Microneedles, microcones and photolithographic fabrication methods

Abstract

The invention relates to a photolithographic manufacturing method for producing polymer microneedles, microprobes and other microstructures with sharp tips. The manufacturing process utilizes a single step of top-down exposure of photosensitive resin through a photomask micro-pattern, which correspondingly changes / increases the refractive index of the resin, forming a meta-state waveguide within the resin that focuses additional transmission energy and forms a converging shape (first harmonic microcone). The energy is diffracted through the tip of the first harmonic microcone as a second harmonic beam, thus forming a second converging shape (second harmonic shape) adjacent to the first microcone, followed by an additional third harmonic microcone, which can be built on these structures by applying additional energy.

Description

[0001] Cross-references to related applications

[0002] This application claims priority to U.S. Provisional Patent Application Serial No. 62 / 961,931, filed January 16, 2020, entitled Microneedles, Microcones and Photolithography Manufacturing Methods, the entire contents of which are incorporated herein by reference. Technical Field

[0003] This invention relates to a novel photolithography technique for fabricating microstructures, particularly microcones and / or microneedles. Background Technology

[0004] The development of microneedles began in 1990, and numerous studies have shown that they offer significant advantages over oral and subcutaneous drug delivery. Microneedles typically have sharper tips than subcutaneous injection needles, with a height of only 10-2000 μm, providing a minimally invasive drug delivery method. Oral administration is convenient, but its efficiency is low due to poor drug degradation and absorption within the body. Transdermal drug delivery also faces the problem that many drugs cannot penetrate the outermost layer of skin, leading to low efficiency. However, recent reports show that microneedles can penetrate the skin and deliver drugs to the epidermis and / or dermis without causing pain.

[0005] The geometry of microneedles plays a crucial role in their insertion behavior and mechanical stability. Sharp microneedle tips with small cone angles and small diameters reduce insertion force but increase the likelihood of fracture and buckling failure. A recent study reported several common types of microneedles based on the cone angles of the tip and body, along with their corresponding average insertion forces into chicken breast. The results showed that an isosceles triangular tip with a 30° cone angle is the optimal tip shape because it exhibits the highest buckling resistance durability among the four shapes, a moderate average insertion force, and avoids fracture failure. However, the three-dimensional forming of non-linear geometries, such as curved or tapered shapes, requires layer-by-layer forming processes or multiple photomask alignment processes, which can increase manufacturing time and costs. Summary of the Invention

[0006] This invention discloses the use of optical diffraction associated with liquid-solid crosslinking to form optical waveguides due to the different refractive indices of non-crosslinked and crosslinked resins, enabling the rapid and direct formation of various types of microcone structures within 30 minutes. This process includes ultraviolet (UV) exposure and development. A unique advantage of the proposed microneedle fabrication method is that different photomask patterns can generate various microneedle shapes, including circular, star-shaped, hexagonal, and triangular substrates, as well as advanced functional microneedles such as hollow and tilted microneedles. Since conventional UV lithography methods require multiple UV exposure and alignment processes to fabricate these microneedles, a universal and direct manufacturing process should be carefully designed for a low-cost, precision drug delivery product.

[0007] This invention broadly relates to a novel manufacturing method for producing microneedles and other microstructures with sharp tips. The manufacturing process utilizes bottom-up exposure of a liquid photosensitive resin through a photomask pattern containing multiple holes, such as holes with a diameter of 200 μm or other shapes. Ultraviolet light is exposed through the photomask pattern. The exposed photosensitive resin polymerizes and grows into a microstructure with a sharp tip. This material has a higher refractive index compared to the surrounding liquid photosensitive resin. The refractive index contrast formed later between the solid and liquid resin causes the ultraviolet light to reflect at the boundary like an optical waveguide, sending the light to the apex of the cone. That is, once the liquid resin solidifies, the cured area focuses additional transmitted light like an optical waveguide, forming a first cone (first harmonic microcone). Further ultraviolet exposure causes the ultraviolet light to radiate through the apex of the cone, forming a small tip. The light diffracts again through the tip as a second harmonic beam, and is even further exposed to form a second cone (second harmonic shape). A third cone is also constructed according to the same principle, but is smaller in size due to lower light intensity. We observed a fourth cone in our experiments.

[0008] Unlike previous studies that used solid resins to form vertical sidewalls, current research uses liquid resins to form converging or tapered sidewalls for creating microneedle-like structures or structures with angled sidewalls. The prepared structures are rinsed with solvent to remove unreacted components. The resulting structures can be used as microneedles and microprobes.

[0009] One aspect of the present invention provides a method for manufacturing a plurality of microstructures having converging tips, the method comprising the steps of: providing a substrate having an upper surface and a back surface, the substrate including a pattern having open regions configured to allow radiation to pass through the substrate and solid regions configured to prevent radiation from passing through the substrate; forming a layer of liquid photosensitive resin on the upper surface; exposing the liquid photosensitive resin to radiation passing through the substrate from the back surface for a first time period, thereby producing light-exposed portions of the liquid photosensitive resin, the light-exposed portions being crosslinked and / or polymerized on the upper surface in a manner aligned with the open regions to form respective solid resin structures having an increased refractive index compared to the liquid photosensitive resin, thus each solid resin structure acting as a waveguide guiding the radiation through the open regions of the substrate to a convergence point, thereby forming a solid resin structure having tapered sidewalls and a converging tip; and contacting the coating with a solvent system to remove the non-light-exposed portions of the liquid photosensitive resin, thereby leaving a plurality of micro solid resin structures having converging tips spanning the upper surface of the substrate. Attached Figure Description

[0010] Figure 1 This is a schematic diagram (not to scale) illustrating an example process of microstructure formation.

[0011] Figure 2 This is a diagram further illustrating the development of the cone-shaped light profile of ultraviolet light through micropores to polymerize the liquid photosensitive resin, as well as the additional harmonic structure that occurs as more energy propagates through the resin over time.

[0012] Figure 3 The image is verified by ultraviolet diffraction experiments, which use a photomask with a pattern size of 200 μm to visualize the propagation of light within the liquid photosensitive resin.

[0013] Figure 4 Several images of microcones prepared using the conditions in Table 1 are shown.

[0014] Figure 5 The image shows a SEM image (left) of a second harmonic microcone with a 120 μm photograph pattern substrate, 884 μm height, and 50 μm “waist”, as well as a close-up image (right) of the second harmonic microcone.

[0015] Figure 6A The image shows the Gaussian intensity distribution of collimated ultraviolet light after passing through a photomask with a circular aperture.

[0016] Figure 6B The light intensity distribution is shown after passing through a photomask with a circular aperture for forming an opaque core. The photomask has a Gaussian distribution.

[0017] Figure 7This is a graph showing the attenuation of ultraviolet intensity (375nm) measured 0.5 inches above the light source in the presence of no slide (dot), one slide (triangle), and two slides (square).

[0018] Figure 8 The image shows (a) an SEM image of a microneedle and (b) a magnified view of its tip.

[0019] Figure 9 Images of microstructures with multiple harmonics are shown: (a) fabricated microneedles, (b) ultraviolet light propagation, (c) array of microstructures with second harmonics, and (d) array of microstructures with third harmonics.

[0020] Figure 10 It shows arrays of microstructures with various basic geometries and heights, fabricated through a single synchronous exposure using corresponding patterned photomasks (embeddings).

[0021] Figure 11 The graph shows the relationship between the height of the microneedle and the applied energy. The secondary y-axis represents the aspect ratio of the corresponding height and the exposure time of the corresponding applied energy.

[0022] Figure 12 Photographic images of the microstructures are shown at different applied energies, corresponding to exposure times of (a) 2 seconds, (b) 3 seconds, (c) 5 seconds and (d) 20 seconds, and the resulting exposure doses.

[0023] Figure 13 (a) is a photographic image of PLA microneedle arrays fabricated using PDMS microforming based on diffraction lithography microstructure templates; (b) is a pigskin with insertion marks.

[0024] Figure 14 The results of the microstructure force-displacement test are shown: the needle body remains durable, while the needle tip deforms.

[0025] Figure 15 Images of a 3x3 circular microstructure array: (a) the conical light profile of UV light propagation, (b) the corresponding microneedles (SEM).

[0026] Figure 16 A graph showing the relationship between microstructure height under different application energies; (secondary x-axis) exposure time; (secondary y-axis) aspect ratio.

[0027] Figure 17 SEM images (embeddings) of microneedle arrays with various basic geometries are shown: (a) circular, (b) hexagonal, (c) triangular, and (d) star-shaped.

[0028] Figure 18 (a) is a SEM image of a hollow microneedle array, and (b) is a SEM image of a tilted circular microneedle array.

[0029] Figure 19 Images of the insertion experiment results: 3x3 PLA circular microneedle array insertion marks on pigskin, including microneedle insertion images before and after insertion.

[0030] Figure 20A SEM images of force-displacement test results for a 3x3 PLA circular microneedle array: before insertion (top image), needle tip damage (middle image), and needle body damage (bottom image).

[0031] Figure 20B It is a graph of force-displacement test data.

[0032] Figure 21 This is a diagram showing the minimum crosslinking energy of the surgical guide resin under different light intensities using a 405nm UVLED.

[0033] Figure 22 This is a measurement diagram of the transmission of 405nm UV light through surgical guide resin of different thicknesses.

[0034] Figure 23 This is a height measurement diagram of cross-linked resin at different energies.

[0035] Figure 24 This is an example diagram of the experimental setup used to prepare solid microneedles in Example 4.

[0036] Figure 25 This is a height measurement diagram of microneedles under different exposure energies and times.

[0037] Figure 26 Images of microcones and microneedles corresponding to the first, second, and third harmonics of the exposure energy marked in the previous image.

[0038] Figure 27A It is a SEM image of a 20x20 solid vertical microneedle array.

[0039] Figure 27B yes Figure 27A Magnified SEM image of a single microneedle.

[0040] Figure 27C yes Figure 27B A further magnified SEM image of a single microneedle tip.

[0041] Figure 28 This is an example diagram of the experimental setup used to prepare hollow microneedles in Example 4.

[0042] Figure 29 It is a photograph of an array of 271 hollow microneedles with a base circle diameter of 280 μm and a height of 550 μm, embedded with an image using a ring mask pattern.

[0043] Figure 30It comes from Figure 29 Close-up images of three different hollow microneedles show that the shape profile is highly consistent across the entire array.

[0044] Figure 31 The results of the insertion test and the insertion SEM images of the microneedle array used are shown.

[0045] Figure 32A The force-displacement test data of the vertical microneedle in Example 4 are shown.

[0046] Figure 32B Show Figure 32A Images of vertical microneedles: (a) before, (b) with broken needle tip, and (c) with broken needle body.

[0047] Figure 33A The force-displacement test data of the tilted microneedle in Example 4 are shown.

[0048] Figure 33B Show Figure 33A Images of tilted microneedles: (a) before, (b) with broken needle tip, and (c) detached from the substrate.

[0049] Figure 34A The data for in-phase and out-of-phase force application of the tilted microneedles in Example 4 are shown.

[0050] Figure 34B The diagram shows the direction of force applied in out-of-phase and in-phase tests. Detailed Implementation

[0051] For more details, see [link to relevant documentation]. Figure 1 The process involves providing a generally planar substrate 10 having an upper surface 12 and a back surface 14. The substrate 10 is typically transparent or substantially transparent to allow activation radiation to be transmitted through it. Suitable substrates include glass, fused silica, polymers, or plastics (acrylic resins, glass-resin resins, etc.). The substrate 10 also includes a pattern (e.g., a photomask) having open regions 16 configured to allow radiation to pass through and solid (opaque) regions 18 configured to prevent or block radiation from passing through. The pattern may be formed integrally as part of the substrate itself, such as... Figure 1As shown, the pattern may be a separate pattern layer adjacent to the upper surface and / or back surface of the substrate. In one or more embodiments, the pattern may include a spaced array of holes (windows) distributed on the surface. It is worth noting that the geometry and size of the holes (e.g., width or diameter) can be designed as needed to produce microstructures with the desired geometry, which will be discussed in detail below. Typically, in the context of the present disclosure, these holes are micro-sized, meaning that their maximum size can reach 1,000 μm, where size refers to the maximum size from edge to edge (e.g., the diameter of a circular hole, the maximum width of a rectangular hole, or the point-to-point size of a star-shaped hole).

[0052] like Figure 1 As shown in (B), liquid photosensitive resin 20 is applied to the upper surface 12 of substrate 10 to form a coating thereon. Preferably, the thickness of the liquid photosensitive resin 20 (measured from the upper surface 12 of substrate 10) is greater than the desired height of the structure to be formed. Typically, the coating thickness is around 50 μm to 9 mm. As used herein, “resin” refers to various monomer, oligomer, and / or polymer compositions, typically including monomers, oligomers, and / or polymers dispersed in a solvent system, and optionally a photoinitiator. Such photosensitive resins are well known in the field, including compositions commonly used as negative photoresists in microelectronics manufacturing, and resins used for 3D printing. Typical resins include various epoxy resins, acrylates, polyurethanes, methacrylate oligomers, monomers or polymers, polyurethane methacrylates, diphenyl(2,4,6-trimethylbenzoyl)phosphine oxide, bisphenol A phenolic varnish glycidyl ether (commercial name SU-8), etc. The viscosity of the composition can be adjusted using solvents such as γ-butyrolactone (GBL) or propylene glycol methyl ether acetate (PGMEA), isopropanol (IPA). For example, the viscosity of the resin can be adjusted if it is necessary to modify the shape of the structural tips. For example, liquid resins with lower viscosity tend to form lower bottom angles and higher top angles, while liquid resins with higher viscosity tend to form higher bottom angles and lower top angles. However, almost any transparent liquid resin with photoreactivity can be used, including those with added photoinitiators, such as acrylic and / or methacrylates with photoinitiators (e.g., benzophenone, acetophenone, and phosphine oxide, phosphates, etc.). Photoinitiators are commercially available, including Irgacure brand products and triarylsulfonium salts (e.g., Cyracure UVI, Union Carbide). Plant photosensitive resins are also commercially available. In some embodiments, a transparent resin is used. In some embodiments, a translucent resin can be used. In some embodiments, the resin can be opaque and is available in any number of colors.

[0053] The resin is then exposed to activating radiation of appropriate wavelength and energy intensity. For example... Figure 1As shown in (C), the substrate 10 and resin 20 are exposed from the back side of the substrate from bottom to top. That is, the substrate 10 having the resin layer 20 is placed above a radiation (light) source, so that the radiation source is applied to the back side of the substrate and transmitted from the back side of the substrate to the upper surface, and then into the photosensitive resin. It is worth noting that as long as the radiation source is applied to the structure from the back side of the substrate as described, the entire structure can be inverted and is still considered to be bottom to top.

[0054] Preferably, the radiation source includes a collimating lens that guides the radiation to make the propagation direction of the energy flow (light) parallel and enter the substrate at an incident angle perpendicular to the back surface of the substrate, and accordingly into the photosensitive resin. As the radiation passes through the open areas of the pattern and then penetrates along a direction away from the upper surface 12 of the substrate 10 and propagates within the photosensitive resin layer, light-exposed and non-exposed portions of the resin layer are created. Specifically, diffraction generates and scatters the radiation intensity in such a way that the intensity is higher in the central region of the radiation within each aperture, gradually decreasing towards the edge of the aperture. It is noteworthy that most resins may be exposed to a certain dose of radiation; therefore, the "non-exposed portion" refers only to the portion of the resin layer that has undergone crosslinking and / or photopolymerization due to insufficient dose. At exposure times with constant radiation intensity, once the accumulated energy of the propagating radiation in the light-exposed portion exceeds the threshold energy for photosensitive resin polymerization, the diffracted radiation causes the liquid photosensitive resin to polymerize. The light-exposed portion crosslinks and / or photopolymerizes, thus transforming the liquid resin into a solid resin structure 22 in these portions. This transformation is accompanied by a change in the refractive index of the resin as it is crosslinked and / or photopolymerized. As radiation penetrates deeper into the resin layer, this change in refractive index also alters the propagation path of the radiation (i.e., manipulates the beam profile). Specifically, the refractive index difference between the solid resin structure 22 and the surrounding liquid resin introduces a diffraction barrier at the interface, thereby limiting and guiding the direction of radiation propagation. Therefore, the resulting solid resin structure 22 typically has a conical structure, whereby the bottom of the crosslinked and / or photopolymerized structure is larger than the top (i.e., the tip) of the structure. This structure is initially defined by a first height (h1), measured from the upper surface of the substrate to the tip.

[0055] As radiation-induced adjacent regions of the resin layer undergo further crosslinking and / or photopolymerization, these crosslinked and / or photopolymerized regions subsequently act as waveguides or lenses to confine and further focus the radiation, where the cross-section of the radiation path decreases with the propagation distance of the light source and converges to a single point (e.g., the radiation beam becomes self-focused). The radiation exhibits a central radiation intensity, greater at the center of the aperture than at the edges, allowing it to propagate further into the resin layer. Figure 1As shown in (D), the self-focusing of radiation and subsequent cross-linking and / or photopolymerization in adjacent regions lead to further elongation of the structure tip. With increasing exposure time, the resulting structure 22' can be defined as a second height (h2) greater than the first height (h1).

[0056] As shown in the examples, the height and shape of the cone can be varied according to the applied energy, expressed in terms of radiation intensity and exposure time. Figure 2 As shown, when the first cured cone acts as a sub-mode light channel or lens, causing a second-order elliptical shape at the top of the first formed cone, further exposures produce second- and third-order harmonic structures. As further illustrated in the embodiments, the microstructures can have sidewalls with varying cone angles. That is, as radiation propagates through the resin, diffraction of the radiation can result in alternating tilts and attenuation angles on the sidewalls, leading to more rhomboid tips rather than a uniform cone shape. The term "cone" as used herein includes all structures having a relative cone shape from the substrate to the tip (apex, or vertex), and is preferably a single tip where the substrate is wider than the tip, and is not limited to a cone or conical shape with a uniform sidewall taper. Advantageously, these complex shapes and microneedles can be formed simply by extending the exposure time and applying a corresponding dose of energy to the resin using a single exposure, meaning that the exposure steps do not require start-up and stop to reposition the substrate or photomask or apply radiation from different angles, etc. More precisely, the exposure steps in the method of the invention are applied continuously until the desired shape is formed.

[0057] It is worth noting that different photosensitive resins have different crosslinking energy requirements. Furthermore, radiation exposure processes have different light intensity capabilities. Typically, the applied energy or dose (mJ / cm²) is... 2 The dose is the most important parameter for calculating crosslinking. Dosage = Intensity (mW / cm²) 2 The exposure time is calculated as (x) seconds. Therefore, at higher light intensities, the exposure time can be reduced to achieve the same applied energy (dose). Similarly, at lower intensities, a longer exposure time can be used to achieve the desired energy dose. Typically, the exposure wavelength can be from 300 nm to 450 nm, and the time period is from 1 second to 1 hour, preferably from 10 seconds to 30 minutes. Generally, the applied energy dose is around 5 mJ / cm². 2 Up to 100,000 mJ / cm 2 It is also worth noting that dosage information may be publicly available or determined experimentally in order to calibrate the manufacturing process according to a particular resin selection without departing from the spirit of the invention.

[0058] After forming the desired structure 22', the structure can be formed by washing the substrate with a suitable solvent system to remove any uncrosslinked or unpolymerized resin remaining on the substrate. Suitable solvents include isopropanol (IPA), acetone, and aqueous compositions (such as deionized water). Mechanical stirring (e.g., orbital vibration) can be used to promote the dissolution of unreacted resin. The substrate can then be dried to obtain a substrate with multiple microstructures 22' formed. Figure 1 (E)).

[0059] It is worth noting that this process requires only one exposure step and / or one photomask to facilitate the formation of intricate microstructures. Furthermore, tapered microstructure shapes can be achieved without the need for complex equipment. For example, in this process, the substrate is preferably a planar substrate. Preferably, the substrate is kept horizontal or at a fixed angle during photolithography. Moreover, the substrate is best kept stationary during the microstructure photolithography process. That is, in a preferred embodiment, it is not necessary to tilt, rotate, or otherwise move the substrate during the exposure step to form tapered microstructures.

[0060] A typical feature of the resulting microstructure is a conical axis. More preferably, the width or diameter of the microstructure is greatest at the bottom end of the microstructure adjacent to the substrate and gradually tapers to a point at the distal end of the substrate. Depending on the shape of the pattern used to form the structure, the microstructure can be formed with an axis having a circular cross-sectional geometry (conical), or any other desired shape, including a square substrate (pyramid), star, triangle, rectangle, etc. The angle of the cone can also be varied. As noted in the compression test below, the steeper the angle, the sharper the tip. Depending on the intended use, the sharpness of the tip can be balanced with the strength of the structure. Generally, if the apex angle is too small (e.g., ≤30°), the microstructure is easily broken under stress. However, it is also worth noting that the point of breakage is also determined by the special material used to manufacture the microstructure and the overall size / width of the tip. In one or more embodiments, this process can be used to manufacture structures with dimensions (edge-to-edge dimensions, i.e., diameter) of approximately 5 μm to 1000 μm, preferably approximately 50 μm to 300 μm, as measured on the substrate. The height of the microstructure, measured from the substrate surface to the tip, can range from about 30 μm to about 9 mm, preferably from about 300 μm to about 1,000 μm. Exposure time generally does not exceed 1 hour, preferably not more than 45 minutes, and most preferably not more than 30 minutes.

[0061] Furthermore, as illustrated in the embodiments, this process can be further modified to achieve the desired microstructure shape. For example, hollow microstructures can be formed using a pattern in which the holes have a solid core to block light transmission and, correspondingly, prevent crosslinking and / or photopolymerization in this central region. Radiation thus propagates through the annular rings in the mask and cures the corresponding portions of the resin adjacent to the mask pattern. After removing the non-crosslinked or non-polymerized resin, the resulting structure is hollow, with essentially annular holes or channels extending from the base to the top of the structure. The microstructures can be fabricated to extend from the upper surface 12 of the substrate in a substantially perpendicular direction. Alternatively, as shown in this example, they can be fabricated at an angle to the substrate surface 12. Depending on the pattern used, by using patterns of holes with different sizes and / or shapes, a hybrid array of microstructures with different geometries and / or sizes and / or angles can be fabricated on a substrate in a single exposure process.

[0062] Additional modifications include applying one or more interlayers adjacent to the upper surface 12 of the substrate prior to the application of the photosensitive resin. Such interlayers facilitate the release of microstructures. The interlayers can also be used to further improve the propagation direction of activation radiation into the resin layer or to improve the pattern used to block propagation. The interlayers can be rigid or flexible. In these examples, a shadow mask is cited as an example of such an interlayer. For example, an interlayer can be applied to a substrate having corresponding holes (e.g., pre-formed or sourced locally) aligned with an array of holes on the substrate. For hollow microstructures, during diffraction lithography, the interlayer can ensure or stabilize the formation of inner sidewalls and hollow holes through the microstructure, and ensure that the hollow holes extend from the bottom to the tip of the structure. The interlayer in this embodiment also facilitates the release of the imaged microstructure array after lithography and development because it stabilizes the formed structure. In a further embodiment, the interlayer can be applied to the substrate as a planarization layer. That is, although a planar substrate is illustrated herein, the substrate surface can be non-planar and have one or more height variations on the substrate surface. Furthermore, the photomask itself can be an interlayer with non-planar surfaces (e.g., openings and solid portions). It is worth noting that certain modifications to the substrate surface structure or the mask can alter the properties of the microstructure formed during the exposure process by changing the path of light. Therefore, a sandwich layer can be applied to the substrate surface (or photomask) to planarize the sandwich layer before applying the photosensitive resin.

[0063] Furthermore, it is noteworthy that the resulting microstructures can serve as templates for conventional microforming techniques, enabling the further fabrication of additional microarray structures using non-photolithography techniques. For example, the substrate and microstructures can be used to create a polydimethylsiloxane (PDMS) mold (negative), which can then be used to fabricate microstructures using imprinting with various non-photosensitive polymer compositions. In this embodiment, PDMS is applied to the microstructure formed by diffraction lithography and cured to create a negative mold. Then, by coating the negative mold with liquid resin, curing the resin, and peeling off the PDMS mold, the corresponding microstructure arrays can be formed using various polymers (e.g., non-photosensitive resins). It is worth noting that the subsequent microforming process options broaden the possible resin systems that can be used to fabricate microstructures, thus the resulting structures are not limited to photosensitive resins. For example, microneedles can be made from various biodegradable materials (e.g., microneedles for coating and / or dissolving) and various hydrogels using microforming.

[0064] Microstructures formed through diffraction lithography (or subsequent microforming) have a variety of potential applications, including microneedles for medical / clinical and cosmetic use, microprobes for electrical signal stimulation or detection, and microprobes for photostimulation or detection. Using the same principles to fabricate them, these microstructures can be used as optical waveguides, where light propagating through a microcone is emitted from the tip of the microcone.

[0065] Other advantages of the various embodiments of the invention will become apparent to those skilled in the art upon reviewing the disclosure herein and the following examples. It is important to note that, unless otherwise stated, the various embodiments described herein are not necessarily mutually exclusive. For example, a feature described or depicted in one embodiment may be included in, but not necessarily in, other embodiments. Therefore, the invention encompasses various combinations and / or integrations of the specific embodiments described herein.

[0066] As the word "and / or" is used here, when used in a list containing two or more items, it means that any one of the listed items can be used individually, or any combination of two or more of the listed items can be used. For example, if a combination is described as including or excluding components A, B, and / or C, then the combination can include or exclude A itself; B itself; C itself; a combination of A and B; a combination of A and C; a combination of B and C; or a combination of A, B, and C.

[0067] This description also uses numerical ranges to quantify certain parameters in relation to various embodiments of the invention. It should be understood that when numerical ranges are provided, these ranges are to be interpreted as providing textual support for claims that only give the lower values ​​of the range and claims that only give the higher values ​​of the range. For example, the disclosed numerical range of approximately 10 to 100 provides textual support for claims that are “greater than 10” (no upper limit) and claims that are “less than 100” (no lower limit).

[0068] Example

[0069] The following examples illustrate the method according to the invention. However, it should be understood that these examples are provided by way of illustration and nothing therein should be considered as a limitation on the overall scope of the invention.

[0070] introduction

[0071] This paper describes a self-focusing, diffraction-based ultraviolet lithography method for fabricating microneedle structures of various microcone shapes. The entire process is as follows: Figure 1 As shown, directly exposing ultraviolet light to liquid photosensitive resin through a photomask produces a unique light diffraction pattern, where the exposed areas of the photosensitive resin become needle-like structures. Photopolymerization and / or cross-linking transform the resin from liquid to solid, altering its refractive index. This allows the photopolymerized resin to act as an optical waveguide, guiding and focusing light as it propagates through the resin, thus forming a novel pointed tip. Uncured resin is removed, leaving a microconical shape. More specifically, collimated light is used, propagating like a plane wave and diffracting upon reaching the aperture of the photomask. The diffracted light intensity exhibits a Gaussian distribution opposite the aperture, known as the Airy disk, with higher intensity at the aperture center and lower intensity at the periphery. The liquid photosensitive resin is cross-linked / cured through diffraction light, forming a small cone with a Gaussian distribution on the aperture. The cured resin has a higher refractive index than the surrounding uncrosslinked liquid resin. Therefore, when light propagates through the solid resin, it is refracted at a larger angle to the angle of incidence when passing through the solid-liquid interface (which defines the sidewalls of the microconical structure), and may even be reflected back from the interface, forming a conical light profile. The sidewalls of this microconical structure act like a waveguide, concentrating all the light at a single point, producing a central light intensity. This causes the cone angle to become steeper, ultimately forming a needle-shaped cone tip (first harmonic).

[0072] like Figure 2As shown, further exposure to ultraviolet energy leads to tip elongation and the formation of second-harmonic and third-harmonic cone shapes with different geometric profiles. Specifically, once the first harmonic is formed, its sharp tip acts like a second-harmonic focusing aperture, allowing the formation of a second-harmonic cone structure by creating a stronger light intensity at the structure's center or tip. At this point, the microneedle's shape is essentially optimal, with a slightly tapered body and an isosceles triangular tip with a cone angle of approximately 30°. With further application of exposure energy, a second-harmonic structure will form, followed by the formation of a third and third harmonic.

[0073] The proposed method is unique and versatile because it can form various conical microstructures with straight, angular, or curved sidewalls through a single backlight exposure on a photomask. These include tip-integrated cones and multiple harmonic cones with different heights and base shapes, as well as microneedles with optimal shapes, standard conical needle structures, and even microconical structures with rounded tips. The height and shape of the microneedles can be modulated using different exposure energies and resin materials. Figure 3 The image shows the results of the UV diffraction experiment using a 4x4,200-μm photomask pattern, in which the microcones formed on the substrate surface are clearly visible.

[0074] Example 1

[0075] In the initial experimental setup, a glass slide with a photomask was coated with photosensitive resin. The photomask had a light pattern with several openings. Beneath the photomask was a UV-LED (ultraviolet light-emitting diode) covered with a collimating lens. Liquid photosensitive resin was poured on top of the photomask until it covered its surface, but was held in place by surface tension. Selectable wavelengths of UVLEDs in the 300nm to 450nm range were suitable for this fabrication. LEDs with peak wavelengths of 365nm, 375nm, 385nm, 395nm, and 405nm were tested and verified to form microcones. Each wavelength provides different optical properties to the photosensitive resin, including transparency and attenuation characteristics.

[0076] A single fabrication was performed using transparent resin from Anycubic POT016 LCD UV 405nm fast resin, employing a photomask array with 200μm apertures. The photosensitive resin on the photomask was approximately 2mm thick, thicker than the target height of the microcone. The UV intensity was 10mW / cm². 2 In this case, the light exposure time varies from 10 seconds to 30 minutes, depending on the target cone profile. After exposure, the sample is immersed in isopropyl alcohol (IPA) at 20 rpm on a vibrating screen for 10 minutes to remove uncured resin. After development with IPA, the sample is dried to complete the development process.

[0077] Table 1. Optical dose for different microcone profiles*

[0078] Time (sec) Height (mm) tip Tip length Tip width 5 0.407 no 10 0.594 no 30 0.739 no no no 65 0.808 It will form no no 120 0.736 yes 0.135 150 0.87 yes 0.212 0.067 180 0.9 yes 0.286 210 0.893 yes 0.259 0.076 240 0.852 yes 0.264 300 1.047 yes 0.346 0.072 360 0.98 yes 0.327 0.091 450 0.989 yes 0.322 0.092

[0079] *Each dose is administered at a wavelength of 365 nm through a 200 µm circular mask, with an intensity of 10 mW / cm². 2

[0080] Photos of various microstructures formed at different exposure times, such as Figure 4 As shown. Figure 5 As shown in (A)-(B), the initial experiments were also able to fabricate second harmonic cones with additional exposure time. These experiments were conducted using a 120 μm photomask.

[0081] Example 2

[0082] Diffraction lithography for 3D microneedle fabrication

[0083] The formation strategies of solid and hollow microstructures, and the subsequent construction of different geometries, such as Figure 6A and Figure 6B As shown, this relies on the principles of light diffraction and intensity distribution, as well as the refractive index change of the photosensitive resin from a liquid state to a solid state of photopolymerization and / or cross-linking / curing. Figure 6A As shown, a bottom-up exposure process using collimated light is employed, wherein: (1) when the substrate structure adjacent to the substrate is exposed to the light source through a photomask aperture, an initial microconical structure is formed. (2) when the liquid resin becomes solid, the sidewalls of the microconical structure now act as waveguides, guiding light to form a first harmonic. (3) when the light propagating through the resin self-focuses on the conical light profile, a first cone tip is formed, thus converging the light intensity at the tip. (4) a second harmonic structure is formed by applying and concentrating more energy at the tip and photopolymerizing and / or crosslinking / curing the resin in that region. Again, the second harmonic structure similarly concentrates the light intensity to form a second sharp tip (5), and a third harmonic can be similarly formed (6) when more energy is applied.

[0084] like Figure 6B As shown, a similar technique can be used to form hollow microstructures, except that the photomask is further patterned and the central region of the aperture is blocked to prevent light from passing through this part of the aperture, thus creating a shadow area in the central region of the structure where the resin is still uncured. Therefore, the central core of the structure can be hollowed out by removing the uncured resin after patterning.

[0085] Utilizing these principles, several different microstructures were formed. In one experiment, a glass slide was used as a transparent substrate, upon which a patterned photomask was placed. The photomask was covered with a photosensitive resin. In these experiments, UV LEDs of different wavelengths (365, 375, and 405 nm) were integrated with collimated waveguides to serve as the light source. Different wavelengths exhibit different attenuation / absorption rates within the liquid photosensitive resin. The longer the wavelength, the lower the attenuation, and therefore the taller the structure. Generally, the thickness of the liquid photosensitive resin should be greater than the desired height of the structure to be fabricated.

[0086] A photomask with a circular aperture array, coated with a transparent photosensitive resin (Formlabs), was placed on a microscope slide 13 mm above the light source. Considering that light needs to pass through two slides (the microscope slide and the photomask slide) to reach the resin in this setup, the light energy was measured at a constant distance of 13 mm above the light source using a spectrometer (Lanbo Micro Spectrometer, Stararnet). Figure 7 The results show that when there is no glass slide in the optical path, the measured peak light energy is 1.7271 mW / cm². 2 The value is 1.7149 mW / cm² when there is one slide. 2 The value is 1.6932 mW / cm² when two slides are present. 2 The light energy attenuated by 0.0339 mW / cm² as it passed through the two glass slides. 2 This is equivalent to the fact that the 2% attenuation can be ignored in this experiment.

[0087] Patterned microstructures were obtained by directly backlighting the photosensitive resin under a 375nm UV light source. The slide was then transferred to isopropyl alcohol (IPA), and uncrosslinked resin was removed by gentle orbital oscillation (20 rpm). Once development was complete, the sample was gently dried with compressed air, completing the cone shape of the microneedles. SEM images ( Figure 8 (A)-(B) show that a microneedle array was successfully fabricated on a photomask with a circular aperture pattern under single-backlight ultraviolet irradiation. The optimal microneedle tip shape was obtained at a cone angle of approximately 30°. The measured microneedle substrate diameter was 180 μm, the height was 550 μm, and the aspect ratio was 3.06. The tip diameter was 3 μm, and the cone angle was 25.7°, sufficiently sharp to penetrate the skin without breaking.

[0088] In another experiment, by applying more exposure energy to a smaller circular aperture photomask, 800 μm second harmonic structure microneedles were successfully fabricated, such as... Figure 9 As shown in Figure A, the microneedle substrate has a diameter of 160 μm, a height of 800 μm, and an aspect ratio of 5. Figure 9In section B, optical images of UV light captured during the fabrication process show the propagation of light in the liquid photosensitive resin, and experiments verify that second harmonics can be obtained when sufficient energy is applied. Microneedle arrays with second and third harmonics are shown... Figure 9 As shown in (c) and 9(d), the fabrication capability of the proposed method and the uniqueness of being able to fabricate complex microneedle structures with only one UV irradiation are demonstrated.

[0089] To further demonstrate this universal fabrication method, microneedles were fabricated using photomask aperture geometries of different aperture sizes (circular, triangular, star-shaped, and triangular with curved bases). Figure 10 Different aperture geometries (embedded elements) are shown to produce different optical diffractions, thereby forming different microneedle shapes on the same substrate using a single ultraviolet irradiation.

[0090] To investigate the minimum energy required for the initial crosslinking of liquid photosensitive resin, a circular aperture of 150 μm (illustration) was exposed to a 375 nm UV light source with a light energy of 1.6932 mW / cm². 2 The photomask is set to a constant, and the exposure time is set to a variable (1 second to 90 seconds). Data ( Figure 11 The diagram shows the relationship between the height of the prepared microneedles and the energy used to crosslink the resin. The quadratic y-axis represents the aspect ratio for the corresponding height, and the quadratic x-axis represents the exposure time for the corresponding applied energy. The minimum crosslinking energy of the photosensitive resin is 3.39 mJ / cm². 2 The measured height was 8.4 μm. The microconical structure grew rapidly in the first 20 seconds, after which an increase of 1 mJ / cm was observed. 2 Energy allows the microconical structure to maintain a constant growth rate of 2.44 μm.

[0091] like Figure 12 The image shows optical images of the microcone structure at exposure times of 2, 3, 5, and 20 seconds. At an exposure time of 20 seconds, the microneedle tip features begin to appear.

[0092] To demonstrate the functionality of the prepared microneedles, insertion and force-displacement tests were conducted. The results showed that the tip of each tested microneedle could withstand a strength of up to 0.15 N before breakage. The prepared tapered-tipped microneedles show great potential in transdermal drug delivery applications. To further demonstrate the functionality of the prepared microneedles, polylactic acid (PLA) was used as the raw material to prepare microneedles via micromolding. Figure 8 The diagram shows a 4×4 microneedle array with the same overall geometry. This geometry was chosen for mechanical testing because it is similar to other microneedle geometries, which have reportedly been able to successfully penetrate the skin. Figure 13As shown in (a), a PLA microneedle array was inserted into the skin of a pig carcass by thumb pressure, and the insertion area was stained with blue tissue marker dye for observation.

[0093] Figure 13 (b) Showing the 4×4 blue insertion marks on the pigskin. Force-displacement tests were also performed using a 4×4 microneedle array. Figure 11 The designed microneedles have a diameter of 150 μm, a height of 500 μm, a tip length of 80 μm, and a cone angle of 27.6°. A force gauge (FC200, Torbal) is mounted on a stepper motor integrated with a threaded rod along the z-axis and controlled by an Arduino (Arduino UNO Rev 3). A 4x4 microneedle array is placed directly below the force gauge, which is then commanded to move downwards at a speed of 1.2 mm / min, recording the force every 1 millisecond. The total test time is converted into micrometer displacement, and the results are plotted. Figure 14 As the microneedles are compressed, the first tip begins to deform at 2.38 N, indicating that each tip can withstand at least 0.15 N without any mechanical failure. After that, the tip bends, causing a sudden drop in force. Once all tips are fully deformed, the detected force increases linearly, indicating that the microneedle body remains attached to the substrate without deformation, as can be seen in the corresponding images. This characteristic is highly applicable to drug delivery methods such as "coating, puncturing, and releasing." In other words, the microneedle tips can be pre-coated with drugs or made from the drug itself, designed to break upon insertion, with the needle body acting as a delivery support, and can be disposed of after use.

[0094] The uniqueness of this method in forming microconical microneedle structures was demonstrated through optical diffraction and the corresponding intensity distribution. Using a simple LED system with optical collimation, microneedle arrays with complex geometries can be fabricated with just one exposure within 30 minutes. Insertion and force-displacement tests were conducted, showing that the prepared microneedle tips have a withstand strength of 0.15 N before deformation, sufficient to penetrate the skin. The prepared conical-tipped microneedles show great potential in transdermal drug delivery applications.

[0095] Example 3

[0096] Papillary tips, hollow and tilted microneedles were fabricated and characterized using UV-LED photolithography.

[0097] This fabrication method builds upon previous work and introduces functional microneedles, such as hollow and angled microneedles prepared using a single UV exposure method. The hollow needles are suitable for liquid drug delivery, while the angled microneedles can act as hooks on non-planar skin surfaces. The fabrication process can be completed within 30 minutes, including sample preparation, UV exposure, development, and cleaning, which significantly reduces production costs. Testing was conducted using UV LEDs of different wavelengths (365, 375, 385, 395, and 405 nm) to produce microneedles of varying shapes.

[0098] Since the attenuation of shorter wavelengths is greater than that of longer wavelengths, the shape prediction of microneedles can be studied using experimental setups. Figure 15 For UV light propagation test inside photosensitive resin. Figure 15 (a) shows the shape of light propagation. Figure 15 (b) is the SEM image of the corresponding 3x3 circular microneedle array. Figure 16 The data in the figure shows the relationship between the height of the microneedles on a 150-μm photomask at different application energies, and the figure also shows the approximate shape of the microneedles at the corresponding application energies. Figure 17 As shown, using this data and various photomask geometries, different microneedles can be formed. For example... Figure 18 As shown, this preparation method can also be used to fabricate hollow microneedles and tilted circular microneedles.

[0099] Insertion and force-displacement experiments were conducted using a 3x3 PLA circular microneedle array. Insertion tests were performed on pigskin marked with blue dye, and the needle insertion points on the pigskin were visible. Figure 19 The force-displacement data are shown in Figure 20. Figure 20A According to Figure 16 SEM images of a 3x3 PLA circular microneedle array with a height of 750 μm were generated from the data. The microneedles were placed below a force gauge with a compression rate set to 1.2 mm / min. The top panel shows the microneedles before any displacement. The middle pane shows the shape of the microneedles after a displacement of 168 μm. After compression, only the needle tips begin to deform, while the needle body remains unchanged. The bottom panel shows the shape of the microneedles after a displacement of 624 μm, with most of the needle body deformed or bent, while the base remains relatively in place. Figure 20B As shown, the force-displacement slope also increases significantly at this time, indicating that the durability of the microneedle meets the requirements for microneedle applications.

[0100] Example 4

[0101] Advanced microneedle preparation

[0102] In this work, the microneedles were fabricated using a surgical guiding resin from Formlabs (Somerville, Massachusetts). This resin is a commercially available, autoclaved, biocompatible resin commonly used for guiding 3D-printed dental surgery for implant placement. The resin is a trade secret formulation of the company and, according to the MSDS, consists of methacrylate monomers (25-45 wt%), urethane (55-75 wt%), and a photoinitiator (1-2 wt%).

[0103] I. Minimum crosslinking energy

[0104] Initial testing investigated the minimum energy required to crosslink the surgical guide resin. It was found that crosslinking energy can more accurately predict the crosslinking height. A 405nm UV LED (UV405nm LED, Shenzhen Chunzheng Technology Co., Ltd.) was used as the UV light source. A 3D-printed waveguide was used for optical collimation with the UV LED. A standard glass slide was placed above the waveguide at a fixed distance of 1 mm to minimize UV ​​intensity loss through the space. A thin layer of surgical guide resin, 50 μm thick, was spin-coated onto the standard glass. Finally, a UV intensity meter was placed 1 mm above the resin surface to monitor the UV light source intensity. To accurately measure the crosslinking time, increments of 0.1, 0.22, 0.3, 0.4, 0.49, and 0.6 mW / cm were used. 2 Apply extremely low UV light intensity. The results are as follows: Figure 21 As shown, the height of the crosslinked resin under different light intensities and exposure energies is displayed in an increasing manner. Regardless of the light intensity, for this resin, when the exposure energy reaches 6.8 mJ / cm², the height is significantly higher. 2 At that time, the cross-linking resin height increased, indicating that the minimum cross-linking energy of the surgical guiding resin was 6.8 mJ / cm. 2 .

[0105] II. Transmission rate of 405nm UV light through surgical guide resin of different thicknesses.

[0106] The transmission rate of 405nm UV light through surgical guide resin of different thicknesses was investigated. Understanding the transmission rate of 405nm UV light also helps to better predict the crosslinking behavior of the surgical guide resin. A 405nm UV LED (UV 405nm LED, Shenzhen Chunzheng Technology Co., Ltd.) was used as the UV light source. A 3D-printed waveguide was used for light collimation with the UV LED. A flat glass slide was placed at a fixed distance of 1 mm above the waveguide to minimize UV ​​intensity loss through the space. Unlike the previous section, surgical guide resin of different thicknesses, ranging from 0 to 3000 μm, was applied to the flat glass slide. Finally, a UV intensity meter was placed at a fixed distance of 11 mm above the flat glass slide to monitor the UV light intensity of surgical guide resin of different thicknesses. Before applying the surgical guide resin, the UV light intensity was measured and recorded as the initial UV intensity I0. The UV light intensity was measured again after the resin was applied, referred to as parameter "I". Using the two recorded intensities, the transmission rate was calculated using the following formula:

[0107]

[0108] The results are as follows Figure 22 As shown. The fitted curve is shown in the formula below, and its R... 2 The attenuation factor a3 of the surgical guidance resin is 0.99565824.

[0109]

[0110] a1 = 0.00000366

[0111] a2 = 0.96265990

[0112] a3 = 0.00287837 (attenuation factor)

[0113] To predict the height of the crosslinked resin, we start with a basic formula for calculating energy based on UV light intensity and exposure time:

[0114] Energy = E = I·t (2)

[0115] Here, I represents the intensity of 405nm UV light, in mW / cm². 2 t is the exposure time in seconds. From formula (1), we know that I is a function of z, where z is the thickness of the surgical guiding resin. Therefore, formula (1) can be rewritten as:

[0116]

[0117] Then, substitute into formula (2):

[0118]

[0119] Where I0 is the UV light intensity when z = 0. From formula (3), it can be seen that if I0 and t are fixed, E is inversely proportional to z; the higher the resin thickness z, the less energy E is received. Knowing this relationship, we can say that for every constant value of I0 and t, there must be a vertical resin thickness z corresponding to the minimum crosslinking energy of the surgical guiding resin, which is the 6.8 mJ / cm² we measured and discussed earlier. 2 .

[0120] To verify the formula, we generated a set of real data using the following conditions:

[0121] parameter numerical values unit Voltage V 2.88 V Current I 14 mA power P 40.32 mW UV wavelength λ 405 nm Light intensity at z=0 <![CDATA[I0]]> 5.75 <![CDATA[mW / cm 2 ]]> Exposure time t 0 to 900 Second energy E 0 to 5175 <![CDATA[mJ / cm 2 ]]>

[0122] Using the same experimental system setup and the above experimental conditions, the height of the crosslinked resin at different energies was measured and recorded, such as... Figure 23 As shown.

[0123] III. Height Characteristics of Microneedles

[0124] Next, the characteristics and height of the microneedles under different exposure energies were investigated. The experimental conditions are shown in the table below:

[0125] parameter numerical values unit Voltage V 3 V Current I 60 mA power P 180 mW UV wavelength λ 405 nm Light intensity at z=0 <![CDATA[I0]]> 19.65 <![CDATA[mW / cm 2 ]]> Exposure time t 0 to 120 Second energy E 0 to 2358 <![CDATA[mJ / cm 2 ]]>

[0126] Figure 24 The system setup for microneedle fabrication used in these experiments is described. Starting from the bottom, a waveguide-integrated 405nm UV LED was used as the UV light source, and the LED light was converted into parallel light by a collimating lens. A patterned photomask with a 150μm aperture pattern was placed at a distance of 25.4mm from the UV light source as the substrate for the surgical guidance resin. A layer of surgical guidance resin was coated on the photomask and then irradiated with 405nm UV light. The exposure process stopped when a certain exposure energy was reached, and the corresponding microneedle height was recorded at the specified exposure energy point. Once the exposure process was complete, the sample was cleaned with isopropanol, completing the microneedle fabrication. Figure 25 The measured height of the microneedle is shown at different exposure energies. In this specific example, the graph is divided into four parts according to the shape of the microneedle structure, including the microcone structure, the first harmonic microneedle, the second harmonic microneedle, and the third harmonic microneedle. Figure 25 ). Figure 26 The images show microcone structures and microneedles, representing the shapes at each stage of exposure energy. This discovery demonstrates that microneedles of various sizes and shapes can be fabricated using a single photomask by simply varying the exposure energy.

[0127] IV. Microneedle Array Fabrication

[0128] Use the above settings ( Figure 24 Various microneedle arrays were fabricated using surgically guided resin. Solid straight microneedles were fabricated using a 20×20 aperture array photomask with a diameter of 150 μm. Figure 27A SEM images of the array obtained after substrate development and removal of uncured resin are shown. It can be seen that the process produces a 20×20 microneedle array of uniform size and shape, with each microneedle having a substrate diameter of 133 μm and an average height of 385 μm. Individual microneedles are also provided (…). Figure 27B ) and a single needle tip ( Figure 27C The image shows a magnified SEM image. The microtip has a width of approximately 2.5 μm and a taper angle of 28.5°.

[0129] Use such as Figure 28 The modified device shown was used to fabricate hollow microneedles.

[0130] As with other experiments, a waveguide-integrated 405nm UVLED was used as the ultraviolet light source. A patterned photomask was positioned 25.4 mm from the UV light source. The photomask array consisted of 271 holes, each with a solid center to prevent light from transmitting through the center of the hole (see [link to experiment]). Figure 29 (Illustration in the image). The outer diameter of the aperture is 300 μm, and the solid diameter is 200 μm, thus leaving a 100 μm wide annular open loop for light transmission. To further enhance the effect, a shadow mask (made of resin) with fully through-holes was fabricated using 3D printing technology and aligned with the photomask apertures using a mask aligner. The shadow mask, placed on top of the photomask, contains 271 fully through-holes (hollow type) with a diameter of 300 μm, complementing the photomask apertures. After the UV exposure process, the sample was cleaned with isopropanol, and the shadow mask and hollow microneedles were separated from the photomask. The resulting images of the 271 microneedles are shown in the image. Figure 29 In the photomask, because the material forming the hollow microneedles is the same as that of the shadow mask, the adhesion strength to the shadow mask is stronger than that to the photomask, allowing the shadow mask and hollow microneedles to be easily removed together. The hollow microneedles were measured to have a substrate diameter of 280 μm and a height of 550 μm. Figure 30 (Enlarged view). Figure 30 As shown, the shape and size of a single needle are consistent with those of multiple needles.

[0131] V. Insertion test

[0132] First, the pigskin was cleaned with isopropanol to remove any potential contaminants. A 20×20 solid straight microneedle array was fabricated using diffraction lithography, and then a PLA array was fabricated using PDMS microforming technology based on this array. In short, after fabricating the diffraction-lithographic microneedle array on a glass substrate, the PDMS process was performed. SYLGARD... TM184 silicone rubber and curing agent were mixed at a ratio of 10:1. Residual air bubbles from the mixing process were degassed using a vacuum oven. The transparent elastomer solution was gently poured onto a diffraction-lithographic microneedle array and cured at 80°C for one hour. After cooling to room temperature, the diffraction-lithographic microneedle array was separated from the cured PDMS, yielding a PDMS mold that served as the negative template for the microneedle array (corresponding to the groove / hole array of the microneedles). The PLA molding process involved covering the PDMS mold with PLA particles (1-2 mm). The sample was heated in an oven at 180°C to melt the PLA particles and fill the grooves in the PDMS mold. After cooling to room temperature, the PLA microneedle array was separated from the PDMS mold, completing the PLA microneedle process.

[0133] The PLA microneedle array was inserted into the pigskin by pressing the back of the PLA substrate with the thumb. The insertion area was then stained with blue tissue marker dye (CDI, Cancer Diagnostics, Inc.) to reveal its location. Figure 31 The results of the pigskin insertion test are shown.

[0134] VI. Force-displacement test

[0135] To further understand the mechanical strength of the microneedles, force-displacement tests were conducted. A 3x3 microneedle array was fabricated and used as a microforming template. A two-step molding process, including PDMS molding and PLA molding, was employed to fabricate a PLA microneedle array. The characteristics of the solid straight microneedle array are shown below:

[0136] Diameter = 133 μm

[0137] • Height = 526μm

[0138] • Tip diameter = 40μm

[0139] • Tip height = 134 μm

[0140] Material = PLA

[0141] ·Number of needles = 9 (3x3 array)

[0142] A 3x3 microneedle array was placed vertically at a speed of 1.2 mm / min while a force gauge was slowly moved downwards. The force gauge first compressed the microneedle tips, then applied forces of 0.552 N / needle and 0.0613 N / needle to completely bend the microneedles. The force gauge continued to compress the microneedle body until the maximum programmed time frame was reached. The maximum compressive forces measured by the force gauge were 9.284 N and 1.0316 N / needle, respectively, and the total compression displacement was 436 μm, which matched the compression height subsequently measured by microscopy. Data are as follows: Figure 32A As shown, Figure 32B Images of each stage of microneedling.

[0143]

[0144] 2x2 solid tilted microneedles were fabricated using diffraction lithography. Except for the introduction of an additional tilt angle in the UV exposure process, the fabrication process was identical to that of solid straight microneedles. The tilt angle of the microneedles was measured to be 14°. In this experiment, the microneedles did not convert to PLA. The conditions for the solid tilted microneedles are as follows:

[0145] Diameter = 300μm

[0146] • Height = 900μm

[0147] • Tip diameter = 90μm

[0148] Tip height = 266μm

[0149] Material = Surgical guiding resin

[0150] Number of needles = 4 (2x2 array)

[0151] A 2x2 tilted microneedle array was placed vertically at a speed of 1.2 mm / min while a force gauge was slowly moved downwards. The force gauge first compressed the microneedle tips, then applied forces of 0.106 N / needle and 0.0265 N / needle to completely bend the microneedles. The force gauge then continued to compress the microneedle bodies until the microneedles detached from the substrate. Because these microneedles were not converted into PLA, the adhesion between the needles and the substrate was weaker compared to the solid straight needle test described above. The measured forces for separation from the substrate were 4.06 N / needle and 1.015 N / needle, respectively. The force gauge continued to compress the sides of the microneedle bodies until the maximum programming time range was reached, at which point the measured forces were 5.276 N and 1.319 N per needle. Data are as follows: Figure 33A As shown, Figure 33B Images of each stage of microneedling.

[0152]

[0153] Finally, the separation force required to separate the tilted microneedles from two directions was investigated. Here, if the direction of motion of the force gauge is opposite to the tilt direction of the microneedle, it is called out-of-phase compression; conversely, if the direction of motion of the force gauge is the same as the tilt direction of the microneedle, it is called in-phase compression. The conditions for solid tilted microneedles are as follows:

[0154] Diameter = 300μm

[0155] • Height = 900μm

[0156] • Tip diameter = 90μm

[0157] Tip height = 266μm

[0158] Material = Surgical guiding resin

[0159] ·Number of needles = 1

[0160] While the force gauge continues to move downwards at a speed of 1.2 mm / min, the position of the microneedle is as follows: Figure 34B As shown, the difference depends on whether the test is for in-phase or out-of-phase separation. The measured out-of-phase separation force is 0.224 N, and the in-phase separation force is 0.574 N. The data are as follows: Figure 34A As shown, Figure 34B The corresponding microneedle image shows the compression direction.

[0161]

Claims

1. A photolithography method for fabricating multiple microstructures with converging tips, characterized in that, Includes the following steps: A substrate having a top surface and a back surface is provided, the substrate including a pattern having an open region configured to allow radiation transmission and a solid region configured to prevent radiation transmission; A layer of liquid photosensitive resin is formed on the upper surface; The liquid photosensitive resin is exposed to radiation passing through the substrate from the back side for a first period of time, thereby creating a light-exposed portion of the liquid photosensitive resin. The light-exposed portion is cross-linked and / or polymerized on the upper surface in a manner aligned with the open area to form respective initial solid resin structures. Compared with the liquid photosensitive resin, the initial solid resin structures have an increased refractive index. Therefore, each initial solid resin structure acts as a waveguide, guiding the radiation through the open area of ​​the pattern to the convergence point, thereby forming a solid resin structure with tapered sidewalls and a converging tip. as well as The coating is brought into contact with a solvent system to remove the non-photo-exposed portion of the liquid photosensitive resin, thereby leaving multiple micro solid resin structures having tapered sidewalls and converging tips across the upper surface of the substrate; The exposure step includes the first time period, and also includes at least one second time period that is continuous with the first time period; Exposure to radiation during the second period induces further crosslinking and / or photopolymerization of the resin layer region adjacent to the convergent tip of the initial micro solid resin structure at the first height, thereby forming one or more additional harmonic structures on the initial micro solid resin structure.

2. The method according to claim 1, characterized in that, The open area is a hole with a geometry selected from a group consisting of circles, rectangles, polygons and stars.

3. The method according to claim 2, characterized in that, The pores have dimensions ranging from 1µm to 1,000µm.

4. The method according to claim 2, characterized in that, The open area has an opaque central portion to prevent radiation from passing through the central portion of each hole.

5. The method according to claim 4, characterized in that, The microstructure with converging tips has a hollow shaft.

6. The method according to claim 1, characterized in that, The pattern is a photomask adjacent to the upper surface and / or back surface of the substrate.

7. The method according to claim 1, characterized in that, The pattern and the substrate form an integral whole.

8. The method according to claim 6 or 7, characterized in that, The pattern includes an array of multiple spaced holes distributed on the substrate.

9. The method according to claim 1, characterized in that, The thickness of the liquid photosensitive resin layer is greater than the height of the micro solid resin structure.

10. The method according to claim 1, characterized in that, The thickness of the liquid photosensitive resin layer is 50µm to 9mm.

11. The method according to claim 1, characterized in that, The radiation is light with a wavelength of 300 nm to 450 nm.

12. The method according to claim 1, characterized in that, The radiation is exposed through a collimating lens, thus making the propagation direction of the energy flow from the radiation source parallel and entering the substrate at an incident angle perpendicular to the back of the substrate.

13. The method according to claim 1, characterized in that, The exposure process takes anywhere from 1 second to 1 hour.

14. The method according to claim 1, characterized in that, The microstructure is formed by a single exposure step, and the method does not include more than one exposure step.

15. The method according to claim 1, characterized in that, The micro solid resin structure having tapered sidewalls and converging tip has a first height after the first time period, and the micro solid resin structure having tapered sidewalls and converging tip has a second height greater than the first height after the second time period.

16. The method according to claim 1, characterized in that, The one or more additional harmonic structures have sidewalls with alternating tilt and attenuation angles, which eventually converge at their respective tips.

17. The method according to claim 1, characterized in that, The micro solid resin structures include their respective axes having cross-sectional geometries selected from the group consisting of circles, rectangles, polygons and ellipses, and combinations of the aforementioned arbitrary geometries can be provided in a single array of microstructures spanning the substrate.

18. The method according to claim 1, characterized in that, Each micro solid resin structure has a basic size ranging from 5µm to 1,000µm and a height ranging from 30µm to 9mm.

19. The method according to claim 1, characterized in that, The substrate is substantially planar and remains stationary during exposure.

20. The method according to claim 1, characterized in that, It also includes the following steps: One or more interlayers are applied to the substrate before the photosensitive resin layer is applied.

21. The method according to claim 1, characterized in that, It also includes the following steps: The aforementioned multiple micro solid resin structures are used as templates for microforming.

Images