of 100 rpm/s for 10 seconds followed by spinning at
1200 rpm with acceleration of 300 rmp/s for 30 seconds to obtain
about 150 .mu.m in thickness. Next, the substrate is soft-baked on
a hotplate at 65.degree. C. for 3 minutes followed by baking at
95.degree. C. for 22.5 minutes. After cooling it down to the room
temperature, the backside of the substrate is exposed under UV
light with a dose of about 400 mJ/cm.sup.2 at a tilted angle of 55
degrees using Kasper Instruments mask aligner. A post exposure bake
is performed at 65.degree. C. for 3 minutes and 95.degree. C. for
15 minutes. The SU-8 layer is developed in a bath with a stirrer
spinning at 700 rpm to enhance developing rate for 25 minutes. The
SU-8 layer is rinsed with isopropylalcohol (IPA) to check the
degrees of development and remove uncrosslinked photoresist. The
substrate is dried with a nitrogen gas to prepare for the next
manufacturing steps of which the microneedle structures will build
on top of the array of the skewed posts (FIG. 3 (g) to FIG. 3 (i)).
The second layer of SU-8 is then carried out to spin-coat over the
skewed post arrays at 300 rpm with acceleration of 100 rpm for 10
seconds and spin at 630 rpm with acceleration of 500 rpm/s for 30
seconds to obtain about 270 .mu.m in thickness. FIG. 3 (g) shows
the cross-section of the patterned geometry in which the dimensions
of the outside and inside diameter of 370 .mu.m and 70 .mu.m,
respectively, were used for the current experiment. It is noted
that the thickness of this layer becomes the length of the
microneedle. This second SU-8 layer is soft-baked on the hotplate
at 65.degree. C. for 3 minutes and 95.degree. C. for 5 hours and
patterned with arrays of wells with a post in the middle in each
well using Electronic Visions EV-420 with a dose of 550
mJ/cm.sup.2. An example of how the post looks like inside of the
well can be seen in FIG. 4. FIG. 4 shows that the configuration of
the interface between the angled surface and the cylindrical post,
which post will be used for creating the hollow section of the
microneedle. Now, the third manufacturing step (FIG. 3 (j) to (k))
starts without post-exposure baking the second SU-8 layer, but
spin-coating the third SU-8 layer over the third layer at 500 rpm
for 10 seconds and 1600 rpm to obtain 100 .mu.m. The purpose of
this step is to extend the post in the middle of the well as well
as to define the base for the entire 5.times.5 microneedle array.
Soft-bake of the third layer on a hotplate results in the second
SU-8 layer becoming cross-linked in addition to removing solvents
from the third layer. Exposing the layer with a dose of 350
mJ/cm.sup.2 and post-bake are performed to cross-link the polymer
layer at 65.degree. C. for 3 minutes and 95.degree. C. for 22.5
minutes. Next step is to develop the second and third layers for 1
hour in the bath with a stirrer rotating at 700 rpm. FIG. 5 shows
an array of wells with a post in the middle of each well created
after development. Finally, the last manufacturing step is to
create the metallic microneedle array (FIG. 3 (l) to (m)). The
array of wells is subject to sputter to deposit a seed layer for
electroplating. Nickel sulfamate bath is then prepared for nickel
electroplating to deposit nickel about 500 .mu.m thick. A selection
of metal includes biocompatible materials such as palladium,
stainless steel, etc. in practice. After nickel electroplating,
Chemical Mechanical Polishing (CMP) is carried out to remove access
material on the top surface of the nickel until SU-8 posts are
exposed. FIG. 6 shows the picture of the protruded SU-8 posts
inside of the microneedle base during the electroplating process.
Removing the mold structure made of SU-8 is the final step to
obtain a beveled metallic microneedle.
[0056] The most critical aspect of creating a microneedle with the
proposed design method depends on the results from the lithography
to create SU-8 mold geometry for electroplating. Especially, the
sharpness of the needle tip is determined by how well SU-8 is
developed and thus creating fine corner geometry. The final product
of a microneedle array fabricated using the proposed manufacturing
method after removing SU-8 layers are shown in FIGS. 7 and 8. The
microneedle structures made of nickel in these pictures are formed
with round post mold geometry. The tip angle shown in the figures
is about 35.degree. although the edges of the tip looks like
somewhat rounded. The roundness is due to the tip geometry in the
bottom of the SU-8 mold which was not well developed. Moreover, the
surface of the microneedle array is neither clean nor smooth. The
uncleanness and roughness come from the left over of SU-8 particles
and craze of SU-8 mold surface resulted from the thermal stress
during the curing of SU-8 polymer layer.
[0057] FIG. 9 shows the microneedle array with a flat tip surface
resulted from misalignment during the lithography process. Since
the proposed manufacturing method requires three SU-8 layers to
complete the molding process, the alignment of each layer
determines the quality of final product.
[0058] An angled view of microneedle with round post can be seen in
FIG. 10 and backside of its needle post can be seen in FIG. 11.
[0059] The advantage of using the new manufacturing method for
creating a microneedle is that it gives the freedom of changing the
angle of the needle tip in microneedle design without scarifying
the needle post strength for easy skin penetration. In addition,
there is a potential use of the proposed manufacturing method such
that various needle tip geometries can be achieved with multiple
exposures during the fabrication of the skewed post.
Example 2
Design of Microneedles and Microneedle Arrays
[0060] Microneedles and microneedle arrays can also be designed as
shown in FIG. 13. A substrate is spin-coated with a layer of
photoresist, softbaked and exposed to a light source. After post
exposure bake, the photoresist is developed resulting in an
inclined post that defines the needle tip. Another layer of
photoresist is spin-coated, softbaked and partially exposed to
create a base and a post that defines the hollow section of a
needle. The photoresist is partially developed to expose the base
and the post that defines the hollow section of the needle. The
photoresist is exposed partially to the light source to create
boundaries of the needle structure. After post exposure bake, the
entire mold structure is developed. A seed layer is deposited onto
the mold structure and a metal layer is electroplated.
Alternatively, the seed layer may be deposited right after the
inclined post is created. Chemical mechanical polishing opens the
hollow area of the needle. The mold structure is removed to obtain
the final needle structure. A layer of elastomer, e.g., PDMS, is
cast over the actual needle structure and therefore, a mold made of
PDMS is obtained.
Example 3
Design of Tapered Microneedles and Microneedle Arrays
[0061] Tapered microneedles and microneedle arrays can be created
as shown in FIG. 14. A negative photoresist is coated on a
substrate, softbaked, and exposed under UV light with an inclined
exposure. After post exposure bake and development, the photoresist
is coated with a mold release agent or a sacrificial layer for easy
release of an elastomer layer (e.g., PDMS). An example for such a
mold release agent is a fluorosilanizing agent. An elastomer is
cast upon the mold release agent or the sacrificial layer to obtain
an elastomer structure, which is then used as a base for further
construction.
[0062] The elastomer base is coated with a layer of negative
photoresist (e.g., SU-8) for creating a needle or needle array mold
structure. The negative photoresist is softbaked and exposed with a
given photomask positioned on the negative photoresist. To create
tapered geometry, a gray scale mask can be used. Alternatively,
adjusting diffraction of the light can also produce similar
geometry.
[0063] Another layer of SU-8 is spin-coated without developing the
previous layer. The entire layers are softbaked, exposed and post
exposure baked. Alternatively, calculated dosage can be used for
exposing only the second SU-8 layer. Development of the layers
results in a SU-8 mold structure. A layer of material, such as
metal, can be cast upon the mold structure and therefore produce an
actual needle structure.
[0064] This example shows that a replicated angled structure, such
as the one made of PDMS, can be used a base for fabricating a
microneedle.
Example 4
Design of a Die Cutter
[0065] A die cutter can be created as shown in FIG. 16. A
photoresist layer is spin-coated on a substrate. Point light
sources, such as laser, write directly on the photoresist at a
defined angle. An arbitrary inclined shaped structure is obtained
after developing the photoresist. A layer of photoresist is
spin-coated on the arbitrary shaped structure. The blade 2D top
layout is patterned using a mask or by direct writing. After the
photoresist is developed, the cavity can be filled with a material
such as ceramics. Removal of the photoresist mold to obtain a die
cutter. A metal cutter can also be obtained by electroplating.
[0066] While this invention has been described in certain
embodiments, the present invention can be further modified within
the spirit and scope of this disclosure. This application is
therefore intended to cover any variations, uses, or adaptations of
the invention using its general principles. Further, this
application is intended to cover such departures from the present
disclosure as come within known or customary practice in the art to
which this invention pertains and which fall within the limits of
the appended claims.
[0067] All references, including publications, patents, and patent
applications, cited herein are hereby incorporated by reference to
the same extent as if each reference were individually and
specifically indicated to be incorporated by reference and were set
forth in its entirety herein. The references discussed herein are
provided solely for their disclosure prior to the filing date of
the present application. Nothing herein is to be construed as an
admission that the inventors are not entitled to antedate such
disclosure by virtue of prior invention.
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