阅读说明：本技术 生物传感用微针及其制造方法 (Microneedle for biosensing and method for producing same ) 是由 李岩 张航 埃里克J.M.布隆迪尔 崔波 于 2019-05-29 设计创作，主要内容包括：一种生物传感用微针及其制造方法。所述方法包括在基板的宽面上沉积至少一层光刻胶,并且所述光刻胶随后被图案化以确定所述微针的特征。以深反应离子蚀刻(DRIE)的形式进行的第一次蚀刻处理用于将所述基板蚀刻到所述蚀刻深度小于所述基板总深度的第一结构中,以产生至少一个与所述光刻胶下所述基板部分相邻的牺牲特征。随后以各向同性湿法蚀刻的所述形式进行第二次蚀刻处理,其中至少一个所述牺牲特征的蚀刻使蚀刻速率沿所述微针的所述长度逐渐变化,从而使所述微针尖变锋利。(A micro-needle for biosensing and a method for manufacturing the same. The method includes depositing at least one layer of photoresist on a broad side of a substrate, and the photoresist is subsequently patterned to define the features of the microneedles. A first etch process in the form of Deep Reactive Ion Etching (DRIE) is used to etch the substrate into a first structure having an etch depth less than the total depth of the substrate to create at least one sacrificial feature adjacent a portion of the substrate under the photoresist. A second etching process is then performed in the form of an isotropic wet etch in which the etching of at least one of the sacrificial features gradually changes the etch rate along the length of the microneedle, thereby sharpening the microneedle tip.)

1. A method of manufacturing a microneedle for biosensing, the method comprising:

providing a semiconductor substrate;

applying a first photoresist to a first surface of the substrate;

patterning the first photoresist to define a first etch pattern;

subjecting the substrate to a first etch process, the first etch pattern causing the substrate to be etched into a first structure, the first structure comprising at least one sacrificial feature; and

performing a second etching process on the first structure to etch the first structure into a second structure, wherein at least one sacrificial feature is at least partially etched during the second etching process, resulting in one or more features of the needle being etched into the second structure.

2. The method of claim 1, wherein the method is an in-plane method of manufacturing a needle.

3. The method of claim 1, further comprising pretreating the substrate comprising baking the substrate, cleaning the substrate, creating a cleaned and dried first surface, enhancing adhesion to the first photoresist, soaking cleaning the substrate with hydrofluoric acid, cleaning with a solvent, rinsing with deionized water, or blow drying.

4. The method of claim 1, further comprising removing the first photoresist, curing the first photoresist, assembling a plurality of needles together, adding a biocompatible material on the needles, or adding a blotting material one or more times.

5. The method of claim 1, wherein the applying comprises applying a single layer of the first photoresist or a double layer of the first photoresist.

6. The method of claim 1, wherein

The patterning includes defining a channel opening having a width in the first photoresist,

the first etch process includes etching a trench into the first structure by an Aspect Ratio Dependent Etch (ARDE) principle, the depth of the trench being determined by the width of the trench opening.

7. The method of claim 6, wherein the at least partial etching of at least one of the sacrificial features during the second etching process produces the one or more of the needle features (including a sharp needle tip).

8. The method of claim 1, wherein the one or more characteristics of the needle include a needle end face shape, a needle length, and an overall needle diameter.

9. The method of claim 1, wherein the first etching process comprises Deep Reactive Ion Etching (DRIE).

10. The method of claim 1, wherein a first etching process is performed to etch portions of the substrate adjacent to the patterned first photoresist to a depth less than a total depth of the substrate to define at least one of the sacrificial features.

11. The method of claim 1, wherein the one or more features of the needle comprise at least one needle section, and the at least one sacrificial feature is etched during the second etching process resulting in a change in etch rate along a length of the at least one needle section such that a first end of the at least one needle section is etched to be a sharp tip.

12. The method of claim 1, wherein the second etching process comprises an isotropic wet etch.

13. The method of claim 1, wherein the second etching process further comprises removing portions of the first structure to a variable depth, thereby creating a bevel.

14. The method of claim 1, wherein the substrate is a low resistivity p-type single side polished silicon wafer having a predetermined crystal orientation.

15. The method of claim 1, wherein the needle has a length of 1mm ~ 2 mm.

16. The method of claim 1, further comprising:

applying a second photoresist to a second surface of the substrate;

patterning the second photoresist to define a second etch pattern defining at least one flow channel for the needle;

subjecting the substrate to a third etching process, the second etching pattern causing at least one of the flow channels to be etched into the second surface of the substrate;

attaching an additional one sacrificial feature to the second surface of the second structure such that at least one of the flow channels is covered by the additional sacrificial feature; and

wherein additional sacrificial features that are at least partially etched away during the second etching process minimize or eliminate any etching of at least one of the flow channels during the second etching process.

17. The method of claim 16, further comprising removing the second photoresist after the third etching process.

18. The method of claim 16, wherein at least one of said flow channels defines a microfluidic network.

19. The method of claim 16, wherein said third etching process comprises DRIE.

20. The method of claim 16, wherein said additional sacrificial feature comprises a silicon wafer.

21. The method of claim 16, wherein the additional sacrificial features are attached to the second surface of the substrate by tape comprising a layer of polyimide film with a silicon adhesive.

22. The method of claim 16, wherein at least one of the channels extends through the tip and is located away from the tip.

23. The method of claim 16, wherein at least one of the channels extends through the tip offset at an axis that is spaced from a longitudinal axis defined by the tip.

24. The method of claim 1, further comprising:

applying a second photoresist to a second surface of the substrate;

patterning the second photoresist to define a second etch pattern defining at least one flow channel for the needle, an

Subjecting the substrate to a third etching process, the second etching pattern causing at least one of the flow channels to be etched into the second surface of the substrate.

25. The method of claim 1, wherein the needle is a microneedle, wherein the tip of the needle has a radius in the micrometer range.

26. The method of claim 1, wherein the tip has a radius less than or greater than the micrometer range.

27. A needle for contacting and sampling interstitial fluid of a user produced according to the method of claim 1.

Technical Field

The present invention relates generally to the field of medical devices, and more particularly to a novel and useful microneedle device for biosensing in the field of medical devices.

Background

Biosensing devices are widely used in the field of medical equipment to sample one or more fluids from a user to detect and monitor chemical reactions of the body. Microneedles and microneedle arrays have shown broad promise in the above-mentioned fields because they can be inserted into the skin of a user in a simple and painless manner and can be handled by the user at home.

However, current manufacturing methods and materials have limitations in manufacturing effective microneedles and microneedle arrays. For example, in an out-of-plane fabrication process that employs semiconductor materials such as silicon, the length of the microneedles is limited by the thickness of the anisotropic Bosch etch process and the substrate wafer used to fabricate the microneedles, and/or the structural integrity of the out-of-plane structure, which may limit the type and amount of fluid that the microneedles can remove from the user's body. While planar fabrication techniques can produce relatively long microneedles, such techniques often produce microneedles that are not sharp enough to overcome skin elasticity upon device insertion, or, even if the microneedles are capable of overcoming skin elasticity, the needle tip (e.g., a wedge-shaped tip) often penetrates the skin like a scalpel, causing bleeding and preventing collection of interstitial fluid.

Therefore, in the field of medical devices, there is a need to create a novel and practical method for manufacturing a biosensor microneedle device.

Disclosure of Invention

One embodiment is a method of microneedle fabrication, the method comprising: providing a semiconductor substrate comprising a first surface; applying a photoresist to a first surface of a substrate; patterning the photoresist to define a specified etch pattern, the etch pattern defining one or more features of the microneedles; performing a first etching process on the substrate, and specifying an etching pattern to enable the substrate to be etched to form a first structure which comprises at least one sacrificial feature; and subjecting the first structure to a second etching process to etch the first structure into a second structure comprising one or more features of the microneedles, wherein etching the at least one sacrificial feature results in a change in etch rate, sharpening the microneedle tips.

Another embodiment describes microneedles manufactured by the methods.

Drawings

Fig. 1 is a schematic view of a microneedle device.

Fig. 2 is a workflow of a microneedle fabrication process.

Fig. 3 is a modified example of the microneedle manufacturing method.

Fig. 4 is a modified example of the microneedle manufacturing method.

Fig. 5 is a modified example of the microneedle manufacturing method.

Fig. 6A and 6B are schematic diagrams of an embodiment of a microneedle device manufactured by a modified example of the microneedle manufacturing method.

Fig. 7 is a schematic view of an embodiment of a microneedle device.

Fig. 8A-8G are schematic diagrams of another embodiment of a microneedle device.

Fig. 9 is a schematic view of an embodiment of a microneedle device manufactured by a modified example of the microneedle manufacturing method.

Fig. 10(a) -10 (c) are schematic views of trench failure etching generated when another modified example of the manufacturing method shown in fig. 2 is used.

Fig. 10(d) -10 (i) are another modified example of the microneedle manufacturing method, which can minimize channel etching.

Detailed Description

The present invention is not limited to the specific embodiments described below, which are intended only to enable one skilled in the art to make and use the invention.

1. Overview

As shown in fig. 1, in one embodiment, a microneedle device comprises an array of microneedles, each microneedle comprising a base, a body, and a tip, and a set of channels disposed at least partially within the array of microneedles. The microneedle array may additionally or alternatively include any number of microneedles, any number of channels arranged in any suitable configuration, reservoirs in fluid connection with one or more channels, or any other suitable components and component arrangements.

As shown in fig. 2, in one embodiment, a microneedle device manufacturing method 200 includes applying a photoresist to a substrate S220, selectively exposing the substrate S230, performing a first etching process S240, and performing a second etching process S250. The method 200 may additionally or alternatively include substrate pre-treatment S210, substrate post-etch treatment S260, or any other step or combination of steps performed in any suitable order.

2. Advantages of

The microneedle device manufacturing method and the microneedle device manufactured thereby have advantages over the existing manufacturing methods and microneedles, as described below.

First, in certain variant examples, the microneedle length is determined using an in-plane fabrication method, wherein the in-plane projection of the needle represents a cross-section along the frontal or medial plane of the needle. In this fabrication apparatus, the needle length is not limited by the Bosch etching process or the substrate thickness, as is the case in out-of-plane fabrication, the needle length is created along the substrate thickness (in-plane projection means a cross-section along the transverse plane of the needle). In-plane fabrication allows for the fabrication of longer needles that can be used to sample fluid (e.g., interstitial fluid) from a relatively deep location beneath the surface of the user's skin.

Second, in certain variant examples, at least a portion of the microneedle device is fabricated by an isotropic etching technique. This sharpens the needle tip in-plane. The painless insertion of the device into the skin is made easier by the sharper needle which penetrates better into the skin, which is usually highly elastic.

In certain variant examples, this can be achieved by using temporary substrate features (e.g., controlled etching of sacrificial walls of certain portions of the microneedles during isotropic etching (e.g., using mass transport features of the etchant and substrate) — e.g., a primary region adjacent to a sacrificial wall is etched more slowly than a secondary region distal to the sacrificial wall, thereby forming a tapered profile extending from the primary region (forming the tip) to the secondary region (proximal end of the base).

In other variant examples, this may be achieved by applying a second mask or a remaining photoresist during the isotropic etching, wherein the mask acts to prevent the substrate adjacent to the mask from being etched, thereby forming a tapered profile extending from the substrate surface proximal mask (forming the tip) to the substrate surface distal mask (proximal needle base). For example, in one set of examples, a "bottom-up" etch (e.g., a dry etch) is performed with a layer of photoresist to create sharp microtip tips.

However, the in-plane needles may be sharpened. For example, in one set of variations, a "top-down" etch (e.g., a wet etch) is performed without photoresist to create sharp microtip tips.

Additionally or alternatively, the methods and systems described below provide advantages over conventional methods of manufacturing and microneedle devices.

3. System-microneedle device

The microneedle device comprises a microneedle array, each microneedle comprising a base, a needle body, a needle tip, and a set of channels disposed at least partially within the microneedle array. The microneedle array may additionally or alternatively comprise a single microneedle, any number of channels arranged in any suitable configuration, a reservoir fluidly connected to one or more channels, or any other suitable assembly and arrangement of assemblies. One embodiment of the microneedle device 100 is shown in fig. 6A and 6B. Another embodiment of the microneedle device 100 is shown in fig. 9.

The microneedle device 100 preferably comprises an array of microneedles 110. The microneedle array preferably comprises a plurality of microneedles arranged in a row, but may additionally or alternatively comprise a single microneedle or a plurality of microneedles arranged in any suitable configuration. As shown in fig. 1, each microneedle comprises a body 114, and each body 114 comprises a base 112 at a distal end and a needle tip 116 opposite base 112 at a proximal end of body 114.

The needle 114 may have any suitable geometry, such as that produced by any single variation or combination of variations of the method 200 described below. In certain variations, for example, the microneedle 114 comprises or is formed in the form of a prism (e.g., a right prism, a tilted prism, etc.), wherein the prism is truncated, the truncation of the prism facilitating the sharpness of the microneedle tip. By truncation, the two end faces of the prism can have different numbers of edges. The truncation may be in the form of a flat, concave or convex pattern. However, the needle 114 can have any suitable configuration or geometry.

In a modified example, one end face of the prism may have a smaller number of sides than the other end face. For example, in one embodiment, a truncated pentagonal prism can have five sides on a first face and four sides on a second face, e.g., where the truncated face intersects only the second face. In another embodiment, the truncated pentagonal prism can have five sides on a first end face and six sides on an opposing second end face, for example, where the truncated face intersects only the second end face. In other examples, the truncation plane may intersect both end faces, creating an arbitrary number of edges for the first and second end faces (e.g., the same number of edges, a different number of edges, two more edges for the first end face than the second end face, etc.). For example, in one embodiment, a cross-section intersecting two end faces, each of which is a portion of a pentagonal prism, may result in a hexagonal first end face and a four-sided second end face.

The pins may additionally or alternatively be formed of any other type of structure (truncated or non-truncated), such as any type of prism (e.g., triangular prism, pentagonal prism, etc.), cylinder, pyramid, polyhedral structure, or any other structure having any suitable geometry (e.g., number of faces, number of sides per face, size, etc.).

As shown in fig. 7, the micro-needle body 114 may be a truncated quadrangular prism having a first wide end surface and an opposite second wide end surface, each of which is aligned with a wide surface of the substrate. One of the broad end faces preferably intersects a truncated face, wherein the truncated face is oriented at a non-zero angle with respect to one broad end face, but both broad end faces may additionally or alternatively intersect the truncated face, none of the broad faces intersect the truncated face, the prism intersects multiple truncated faces, or any other suitable portion of the prism may be truncated in any suitable manner.

The microneedle body 114 can be solid, hollow, serrated, or have any area of removed material or negative space (e.g., the microneedle has a channel running along the broad face of the needle body or a channel with a bisecting needle tip, etc.).

The needle tip 116 preferably has a cross-sectional dimension (e.g., a radius, a diameter, etc.) small enough to penetrate the skin of the user (e.g., overcome a skin elasticity threshold, or overcome a skin elasticity threshold with an insertion force below a predetermined force threshold) without breaking during or after insertion.

The microneedle devices are preferably fabricated entirely from a substrate 118, but may also be fabricated partially (e.g., by etching) from the substrate 118. the substrate 118 preferably comprises silicon (e.g., 99.999999999% pure, greater than 99%, 98% ~ 100%, less than 98%, etc.), and further preferably low resistivity p-type silicon. the silicon may additionally or alternatively be n-type silicon having a relative resistance, any suitable purity, or any other property. the wafer may further additionally or alternatively comprise any number of semiconductor materials, non-metallic materials (e.g., glass, wood, paper, fabric, etc.), semi-metallic materials, metallic materials (e.g., aluminum, gold, etc.), core materials (e.g., paper, fabric, etc.), or any other suitable material or combination of materials.

The thickness (e.g., in the z-direction) is preferably determined based on the maximum aspect ratio achievable with a subsequent etching step (e.g., thickness exceeding the maximum possible etch depth) such that the channels and reservoirs are not etched through the entire substrate thickness, but may additionally or alternatively be determined based on any other parameter.

In certain variant examples, the microneedle device comprises a set of one or more channels 120, wherein the set of channels 120 function to remove one or more liquids from a user. In certain variant examples, the liquid may be further transferred to a collection region 124 of the microneedle device, which collection region 124 may be fluidly connected to one or more microneedle bases. The collection region 124 is preferably disposed distal to a set of microneedle bases, but may additionally or alternatively be disposed adjacent to the microneedle bases, distal to a single microneedle base, or otherwise disposed. The channel set 120 can be partially enclosed (e.g., a triple walled channel), completely enclosed, or not enclosed at all (e.g., when the surface of the microneedle device allows for sufficient wicking action) within the microneedle device. The one or more channel groups 120 may be distributed in any permutation of the microneedle groups: each microneedle 110 may have a single channel 120, each microneedle 110 may have multiple channels, multiple microneedles may share a channel, or any other suitable distribution and arrangement of channels. In certain variant examples, the microneedle device has a plurality of channels 120, and the channels 120 can be isolated (e.g., for independent microneedle testing), fluidly connected (e.g., grouped in reservoirs, as shown in fig. 8C-8D), or otherwise arranged.

Each channel of a set of channels may have a uniform width along its entire length (e.g., 500 [ mu ] m, 1mm, 100 [ mu ] m ~ 1mm, less than 100 [ mu ] m, greater than 1mm, etc.), a width that varies along its entire length, a width that is different from the width of another channel of the set of channels, the same width as the width of another channel of the set of channels, or any suitable width.

The channel may be a straight path, a curved path, a random path, or any other suitable path. Each of the channels preferably has a depth less than the thickness of the substrate, but optionally extends through the entire thickness of the substrate along part or all of the length of the needle body, e.g., in certain variant examples, the channels have a core material disposed within part or all of the channels.

The microneedle device can include a set of channels (e.g., channels as shown in fig. 7 and channels as shown in fig. 8A-8G) disposed in at least a portion of each microneedle. In one specific example, each set of the channels can comprise three-sided walls of one groove in a broad face (e.g., in a plane) of the microneedle device, wherein liquid from a user moves in a needle tip-to-base direction through capillary action permitted by the three-sided walls of the channels. The channels may be grouped together in a shared reservoir or may each remain independent.

In one variation, the microneedle device comprises one channel extending along the microneedle body, the channel encompassing the entire microneedle length from the needle tip to the base. The channel optionally extends to a portion of the length of the microneedle between the needle tip and the base.

In another variation, the microneedle device comprises a channel extending from the base in a direction away from the needle tip.

In another variation, the microneedle device may have a main channel (e.g., a relatively large width) at the distal end of each base of a set of microneedles, wherein the main channel is fluidly connected to a set of microchannels, each of which is aligned along the set of microneedles. In one specific example, the main channel is perpendicular to each set of the microchannels. In other examples, the main channel and the micro channel are arranged in any suitable manner.

The microneedle device can include any number of reservoirs 122 disposed in a collection region 124 of the microneedle device, preferably fluidly connected to each channel of a set of channels, but can additionally or alternatively be fluidly connected to one or more channels, fluidly connected to a wicking material, or otherwise disposed. The reservoir 122 may be connected to an auxiliary component (e.g., a test strip), or coupled to a collection device (e.g., a collection vial), or closed to the environment, or open to the environment, or configured in any other suitable manner. The reservoirs preferably have the same depth perpendicular to the broad face of the substrate as the one or more channels, but optionally have different depths, substantially non-zero depths (e.g., liquid collects on the surface of the microneedle device), or any other suitable depth. In one example variation, the microneedle device includes a single reservoir 122 fluidly connected to the plurality of channels 120. In another variant example, each channel has its own reservoir. In another variant example, each channel functions as a reservoir. The microneedle device may additionally or alternatively include any other suitable number and arrangement of reservoirs relative to any number of channels.

4. Method-summary

The microneedle device manufacturing method 200 may include applying photoresist to a substrate S220, selectively exposing the substrate S230, performing a first etching process S240, and performing a second etching process S250. The method 200 may additionally or alternatively include a substrate pre-treatment S210, a supplemental treatment S260, or any other step or combination of steps performed in any suitable order. The method preferably produces any or all of the microneedle devices 100 described above, but any suitable microneedle device 100 may additionally or alternatively be produced.

4.1 method-applying Photoresist to substrate S220

The method 200 may include applying a photoresist to a substrate S220 for creating a specified etch pattern to form a predetermined set of microneedle features (e.g., length, radius, shape, etc.). S220 may additionally or alternatively create one or more microneedle device features (e.g., by applying a curable, non-strippable photoresist).

S220 is preferably performed first in the method 200, but step S220 may additionally or alternatively be performed multiple times throughout the method 200 (e.g., before each step of the set etching step), or at any other point in time in the method 200.

As shown in fig. 3, the photoresist is preferably applied to one broad side (e.g., broad side, polished side, etc.) of a substrate (e.g., a silicon wafer), but may additionally or alternatively be applied to multiple surfaces (e.g., broad sides and sides) of the substrate, all surfaces, portions of surfaces, or any other area or surface of the substrate. The photoresist may be applied by any or all of the following processes: immersion (e.g., dip coating), spray coating, spin coating (e.g., 200 revolutions per minute for 40 seconds), dry film photoresist, painting, or any other suitable application process. A positive photoresist (e.g., photopolymer photoresist, photocrosslinked photoresist, etc.), a negative photoresist (e.g., photoresist), a permanent photoresist (e.g., non-strippable, curable, etc.), a temporary photoresist (e.g., strippable, soluble, etc.), or any other suitable photoresist or combination of photoresists may be applied over the substrate. The photoresist preferably has a lower or negligible etch rate relative to the etch rate of the substrate material, but may alternatively have any suitable etch rate.

In one variation, a positive photoresist is used, where the corresponding mask includes microneedle features (e.g., pin cross-sections). In one embodiment, AZ4620 (microchemical) positive photoresist is used. A negative photoresist is optionally used, wherein the corresponding mask comprises a cross section of the trenches and reservoirs.

The photoresist may be applied to any suitable thickness (e.g., 11 μm, 24 μm, greater than 11 μm, 5 ~ 30 μm, etc.) and have any number of layers (e.g., a single layer, pre-baked double layers between layers, etc.).

Step S220 may additionally include, but is not limited to, any suitable sub-process, such as: curing the photoresist, drying the substrate to which the photoresist has been applied, baking the substrate (e.g., prebaking at 90 degrees celsius for 5 minutes), or any other suitable sub-process.

4.2 method-patterning of photoresists S230

The method 200 may include patterning of the photoresist S230 to pattern the substrate according to a mask to define one or more microneedle features (e.g., needles, pedestals, tips, channels, reservoirs, needle contours, etc.) in a subsequent etching step. S230 may additionally or alternatively be used to determine one or more temporary features (e.g., sacrificial walls) of the microneedle device, wherein the temporary features are determined in a first etching step and subsequently deleted in a second etching step.

The substrate with the photoresist is preferably patterned by selectively exposing the photoresist using a mask (e.g., a photomask) that defines a set of predetermined microneedle device features corresponding to the microneedle device features (e.g., the front face locations or mid-plane locations of the needles, etc.) at predetermined locations aligned with the broad face of the substrate. When exposed, features having predetermined locations defined by the mask form a pattern in the photoresist. The predetermined set of features preferably includes a needle cross-section (having a predetermined needle length and a predetermined tip radius), and may optionally include one or more temporary features, such as one or more sacrificial walls (e.g., a sacrificial wall as shown in fig. 3 and a sacrificial wall as shown in fig. 5), but may additionally or alternatively include other microneedle features (e.g., multiple needle profiles, multiple tips, needle diameters, channels, reservoirs, etc.), placement features (e.g., spacing between microneedles, connections between channels and reservoirs, etc.), temporary features (e.g., sacrificial features, sacrificial walls, etc.), or any other feature of a microneedle device.

The mask preferably includes a base having a set of predetermined patterns of features. The base preferably comprises a transparent material (e.g., glass, plastic, etc.), but may additionally or alternatively be constructed of a translucent material, a non-transparent material, a coated material (e.g., a painted material), or any other suitable material. The predetermined set of features is preferably patterned onto the base with chrome, but may additionally or alternatively be patterned with ink, film, or any other suitable material. The mask may be a positive mask whose patterned predetermined features correspond to microneedle features to be retained during the etching process, or a negative mask whose patterned predetermined features correspond to microneedle features to be removed during the etching process.

In a variant example, the mask is a positive mask, the predetermined features patterned of which comprise a microneedle section and an optional sacrificial wall.

In a second example variation, the mask is a negative mask, and the patterned predetermined features include a channel and a reservoir. However, the mask may define any suitable microneedle features.

The pattern features can be substantially the same size as the corresponding microneedle device features (e.g., the patterned microneedle length is the same as the produced microneedle length). Any or all of the pattern features may be additionally or alternatively over-set (e.g., a patterned needle length of greater than 20 μm of the desired needle length, a patterned needle tip radius of greater than 5 μm of the desired needle tip radius, etc.), which may be used for additional etching or post-etch treatment; portions that are not drawn (e.g., patterned needle radii less than 1 μm of the desired needle radius, patterned needle lengths less than 10 μm of the desired needle length, etc.) may also function, e.g., to account for added coatings.

Step S230 is preferably performed after step S220, but may additionally or alternatively be performed multiple times throughout the process (e.g., before performing each of multiple etching steps), or at any other point during the process.

The substrate is preferably exposed directly on one broad side of the substrate with the photoresist coating (e.g., a light source directed at the broad side). The light source may additionally or alternatively be directed at one surface of the substrate at an angle (e.g., oriented at a 45 degree angle relative to the broad face), multiple light sources may be directed at the substrate (e.g., multiple light sources for multiple photoresist coating surfaces), or the wafer and light sources may be arranged in any other suitable configuration.

The light source preferably comprises Ultraviolet (UV) light (e.g., 10 nm ~ 400 nm wavelength), but may additionally or alternatively comprise light of shorter wavelengths (e.g., less than 10 nm), longer wavelengths (e.g., greater than 400 nm), or any other wavelength or combination of wavelengths²) Of (2) is detected.

In a first variant example, the mask comprises a patterned needle section resulting from a predetermined location along the front or mid-plane of the microneedles. The needle cross-section can have any suitable shape, such as trapezoidal (e.g., all right angles, no right angles, partial right angles, etc.), pentagonal (e.g., one or more right angles, no right angles, etc.), triangular (e.g., one right angle, no right angles, etc.), or any suitable shape. The shape of the needle cross-section preferably corresponds to the shape of one or more end faces of a prismatic needle body, but optionally has fewer sides, more sides or any other shape. In a first specific example (e.g., as shown in fig. 4), the mask includes a quadrilateral patterned needle cross-section. In a second specific example, the mask includes a pentagonal patterned needle cross-section.

In certain variant examples (e.g., as shown in fig. 3), the photoresist is patterned to define a set of multiple predetermined needle features, such as a set of needle sections, sacrificial walls, channels, and reservoirs.

In certain variant examples, where the patterned needle cross-section is over-stretched compared to the desired needle cross-sectional dimension, removal of material in a second etching step may be considered. The patterned needle cross-section is optionally substantially equal to the desired or selected dimension.

Step S230 may additionally include, but is not limited to, any additional sub-processes, such as applying a developer (e.g., AZ400K4:1 developer).

4.3 method-carry out first etching treatment S240

The method may include performing a first etch process S240 that creates a first structure based on a set of pattern features. The first structure is preferably altered in a second etching process described below to form a complete microneedle device (e.g., removing a sacrificial wall, sharpening a needle tip, etc.), but may alternatively be formed without further modification. The first structure preferably comprises one longitudinal needle section formed by removal of material adjacent to the patterned predetermined needle section and one sacrificial wall section formed by removal of material adjacent to the patterned sacrificial wall section, but may additionally or alternatively comprise any other suitable feature or section.

The first etch process is preferably performed after the photoresist is applied and patterned (e.g., with a mask), but may be performed multiple times throughout the flow of the method, or after additional steps (e.g., baking the substrate, curing the photoresist, etc.), or at any other time during the method.

The first etching treatment is preferably performed by anisotropic etching (e.g. Bosch process Deep Reactive Ion Etching (DRIE), low temperature DRIE, etc.), further preferably during DRIE, but may additionally or alternatively be performed in any other etching process the first etching treatment preferably removes substrate material positively along the substrate broad face, e.g. along the z-direction in fig. 3 the etching may additionally or alternatively remove material in a direction parallel to the substrate broad face or in any other suitable direction the first etching preferably removes substrate material to a predetermined depth by any suitable number of times with any suitable run time the first etching is preferably etched to a depth of at least 10 μm, but may additionally or alternatively be up to 10 ~ 20 μm, 10 ~ 50 μm, 2 μm ~ 0.5 mm, more than 0.5 mm or any other suitable depth the first etching may be performed at any suitable etching rate, such as 1 μm/min, less than or equal to 10 μm, 10 ~ 20 μm/min, or more than 20 μm, ~ μm/3520 min or any other suitable etching rate.

The first etch may be performed at a low temperature by pulsed etching, continuous etching, time division multiplexed etching, and/or any other suitable form of etching. The first etch may be performed using a dry process (e.g., using sulfur hexafluoride (SF 6) plasma, nitrogen trifluoride, dichlorodifluoromethane, etc.), but may additionally or alternatively be performed using a wet process (e.g., using potassium hydroxide/isopropanol, ethylenediamine pyrocatechol, tetramethylammonium hydroxide, hydrofluoric acid/nitric acid, etc.), or using any type and combination of etchants. The first etching process may further additionally or alternatively include an isotropic etch.

The first etching step is preferably performed to a depth less than the thickness of the substrate, which may form one or more connected sacrificial features (e.g., sacrificial walls). The substrate used is preferably thicker than the desired microneedle thickness (e.g., to accommodate the sacrificial material), but may additionally or alternatively have the same thickness as the desired microneedles. To this end, the first etching step may be monitored continuously, checked at regular or random intervals, stopped after a predetermined amount of time has passed, or performed in any other suitable manner.

Any parameters of the sacrificial features (such as thickness, length, width, volume, mass, distance from the needle cross-section, etc.) may be determined based on the desired needle sharpness, which is preferably at least partially formed in the secondary etching step, but may optionally be formed completely or not at all in the secondary etching step. In a first variant example, the victim feature parameter is calculated according to any or all of: isotropic etch rate, etchant mass transfer rate through the substrate material (e.g., silicon) (e.g., expected rate of change of mass transfer), needle sharpness (e.g., tip radius), or any other suitable parameter.

In one variant example, the length of the sacrificial wall and its distance from the tip depend on the mass transfer characteristics of the substrate material (e.g., silicon) and the desired sharpness of the tip.

The first etching step may include, but is not limited to, any additional sub-processes, such as: passivation, re-application of photoresist, polymer deposition, multiple etching steps with any number of etchant types, drying, curing, or any other sub-process.

In a variant example of the first etching step by DRIE etching, step S40 may comprise alternating etching (e.g. alternating with a fluorine-based gas such as SF6 gas) with polymer deposition (e.g. gas deposition such as C4F 8).

In a second modified example, DRIE etching is performed in a plurality of circulation blocks. For example, in one specific example, the substrate is etched to a first depth (e.g., 100 μm depth) for 300 DRIE cycles (e.g., by a Bosch process), and then etched to a second depth (e.g., 200 μm, 300 μm, etc.) for 600 DRIE cycles (e.g., by a Bosch process). A baking step (e.g., 30 minutes at 250 degrees celsius) is preferably performed after the second circulation block to harden any remaining photoresist, but a baking step may additionally or alternatively be performed between circulation blocks. In some examples, the photoresist is partially or completely removed during or after DRIE.

4.4 method-perform second etch Process S250

The method can include performing a second etching process S250 for creating a second structure from the first structure, the second structure having one or more pin features along a pin thickness (e.g., along the y-direction in fig. 3). These pin features (e.g., undercuts) are used to sharpen the pins, but may additionally or alternatively be used to change the shape of the pin faces (e.g., reduce the number of prismatic faces), shorten the pins of the first structure, reduce the overall diameter of the pins of the first structure, remove one or more sacrificial features of the first structure, or perform any other suitable function.

The second etching process is preferably performed after the first etching process S240, but may additionally or alternatively be performed during the first etching process, in place of the first etching process, prior to the first etching process (e.g., in reverse order to the first etching process), multiple times throughout the process, or at any other point in time during the process.

The second etching process is preferably performed by isotropic etching, but may additionally or alternatively be performed by anisotropic etching. The second etching process preferably removes substrate material in a forward direction of the substrate thickness (e.g., in the y-direction as shown in fig. 4), thereby creating acicular features along the needle thickness (e.g., undercuts). The etch may additionally or alternatively remove material in a forward direction with respect to the broad side of the substrate, in a second direction perpendicular to the thickness of the substrate (e.g., the x-direction), or in any other suitable direction.

The second etch may be performed at a low temperature by pulsed etching, continuous etching, time division multiplexed etching, and/or any other suitable form of etching. The second etch may be performed using a dry process (e.g., using sulfur hexafluoride (SF 6) plasma, nitrogen trifluoride, dichlorodifluoromethane, etc.), a wet process (e.g., using potassium hydroxide/isopropanol, ethylenediamine pyrocatechol, tetramethylammonium hydroxide, hydrofluoric acid/nitric acid, etc.), or using any type and combination of etchants. The photoresist may remain after the second etch (e.g., isotropic dry etch), but the photoresist may be partially or completely removed during or before the second etch (e.g., isotropic wet etch). The first etching process may additionally or alternatively include an anisotropic etch.

In certain variant examples, the second etch is performed by a "bottom-up" etch process, such as a dry etch (e.g., as shown in fig. 4) in which the tip is sharpened bottom-up (e.g., along the negative z-axis direction in fig. 4). In one embodiment, a photoresist layer is present in the second etch process that prevents the substrate (e.g., the upper broad face) adjacent the photoresist from being etched during the bottom-up etch.

In other variation examples, a "top-down" etching process (as shown in fig. 8A-8G) is employed, such as a wet etch (e.g., as shown in fig. 4) to sharpen the tip in a lower direction (e.g., along the positive z-axis in fig. 4). In one embodiment, the tip is sharpened by a wet second etching step without a photoresist layer.

The second etching step preferably utilizes one or more sacrificial features (e.g., walls, edges, tabs, posts, etc.) adjacent the first structural tip to sharpen the tip, such as, but not limited to, the sacrificial walls shown in FIG. 3. the tip may additionally or alternatively be arranged at the proximal end of the tip, near the hub, adjacent to a plurality of needles, or otherwise arranged with any number of sacrificial features due to mass transfer principles, the tip etches at different rates along its thickness because the tip will etch slower than in areas that are not in contact with any substrate material (e.g., the sacrificial walls). this process creates a bevel along the tip thickness (e.g., based on the aforementioned truncation), thereby sharpening the needle.

The second etching preferably removes substrate material to a variable depth that is the same as the thickness of the substrate, thereby creating a bevel, but optionally removes material to a uniform depth the depth may have any suitable value, such as 10 μm, 10 ~ 20 μm, 10 ~ 50 μm, 2 μm ~ 0.5 mm, greater than 0.5 mm, or any other suitable value the second etching may be performed at any thickness of the needle tip at any suitable etching rate, such as a first thickness of 1 μm/min, a second thickness of 2 μm/min, any thickness of less than or equal to 10 μm/min, any thickness of less than or equal to 20 μm/min, any thickness of 10 ~ 20 μm/min, any thickness of greater than 20 μm/min, or any other suitable etching rate.

The parameters of the second etch (e.g., etch rate, etch time, temperature, humidity, etc.) are preferably configured as a needle having a predetermined set of characteristics as previously described, and may be determined based on one or more desired dimensions (e.g., desired tip radius, desired needle length, desired needle thickness, etc.), one or more characteristics of the substrate (e.g., oxidation rate, thickness, etc.), or any other suitable or desired characteristics. The resulting tip may have any suitable shape (e.g., prism, truncated prism, cone, pyramid, cylinder, etc.) and have any suitable number of facets with a suitable number of sides. During the second etching process, the tip may remain unchanged (e.g., stationary), but may additionally or alternatively be adjusted (e.g., dynamically moved according to a predetermined plan), translated, rotated (e.g., to create a smooth edge of the tip, form a tapered tip, etc.), or otherwise manipulated during the second etching process.

In some variant examples, the second etching step is performed with a mask. The mask (e.g., previously applied photoresist) may additionally or alternatively be removed prior to the S250 step. The mask may serve to prevent or slow etchant ingress (e.g., no sharp pin features), protect one or more features (e.g., pin features, sacrificial features, etc.), or perform any other suitable function. The mask may be constructed of any of the foregoing materials (e.g., a previously applied photoresist layer) including a simple mechanical barrier (e.g., including only one pedestal) or a simple optical barrier (e.g., a colored film), or any other suitable material. The second etching step further includes applying photoresist (e.g., etching the pattern to the thickness if desired). The mask may be applied to the tip side of the second structure or elsewhere. The mask is preferably applied before the second etch, but may additionally or alternatively be applied before the first etch, during the first etch, or at any other point in time during the process.

The second etching step may include, but is not limited to, any additional sub-processes, such as: passivation, re-application of photoresist, multiple etching steps with any number of etchant types, drying, curing, or any other sub-process.

In a modified example, the second etching is performed by dry etching (e.g., SF6 plasma etching). In one embodiment (e.g., as shown in fig. 4), the tip cross-section is viewed from one side (e.g., from the forward direction to the thickness) as a result of the second etch, sloping inward.

In a second modified example, the second etching is performed by wet etching (e.g., hydrofluoric acid/nitric acid etching). In one embodiment (e.g., as shown in fig. 4), the tip section is tilted outward as viewed from one side (e.g., from the forward direction to the thickness) through the second etch.

In a third variant example of the second etching step, the second etching step is at least partially carried out by wet etching (e.g. using nitric acid and hydrofluoric acid), wherein the etching rate of the substrate (e.g. silicon) is limited to the oxide removal rate of the substrate. In one specific example of etching a silicon wafer substrate using a mixture of nitric and hydrofluoric acids, nitric acid first oxidizes silicon to silicon dioxide, and hydrofluoric acid then etches away the silicon dioxide, with the etch rate of silicon being based on (e.g., limited to) the oxide removal rate.

In a fourth modified example, for a substrate initially having a bilayer of photoresist, an 80 minute SF6 etch may be performed. In one embodiment, the etching is performed in a machine configured for DRIE etching.

In a fifth variation, for a substrate initially having a single layer of photoresist, a purely isotropic etch with SF6 may be performed (e.g., 30 minutes at a flow rate of 160 sccm) followed by a wet etch (e.g., 60 minutes).

4.6 method-supplementary step

The method 200 may optionally include any number of additional steps, such as pre-treating the substrate S210 for preparing the substrate for any or all of the remaining steps of the method (e.g., creating a clean and dry surface, enhancing adhesion to photoresist, creating a substrate of a predetermined shape and size, etc.). Step S210 is preferably performed before S220, but may additionally or alternatively be performed before any step of the method, throughout the method, or at any other point in time. Pre-treating the substrate may include any or all of the following processes: baking the substrate (e.g., at 200 degrees celsius for 3 minutes), storing the substrate in a desiccator, rinsing the substrate (e.g., with acetone, isopropanol, ethanol, etc.), or any other suitable pretreatment. In a variant example, step S210 includes rinsing the wafer with a hydrofluoric acid dip, followed by solvent cleaning, rinsing with Deionized (DI) water, and blow drying.

The method may additionally or alternatively include, but is not limited to, any number of sub-processes to prepare microneedle devices using S260, such as: removing the photoresist (e.g., during an etching process, during a wet etching process, by an oxygen plasma process, etc.), curing the photoresist, assembling a plurality of microneedle devices (e.g., rows of microneedles) together (e.g., forming a microneedle patch), attaching one or more microneedle devices to a base or housing or other packaging, adding a biocompatible material (e.g., a biocompatible coating) to the microneedle devices, adding a core material (e.g., paper, fabric, etc.), or any other suitable sub-process. Step S260 is preferably performed after step S250, but may additionally or alternatively be performed at any other point during the method.

The method 200 may additionally or alternatively include any other suitable steps performed in any suitable order.

In a variant example of the method 200, the method comprises: coating the surface of the silicon wafer with photoresist; paving a mask on the wide surface of the silicon wafer; the mask defining a set of pattern features including a plurality of pin sections, a sacrificial boundary, a set of channels, and a reservoir; exposing the mask to ultraviolet light; performing a deep reactive ion etch to create a first structure defining a set of microneedles with etched channels, an etched reservoir, and partially etched sacrificial walls; an isotropic etch is performed to create an undercut on the needle tip, thereby sharpening the needle.

As one skilled in the art may recognize, in embodiments where the second etch is performed by an isotropic wet etch, the open trenches and reservoirs formed on the first structure of the first etch are also exposed to the etchant of the second etch and are at least partially etched away, as shown in fig. 10(a) through 10 (c). Specifically, fig. 10(a) shows an exemplary substrate 300 with a spin-on coating of photoresist 302. The photoresist 302 is then patterned using any suitable method, such as photolithography, to create one or more features of the microneedles. In the non-limiting exemplary embodiment shown in fig. 10(a), a trench opening 304 is formed in the patterned photoresist 302. The first etch is then applied to the substrate 100, allowing the DRIE process to simultaneously etch portions of the substrate not protected by the patterned photoresist 302. The first structure resulting from the first etching is shown in fig. 10 (b). As shown, the portion of the substrate 300 directly underneath the patterned photoresist 302 is preserved. Adjacent portions of the substrate 300 are etched to an etch depth that is less than the total thickness of the substrate 300 to create sacrificial features in the form of sacrificial layers 306. Due to the Aspect Ratio Dependent Etch (ARDE) principle, the trench 308 is etched to a depth less than the etch depth, with the etch rate rapidly decreasing with the aspect ratio of the etched structure. Thus, the depth of the trench 308 can be controlled by the size of the trench opening 304 formed in the photoresist 302. The needle shaft structure is then sharpened using isotropic etching (e.g., wet chemical etching), among other functions, in the presence of the sacrificial layer 306. In an example embodiment, the isotropic wet etch uses a chemical etching process using nitric acid (HNO)₃) And hydrofluoric acid (HF) at a volume ratio of 19: 1. In this particular exemplary embodiment, HNO₃Oxidation of silicon to silicon dioxide (SiO)₂) And subsequently etched away by HF. Those skilled in the art will appreciate that the etch rate of silicon is limited by the oxide removal rate. Thus, HF diffusion to the silicon surface is the rate limiting factor. Due to etching of sacrificial featuresThe HF in the surrounding etching solution is consumed, causing the etching rate to be slower than the etching rate at the tip of the needle shaft. Thus, over time, the needle shaft tip is sharpened, while the base remains mostly, leaving little or no sacrificial features, as shown in fig. 10 (c). As can be seen from fig. 10(c), the depth of the trench 308 after the second etching is smaller than the depth of the trench 308 after the first etching, as shown in fig. 10 (b).

Thus, in another exemplary embodiment of the present invention, a duplex processing method 400 for fabricating in-plane microneedles is provided that may facilitate minimizing unintended etching of the channel during the second etching process. Exemplary embodiments of the method 400 are shown in fig. 10(d) through 10 (i).

Specifically, fig. 10(d) shows a substrate 402 having a first broad face 404 and an opposing second broad face 406. As described above, at least one layer of photoresist is applied to the second surface 406 using any suitable method. The photoresist 406 is then patterned using any suitable method previously described to define a microfluidic network including at least one channel opening 408, as shown in fig. 10 (e). A first etch, such as a Bosch DRIE process or any other suitable process, is then performed on the substrate 402 to obtain a first structure 407 having an etched microfluidic network. As shown in fig. 10(f), in the first structure 407, channels 410 of the microfluidic network are etched from the second surface 406 of the substrate 402. As described above, the channel depth of the channel 410 may be similarly based on the ARDE principle. At least one photoresist layer 412 may then be applied to the first broad face 402 and patterned to define one or more features of one microneedle as shown in fig. 10 (g). A second etching process, such as a BoschDRIE process, is applied to the first structure 407 from the first surface 402. As shown in fig. 10(h), the first structure 407 is etched during the second etching process to define the second structure 407 as a microneedle axis, while channels 410 remain on the second surface 404. In the example embodiment shown in the figures, the photoresist 412 on the first surface 402 may be patterned to align with the channels 410 formed on the second surface 404. This alignment advantageously allows for more precise placement of the channel offset from the needle shaft axis, which is located at a distance from the tip, which reduces coring of the tissue of the channel. Any photoresist 412 on the first surface 402 may be removed using any suitable cleaning method. A clean silicon wafer 414 is attached to the secondary structure 409 from the second surface 404 by any suitable method, for example with the channels 410 in direct contact with the polished side of the wafer 414, to minimize the space between them, thereby reducing the volume of wet etchant that may enter. In some example embodiments, the second structure 409 is adhered to the wafer 414 using kapton (r) tape. Kapton (r) tape is known as a polyimide film with a silicon adhesive. In the second structure, at least the wafer 414 acts as a sacrificial feature. A third etching process (e.g., isotropic wet etching) is applied to the second structure to create a third structure comprising at least one sharp tip 416 of the microneedle, while the channel 410 remains intact and minimally etched in the third etching process, as shown in fig. 10 (i). The sacrificial features comprising at least the wafer 414 may consume large amounts of etchant, such as HF in the example embodiments described above, resulting in depletion of such etchant at the surface of the sacrificial structures, since the depleted etchant can only be transported from the bulk solution by slow diffusion of the static solution. However, the concentration of the same etchant is higher near the tip because it is closer to the bulk solution. Thus, the introduction of the sacrificial feature may cause the concentration of the etchant to increase in steps, thereby causing the rate of etching near the top of the microneedle shaft to be faster than at the bottom, which is closer to the sacrificial feature, thereby forming a wedge-shaped structure with a sharp tip that smoothly tapers to the bottom of the needle shaft.

Although portions have been omitted for brevity, embodiments of the present invention include all combinations and permutations of various system components, method processes, variations and examples.

It will be apparent to those skilled in the art from the foregoing detailed description and accompanying drawings that modifications and embodiments of the invention can be made without departing from the scope of the invention.