WO2012020332A2 - Injection molded microneedle array and method for forming the microneedle array - Google Patents
Injection molded microneedle array and method for forming the microneedle array Download PDFInfo
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- WO2012020332A2 WO2012020332A2 PCT/IB2011/051860 IB2011051860W WO2012020332A2 WO 2012020332 A2 WO2012020332 A2 WO 2012020332A2 IB 2011051860 W IB2011051860 W IB 2011051860W WO 2012020332 A2 WO2012020332 A2 WO 2012020332A2
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- microneedle
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- microneedles
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Definitions
- Primary drug delivery methods include oral delivery and injections, but both methods present difficulties. For instance, injections are painful and both methods tend to provide bursts of agents rather than a preferred steady-state delivery. Additionally, the successful long term use of both oral delivery and injected delivery requires the patient to consistently meet the time requirements for the delivery method.
- Transdermal delivery materials have been developed in an attempt to provide a painless route for delivery of active agents over a sustained period with little or no interruption of the patient's daily routine.
- natural dermal characteristics such as the overlapping corneocytes of the stratum corneum, the tight junction of the stratum granulosum, and Langerhans cells of the stratum spinosum that institute an immune response and/or a foreign body response all present barriers to successful transdermal delivery of an active agent.
- a microneedle transdermal device includes an array of needles that may penetrate at least the stratum corneum and reach an underlying layer of the skin. In some devices, the microneedles are designed so as to penetrate to a depth that does not stimulate the nerve endings and institute a pain response. Examples of microneedle devices have been described in U.S. Patent No. 6,334,856 to Allen, et al. and U.S. Patent No.
- 2007/0191761 to Boone, et al. describes a method including injecting a moldable material into a negative mold insert that is characterized by a negative image of a microneedle.
- U.S. patent Application Publication No. 2008/0088066 to Ferguson, et al. describes a method that utilizes a mold apparatus including a mold insert that has a negative image of a microneedle and a compression core. The mold housing allows reciprocal motion between the mold insert and the compression core and when the housing is in a closed position, a polymeric material is injected into the closed apparatus.
- transdermal devices are presently limited to delivery of low molecular weight agents that have a moderate lipophilicity and no charge. Even upon successful crossing of the natural dermal boundary, problems still exist with regard to maintaining the activity level of delivered agents and avoidance of foreign body and immune response.
- microneedle devices that may be utilized for delivery of a wide variety of agents, including high molecular weight agents.
- an efficient method for forming the devices that may be translated to a mass production facility, such as an injection molding method.
- a method may include injecting a moldable material into a microneedle negative cavity, wherein the microneedle negative cavity defines a plurality of fabricated nanostructures on a surface, the nanostructures being arranged in a pattern.
- the microneedle array may include a substrate, a plurality of microneedles extending from a surface of the substrate, and a plurality of nanostructures on a surface of at least one of the microneedles.
- the plurality of nanostructures may be arranged in a
- a transdermal patch including the injection molded microneedle array is also disclosed.
- Fig. 1 schematically illustrates one embodiment of a microneedle device.
- Fig. 2 is a scanning electron micrograph (SEM) image of another
- Fig. 3 schematically illustrates one mold segment, the mold segment including two microneedle segments.
- Fig. 4 schematically illustrates one embodiment of a microneedle including a surface that defines a nanotopography that may interact with an extracellular matrix (ECM).
- ECM extracellular matrix
- Fig. 5 illustrates one embodiment of a complex pattern that may be formed on a microneedle surface.
- Fig. 6 illustrates a pattern including multiple iterations of the complex pattern of Fig. 5.
- Figs. 7A-7C illustrates exemplary packing densities as may be utilized for nano-sized structures as described herein including a square packing design (Fig. 7A), a hexagonal packing design (Fig. 7B), and a circle packing design (Fig. 7C).
- Figs. 8A-8D illustrate complex fractal and fractal-like nanotopographies.
- Fig. 9 illustrates another complex pattern that may be formed on a microneedle surface.
- Fig. 10 schematically illustrates an injection mold segment aligned with a capping segment of a mold.
- Fig. 1 1 schematically illustrates a cross sectional view of a mold following assembly.
- Fig. 12 schematically illustrates a top view of a microneedle array following assembly of a plurality of mold segments.
- Fig. 13 schematically illustrates a mold including a single microneedle array.
- Figs. 14 and 15 are partial cross-sectional views of microneedle arrays that may be formed in accordance with an embodiment of the present disclosure.
- FIG. 16 illustrates a Sierpinski triangle fractal.
- Figs. 17A and 17B schematically illustrate one embodiment of a device in an exploded view (Fig. 17A) and assembled (Fig. 17B).
- Fig. 8 is a perspective view of one embodiment of a transdermal patch prior to delivery of a drug compound.
- Fig. 19 is a front view of the patch of Fig. 18.
- Fig. 20 is a perspective view of the patch of Fig. 18 in which the release member is partially withdrawn from the patch.
- Fig. 21 is a front view of the patch of Fig. 20.
- Fig. 22 is a perspective view of the transdermal patch of Fig. 18 after removal of the release member and during use.
- Fig. 23 is a front view of the patch of Fig. 22.
- Fig. 24 is a perspective view of another embodiment of a transdermal patch prior to delivery of a drug compound.
- Fig. 25 is a front view of the patch of Fig. 24.
- Fig. 26 is a perspective view of the patch of Fig. 24 in which the release member is partially peeled away from the patch.
- Fig. 27 is a front view of the patch of Fig. 26.
- Fig. 28 is a perspective view of the patch of Fig. 24 in which the release member is completely peeled away from the patch.
- Fig. 29 is a perspective view of the transdermal patch of Fig. 24 after removal of the release member and during use.
- Figs. 30A-30E illustrate several nanotopography patterns as described herein.
- Fig. 31 is an SEM of a film including a nanopatterned surface.
- Figs. 32A and 32B are two SEM of a film including another nanopatterned surface.
- Fig. 33 is an SEM of a film including another nanopatterned surface.
- Fig. 34 is an SEM of a film including another nanopatterned surface.
- Fig. 35 is an SEM of a film including another nanopatterned surface.
- Fig. 36 is an SEM of a film including another nanopatterned surface.
- Fig. 37 is an SEM of a film including another nanopatterned surface.
- Fig. 38 is an SEM of a film including another nanopatterned surface.
- Fig. 39 is an SEM of a film including another nanopatterned surface. Detailed Description of Representative Embodiments
- the injection molded microneedle array may include a pattern of structures fabricated on a surface of the needles, at least a portion of which are nanostructures fabricated on a nano-sized scale.
- the term 'fabricated' generally refers to a structure that has been specifically designed, engineered, and/or constructed so as to exist at a surface of the microneedle and is not to be equated with a surface feature that is merely an incidental product of the injection molding formation process.
- the injection molded microneedle array may be formed according to a process that utilizes multiple mold segments to form each microneedle. More specifically, each mold segment defines at least one microneedle segment. Mold segments may be aligned with one another to form a complete mold. Mold segments are aligned such that the microneedle segments on the adjacent mold segments are also aligned with one another. Upon alignment of two or more microneedle segments, a complete microneedle cavity may be defined, with each microneedle segment defining a portion of the complete microneedle cavity. In addition, the microneedle segments may define upon a surface the predetermined pattern of nanostructures.
- Fig. 1 illustrates a typical microneedle array 10.
- the array includes multiple individual needles 12; each formed to a size and shape so as to penetrate a biological barrier without breakage of the individual microneedles.
- Microneedles may be solid, porous, or may include a hollow portion.
- microneedle may include a hollow portion, e.g., an annular bore that may extend throughout all or a portion of the needle, extending parallel to the direction of the needle axis or branching or exiting at a side of the needle, as appropriate.
- Fig. 2 illustrates an array of microneedles 14 each including a channel 16 along a length of the needles as may be utilized for, e.g., delivery of an agent to a subdermal location.
- a channel 16 may be in at least partial alignment with an aperture in base 15 so as to form a junction between the aperture and channel 16 allowing the passage of a substance through the channel 16.
- An injection molded microneedle array may be formed by use of a mold that defines on a surface of a microneedle a predetermined pattern including
- the mold may be formed from a plurality of aligned mold segments.
- Fig. 3 schematically illustrates one embodiment of a single mold segment 30 including two adjacent microneedle segments 31. Each microneedle segment 31 defines only a portion of a single microneedle. A complete negative cavity for a microneedle will be formed by alignment of microneedle segments that are on adjacent mold segments.
- the microneedle negative mold cavity may provide a microneedle of any desired geometry.
- the microneedle formed from a microneedle segment 31 may generally conform to the shape of the microneedle segment 31 that includes a straight (untapered) portion 32, a tapered tip portion 33, and a tapered base portion 34.
- a microneedle segment may alternatively have a shaft that is straight along the entire length or a tapered shaft.
- the cross section of a microneedle segment may be greatest at the base end of the microneedle segment and taper to a point at the end distal the base.
- a microneedle segment may define a portion of a microneedle shaft that is circular or non-circular in cross-section.
- the cross-section of a molded microneedle may be polygonal (e.g. star-shaped, square, triangular), oblong, or any other shape.
- the size of individual microneedle mold segments 31 may be optimized depending upon the desired size of the microneedle, for instance depending upon the targeting depth of the microneedle, the strength requirements of the needle to avoid breakage in a particular tissue type, etc.
- the cross-sectional dimension of mold segments 31 are 100 micrometers, but an injection molded transdermal microneedle may have a cross sectional dimension between about 10 nm and 1 millimeter, or between about 1 micrometer and about 200 micrometers, or between about 10 micrometers and about 100 micrometers.
- An array of microneedles need not include microneedles that are all identical to one another.
- An array may include a mixture of microneedles having various lengths, outer diameters, inner diameters, cross-sectional shapes, nanostructured surfaces, and/or spacings between the microneedles.
- the microneedles may be spaced apart in a uniform manner, such as in a
- microneedles rectangular or square grid or in concentric circles.
- the spacing may depend on numerous factors, including height and width of the microneedles, as well as the amount and type of any substance that is intended to be moved through the microneedles. While a variety of arrangements of microneedles is useful, a particularly useful arrangement of microneedles is a "tip-to-tip" spacing between microneedles of about 50 micrometers or more, in some embodiments about 100 to about 800 micrometers, and in some embodiments, from about 200 to about 600 micrometers.
- the size and shape of the microneedles may also vary as desired.
- the microneedle segments 31 of Fig. 3 include a rectangular portion 32 upon which is positioned a tip portion 33 having a tapering edge.
- the microneedles formed by use of a microneedle segment may have a cylindrical shaft and a conical tip portion, or may have an overall pyramidal shape or an overall conical shape.
- the microneedle mold segment 31 typically includes a base 40 and a tip 42.
- the base 320 is the portion of the microneedle 14 that is proximate to the surface of the support 15.
- the tip 322 of the microneedle 14 is the point of the microneedle that is furthest from the base 320.
- the tip 322 may be variously formed, it typically has a radius that is less than or equal to about 1 micrometer.
- microneedles formed by a microneedle segment 31 are typically of a length sufficient to penetrate the stratum corneum and pass into the epidermis, but not penetrate through the epidermis and into the dermis in applications where it is desirable to minimize pain.
- the microneedle segments 31 have a length (from their tip 42 to their base 36) between about 1 micrometer and about 1 millimeter in length, for instance about 500 micrometers or less, in some embodiments from 10 to about 500 micrometers, and in some embodiments, from about 30 to about 200 micrometers.
- a microneedle segment 31 of a negative mold cavity may define features of a microneedle.
- a microneedle segment 31 may include a microneedle channel mold 35 so as to form a channel along a length of a microneedle, for instance as is illustrated in Fig. 2 at 16.
- the channel mold may form a channel along a length of the nascent microneedle.
- the dimensions of the channel 16, when present, may be specifically selected to induce capillary flow of a drug compound.
- Capillary flow generally occurs when the adhesive forces of a fluid to the walls of a channel are greater than the cohesive forces between the liquid molecules.
- capillary pressure is inversely proportional to the cross-sectional dimension of the channel 16 and directly proportional to the surface tension of the liquid, multiplied by the cosine of the contact angle of the fluid in contact with the material forming the channel.
- the cross-sectional dimension (e.g., width, diameter, etc.) of the channel 16 may be selectively controlled, with smaller dimensions generally resulting in higher capillary pressure.
- the cross-sectional dimension of the channel typically ranges from about 1 micrometer to about 100 micrometers, in some embodiments from about 5 micrometers to about 50 micrometers, and in some embodiments, from about 10 micrometers to about 30 micrometers.
- the length of the channel may also vary to accommodate different volumes, flow rates, and dwell times for the drug compound.
- the length of the channel may be from about 10 micrometers to about 800 micrometers, in some embodiments from about 50 micrometers to about 500 micrometers, and in some embodiments, from about 100 micrometers to about 300 micrometers.
- the cross-sectional area of the channel may also vary.
- the cross- sectional area may be from about 50 square micrometers to about 1 ,000 square micrometers, in some embodiments from about 100 square micrometers to about 500 square micrometers, and in some embodiments, from about 150 square micrometers to about 350 square micrometers.
- the aspect ratio may be from about 50 square micrometers to about 1 ,000 square micrometers, in some embodiments from about 100 square micrometers to about 500 square micrometers, and in some embodiments, from about 150 square micrometers to about 350 square micrometers.
- length/cross-sectional dimension of the channel may range from about 1 to about 50, in some embodiments from about 5 to about 40, and in some embodiments from about 10 to about 20.
- the cross-sectional dimension and/or length vary as a function of length, the aspect ratio can be determined from the average dimensions.
- Microneedle segments 31 may be formed such that they are oriented at any suitable angle to the base 36 of the mold segment, the base 36 forming a surface of a supporting substrate.
- the microneedle segments 31 may be oriented perpendicular to the base 36 and a larger density of microneedles per unit area of substrate may be formed.
- this is not a requirement, and the angle of the microneedle segments 31 with respect to the base 36, where the formed microneedles will join a substrate, may be varied to orient the injection molded microneedles on the supporting substrate as desired.
- a microneedle segment 31 may define on a surface a plurality of fabricated nano-sized structures or negative nano-sized structures that may form a predetermined pattern including nanostructures (a nanotopography) on a surface of an injection molded microneedle.
- microneedles 22 schematically illustrates the ends of two representative microneedles 22 that include fabricated nanostructures on a surface.
- microneedles 22 define a central bore 24 as may be used for delivery of an agent via the microneedles 22.
- the surface 25 of microneedle 22 defines
- the nanotopography 26 defines a random pattern on the surface 25 of the microneedle 22.
- a microneedle segment 31 may include a pattern of a plurality of identical structures formed on the surface or may include a pattern of multiple different structures formed of various sizes, shapes and combinations thereof.
- predetermined pattern of structures may include a mixture of structures having various lengths, diameters, cross-sectional shapes, and/or spacings between the structures.
- the structures may be spaced apart in a uniform manner, such as in a rectangular or square grid or in concentric circles.
- the pattern components may vary with regard to size and/or shape and may form a complex nanotopography.
- a complex nanotopography may define a fractal or fractal-like geometry.
- fractal generally refers to a geometric or physical structure having a fragmented shape at all scales of measurement between a greatest and a smallest scale such that certain mathematical or physical properties of the structure behave as if the dimensions of the structure are greater than the spatial dimensions.
- Mathematical or physical properties of interest may include, for example, the perimeter of a curve or the flow rate in a porous medium.
- the geometric shape of a fractal may be split into parts, each of which defines self-similarity. Additionally, a fractal has a recursive definition and has a fine structure at arbitrarily small scales.
- fractal-like generally refers to a geometric or physical structure having one or more, but not all, of the characteristics of a fractal.
- a fractal-like structure may include a geometric shape that includes self-similar parts, but may not include a fine structure at an arbitrarily small scale.
- a fractal-like geometric shape or physical structure may not decrease (or increase) in scale equally between iterations of scale, as may a fractal, though it will increase or decrease between recursive iterations of a geometric shape of the pattern.
- a fractal-like pattern may be simpler than a fractal. For instance, it may be regular and relatively easily described in traditional
- the structures on a molded microneedle may all be formed with the same general shape (e.g., pillars) and to the same or different scales of measurement (e.g., nano-scale pillars as well as micro-scale pillars). Alternatively, the structures may vary in both size and shape or may vary only in shape while formed to the same nano-sized scale. Additionally, structures may be formed in an organized array or in a random distribution. At least a portion of the structures may be nanostructures formed on a nano-sized scale, e.g., defining a cross-sectional dimension of less than about 500 nm, for instance less than about 400 nm, less than about 250 nm, or less than about 100 nm.
- the cross sectional dimension of the nanostructures may generally be greater than about 5 nanometers, for instance greater than about 10 nanometers, or greater than about 20 nanometers.
- the nanostructures may define a cross sectional dimension between about 5 nanometers and about 500 nanometers, between about 20 nanometers and about 400 nanometers, or between about 100 nanometers and about 300 nanometers.
- the cross sectional dimension can be determined as an average from the base to the tip of the nanostructures, or as the maximum cross sectional dimension of the structure, for example the cross sectional dimension at the base of a cone-shaped nanostructure.
- Fig. 4 illustrates one embodiment of a complex nanotopography as may be formed on a surface.
- This particular pattern includes a central large pillar 100 and surrounding pillars 102, 104, of smaller dimensions provided in a regular pattern. As may be seen, this pattern includes an iteration of pillars, each of which is formed with the same general shape, but vary with regard to horizontal dimension.
- This particular complex pattern is an example of a fractal-like pattern that does not include identical alteration in scale between successive recursive iterations.
- the pillars 102 are first nanostructures that define a horizontal dimension that is about one third that of the larger pillar 100, which is a
- the pillars 104 are second nanostructures that define a horizontal dimension that is about one half that of the pillars 102.
- a pattern that includes structures of different sizes may include larger structures having a cross-sectional dimension formed on a larger scale, e.g., microstructures having a cross-sectional dimension greater than about 500 nanometers in combination with smaller nanostructures.
- microstructures of a complex nanotopography may have a cross-sectional dimension between about 500 nanometers and about 10 micrometers, between about 600 nanometers and about 1.5 micrometers, or between about 650 nanometers and about 1 .2 micrometers.
- the complex nanotopography may have a cross-sectional dimension between about 500 nanometers and about 10 micrometers, between about 600 nanometers and about 1.5 micrometers, or between about 650 nanometers and about 1 .2 micrometers.
- the complex nanotopography may have a cross-sectional dimension between about 500 nanometers and about 10 micrometers, between about 600 nanometers and about 1.5 micrometers, or between about 650 nanometers and about 1 .2 micrometers.
- the complex nanometers may have
- nanotopography of Fig. 5 includes micro-sized pillars 100 having a cross sectional dimension of about 1 .2 micrometers.
- a pattern includes one or more larger microstructures, for instance, having a cross-sectional dimension greater than about 500 nanometers, determined either as the average cross sectional dimension of the structure or as the largest cross sectional dimension of the structure, the complex
- nanotopography will also include nanostructures, e.g., first nanostructures, second nanostructures of a different size and/or shape, etc.
- pillars 102 of the complex nanotopography of Fig. 5 have a cross-sectional dimension of about 400 nanometers
- pillars 104 have a cross-sectional dimension of about 200 nanometers.
- a nanotopography may be formed of any number of different elements.
- a pattern of elements may include two different elements, three different elements, an example of which is illustrated in Fig. 5, four different elements, or more.
- the relative proportions of the recurrence of each different element may also vary.
- the smallest elements of a pattern will be present in larger numbers than the larger elements. For instance in the pattern of Fig. 5, there are eight pillars 104 for each pillar 102, and there are eight pillars 102 for the central large pillar 100. As elements increase in size, there may generally be fewer recurrences of the element in the nanotopography.
- a first element that is about 0.5, for instance between about 0.3 and about 0.7 in cross-sectional dimension as a second, larger element may be present in the topography about five times or more than the second element.
- a first element that is approximately 0.25, or between about 0.15 and about 0.3 in cross-sectional dimension as a second, larger element may be present in the topography about 10 times or more than the second element.
- center-to- center spacing of individual structures may be between about 50 nanometers and about 1 micrometer, for instance between about 100 nanometers and about 500 nanometers.
- center-to-center spacing between structures may be on a nano-sized scale.
- the center-to-center spacing of the structures may be less than about 500 nanometers. This is not a requirement of a topography, however, and individual structures may be farther apart.
- the center-to-center spacing of structures may vary depending upon the size of the structures.
- the ratio of the average of the cross-sectional dimensions of two adjacent structures to the center-to-center spacing between those two structures may be between about 1 :1 (e.g., touching) and about 1 :4, between about 1 :1 .5 and about 1 :3.5, or between about 1 :2 and about 1 :3.
- the center to center spacing may be approximately double the average of the cross-sectional dimensions of two adjacent structures.
- two adjacent structures each having a cross-sectional dimension of about 200 nanometers may have a center-to-center spacing of about 400 nanometers.
- the ratio of the average of the diameters to the center-to-center spacing in this case is :2.
- Structure spacing may be the same, i.e., equidistant, or may vary for structures in a pattern.
- the smallest structures of a pattern may be spaced apart by a first distance, and the spacing between these smallest structures and a larger structure of the pattern or between two larger structures of the pattern may be the same or different as this first distance.
- the smallest structures 104 have a center-to-center spacing of about 200 nanometers.
- the distance between the larger pillars 102 and each surrounding pillar 104 is less, about 100 nanometers.
- the distance between the largest pillar 100 and each surrounding pillar 104 is also less than the center-to-center spacing between to smallest pillars 104, about 100 nanometers.
- this is not a requirement, and all structures may be equidistant from one another or any variation in distances.
- different structures may be in contact with one another, for instance atop one another, as discussed further below, or adjacent one another and in contact with one another.
- Structures of a topography may all be formed to the same height, generally between about 10 nanometers and about 1 micrometer, but this is not a
- individual structures of a pattern may vary in size in one, two, or three dimensions. In one embodiment, some or all of the structures of a
- topography can have a height of less than about 20 micrometers, less than about 10 micrometers, or less than about 1 micrometer, for instance less than about 750 nanometers, less than about 680 nanometers, or less than about 500 nanometers.
- the structures can have a height between about 50 nanometers and about 20 micrometers or between about 100 nanometers and about 700 nanometers.
- nanostructures or microstructures can have a height between about 20 nm and about 500 nm, between about 30 nm and about 300 nm, or between about 100 nm and about 200 nm, though it should be understood that structures may be nano-sized in a cross sectional dimension and may have a height that may be measured on a micro-sized scale, for instance greater than about 500 nm.
- Micro-sized structures can have a height that is the same or different from nano-sized structures of the same pattern. For instance, micro-sized structures can have a height of between about 500 nanometers and about 20 micrometers, or between about 1 micrometer and about 10 micrometers, in another embodiment.
- Micro-sized structures may also have a cross sectional dimension on a micro-scale greater than about 500 nm, and may have a height that is on a nano-sized scale of less than about 500 nm.
- the aspect ratio of the structures (the ratio of the height of a structure to the cross sectional dimension of the structure) can be between about 0.15 and about 30, between about 0.2 and about 5, between about 0.5 and about 3.5, or between about 1 and about 2.5.
- nanostructures may have an aspect ratio falling within any of these ranges.
- the microneedle surface may include a single instance of a pattern, as shown in Fig. 5, or may include multiple iterations of the same or different patterns.
- Fig. 6 illustrates a surface pattern including the pattern of Fig. 5 in multiple iterations over a surface.
- the packing density of the structures may be maximized. For instance, square packing (Fig. 7A), hexagonal packing (Fig. 7B), or some variation thereof may be utilized to pattern the elements on a microneedle segment.
- circle packing as indicated in Fig. 7C may be utilized.
- center to center spacing of individual structures may be between about 50 nm and about 1 micrometer, for instance between about 100 nm and about 500 nm.
- Figs. 8A and 8B illustrate increasing magnification images of another example of a complex nanotopography.
- the nanotopography of Figs. 8A and 8B includes an array of fibrous-like pillars 70 located on a substrate. At the distal end of each individual pillar, the pillar splits into multiple smaller fibers 61. At the distal end of each of these smaller fibers 61 , each fiber splits again into multiple filaments (not visible in Figs 8A and 8B).
- Structures formed on a surface that have an aspect ratio greater than about 1 may be flexible, as are the structures illustrated in Figs. 8A and 8B, or may be stiff.
- Figs. 8C and 8D illustrate another example of a complex nanotopography.
- a plurality of pillars 72 each including an annular hollow therethrough 71 are formed on a substrate.
- a plurality of smaller pillars 62 is formed at the distal end of each hollow pillar.
- the pillars of Figs. 8C and 8D maintain their stiffness and upright orientation.
- the smaller pillars 62 of this embodiment differ in shape from the larger pillars 72.
- the smaller pillars 62 are not hollow, but are solid.
- nanotopography including structures formed to a different scale need not have all structures formed with the same shape, and structures may vary in both size and shape from the structures of a different scale.
- Figure 9 illustrates another pattern including nano-sized structures as may be formed on the surface of the microneedles of an array.
- individual pattem structures may be formed at the same general size, but with different orientations and shapes from one another.
- a mold segment 30 may be prepared by a single- step process in which the microneedle segments 31 , the negative of the
- any other structures of the microneedle mold e.g., a channel mold 35
- the basic microneedle segments 31 may be pre-formed to the general shape of the microneedle portion to be formed by the segment, and then added features such as the nanotopography and a channel mold 35 may be added to the mold segment 31.
- a combination of processes may be utilized.
- the microneedle segment including the nanostructures may be formed in a single step and a mold segment may be added in a second step.
- a positive mold master may be first formed, which corresponds to the desired shape of the formed microneedles, and then a mold segment 31 may be formed from the positive mold master, the mold segment 31 being a negative of the positive mold master.
- Any suitable material or combination thereof may be utilized in forming a mold segment including, without limitation, metals such copper, steel, nickel, aluminum, brass, and other metals, as well as thermoplastic or thermoset polymers.
- a positive mold master and/or negative mold segment may be formed according to any standard microfabrication technique or combination thereof including, without limitation, lithography; etching techniques, such as wet chemical, dry, and photoresist removal; thermal oxidation of silicon; electroplating and electroless plating; diffusion processes, such as boron, phosphorus, arsenic, and antimony diffusion; ion implantation; film deposition, such as evaporation (filament, electron beam, flash, and shadowing and step coverage), sputtering, chemical vapor deposition (CVD), epitaxy (vapor phase, liquid phase, and molecular beam), electroplating, screen printing, lamination, stereolithography, laser machining, embossing molding, metal stamping, and laser ablation (including projection ablation).
- lithography etching techniques, such as wet chemical, dry, and photoresist removal
- thermal oxidation of silicon such as boron, phosphorus, arsenic, and antimony diffusion
- ion implantation
- electrochemical etching of solid silicon to porous silicon is used to create extremely fine (on the order of 0.01 ⁇ ) silicon networks that may be used as positive mold master structures.
- This method may use electrolytic anodization of silicon in aqueous hydrofluoric acid, potentially in combination with light, to etch channels into the silicon.
- electrolytic potential during etching, the incident light intensity, and the electrolyte concentration control over the ultimate pore structure may be achieved.
- the material not etched i.e. the silicon remaining) forms the microneedles on a positive mold master.
- Plasma etching may also be utilized, in which deep plasma etching of silicon is carried out to create microneedles of a positive mold master with diameters on the order of 0.1 ⁇ or larger. Needles may be fabricated indirectly by controlling the voltage (as in electrochemical etching).
- Lithography techniques including photolithography, e-beam lithography, X- ray lithography, and so forth may be utilized for primary pattern definition and formation of a mold segment.
- Self-assembly technologies including phase- separated block copolymer, polymer demixing and colloidal lithography techniques may also be utilized in forming the mold segments.
- a negative mold segment may be formed by laser ablation of a substrate (using, e.g., an excimer laser) to provide cavities in the shape of the desired microneedle segments.
- Negative mold components may also be formed by conventional photolithography, chemical etching, ion beam etching, or any other conventional processes known in the art.
- the negative of the nanotopography may be formed on the surface of the mold segments or the positive nanotopography may be formed on the surface of the positive mold master according to any suitable process.
- the nanotopography may be formed on the entire microneedle segment surface, or only on a portion thereof.
- the nanotopography may extend to the surface of the supporting substrate, or may be confined to microneedles of an array, as desired.
- Structure diameter, shape, and pitch may be controlled via selection of appropriate materials and methods.
- metals may be evaporated onto colloidal-patterned substrates followed by colloidal lift-off, which generally results in prism-shaped pillars.
- An etching process may then be utilized to complete the structures as desired.
- substrates patterned with colloids may be exposed to reactive ion etching (RIE, also known as dry etching) so as to refine the characteristics of a fabricated nanostructure such as nanopillar diameter, profile, height, pitch, and so forth.
- RIE reactive ion etching
- Wet etching may also be employed to produce alternative profiles for fabricated nanostructures initially formed according to a different process, e.g., polymer de-mixing techniques.
- Ordered non-spherical polymeric nanostructures may also be fabricated via temperature-controlled sintering techniques, which form a variety of ordered trigonal nanometric features in colloidal interstices following selective dissolution of polymeric nanoparticles. These and other suitable formation processes are generally known in the art (see, e.g., Wood, J R Soc Interface, 2007 February 22; 4(12): 1 -17, incorporated herein by reference).
- Structures may be formed according to chemical addition processes. For instance, film deposition, sputtering, chemical vapor deposition (CVD), epitaxy (vapor phase, liquid phase, and molecular beam), electroplating, and so forth may be utilized for building nanostructures on a surface of a positive mold master.
- CVD chemical vapor deposition
- epitaxy vapor phase, liquid phase, and molecular beam
- electroplating and so forth may be utilized for building nanostructures on a surface of a positive mold master.
- Self-assembled monolayer processes as are known in the art may be utilized to form a pattern of nanostructures on a surface.
- the ability of block copolymers to self-organize may be used to form a monolayer pattern on a surface.
- the pattern may then be used as a template for the growth of desired structures, e.g., colloids, according to the pattern of the monolayer.
- desired structures e.g., colloids
- a two-dimensional, cross-linked polymer network may be produced from monomers with two or more reactive sites.
- Such cross-linked monolayers have been made using self-assembling monolayer (SAM) (e.g., a gold/alkyl thiol system) or Langmuir-Blodgett (LB) monolayer techniques (Ahmed et al., Thin Solid Films 187: 141 -153 (1990)) as are known in the art.
- SAM self-assembling monolayer
- LB Langmuir-Blodgett
- the monomers used to form a patterned monolayer may incorporate all the structural moieties necessary to affect the desired polymerization technique and/or monolayer formation technique, as well as to influence such properties as overall solubility, dissociation methods, and lithographic methods.
- a monomer may contain at least one and more often at least two, reactive functional groups.
- a molecule used to form an organic monolayer may include any of various organic functional groups interspersed with chains of methylene groups.
- a molecule may be a long chain carbon structure containing methylene chains to facilitate packing. The packing between methylene groups may allow weak Van der Waals bonding to occur, enhancing the stability of the monolayer produced and counteracting the entropic penalties associated with forming an ordered phase.
- different terminal moieties such as hydrogen-bonding moieties may be present at one terminus of the molecules, in order to allow growth of structures on the formed monolayer, in which case the polymerizable chemical moieties may be placed in the middle of the chain or at the opposite terminus.
- Any suitable molecular recognition chemistry may be used in forming the assembly. For instance, structures may be assembled on a monolayer based on electrostatic interaction, Van der Waals interaction, metal chelation, coordination bonding (i.e., Lewis acid/base interactions), ionic bonding, covalent bonding, or hydrogen bonding.
- an additional molecule may be utilized to form the template.
- This additional molecule may have appropriate functionality at one of its termini in order to form a SAM.
- a terminal thiol may be included.
- organic molecules that may be employed to effect replication. Topochemically polymerizable moieties, such as dienes and diacetylenes, are particularly desirable as the polymerizing components. These may be interspersed with variable lengths of methylene linkers.
- LB monolayer For an LB monolayer, only one monomer molecule is needed because the molecular recognition moiety may also serve as the polar functional group for LB formation purposes. Lithography may be carried out on a LB monolayer transferred to a substrate, or directly in the trough. For example, an LB monolayer of diacetylene monomers may be patterned by UV exposure through a mask or by electron beam patterning.
- Monolayer formation may be facilitated by utilizing molecules that undergo a topochemical polymerization in the monolayer phase.
- a film By exposing the assembling film to a polymerization catalyst, a film may be grown in situ, and changed from a dynamic molecular assembly to a more robust polymerized assembly for use as a negative mold segment or a positive mold master.
- Techniques useful in patterning a monolayer include, but are not limited to, photolithography, e-beam techniques, focused ion-beam techniques, and soft lithography.
- Various protection schemes such as photoresist may be used for a SAM-based system.
- block copolymer patterns may be formed on gold and selectively etched to form patterns. For a two-component system, patterning may also be achieved with readily available techniques.
- Soft lithography techniques may be utilized to pattern the monolayer in which ultraviolet light and a mask may be used for patterning.
- an unpatterned base monolayer may be used as a platform for assembly of a
- the monomer monolayer may then be patterned by UV photolithography, e-beam lithography, or ion beam lithography, even though the base SAM is not patterned.
- Growth of structures on a patterned monolayer may be achieved by various growth mechanisms, such as through appropriate reduction chemistry of a metal salts and the use of seed or template-mediated nucleation.
- inorganic growth may be catalyzed at this interface by a variety of methods.
- inorganic compounds in the form of colloids bearing the shape of the patterned organic monolayer may be formed.
- calcium carbonate or silica structures may be templated by various carbonyl functionalities such as carboxylic acids and amides.
- By controlling the crystal growth conditions it is possible to control the thickness and crystal morphology of the mineral growth. Titanium dioxide may also be templated.
- Templated electroless plating techniques may be used to synthesize metals using existing organic functional groups.
- electroless metal deposition may be catalyzed on the pattern, forming patterned metallic colloids.
- Cu, Au, Ni, Ag, Pd, Pt and many other metals plateable by electroless plating conditions may be used to form metal structures in the shape of the organic monolayer. By controlling the electroless plating conditions, it is possible to control the thickness of the plated metal structures.
- a conducting or semiconducting substrate for example, a metal, such as gold
- a block copolymer film for example, a block copolymer of methyl methacrylate and styrene
- a conducting layer may then be placed on top of the copolymer to form a composite structure.
- some of the first component may be removed, for instance by exposure to UV radiation, an electron beam, or ozone, degradation, or the like to form nanoscopic pores in that region of the second component.
- copolymer structures may be formed by exposing a substrate with an imaging layer thereon, for instance an alkylsiloxane or an octadecyltrichlorosilane self assembled monolayer, to two or more beams of selected wavelengths to form interference patterns at the imaging layer to change the wettability of the imaging layer in accordance with the interference patterns.
- an imaging layer for instance an alkylsiloxane or an octadecyltrichlorosilane self assembled monolayer
- a layer of a selected block copolymer for instance a copolymer of polystyrene and poly(methyl methacrylate) may then be deposited onto the exposed imaging layer and annealed to separate the components of the copolymer in accordance with the pattern of wettability and to replicate the pattern of the imaging layer in the copolymer layer. Stripes or isolated regions of the separated components may thus be formed with periodic dimensions in the range of 100 nm or less.
- this master may be utilized to form the negative mold segments used during the injection molding process.
- a negative mold segment may be prepared by an electroforming process around a positive mold master.
- a process of electroforming involves placing the positive mold master into an electroforming tank that deposits a metal around the features of the master. This may be any suitable metal. The metal is deposited to a desired thickness at which point the positive mold master is separated from the electroformed metal creating the negative mold components. This form of a mold is typically called an electroform. Following formation, an electroform may then be cut to fit into an injection molding apparatus.
- a complete mold will also include a capping portion 42.
- the capping portion 42 will be located in association with a mold segment 30 so as to define a substrate cavity 38 between the two.
- the substrate cavity 38 will be filled to form a substrate from which the multiple microneedles will extend.
- the substrate cavity may vary in thickness to meet the needs of the device, such as about 1000 micrometers or less, in some embodiments from about 1 to about 500 micrometers, and in some embodiments, from about 10 to about 200 micrometers.
- the capping portion 42 includes an insert 37.
- the insert 37 may contact the ends of the channel molds 35 in the microneedle segments 31 .
- the capping portion 42 is otherwise unstructured, but this is not a requirement.
- a capping portion 42 may define other shapes, e.g., positive and/or negative structural features, such as grooves, slots, pins, etc., for instance for attachment of the substrate to another portion of a device such as a reservoir that contains an agent for delivery via the microneedle device.
- a capping portion may include a channel mold.
- a channel mold may extend from the insert 37 of the capping portion 42.
- the channel mold of the capping portion may extend down into the center of the microneedle mold cavity, so as to form a central bore or channel in the injection molded microneedle.
- the outer diameter of the needle may be between about 10 micrometers and about 100 micrometers and the inner diameter of a hollow needle may be between about 3 micrometers and about 80 micrometers.
- Fig. 1 1 illustrates a side view of the mold segment 30 aligned with the capping portion 42.
- each microneedle segment 31 is aligned with an insert 37.
- the capping portion 42 may be lowered during assembly until each insert 37 contacts the respective channel segment 35.
- the substrate cavity 38 remaining between the mold segment 30 and the capping portion 42 may be utilized to mold the substrate from which the plurality of microneedles may extend.
- Fig. 12 illustrates a plurality of negative mold segments 30a, 30b, 30c, 30d, 30e, following alignment and assembly to form a complete 10x10 microneedle array mold 50.
- Each negative mold segment 30a, etc. defines multiple negative mold segments 30a, etc.
- microneedle segments 31 A complete microneedle negative mold cavity 45a, 45b, 45c is formed by two microneedle segments 31 , each of which defines a portion of the surface of a microneedle.
- the negative mold cavity of a single microneedle may be formed of three, four, or more individual components.
- each microneedle negative mold cavity 45a, 45b, 45c, 55a, 55b, 55c will define the microneedle proper as well as the nanotopography on a surface of the microneedle and any other structures formed on the surface of the microneedles, e.g., a channel.
- each negative mold cavity 45 may include two channel molds 35, one on each side of the mold cavity 45.
- microneedles shown in the figures is for illustrative purposes only.
- the actual number of microneedles formed in an injection molded array may, for example, range from about 500 to about 10,000, in some embodiments from about 2,000 to about 8,000, and in some embodiments, from about 4,000 to about 6,000.
- Fig. 13 illustrates an assembled mold 60 including a single microarray mold 50 in the center. It should be understood that a single mold may include one or more microarray molds. The number of micronnedle array molds on a single mold 60 can, for example, range from one to several hundred, for instance from 10 to about 500, or from about 100 to about 300.
- mold segments 30a, 30b may form between them negative mold cavities 45a, 45b, 45c, of a first size and/or shape.
- mold segments 30a, 30b, 30c, 30d, 30e, etc. may be aligned with one another.
- Mold segments 30c, 30d may form between them negative mold cavities 55a, 55b, 55c, which may vary with regard to size, shape, features, etc. from mold cavities 45a, 45b, 45c. Accordingly a large variety of microneedles may be formed in a single array by merely mixing and matching the modular mold segments used to form the complete mold.
- the various components that are assembled to form a complete mold may be formed of any suitable material or mixture of materials. Preferred materials may depend upon the material of the positive mold master (when utilized) as well as the moldable material that will be used to form the array during an injection molding process.
- the negative mold segments 30a, 30b, etc. and the capping portion 42 may comprise a nickel material that may be formed and separated from a positive mold master.
- the complete mold 60 is heated, for instance to a temperature of more than about 10°C above the softening
- the mold 60 is heated to a temperature of more than about 20°C above the softening temperature of the material to be molded prior to injection of the material. In another embodiment, the mold 60 is heated to a temperature of more than about 30°C above the softening temperature of the material prior to injection of the material.
- softening temperature refers to the temperature at which a material will soften and deform when subject to ordinary forces, such as those encountered during detachment of a molded part from a mold segment. This may be conveniently measured by the Vicat softening temperature, which measures the temperature at which a flat-ended needle penetrates into a test sample (under conditions, for example, of a 50 N loading on the needle and a rate of temperature increase of 120°C/h as described in ASTM D1525-00). For amorphous materials, the softening temperature will be governed by the glass transition of the material, and in some instances the glass transition temperature will be essentially
- the glass transition temperature may be measured by methods known to one skilled in the art, such as by
- the softening temperature is governed by the melting of the material and may be characterized by Vicat softening temperature.
- materials include polypropylene, polybutylene terephthalate, polystyrene, polyethylene,
- polyetherimide polyethylene terephthalate, and blends thereof.
- the moldable material is also heated to a molding temperature in a chamber separate from the mold 60.
- the preferred temperature to which the material to be molded should be heated will generally depend on the specific material.
- a polymeric material may be heated to a temperature above the melting temperature such that it is molten according to standard practice.
- the material to be molded according to the process may include any of a variety of materials that may be injection molded, including metals, ceramics, polymers, etc., as well as composites thereof.
- silicon e.g., liquid silicon rubber
- polymers, and composites such as a polymeric binder in conjunction with a powdered metal, may be utilized.
- the microneedle array is formed of a biocompatible material.
- biocompatible generally refers to a material that does not substantially adversely affect the cells or tissues in the area where the device is to be delivered. It is also intended that the material does not cause any substantially medically undesirable effect in any other areas of the living subject.
- Biocompatible materials may be synthetic or natural.
- suitable biocompatible materials include polymers of hydroxy acids such as lactic acid and glycolic acid polylactide, polyglycolide, polylactide-co-glycolide, copolymers with PEG, polyanhydrides, poly(ortho)esters, polyurethanes, poly(butyric acid), poly(valeric acid), and poly(lactide-co-caprolactone).
- suitable materials may include, without limitation, polycarbonate, polystyrene, polypropylene, polymethacrylic acid, ethylenevinyl acetate, polytetrafluorethylene, and polyesters.
- the mold 60 may be heated according to any known method, for instance by use of an oil heating system that may be used to control the temperature of the components that form the cavities.
- electromagnetic induction (EMI) heating may be used to apply rapid, localized heating to the mold 60.
- EMI heaters are known, and may generally include an induction coil housing containing an electromagnetic induction coil. An induction heater may be positioned close to the mold, for instance with the induction coil within about 2 mm of the mold cavity surface to provide rapid, localized heating of the surfaces of the mold cavity.
- the temperature of the surfaces to which the polymer melt is exposed may affect the quality of the molded article, and EMI heating may be utilized to rapidly raise the surface temperature of the mold for each mold cycle.
- the heated material to be molded may fill at least about 90%, for instance at least about 95%, of the volume of the mold 60. In one embodiment, the heated material may fill substantially the entire volume of the mold 60. During the molding process, the heated material may flow to fill each successive microneedle negative mold cavity and thus fill the entire mold. The material that is molded to form the microneedle should not substantially cool before filling all of the mold cavities of the mold, since it may "skin over" or solidify in the channel prior to complete filling and block further flow of material.
- the negative mold cavities may be cooled prior to removal of the molded microneedle array.
- the negative mold cavities may be cooled to a temperature of less than about 5°C below the softening temperature of the molded material prior to separating the components from one another and removing the molded array of microneedles.
- the negative mold cavities are cooled to a temperature of less than about 10°C below the softening temperature of the material prior to demold.
- the injection of the material to be molded may be performed in conjunction with a packing or injection pressure used to aid in allowing the material to fill the negative mold cavity.
- this pressure may be greater than about 6,000 psi. In another embodiment, this pressure may be greater than about 10,000 psi. In yet another embodiment, this pressure may be greater than about 20,000 psi.
- compressive force methods as may be utilized include those described in U.S. Pat. No. 4,489,033 to Uda, et al.. U.S. Pat. No. 4,515,543 to Hamner, and U.S. Pat. No. 6,248,281 to Abe, et al., all of which are incorporated herein by reference.
- ultrasonic energy may be utilized during fill of the mold, which may assist in complete filling of the microneedle cavities.
- ultrasonic energy may be applied to a mold cavity by means of a piezoelectric generator and an ultrasonic horn placed in conjunction with the mold.
- An ultrasonic horn may amplify the vibration that is generated from the
- a molding apparatus may include an overflow vent connected to the mold, as is generally known in the art. Molten polymeric material fed through the input line passes through the injection gate and into the mold cavity. As the polymeric material fills the mold cavity it displaces air that was in the cavity and the displaced air may escape through the overflow vent. As such, little or no displaced air becomes trapped in pockets within the mold cavity.
- An overflow vent serves as an exit gate to allow displaced air to leave the cavity thus allowing for more uniform filling of the mold cavity with polymeric material.
- the overflow vent may be positioned anywhere on the outer surface of the mold.
- the cycle time of a molding process i.e., the amount of time between injection of the material into the mold and detachment of the molded microneedle array, is generally sufficient to allow the mold to be substantially filled with material and the material to be subsequently cooled to a temperature below its softening point.
- the cycle time may be less than about 5 minutes, less than about 3 minutes, or less than about 90 seconds in one embodiment.
- the molded array including a plurality of microneedles and a base to which the microneedles are joined may be non-porous or porous in nature, may be homogeneous or heterogeneous across the device with regard to materials, solidity, and so forth, and may have a rigid fixed or a semi-fixed shape.
- the entire array including a substrate base, the microneedles, and any features formed on the array may be formed in a single shot injection molding step that forms a unitary construct microneedle array.
- Fig. 14 is a cross sectional view of an injection molded array of
- an aperture 328 is aligned with a single channel 330 via a junction 332.
- a single aperture may feed two or more separate channels 330.
- the channel 330 may extend from the junction 332 at the base 320 of the microneedle to the tip 322. In other embodiments, the channel 330 may not extend the full length of the microneedle 318 to the tip 322.
- Each microneedle 318 may include more than one channel 330, as seen in the embodiments of Figs. 14 and 15. Alternate embodiments may include more channels if desired.
- the channel 330 may be variously positioned on the exterior surface, forming a substantially linear path from the base 320 towards the tip 322, or forming a winding or circuitous path along the exterior surface. In microneedles where two or more channels are present, the channels 330 may be variously spaced around the microneedle 318 in a symmetrical or asymmetrical manner.
- Fig. 14 illustrates embodiments of the microneedle 318 in which the aperture 328 and channel 330 have sides that are not only coextensive with each other but may also be planar for at least some distance along the length of the pathway 326.
- Fig. 14 illustrates an embodiment where a single aperture 328 is aligned with more than one channel 330 on a particular microneedle 318.
- Other variations in geometry as are known to those of skill in the art are encompassed herein.
- nanotopography on a microneedle surface may increase the surface area without a corresponding increase in volume.
- Increase in the surface area to volume ratio is believed to improve the interaction of a surface with surrounding biological materials. For instance, increase in the surface area to volume ratio is believed to encourage mechanical interaction between the
- protein generally refers to a molecular chain of amino acids that is capable of interacting structurally, enzymatically or otherwise with other proteins, polypeptides or any other organic or inorganic molecule.
- the surface area to volume ratio of the microneedle array may be greater than about 10,000 cm “1 , greater than about 150,000 cm “1 , or greater than about 750,000 cm “1 . Determination of the surface area to volume ratio may be carried out according to any standard methodology as is known in the art. For instance, the specific surface area of a surface may be obtained by the physical gas adsorption method (B.E.T. method) with nitrogen as the adsorption gas, as is generally known in the art and described by Brunauer, Emmet, and Teller (J. Amer. Chem. Soc, vol. 60, Feb., 1938, pp. 309-319), incorporated herein by reference.
- B.E.T. method physical gas adsorption method with nitrogen as the adsorption gas
- the BET surface area may be less than about 5 m 2 /g, in one embodiment, for instance between about 0.1 m 2 /g and about 4.5 m 2 /g, or between about 0.5 m 2 /g and about 3.5 m 2 /g.
- Values for surface area and volume may also be estimated from the geometry of molds used to form a surface, according to standard geometric calculations. For example, the volume may be estimated according to the calculated volume for each pattern element and the total number of pattern elements in a given area, e.g., over the surface of a single microneedle.
- the nanotopography of a microneedle surface may be characterized through determination of the fractal dimension of the pattern on the microneedle.
- the fractal dimension is a statistical quantity that gives an indication of how completely a fractal appears to fill space as the recursive iterations continue to smaller and smaller scale.
- N(e) is the number of self-similar structures needed to cover the whole object when the object is reduced by /e in each spatial direction.
- the fractal dimension is calculated as follows:
- the Sierpenski triangle fractal exhibits an increase in line length over the initial two dimensional equilateral triangle. Additionally, this increase in line length is not accompanied by a corresponding increase in area.
- nanotopography of a surface of the device may exhibit a fractal dimension of greater than about 1 , for instance between about 1.2 and about 5, between about 1 .5 and about 3, or between about 1 .5 and about 2.5.
- a microneedle surface including a fabricated nanotopography thereon may be characterized by other methods including, without limitation, surface roughness, elastic modulus, surface energy, and so forth.
- Methods for determining surface roughness are generally known in the art. For instance, an atomic force microscope process in contact or non-contact mode may be utilized according to standard practice to determine the surface roughness of a material. Surface roughness that may be utilized to characterize a
- microneedle may include the average roughness (RA), the root mean square roughness, the skewness, and/or the kurtosis.
- RA average roughness
- the average surface roughness (i.e., the arithmetical mean height of the surface are roughness parameter as defined in the ISO 25178 series) of a surface defining a fabricated nanotopography thereon may be less than about 200 nanometers, less than about 190 nanometers, less than about 100 nanometers, or less than about 50
- the average surface roughness may be between about 10 nanometers and about 200 nanometers, or between about 50 nanometers and about 190 nanometers
- the microneedles may be characterized by the elastic modulus of the nanopatterned surface, for instance by the change in elastic modulus upon the addition of a nanotopography to a surface.
- the addition of a plurality of structures forming nanotopography on a surface may decrease the elastic modulus of a material, as the addition of nano-sized structures on a surface will lead to a reduction in continuity of the surface and a related change in surface area.
- the device including nanotopography thereon may exhibit a decrease in elastic modulus of between about 35% and about 99%, for instance between about 50% and about 99%, or between about 75% and about 80%.
- the effective compression modulus of a nanopatterned surface may be less than about 50 MPa, or less than about 20 MPa. In one embodiment the effective compression modulus may be between about 0.2 MPa and about 50 MPa, between about 5 MPa and about 35 MPa, or between about 10 MPa and about 20 MPa.
- the effective shear modulus may be less than about 320 MPa, or less than about 220 MPa. For instance, the effective shear modulus may be between about 4 MPa and about 320 MPa, or between about 50 MPa and about 250 MPa, in one embodiment.
- the microneedle including nanotopography thereon may also exhibit an increase in surface energy as compared to a similar microneedle that does not have a surface defining a pattern of nanotopography thereon.
- a microneedle including a nanotopography formed thereon may exhibit an increase in surface energy as compared to a similar microneedle of the same materials and formed according to the same injection molding methods, but for the inclusion of a pattern of nanotopography on a surface.
- the water contact angle of a surface including a nanotopography thereon may be greater than about 80°, greater than about 90°, greater than about 100°, or greater than about 1 10°.
- the water contact angle of a surface may be between about 80° and about 150°, between about 90° and about 130°, or between about 100° and about 120°, in one embodiment.
- the microneedle array may be used for interaction with tissue, such as in delivery of a bioactive agent to a cell.
- the microneedle array may be a component of a transdermal patch used to deliver an agent to the tissue or to one or more cell types of the tissue, for structural support of a tissue, for removal of a portion or component of the tissue, and so forth.
- the microneedle array may be used in one embodiment for transport of a substance across one or more layers of the skin.
- the microneedles of the array may interact with surrounding biological components and regulate or modulate (i.e., change) intracellular and/or intercellular signal transduction associated with cell/cell interactions, endocytosis, inflammatory response, and so forth.
- the device may regulate and/or modulate membrane potential, membrane proteins, and/or intercellular junctions (e.g., tight junctions, gap junctions, and/or desmasomes).
- the microneedle array may be utilized for transdermal delivery of agents or withdrawal of materials across biological barriers such as the skin, the blood-brain barrier, mucosal tissues, blood and lymph vessels, and so forth without instigating a foreign body or immune response.
- Structures of the nanotopography may mimic and/or interact with one or more ECM protein such as collagen, laminin, fibronectin, etc.
- ECM protein such as collagen, laminin, fibronectin, etc.
- Cells in the local area surrounding the microneedles may maintain an anti-inflammatory microenvironment as the microneedle surfaces may better mimic the local environment either directly or indirectly, e.g., due to protein adsorption at the surface.
- materials may be delivered by use of the device without
- the microneedles of an array may interact with one or more components of the contacting epithelial tissue to increase porosity of the tissue via paracellular and/or transcellular transport mechanisms.
- Epithelial tissue as may be rendered more porous by use of a microneedle array may include both simple and stratified epithelium, including both keratinized epithelium and
- Epithelial tissue encompassed herein may include any cell types of an epithelial layer including, without limitation, keratinocytes, squamous cells, columnar cells, cuboidal cells and pseudostratified cells.
- Interaction of the microneedles with components of a cell network or layer of the epidermis may modulate (i.e., change) the structure of intercellular junctions therein.
- An intracellular junction may be at least one junction selected from the group consisting of tight junctions, gap junctions, and desmasomes.
- nanotopography may modulate proteins of a cellular network so as to induce the opening of tight junctions of the stratum granulosum, thereby providing improved delivery of an active agent across the epidermis, and in one particular embodiment, a high molecular weight active agent.
- Tight junctions have been found in the stratum granulosum and opening of the tight junctions may provide a paracellular route for improved delivery of active agents, particularly large molecular weight active agents and/or agents that exhibit low lipophilicity that have previously been blocked from transdermal delivery.
- the devices may facilitate improved uptake of a delivered agent.
- the pharmacokinetic (PK) profile i.e., the profile of absorption through the epithelial membranes
- a protein therapeutic having a molecular weight of over 100 kDa, for instance between about 100 kDa and about 200 kDa, or about 150 kDa, may be delivered transdermally via a patch including an injection molded microneedle array.
- a patch may be utilized to deliver a single dose of the protein therapeutic, for instance between about 200 and about 500 ⁇ _, or about 250 ⁇ _.
- the recipient may exhibit a PK profile that reflects a rapid rise in blood serum concentration up to between about 500 and about 1000 nanograms therapeutic per milliliter per square centimeter of patch area, for instance between about 750 and about 850 nanograms therapeutic per milliliter per square centimeter patch area, within about 1 to about 4 hours of administration.
- This initial rapid rise in blood serum level which reflects rapid uptake of the therapeutic across the dermal barrier, may be followed by a less rapid decline of blood serum concentration over between about 20 and about 30 hours, for instance over about 24 hours, down to a negligible blood serum concentration of the therapeutic.
- the rapid uptake of the delivered therapeutic may be accompanied by little or no inflammation.
- the devices may also limit foreign body response and other undesirable reactions, such as inflammation.
- the surface of a microneedle including fabricated nanotopography thereon may be functionalized for improved interaction with tissues or individual cells during use.
- one or more biomolecules such as polynucleotides, polypeptides, entire proteins, polysaccharides, and the like may be bound to a structured surface prior to use.
- a surface including structures formed thereon may already contain suitable reactivity such that additional desired functionality may spontaneously attach to the surface with no pretreatment of the surface necessary.
- pretreatment of the structured surface prior to attachment of the desired compound may be carried out. For instance, reactivity of a structure surface may be increased through addition or creation of amine, carboxylic acid, hydroxy, aldehyde, thiol, or ester groups on the surface.
- a microneedle surface including a pattern of nanostructures formed thereon may be aminated through contact with an amine- containing compound such as 3-aminopropyltriethoxy silane in order to increase the amine functionality of the surface and bind one or more biomolecules to the surface via the added amine functionality.
- an amine- containing compound such as 3-aminopropyltriethoxy silane
- Materials as may be desirably bound to the surface of a microneedle array may include ECM proteins such as laminins, tropoelastin and/or elastin,
- fragments may be bound to the surface of a patterned device such as an RGD sequence, which is part of the recognition sequence of integrin binding to many ECM proteins.
- RGD sequence which is part of the recognition sequence of integrin binding to many ECM proteins.
- An injected molded microneedle array may be associated with an agent for delivery via the microneedle array.
- a transdermal microneedle patch may be utilized for delivery of materials beneath the stratum corneum to the stratum spinosum or the stratum germinativum, or even deeper into the dermis.
- an agent may be transported across the stratum corneum in conjunction with the microneedle, e.g., within the microneedle or at the surface of the
- the device may include a reservoir, e.g., a vessel, a porous matrix, etc., that may store and agent and provide the agent for delivery.
- the device may include a reservoir within the device itself.
- the device may include a hollow, or multiple pores that may carry one or more agents for delivery.
- the agent may be released from the device via degradation of a portion or the entire device or via diffusion of the agent from the device.
- Figs. 17A and 17B are perspective views of a device including a reservoir.
- the device 1 10 includes a reservoir 1 12 defined by an impermeable backing layer 1 14 and a microneedle array 1 16.
- the backing layer and the microneedle array 1 16 are joined together about the outer periphery of the device, as indicated at 1 18.
- the impermeable backing layer 114 may be joined by an adhesive, a heat seal or the like.
- the device 1 10 also includes a plurality of microneedles 120.
- a release liner 122 may be removed prior to use of the device to expose microneedles 120.
- a formulation including one or more agents may be retained within the reservoir 1 12.
- Materials suitable for use as impermeable backing layer 1 14 may include materials such as polyesters, polyethylene, polypropylene and other synthetic polymers. The material is generally heat or otherwise sealable to the backing layer to provide a barrier to transverse flow of reservoir contents.
- Reservoir 1 12 defined by the space or gap between the impermeable backing layer 1 14 and the base of the microneedle array 1 16, provides a storage structure in which to retain the suspension of agents to be administered.
- the reservoir may be formed from a variety of materials that are compatible with an agent to be contained therein.
- natural and synthetic polymers, metals, ceramics, semiconductor materials, and composites thereof may form the reservoir.
- the reservoir may be attached to the base upon which the microneedles are located.
- the reservoir may be separate and removably connectable to the microneedle array or in fluid communication with the microneedle array, for instance via appropriate tubing, leur locks, etc.
- the device may include one or a plurality of reservoirs for storing agents to be delivered.
- the device may include a single reservoir that stores a single or a multiple agent-containing formulation, or the device may include multiple reservoirs, each of which stores one or more agents for delivery to all or a portion of the array of microneedles.
- Multiple reservoirs may each store a different material that may be combined for delivery.
- a first reservoir may contain an agent, e.g., a drug
- a second reservoir may contain a vehicle, e.g., saline.
- the different agents may be mixed prior to delivery. Mixing may be triggered by any means, including, for example, mechanical disruption (i.e.
- Multiple reservoirs may contain different active agents for delivery that may be delivered in conjunction with one another or sequentially.
- the reservoir may be in fluid communication with one or more microneedles of the transdermal device, and the microneedles may define a structure (e.g., a central or lateral bore) to allow transport of delivered agents beneath the barrier layer.
- a structure e.g., a central or lateral bore
- a device may include a microneedle assembly and a reservoir assembly with flow prevention between the two prior to use.
- a device may include a release member positioned adjacent to both a reservoir and a microneedle array. The release member may be separated from the device prior to use such that during use the reservoir and the microneedle array are in fluid communication with one another. Separation may be
- a release member is shown that is configured to be detached from a transdermal patch to initiate the flow of a drug compound.
- Figs. 18-19 show a transdermal patch 300 that contains a drug delivery assembly 370 and a microneedle assembly 380.
- the drug delivery assembly 370 includes a reservoir 306 positioned adjacent to a rate control membrane 308.
- the rate control membrane may help slow down the flow rate of the drug compound upon its release. Specifically, fluidic drug compounds passing from the drug reservoir to the microneedle assembly via microfluidic channels may experience a drop in pressure that results in a reduction in flow rate. If this difference is too great, some backpressure may be created that may impede the flow of the compound and potentially overcome the capillary pressure of the fluid through the microfluidic channels. Thus, the use of the rate control membrane may ameliorate this difference in pressure and allow the drug compound to be introduced into the microneedle at a more controlled flow rate.
- the particular materials, thickness, etc. of the rate control membrane may vary based on multiple factors, such as the viscosity of the drug compound, the desired delivery time, etc.
- the rate control membrane may be fabricated from permeable, semipermeable or microporous materials that are known in the art to control the rate of drug compounds and having permeability to the permeation enhancer lower than that of drug reservoir.
- the material used to form the rate control membrane may have an average pore size of from about 50 nm to about 5 micrometers, in some embodiments from about 100 nm to about 2 micrometers, and in some embodiments, from about 300 nm to about 1 micrometer (e.g., about 600 nm).
- Suitable membrane materials include, for instance, fibrous webs (e.g., woven or nonwoven), apertured films, foams, sponges, etc., which are formed from polymers such as polyethylene, polypropylene, polyvinyl acetate, ethylene n-butyl acetate and ethylene vinyl acetate copolymers. Such membrane materials are also described in more detail in U.S. Patent Nos.
- the assembly 370 also contains an adhesive layer 304 that is positioned adjacent to the reservoir 306.
- the microneedle assembly 380 likewise includes a support 312 from which extends a plurality of microneedles 330 having channels 331 , such as described above.
- the layers of the drug delivery assembly 370 and/or the microneedle assembly 380 may be attached together if desired using any known bonding technique, such as through adhesive bonding, thermal bonding, ultrasonic bonding, etc.
- the patch 300 also contains a release member 310 that is positioned between the drug delivery assembly 370 and the microneedle assembly 380. While the release member 310 may optionally be bonded to the adjacent support 312 and/or rate control
- the release member 310 may be easily withdrawn from the patch 300.
- the release member 310 may also contain a tab portion 371 (Figs. 18-19) that extends at least partly beyond the perimeter of the patch 300 to facilitate the ability of a user to grab onto the member and pull it in the desired direction.
- the drug delivery assembly 370 of the patch 300 securely retains a drug compound 307 so that it does not flow to any significant extent into the microneedles 330.
- the patch may be "activated” by simply applying a force to the release member so that it is detached from the patch.
- a drug compound 107 may begin to flow from the drug delivery assembly 170 and into the channels 131 of the microneedles 130 via the support 1 2.
- An exemplary illustration of how the drug compound 307 flows from the reservoir 306 and into the channels 331 is shown in Figs. 22-23. Notably, the flow of the drug compound 307 is passively initiated and does not require any active displacement mechanisms (e.g., pumps).
- the detachment of the release member immediately initiates the flow of the drug compound to the microneedles because the drug delivery assembly is already disposed in fluid communication with the microneedle assembly. In certain embodiments, however, it may be desired to provide the user with a greater degree of control over the timing of the release of the drug compound. This may be accomplished by using a patch configuration in which the microneedle assembly is not initially in fluid
- the user may physically manipulate the two separate assemblies into fluid communication.
- the release member may be separated either before or after such physical manipulation occurs.
- Figs. 24-29 for example, one particular embodiment of a patch 200 is shown.
- Figs. 24-25 illustrate the patch 200 before use, and shows a first section 250 formed by a microneedle assembly 280 and a second section 260 formed by a drug delivery assembly 270.
- the drug delivery assembly 270 includes a reservoir 206 positioned adjacent to a rate control membrane 208 as described above. Although optional, the assembly 270 also contains an adhesive layer 204 that is positioned adjacent to the reservoir 206.
- the microneedle assembly 280 likewise includes a support 212 from which extends a plurality of microneedles 230 having channels 231 , such as described above.
- the support 212 and the rate control membrane 208 are initially positioned horizontally adjacent to each other, and a release member 210 extends over the support 212 and the rate control member 208.
- a release member 210 extends over the support 212 and the rate control member 208.
- the release member 210 is releasably attached to the support 212 and the rate control membrane 208 with an adhesive (e.g., pressure-sensitive adhesive).
- an adhesive e.g., pressure-sensitive adhesive
- the release member 210 may be peeled away and removed, such as illustrated in Figs. 26-27, to break the seal previously formed between the release member 210 and the aperture (not shown) of the support 212. Thereafter, the second section 260 may be folded about a fold line "F" as shown by the directional arrow in Fig. 28 so that the rate control member 208 is positioned vertically adjacent to the support 212 and in fluid communication therewith. Alternatively, the first section 250 may be folded.
- folding of the sections 250 and/or 260 initiates the flow of a drug compound 207 from the drug delivery assembly 270 and into the channels 231 of the microneedles 230 via the support 212 (See Fig. 29).
- a transdermal device may include a housing with
- the device may include a material at a surface having a predetermined degradation rate, so as to control release of an agent contained within the device.
- a delivery rate may be controlled by manipulating a variety of factors, including the characteristics of the formulation to be delivered (e.g., viscosity, electric charge, and/or chemical composition); the dimensions of each device (e.g., outer diameter and the volume of any openings); the number of microneedles on a transdermal patch; the number of individual devices in a carrier matrix; the application of a driving force (e.g., a concentration gradient, a voltage gradient, a pressure gradient); the use of a valve; and so forth.
- characteristics of the formulation to be delivered e.g., viscosity, electric charge, and/or chemical composition
- the dimensions of each device e.g., outer diameter and the volume of any openings
- the number of microneedles on a transdermal patch e.g., the number of individual devices in a carrier matrix
- the application of a driving force e.g., a concentration gradient, a voltage gradient, a pressure gradient
- the use of a valve e.g.
- Transportation of agents through the device may be controlled or monitored using, for example, various combinations of valves, pumps, sensors, actuators, and microprocessors. These components may be produced using standard manufacturing or microfabrication techniques. Actuators that may be useful with the device may include micropumps, microvalves, and positioners. For instance, a microprocessor may be programmed to control a pump or valve, thereby controlling the rate of delivery.
- Flow of an agent through the device may be based on diffusion or capillary action, or may be induced using conventional mechanical pumps or
- nonmechanical driving forces such as electroosmosis or electrophoresis, or convection.
- electrodes are positioned on a biological surface (e.g., the skin surface), a microneedle, and/or a substrate adjacent a microneedle, to create a convective flow which carries oppositely charged ionic species and/or neutral molecules toward or into the delivery site.
- Flow of an agent may be manipulated by selection of the material forming the microneedle surface.
- one or more large grooves adjacent the microneedle surface of the device may be used to direct the passage of drug, particularly in a liquid state.
- the physical surface properties of the device may be manipulated to either promote or inhibit transport of material along the surface, such as by controlling hydrophilicity or hydrophobicity.
- valves or gates as is known in the art.
- Valves may be repeatedly opened and closed, or they may be single-use valves.
- a breakable barrier or one-way gate may be installed in the device between a reservoir and the patterned surface. When ready to use, the barrier may be broken or gate opened to permit flow through to the microneedle surface.
- Other valves or gates used in the device may be activated thermally, electrochemically, mechanically, or magnetically to selectively initiate, modulate, or stop the flow of molecules through the device. In one embodiment, flow is controlled by using a rate-limiting membrane as a "valve.”
- any agent delivery control system including reservoirs, flow control systems, sensing systems, and so forth as are known in the art may be incorporated with devices.
- U.S. Patent Nos. 7,250,037, 7,315,758, 7,429,258, 7,582,069, and 7,6 1 ,481 describe reservoir and control systems as may be incorporated in devices.
- Agents as may be delivered by the device may be intended for the local area near the device or may be intended for wider distribution.
- the device may deliver agents for pain management or inflammation management to a local area around a joint, for instance in treatment of osteoarthritis or rheumatoid arthritis.
- the nanotopography of the device may improve delivery of agents while minimizing foreign body and immune response. This may prove particularly beneficial when considering delivery of oligonucleotides and other therapeutics to the nuclear envelope.
- delivery of materials e.g., plasmids, siRNA, RNAi, and so forth
- materials e.g., plasmids, siRNA, RNAi, and so forth
- microneedle with the ECM may prevent foreign body response within a cell following endocytosis and encourage delivery of the materials to the nucleus.
- protein therapeutics generally refers to any biologically active proteinaceous compound including, without limitation, natural, synthetic, and recombinant compounds, fusion proteins, chimeras, and so forth, as well as compounds including the 20 standard amino acids and/or synthetic amino acids.
- the presence of the device in or near the stratum granulosum may open tight junctions and allow paracellular transport of high molecular weight agents.
- the device may be utilized in transdermal delivery of high molecular weight agents (e.g., agents defining a molecular weight greater than about 400 Da, greater than about 10 kDa, greater than about 20 kDa, or greater than about 100 kDa, e.g., about 150 kDa).
- variation of the surface area to volume ratio of the device may be utilized to alter protein adsorption at the surface of the device, which may in turn alter delivery and cellular uptake of materials.
- deliver of a particular material may be optimized through optimization of the surface area/volume ratio of the device.
- the device may provide increased efficiency and improved uptake due to interaction of the device with components of the dermal connective tissue and accompanying decrease in foreign body response and improvement in localized chemical potential of the area.
- devices are not limited to targeted delivery of agents.
- Systemic deliver of agents is also encompassed herein as is withdrawal of an agent from a subject via the device.
- Agents may include proteinaceous agents such as insulin,
- immunoglobulins e.g., IgG, IgM, IgA, IgE), TNF-a, antiviral medications, and so forth; polynucleotide agents including plasmids, siRNA, RNAi, nucleoside anticancer drugs, vaccines, and so forth; and small molecule agents such as alkaloids, glycosides, phenols, and so forth.
- Agents may include anti-infection agents, hormones, drugs regulating cardiac action or blood flow, pain control, and so forth. Still other substances which may be delivered in accordance with the present disclosure are agents useful in the prevention, diagnosis, alleviation, treatment, or cure of disease.
- agents includes anti- Angiogenesis agents, anti-depressants, antidiabetic agents, antihistamines, anti- inflammatory agents, butorphanol, calcitonin and analogs, COX-II inhibitors, dermatological agents, dopamine agonists and antagonists, enkephalins and other opioid peptides, epidermal growth factors, erythropoietin and analogs, follicle stimulating hormone, glucagon, growth hormone and analogs (including growth hormone releasing hormone), growth hormone antagonists, heparin, hirudin and hirudin analogs such as hirulog, IgE suppressors and other protein inhibitors, immunosuppressives, insulin, insulinotropin and analogs, interferons, interleukins, leutenizing hormone, leutenizing hormone releasing hormone and analogs, monoclonal or polyclonal antibodies, motion sickness preparations, muscle relaxants, narcotic analgesics, nicotine, non-steroid anti
- Vaccine formulations may include an antigen or antigenic composition capable of eliciting an immune response against a human pathogen or from other viral pathogens.
- the device may be utilized in treatment of a chronic condition, such as rheumatoid arthritis, to deliver a steady flow of an agent, to a subject in need thereof.
- RA drugs that may be delivered via disclosed devices may include symptom suppression compounds, such as analgesics and antiinflammatory drugs including both steroidal and non-steroidal anti-inflammatory drugs (NSAID), as well as disease-modifying antirheumatic drugs (DMARDs).
- NSAID steroidal and non-steroidal anti-inflammatory drugs
- DMARDs disease-modifying antirheumatic drugs
- the device may include and deliver symptom suppression compounds, such as analgesics and anti-inflammatory drugs, as well as DMARD compounds, including biological DMARDs. While not wishing to be bound to any particular theory, it is understood that the nanometer-scale structures fabricated on the surface of the device improve deliver of the compounds across the dermal barrier. Through utilization of the device, RA drugs may be delivered at a steady state of symptom suppression compounds, such as analgesics and anti-inflammatory drugs, as well as DMARD compounds, including biological DMARDs. While not wishing to be bound to any particular theory, it is understood that the nanometer-scale structures fabricated on the surface of the device improve deliver of the compounds across the dermal barrier. Through utilization of the device, RA drugs may be delivered at a steady
- the device may prevent the initial burst of concentration common when utilizing previously known methods for delivery of RA drugs, including oral delivery and injection.
- the formed molds may be utilized as a positive mold master for forming a negative mold segment as described herein.
- silicon substrates were prepared by cleaning with acetone, methanol, and isopropyl alcohol, and then coated with a 258 nanometer (nm) layer of silicon dioxide according to a chemical vapor deposition process.
- a pattern was then formed on each substrate via an electron beam lithography patterning process as is known in the art using a JEOL JBX-9300FS EBL system.
- the processing conditions were as follows:
- Beam current 1 1 nA
- Resist ZEP520A, -330 nm thickness
- a silicon dioxide etch was then carried out with an STS Advanced Oxide Etch (AOE).
- Etch time was 50 seconds utilizing 55 standard cubic centimeters per minute (seem) He, 22 seem CF 4 , 20 seem C F 8 at 4 mTorr, 400 W coil, 200 W RIE and a DC Bias of 404 - 41 1 V.
- a silicon etch was carried out with an STS silicon oxide etch (SOE). Etch time was 2 minutes utilizing 20 seem Cl 2 and 5 seem Ar at 5 mTorr, 600 W coil, 50 W RIE and a DC Bias of 96 - 02 V. The silicon etch depth was 500 nm.
- SOE STS silicon oxide etch
- a buffered oxide etchant (BOE) was used for remaining oxide removal that included a three minute BOE immersion followed by a deionized water rinse.
- An Obducat NIL-Eitre ® 6 nanoimprinter was used to form nanopatterns on a variety of polymer substrates. External water was used as coolant.
- the UV module utilized a single pulsed lamp at a wave length of between 200 and 1000 nm at 1 .8 W/cm 2 . A UV filter of 250 - 400 nm was used. The exposure area was 6 inches with a maximum temperature of 200°C and 80 Bar.
- the nanoimprinter included a semi-automatic separation unit and automatic controlled demolding.
- the molds were treated with Trideca-(1 ,1 ,2,2-tetrahydro)-octytrichlorosilane (F13-TCS).
- F13-TCS Trideca-(1 ,1 ,2,2-tetrahydro)-octytrichlorosilane
- the silicon mold was first cleaned with a wash of acetone, methanol, and isopropyl alcohol and dried with a nitrogen gas.
- a Petri dish was placed on a hot plate in a nitrogen atmosphere and 1 -5ml of the F-13-TCS was added to the Petri dish.
- a silicon mold was placed in the Petri dish and covered for 10-15 minutes to allow the F13-TCS vapor to wet out the silicon mold prior to removal of the mold.
- Figs. 30A-30D The nanotopography pattern illustrated in Figure 30E was a surface of a flat substrate purchased from NTT Advanced Technology of Tokyo, Japan. The patterns were designated DN1 (Fig. 30A), DN2 (Fig. 30B), DN3 (Fig. 30C), DN4 (Fig. 30D) and NTTAT2 (Fig. 30E). SEM images of the molds are shown in Figs. 30A, 30B, and 30C, and images of the films are shown in Figs. 30D and 30E.
- Fig. 15 illustrates a nanopatterned film formed by use of the mold of Fig. 30A (DN1 ). In this particular film, the polymer features were drawn by temperature variation as previously discussed. The surface roughness of the pattern of Fig. 30E was found to be 34 nm.
- Figs. 14C and 14D The pattern illustrated in Figs. 14C and 14D was also formed according to this nanoimprinting process.
- This pattern included the pillars 72 and pillars 62, as illustrated.
- Larger pillars 72 were formed with a 3.5 micrometer ( ⁇ ) diameter and 30 ⁇ heights with center-to-center spacing of 6.8 ⁇ .
- Pillars 62 were 500 nm in height and 200 nm in diameter and a center-to-center spacing of 250 nm.
- the nanoimprinting process conditions used with polypropylene films are provided below in Table 2.
- Example 1 Films were formed as described above in Example 1 including various different patterns and formed of either polystyrene (PS) or polypropylene (PP).
- PS polystyrene
- PP polypropylene
- Patterns utilized were DN2, DN3, or DN4 utilizing formation processes as described in Example 1 .
- the underlying substrate varied in thickness.
- the pattern molds were varied with regard to hole depth and feature spacing to form a variety of differently-sized features having the designated patterns.
- BB1 (designated BB1 ) was formed by use of a 0.6 ⁇ millipore polycarbonate filter as a mold. A 25 ⁇ polypropylene film was laid over the top of the filter and was then heated to melt such that the polypropylene could flow into the pores of the filter. The mold was then cooled and the polycarbonate mold dissolved by use of a methylene chloride solvent.
- 3Feature heights are provided as the average of several individually determined feature heights
- Characterizations included formation of scanning electron micrograph (SEM), determination of surface roughness, determination of maximum measured feature height, and determination of fractal dimension.
- the atomic force microscopy (AFM) probe utilized was a series 16 silicon probe and cantilever available from ⁇ .
- the cantilever had a resonant frequency of 170 kHz, a spring constant of 40 N/m, a length of 230 ⁇ 5 ⁇ , a width of 40 ⁇ 3 ⁇ , and a thickness of 7.0 ⁇ 0.5 ⁇ .
- the probe tip was an n-type phosphorous-doped silicon probe, with a typical probe tip radius of 10 nm, a full tip cone angle of 40°, a total tip height of 20-25 ⁇ , and a bulk resistivity 0.01-0.05 ohm-cm.
- the surface roughness value given in Table 3 is the arithmetical mean height of the surface (Sa) areal roughness parameter as defined in the ISO 25 78 series.
- the Fractal Dimension was calculated for the different angles by analyzing the Fourier amplitude spectrum; for different angles the amplitude Fourier profile was extracted and the logarithm of the frequency and amplitude coordinates calculated. The fractal dimension, D, for each direction is then calculated as
- the fractal dimension may also be evaluated from 2D Fourier spectra by application of the Log Log function. If the surface is fractal the Log Log graph should be highly linear, with at negative slope (see, e.g., Fractal Surfaces, John C. Russ, Springer-Verlag New York, LLC, July, 2008).
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- Animal Behavior & Ethology (AREA)
- Dermatology (AREA)
- Medicinal Chemistry (AREA)
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- Heart & Thoracic Surgery (AREA)
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- Surgery (AREA)
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Abstract
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EP11816158.7A EP2563454A4 (en) | 2010-04-28 | 2011-04-27 | Injection molded microneedle array and method for forming the microneedle array |
RU2012150731/14A RU2560646C9 (en) | 2010-04-28 | 2011-04-27 | Array of microneedles manufactured by injection-compression moulding and method of moulding array of microneedles |
US13/641,507 US9545507B2 (en) | 2010-04-28 | 2011-04-27 | Injection molded microneedle array and method for forming the microneedle array |
JP2013506795A JP5868953B2 (en) | 2010-04-28 | 2011-04-27 | Injection mold microneedle array and manufacturing method thereof |
BR112012027737A BR112012027737A2 (en) | 2010-11-08 | 2011-04-27 | "METHOD FOR FORMING A MICRONEEDLE ASSEMBLY, INJECTION MOLDED MICRONEEDLE ASSEMBLY AND TRANSDERMAL PATCH" |
MX2012012317A MX2012012317A (en) | 2010-04-28 | 2011-04-27 | Injection molded microneedle array and method for forming the microneedle array. |
CA2797202A CA2797202A1 (en) | 2010-04-28 | 2011-04-27 | Injection molded microneedle array and method for forming the microneedle array |
KR1020127031014A KR20130058012A (en) | 2010-04-28 | 2011-04-27 | Injection molded microneedle array and method for forming the microneedle array |
AU2011288209A AU2011288209C1 (en) | 2010-04-28 | 2011-04-27 | Injection molded microneedle array and method for forming the microneedle array |
CN2011800321007A CN102958555A (en) | 2010-04-28 | 2011-04-27 | Injection molded microneedle array and method for forming the microneedle array |
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